* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 14-15, p. 2531 - 2537
[2] Research on Chemical Intermediates, 2014, vol. 40, # 6, p. 2157 - 2164
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4119 - 4121
2
[ 62-57-7 ]
[ 124-68-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1953, vol. 84, p. 1097
[2] Chimica Therapeutica, 1969, vol. 4, p. 80 - 88
[3] European Journal of Organic Chemistry, 2008, # 2, p. 350 - 355
[4] Synlett, 2008, # 12, p. 1829 - 1832
3
[ 19355-69-2 ]
[ 16252-90-7 ]
[ 13027-88-8 ]
[ 62-57-7 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, p. 1243 - 1247[2] Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 7, p. 1367 - 1371
[3] Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, p. 1243 - 1247[4] Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 7, p. 1367 - 1371
4
[ 62-57-7 ]
[ 2052-01-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 17, p. 2037 - 2039
5
[ 24424-99-5 ]
[ 62-57-7 ]
[ 30992-29-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydroxide In 1,4-dioxane at 20℃; for 16 h;
Preparational Example 26 Preparation of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid 200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80percent). 1H NMR (400 MHz, CDCl3) δ 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
80%
With sodium hydroxide In 1,4-dioxane at 20℃; for 16 h;
200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80percent). 1H NMR (400 MHz, CDCl3) δ 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
67%
With sodium hydroxide; water In 1,4-dioxane at 20℃; for 15 h;
α-Aminoisobutyric acid (1.0 g, 9.70 mmol) was dissolved in a mixture of dioxane (15.0 mL) and 0.5 M NaOH (15.0 mL). To this solution was added di-tert-butyl dicarbonate (2.5 g, 11.64 mmol, 1.2 equiv.) and the resulting mixture stirred at RT for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL) and 1 M HCl (30 mL). The aqueous solution was extracted with EtOAc (2*30 mL) and the combined organic phases were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (1.3 g, 67percent) as a white solid: mp 122-123° C.; 1H NMR (CDCl3+methanol-d4) δ 1.44 (s, 9H), 1.51 (s, 6H), 3.99 (br s, NH).
66%
With sodium hydroxide In 1,4-dioxane at 0 - 20℃;
To a stirred solution of 2-Amino-2-methylpropanoic acid (50 g, 484.87 mmol, 1.0 eq)in 1,4-dioxane (500 mL) at 0 oc was added 2N NaOH solution (500 mL) followed by di-tertbutyldicarbonate(158.55 g, 727.30 mmol, 1.5 eq). The reaction mixture was allowed to stir atroom temperature for overnight. After completion of the reaction (monitored by TLC), the organic phase was evaporated under reduced pressure, reaction mixture was diluted withwater (100 mL), cooled to 0 °C, pH adjusted to 5 with IN HCI and then extracted with DCM(3x500 mL). The combined organic extracts were washed with water (500 mL) and brinesolution (200 mL). The organic layer was dried over Na2S04, filtered and evaporated underreduced pressure. The residue was stirred with n-hexane (500 mL) at room temperature for about 30 minutes. The solid was filtered and dried under vacuum to obtain the title compound(65 g, yield: 66percent) as a white solid. 1H NMR (300 MHz, CDCh): 8 ppm 9.50 (brs, IH), 1.53(s, 6H), 1.44 (s, 9H); ESI-MS: m/z 226.03 (M+Nat
64.4%
With sodium hydroxide In 1,4-dioxane; water at 20℃;
Method 1 : To a stirred solution of 2-Amino-2-methylpropanoic acid (30 g, 290.92 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 °C was added 2N NaOH solution (300 ml) followed by (Boc)20 (95.13 g, 436.38 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml), cooled to 0 °C, pH adjusted to 5 with IN HC1 and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room temperature for about 30 minutes. The obtained solid was filtered and dried under vacuum to obtain the desired product (38.0 g, yield: 64.4percent) as a white solid.
61%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16 h; Inert atmosphere
A solution of compound 14 (10.0 grams, 97.0 mmol) in dioxane (150 ml) and NaOH (5percent, 150 ml) was cooled to 0° C., then Boc2O was added dropwised. The mixture was stirred for 16 hours at room temperature under N2 atmosphere, then added HCl (concentrated) to make PH to 3, and the mixture was extracted with EtOAc (100 ml×3), washed with brine (50 ml), dried over Na2SO4, concentrated in vacuo and purified on silica gel column (PE/EtOAc=5:1) to give the product as white solid (12.1 grams, 61percent yield).
49%
With triethylamine In methanol at 60℃; for 0.5 h;
The starting materials N1, 2-dimetliylalaninamide and 2-methylalaninamide used in Examples 95 and 97 were prepared from 2-aminoisobutyric acid (ex. Aldrich) following the procedure below: Di-tert-butlydicarbonate (6.98 g, 32.0 mmol) was added to a stirred solution of the 2- aminoisobutyric acid (3 g, 29.13 mmol) in methanol/triethylmine (10/90) (100 ml). The reaction mixture was heated at 60°C/30 minutes, cooled to room temperature and concentrated to dryness. The residue was taken up in dichloromethane (100 ml), washed with 10percent aqueous potassium hydrogensulfate, water, dried over magnesium sulfate, filtered and evaporated to dryness to give N-(tert-butoxycarbonyl)-2-methylalanine (2.87 g, 49percent) as a white solid ; 1H NMR Spectrum : (CDC13) 1.45 (s, 6H), 1.53 (s, 9H), 5.2 (br s, 1H).
45.44%
With hydrogenchloride; sodium hydroxide In tetrahydrofuran
E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2-Aminoisobutyric acid (140 g, 1.36 mol), 1 N NaOH (1620 mL, 1.63 mol), (Boc)2O (375 mL, 1.63 mol) and THF 420 mL were mixed together and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (700 mL) and adjusted to about pH 3.0 by adding 6 N HCl. The organic phase separated was washed with saturated NaCl solution and concentrated to approximately 1/4 of the original volume. After treatment with hexane a white solid product was isolated and collected (125.8 g, yield 45.44 percent). An additional 7.8 g of product was recovered from the mother liquor.
44%
With sodium hydroxide In tetrahydrofuran at 20℃;
Step 1To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and Tiff (30 mL) was added (Boc)20 (26 g, 0.12 rnol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2), The organic phases were combined, washed with brine, dried over Na2SC>4. concentrated to give 9 g (44percent) of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid
44%
With sodium hydroxide In tetrahydrofuran at 20℃;
Step 1. To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and THF (30 mL) was added (Boc)2O (26 g, 0.12 mol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2). The organic phases were combined, washed with brine, dried over Na2SO4, concentrated to give 9 g (44percent)of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid.
40.7%
With sodium hydroxide In tetrahydrofuran; water at 20℃;
To a solution of 2-amino-2-methylpropanoic acid (4.0 g, 39 mmol) , NaOH (1.55 g, 38.8 mmol) , water (50 mL) , and THF (20 mL) was added (Boc)2O (10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirred overnight at rt, then concentrated to dryness, and extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound as a white solid (3.21 g, 40.7yield) .
Reference：
[1] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 4, p. 1391 - 1397
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 20, p. 5679 - 5683[3] Angew. Chem., 2018, vol. 130, p. 5781 - 5785,5
[4] Patent: US2015/210635, 2015, A1, . Location in patent: Paragraph 0502-0504
[5] Patent: EP2865664, 2015, A1, . Location in patent: Paragraph 0118; 0119
[6] Journal of Molecular Structure, 2003, vol. 646, # 1-3, p. 111 - 123
[7] Chemistry - A European Journal, 2012, vol. 18, # 31, p. 9516 - 9520
[8] Patent: US7202279, 2007, B1, . Location in patent: Page/Page column 49
[9] Patent: WO2018/29604, 2018, A1, . Location in patent: Page/Page column 28; 29
[10] Patent: WO2016/178092, 2016, A2, . Location in patent: Page/Page column 39
[11] Tetrahedron, 2004, vol. 60, # 40, p. 8929 - 8936
[12] Patent: US9096645, 2015, B2, . Location in patent: Page/Page column 39; 40
[13] Polish Journal of Chemistry, 1991, vol. 65, # 7-8, p. 1427 - 1431
[14] Tetrahedron Letters, 1996, vol. 37, # 40, p. 7319 - 7322
[15] Patent: WO2005/75439, 2005, A1, . Location in patent: Page/Page column 198-199
[16] Patent: US6448263, 2002, B1,
[17] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 229
[18] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 108; 109
[19] Patent: WO2018/103058, 2018, A1, . Location in patent: Page/Page column 349
[20] Patent: WO2005/19174, 2005, A1, . Location in patent: Page/Page column 51-52
[21] Patent: US2012/322811, 2012, A1, . Location in patent: Page/Page column 18
[22] Patent: WO2017/100668, 2017, A1, . Location in patent: Page/Page column 349
6
[ 62-57-7 ]
[ 142842-93-1 ]
[ 30992-29-1 ]
Yield
Reaction Conditions
Operation in experiment
44%
With sodium hydroxide In tetrahydrofuran at 20℃;
Step 1To a solution of 2-amino-2-methylpropanoic acid (10.30.1 mol, 1.0 equiv) in 1 N NaOH (100 mE) and THF (30 mE) was added (l3oc)20 (26 g, 0.12 mol, 1.2 equiv) portionwiseroom temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mEx2). The aqueous phase was adjusted to PH=34, then extracted with ethyl acetate (200 mEx2). The organic phases were combined, washed with brine, dried over Na2504, concentrated to give 9 g (44percent) of the desired product 2-(tert-butoxycarbonylamino)-2-me- thylpropanoic acid as a white solid.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 19, p. 5133 - 5140
[2] Journal of the American Chemical Society, 1981, vol. 103, # 20, p. 6127 - 6132
Reference：
[1] Tetrahedron, 1982, vol. 38, # 14, p. 2165 - 2182
[2] Journal of medicinal chemistry, 1971, vol. 14, # 10, p. 904 - 906
11
[ 62-57-7 ]
[ 501-53-1 ]
[ 15030-72-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 18 h;
Preparation 56 N-[(Benzyloxy)carbonyl1-2-methylalanine To a solution of 2-methylalanine (50 g, 0.49 mmol) and Na2CO3 (156 g, 1 .47 mol) in water (1 L) was added a solution of CbzCI (91 g, 0.54 mmol) in dioxane (500 mL) at 0°C over 15 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction was extracted with Et2O (2 x 500 mL), and the aqueous layer collected, acidified to pH=1 with cHCI and extracted with EtOAc (2 x 500 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford a white solid as the title compound that was used directly in the next step (1 1 1 g, 97percent).
72%
With sodium carbonate In 1,4-dioxane; water at 23℃; for 24 h;
A mixture containing sodium carbonate (3 equiv.), 2-amino-2-methylpropanoic acid (1.0 equiv.) and benzyl chloroformate (1.1 equiv.) in water and 1 ,4-dioxane (2:1) was stirred at 23 °C for 24 h. The mixture was diluted in ethyl acetate and washed with IN HC1 solution. The organic layer was dried, filtered and evaporated to deliver the desired intermediate 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (825 mg, 72percent yield) as a clear oil. 'H NMR (500 MHz, CD3OD) δ ppm 7.32 - 7.38 (m, 5 H), 5.03 - 5.09 (m, 2 H), 1.43 - 1.50 (m, 6 H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 533 - 548
[2] Patent: WO2013/114250, 2013, A1, . Location in patent: Page/Page column 163
[3] Helvetica Chimica Acta, 2011, vol. 94, # 6, p. 993 - 1011
[4] Tetrahedron, 1982, vol. 38, # 14, p. 2165 - 2182
[5] Helvetica Chimica Acta, 1988, vol. 71, p. 140 - 154
[6] Patent: WO2016/44447, 2016, A1, . Location in patent: Paragraph 00326
[7] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2001, vol. 40, # 1, p. 70 - 74
[8] Helvetica Chimica Acta, 1987, vol. 70, p. 102 - 115
[9] Tetrahedron, 1960, vol. 11, p. 39 - 51
[10] Tetrahedron, 1967, vol. 23, # 5, p. 2017 - 2030
[11] Bulletin of the Chemical Society of Japan, 1970, vol. 43, # 11, p. 3457 - 3461
[12] Journal fuer Praktische Chemie (Leipzig), 1960, vol. 11, p. 153 - 164
[13] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2448 - 2451
[14] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 17, p. 8054 - 8062
[15] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 361 - 369
[16] Patent: US2012/316147, 2012, A1, . Location in patent: Page/Page column 30
[17] Patent: WO2012/168350, 2012, A1, . Location in patent: Page/Page column 73; 74
[18] Patent: WO2010/95768, 2010, A1, . Location in patent: Page/Page column 40-42
12
[ 13139-17-8 ]
[ 62-57-7 ]
[ 15030-72-5 ]
Yield
Reaction Conditions
Operation in experiment
97.8%
With sodium carbonate In tetrahydrofuran; water at 20℃; for 16 h;
Step 1. Cbz-OSu (57 g, 0.23 mol) in THF (150 mL) was added a mixture of aq Na2C03 (82 g, 0.78 mol) and 80-1 (20 g, 0.19 mol). After it was stirred at r.t. for 16 h, it was adjusted to pH > 10 and washed with EtOAc (400 mL x 2). The aqueous layer was pooled and acidified to pH < 1 with cone. HC1. It was extracted with EtOAc (500 mL x 2). The organic layer was dried over Na2S04 and evaporated to give 80-2 (45 g, 97.8percent).
72%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 12 h; Stage #2: at 0℃;
Synthesis of Compound S.2. To S.1 (10 g, 0.0969 mol) in THF (60 ml) and water (60 mL) at 0° C. was added sodium bicarbonate (16.27 g, 0.193 mole) followed by N-(benzyloxy carbonyloxy) succinimide (60.37 g, 0.242 mol). The reaction mixture was stirred at RT for 12 hr. The THF was removed under vacuum and the aqueous phase was washed with ether (2.x.100 mL). The aqueous phase was cooled to 0° C. and acidified to pH=2 with 5N HCL (50 mL). The reaction mixture was extracted with ethyl acetate (2.x.100 mL); the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (1percent MeOH in dichloromethane) to give S.2 (16 g, 72percent). 1H NMR (CDCl3, 200 MHz) δ 7.45-7.32 (m, 5H), 5.40 (bs, 1H,) 5.12 (s, 2H), 1.82 (s, 6H); MS: m/z 238 [M+1]+.
72%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 12 h; Stage #2: With hydrogenchloride In water
To S.1 (10 g, 0.0969 mol) in THF (60 ml) and water (60 mL) at 0° C. was added sodium bicarbonate (16.27 g, 0.193 mole) followed by N-(benzyloxy carbonyloxy) succinimide (60.37 g, 0.242 mol). The reaction mixture was stirred at RT for 12 hr. The THF was removed under vacuum and the aqueous phase was washed with ether (2.x.100 mL). The aqueous phase was cooled to 0° C. and acidified to pH=2 with 5N HCL (50 mL). The reaction mixture was extracted with ethyl acetate (2.x.100 mL); the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (1percent MeOH in dichloromethane) to give S.2 (16 g, 72percent). 1H NMR (CDCl3, 200 MHz) δ 7.45-7.32 (m, 5H), 5.40 (bs, 1H,) 5.12 (s, 2H), 1.82 (s, 6H); LCMS: m/z 238 [M+1]+.
Reference：
[1] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 215
[2] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 48-49
[3] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 93
[4] Chemical Communications, 2013, vol. 49, # 86, p. 10133 - 10135
[5] Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3849 - 3856
13
[ 62-57-7 ]
[ 15030-72-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1970, vol. 43, p. 3873,3881
14
[ 62-57-7 ]
[ 501-53-1 ]
[ 15030-72-5 ]
[ 79775-03-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1371 - 1376
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1371 - 1376
15
[ 67-56-1 ]
[ 62-57-7 ]
[ 15028-41-8 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 3 h; Cooling with ice
2-amino-2-methylpropionic acid (10 g, 96.9 mmol) and methanol (330 ml) were charged. An ice bath was set and thionyl chloride (17.68 ml, 242.25 mmol) was slowly added thereto. Then, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The resultant product was vacuum-distilled to remove a solvent, and dried in a 60 oven so as to obtain methyl-2-amino-2-methylpropanoate hydrochloride (14.59 g, 94.9 mmol, 98 percent).[938] 1H NMR (400 MHz, DMSO-d6) 8.75 (br, 3H), 3.75 (s, 3H), 1.45 (s, 6H).
98%
at 20℃; for 3 h; Cooling with ice
2-amino-2-methylpropionic acid (10 g, 96.9 mmol) and methanol (330 ml) were charged. An ice bath was set and thionyl chloride (17.68 ml, 242.25 mmol) was slowly added thereto. Then, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The resultant product was vacuum-distilled to remove a solvent, and dried in a 60° C. oven so as to obtain methyl-2-amino-2-methylpropanoate hydrochloride (14.59 g, 94.9 mmol, 98percent). [0514] 1H NMR (400 MHz, DMSO-d6) 8.75 (br, 3H), 3.75 (s, 3H), 1.45 (s, 6H).
80%
for 12 h; Reflux
To a suspension of 2-aminoisobutyric acid (25.0 g, 243 mmol) in methanol (300 ml.) was added thionyl chloride (27.0 ml_, 43.0 g, 365 mmol) and the reaction was heated at reflux for 12 hours. The resulting solution was concentrated and triturated with diethyl ether - tetrahydrofuran to yield the product as a white powder, 29.8 g (80 percent).1H NMR (DMSO-d6, 300 MHz): δ 8.80 (broad s, 3H, NH3+), 3.74 (s, 3H, CH3O), 1.48 (s, 6H, 2 x CH3).
79%
at 0 - 60℃; for 26.25 h;
Aminoisobutyric acid (29.80 g, 0.2890 mol) was suspended in MeOH (300 mE) and the suspension cooled to 0°C. (ice bath). Thionyl chloride (36.10 g, 0.3034 mol) was added dropwise over 15 mm. The ice bath was removed and the reaction mixture stirred at 60°C. for 4 h. The oil bath was then removed and stirring continued at room temperature for another 22 h. The solvent and excess thionyl chloride were evaporated affording a white solid with a strong sulfur smell. Methanol (5x 150 mE) was added and evaporated. The residue was dissolved in MeOH (120 mE), precipitated by addition of Et20 (720 mE) and collected by filtration under suction affording the title compound as a white solid (35.12 g, 79percent), with spectral characteristics in accordance with literature data’; ‘H NMR (200 MHz, DMSO-d5) ö 8.87 (br s, 3H, NH3), 3.72 (s, 3H, OCH3), 1.48 (s, 6H, CH3); ‘3CNMR(75 MHz, DMSO-d5) ö 172.0,55.8, 53.1, 23.3; HRMS (mlz): M calcd. for C5,H,2N02, 118.0868. found, 118.0871; Anal. Calcd. for C5H,2C1N02: C, 39.10; H, 7.87; N, 9.12. Found:C, 38.9; H, 7.8; N, 9.0.
Reference：
[1] Organic Letters, 2012, vol. 14, # 18, p. 4798 - 4801
[2] European Journal of Organic Chemistry, 2004, # 20, p. 4167 - 4176
[3] Patent: WO2013/19091, 2013, A2, . Location in patent: Paragraph 936-938
[4] Patent: US2014/206875, 2014, A1, . Location in patent: Paragraph 0513-0514; 0568-0569; 0599-0600; 0658-0660
[5] Tetrahedron, 1982, vol. 38, # 14, p. 2165 - 2182
[6] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10132 - 10142
[7] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 8, p. 1942 - 1944
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 10, p. 1013 - 1021
[9] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2982 - 2987
[10] Tetrahedron, 2007, vol. 63, # 36, p. 8855 - 8871
[11] Patent: WO2010/70318, 2010, A1, . Location in patent: Page/Page column 21
[12] Journal of Organic Chemistry, 2011, vol. 76, # 5, p. 1228 - 1238
[13] Patent: US9227995, 2016, B2, . Location in patent: Page/Page column 37
[14] Journal of Medicinal Chemistry, 1984, vol. 27, # 12, p. 1663 - 1668
[15] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 204
[16] Heterocycles, 1991, vol. 32, # 10, p. 1879 - 1895
[17] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 6, p. 910 - 920
[18] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7215 - 7226
[19] Chemistry - A European Journal, 2000, vol. 6, # 24, p. 4498 - 4504
[20] Organic Letters, 2007, vol. 9, # 25, p. 5275 - 5278
[21] Synlett, 2009, # 8, p. 1227 - 1232
[22] Patent: US6353006, 2002, B1, . Location in patent: Page column 138
[23] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 12, p. 3502 - 3506
[24] Patent: WO2011/69951, 2011, A1, . Location in patent: Page/Page column 82
[25] Acta Crystallographica Section C: Crystal Structure Communications, 2011, vol. 67, # 8, p. o283-o287
[26] Journal of the American Chemical Society, 2014, vol. 136, # 51, p. 17818 - 17826
[27] Molecules, 2015, vol. 20, # 2, p. 1755 - 1774
[28] Physical Chemistry Chemical Physics, 2016, vol. 18, # 36, p. 25512 - 25527
16
[ 62-57-7 ]
[ 15028-41-8 ]
Reference：
[1] Chemical Communications, 2012, vol. 48, # 49, p. 6181 - 6183
[2] Patent: US2002/19539, 2002, A1,
[3] Patent: US5475013, 1995, A,
[4] Patent: US3966796, 1976, A,
17
[ 62-57-7 ]
[ 74-88-4 ]
[ 15028-41-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2004, vol. 77, # 6, p. 1187 - 1193
Stage #1: at 0 - 20℃; for 1 h; Stage #2: Heating / reflux
(B) General Procedure for Preparing amino acid ester hydrochloric Salts Thionyl chloride (2.0 mol. equivalents) was added dropwise to a stirred solution of the appropriate anhydrous alcohol (10.0 mol equivalents) under argon atmosphere and cooled to 0° C. The mixture was stirred at 0° C. for 1 h and then slowly allowed to warm to RT. The appropriate amino acid (1.0 mol. equivalents) was added and the mixture was heated at reflux overnight. The solvent was removed under reduced pressure (last traces of solvent were removed by co-evaporation with increasingly more volatile solvents). The crude product was then triturated with Et2O to afford the pure amino acid ester hydrochloric salt. EXAMPLE 14 2-[(2R,3S,4R,5R)-5-(4-Amino-2-oxo-2H-pyrimidin- 1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-2-methyl-propionic acid ethyl ester (I-10) and 2-[(2R,3S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylamino}-2-methyl-propionic acid; compound with ammonia (I-69) step 1-Ethyl 2-amino-2-methylpropanoate hydrochloride salt The title compound was prepared according to Example 1 (A) utilizing 2-amino-isobutyric acid (8.0 g, 77.6 mmol), thionyl chloride (11.3 mL, 155.2 mmol) and anhydrous EtOH (45.5 mL, 776.0 mmol). The product 14n was isolated as a white solid (9.12 g, yield 70percent). 1H-NMR (CDCl3; 300 MHz): δ 8.93 (3H, bs, NH3Cl), 4.25 (2H, q, J=7.1 Hz, OCH2CH3), 1.72 (6H, s, [CH3]2C), 1.30 (3H, t, J=7.1 Hz, OCH2CH3); 13C-NMR (CDCl3; 75 MHz): δ 14.4 (OCH2CH3), 24.3 ([CH3]2C), 57.8 (C[CH3]2), 63.0 (OCH2CH3), 171.5 (CO).
Reference：
[1] Patent: US2007/42988, 2007, A1, . Location in patent: Page/Page column 18; 22
[2] Patent: US6028032, 2000, A,
20
[ 64-17-5 ]
[ 62-57-7 ]
[ 17288-15-2 ]
Reference：
[1] Australian Journal of Chemistry, 1999, vol. 52, # 5, p. 379 - 385
[2] Tetrahedron Letters, 2007, vol. 48, # 34, p. 5973 - 5975
[3] ChemBioChem, 2017, vol. 18, # 3, p. 300 - 315
[4] Canadian Journal of Chemistry, 1992, vol. 70, # 5, p. 1328 - 1337
[5] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 19, p. 2699 - 2711
[6] Journal of the American Chemical Society, 1924, vol. 46, p. 412
[7] Patent: WO2012/52781, 2012, A1, . Location in patent: Page/Page column 23-24; 30-31
[8] Patent: US2013/211083, 2013, A1, . Location in patent: Paragraph 0094; 0095
21
[ 28920-43-6 ]
[ 62-57-7 ]
[ 94744-50-0 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2001, vol. 40, # 1, p. 70 - 74
22
[ 749927-69-3 ]
[ 62-57-7 ]
[ 1289942-66-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
With water; potassium carbonate; <i>L</i>-proline; copper(l) chloride In N,N-dimethyl-formamide at 100℃; for 24 h; Inert atmosphere
4-bromo-2-fluoro -N- methylbenzamide, 2-amino - isobutyric acid molar ratio, catalyst, co-catalyst, acid binding agent, followed by water 1:1.5:0.1:0.1:4:2.3 In a single-neck flask was added4-bromo-2-fluoro -N- methylbenzamide (10g, 43.1mmol), 2- amino - isobutyric acid (6.7g, 64.7mmol), potassium carbonate (23.8g, 172.4mmol), proline (0.7g, 4.31mmol), water (1.8ml, 100mmol) was dissolved in DMF (60ml), andStirring under nitrogen replacementAfter addition of CuCl (0.45g, 4.31mmol), was heated to 100 , reaction 24h.After completion of the reaction first added water (120ml) the mixture was diluted, added and extracted with dichloromethane, the organic phase was removed, the aqueous phase was adjusted pH = 4 with 1mol / L citric acid solution, and the precipitated solid was filtered. The solid washed with water and ethanol (100: 1) mixed solution was washed three times to give pure white solid 9.5g. Yield 87percent
75.4%
Stage #1: With potassium carbonate In water; N,N-dimethyl-formamide at 30℃; Stage #2: With 2-acetylcyclohexanone In water; N,N-dimethyl-formamide at 105℃; Inert atmosphere Stage #3: With citric acid In Isopropyl acetate; water
The bromobenzamide A-2 (10 g, 43.1 mmol), aminoisobutyric acid B-l (6.7 g, 64.6 mmol, 1.5 equiv), K2C03 (15 g, 2.5 equiv), 99percent CuCl (0.8 g, 8.1 mmol, 0.2 equiv), DMF (60 mL, 6 vol) and water (1.8 mL) were added to the flask and the reaction slurry was heated to 30 °C. 2-Acetylcyclohexanone (1.14 mL, 8.1 mmol, 0.2 equiv) was added to the reaction slurry followed by stirring at 105 °C under nitrogen for 12-14 h. HPLC analysis showed 96.6percent conversion to the desired product. The reaction mixture was then cooled to RT and extracted with water (120 mL) and IP Ac (60 mL). The lower aqueous layer was re-extracted with IP Ac (60 mL) and acidified with 180 mL of 1M citric acid to a pH of 4.0. The product began to crystallize at RT and the batch was further cooled to 5-7 °C, filtered, washed with water (40 mL) and dried under vacuum at 50 °C for 12 h. The reaction yielded 8.3 g of product C-1 (75.4percent yield) as a tan solid with HPLC purity of 99.6percent.
26 g
Stage #1: With potassium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide for 0.333333 h; Inert atmosphere Stage #2: With <i>L</i>-proline; copper(l) chloride In 1,4-dioxane; water; N,N-dimethyl-formamide for 24.33 h; Inert atmosphere; Reflux
4-bromo-2-fluoro-N-methyl benzamide (48.0 gm, 0.21mol) and K2C03 (52.8 gm, 0.38 mol) was charged in to reaction flask containing DMF (67.2 mL), 1,4-dioxane (268mL) and DM water (8.6mL). The reaction mixture was purged with nitrogen gas for 20 min and then charged CuCl (6.24 gm, 0.06 mol),L-proline(9.6 gm, 0.08 mol) and 2-aminoisobutyric acid (31.6 gm, 0.31mol). Continue purging nitrogen gas for 20 min followed by refluxed for 24 hrs. Solvent is distilled off completely from the obtained reaction mixture under vacuum at 70°C. The reaction mass was cooled to 10 to 15 °C and then charged DM water (20 mL). The pH of the reaction mass adjusted to 3-5 with 1 M citric acid solution to obtain the title product. Yield: 26.0 gm Chromatographic Purity (By HPLC): 95.38 percent
With thionyl chloride at 0℃; for 2h; Inert atmosphere;
To a solution of 2-amino-2-methylpropanoic acid (5.0 g) in MeOH (15 mL) was added SOCb (4 mL) at 0 0C under an inert atmosphere. The mixture was then stirred for 2 h. The reaction mixture was concentrated in vacuo and washed with ether to afford methyl 2-amino-2-methylpropanoate (4.8 g, 82.7 %) as a white solid.
With thionyl chloride
With hydrogenchloride
With hydrogenchloride for 6h; Heating;
With thionyl chloride for 3h; Heating;
In acetyl chloride at 70℃;
With thionyl chloride at 0℃; for 1h; Reflux;
1.35 g
With thionyl chloride for 5.5h; Reflux;
11.1 Example 11 Synthesis of Compound I-11
1) Add 2-methylalanine (1.00g) to methanol (3.11g),Thionyl chloride (1.38g) was added dropwise at room temperature,After dropping, it was refluxed for 5.5h and concentrated under reduced pressure.2-Methylalanine methyl ester hydrochloride (1.35 g) was obtained.
With thionyl chloride; at 20℃; for 3h;Cooling with ice;
<strong>[62-57-7]2-amino-2-methylpropionic acid</strong> (10 g, 96.9 mmol) and methanol (330 ml) were charged. An ice bath was set and thionyl chloride (17.68 ml, 242.25 mmol) was slowly added thereto. Then, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The resultant product was vacuum-distilled to remove a solvent, and dried in a 60 oven so as to obtain methyl-2-amino-2-methylpropanoate hydrochloride (14.59 g, 94.9 mmol, 98 %).[938] 1H NMR (400 MHz, DMSO-d6) 8.75 (br, 3H), 3.75 (s, 3H), 1.45 (s, 6H).
98%
With thionyl chloride; at 20℃; for 3h;Cooling with ice;
<strong>[62-57-7]2-amino-2-methylpropionic acid</strong> (10 g, 96.9 mmol) and methanol (330 ml) were charged. An ice bath was set and thionyl chloride (17.68 ml, 242.25 mmol) was slowly added thereto. Then, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The resultant product was vacuum-distilled to remove a solvent, and dried in a 60 C. oven so as to obtain methyl-2-amino-2-methylpropanoate hydrochloride (14.59 g, 94.9 mmol, 98%). [0514] 1H NMR (400 MHz, DMSO-d6) 8.75 (br, 3H), 3.75 (s, 3H), 1.45 (s, 6H).
80%
With thionyl chloride; for 12h;Reflux;
To a suspension of 2-aminoisobutyric acid (25.0 g, 243 mmol) in methanol (300 ml.) was added thionyl chloride (27.0 ml_, 43.0 g, 365 mmol) and the reaction was heated at reflux for 12 hours. The resulting solution was concentrated and triturated with diethyl ether - tetrahydrofuran to yield the product as a white powder, 29.8 g (80 %).1H NMR (DMSO-d6, 300 MHz): delta 8.80 (broad s, 3H, NH3+), 3.74 (s, 3H, CH3O), 1.48 (s, 6H, 2 x CH3).
79%
With thionyl chloride; at 0 - 60℃; for 26.25h;
Aminoisobutyric acid (29.80 g, 0.2890 mol) was suspended in MeOH (300 mE) and the suspension cooled to 0C. (ice bath). Thionyl chloride (36.10 g, 0.3034 mol) was added dropwise over 15 mm. The ice bath was removed and the reaction mixture stirred at 60C. for 4 h. The oil bath was then removed and stirring continued at room temperature for another 22 h. The solvent and excess thionyl chloride were evaporated affording a white solid with a strong sulfur smell. Methanol (5x 150 mE) was added and evaporated. The residue was dissolved in MeOH (120 mE), precipitated by addition of Et20 (720 mE) and collected by filtration under suction affording the title compound as a white solid (35.12 g, 79%), with spectral characteristics in accordance with literature data?; ?H NMR (200 MHz, DMSO-d5) oe 8.87 (br s, 3H, NH3), 3.72 (s, 3H, OCH3), 1.48 (s, 6H, CH3); ?3CNMR(75 MHz, DMSO-d5) oe 172.0,55.8, 53.1, 23.3; HRMS (mlz): M calcd. for C5,H,2N02, 118.0868. found, 118.0871; Anal. Calcd. for C5H,2C1N02: C, 39.10; H, 7.87; N, 9.12. Found:C, 38.9; H, 7.8; N, 9.0.
With thionyl chloride;
Methyl aminoisobutyric acid was converted to methyl aminoisobutyrate HCl salt according to method B1c, Step 1
With thionyl chloride; at 0℃;Reflux;
Intermediate 107H-CI2-amine-2-methylpropionic acid (25 g, 242.43 mmol) was dissolved in methanol (150 mL). Thionyl chloride (25 mL) was added dropwise at 0C to the reaction mixture. The reaction was refluxed for 3 hours, evaporated and dried under vacuum. The solid was washed several times with Et20 and dried, to afford the title compound (37 g) as a white solid.H NMR (400 MHz, DMSO-c/6): delta ppm 8.71 (3H, s), 3.77 (3H, s), 1.5 (6H, s).
With thionyl chloride; at 20℃; for 6h;Reflux; Industry scale;
2A. 2-aminoisobutyric acid ethyl ester hydrochloride Stage 2aEthanol (395L) was added to 2-aminoisobutyric acid (79Kg) and the mixture stirred at 20C. Thionyl chloride (91.2Kg) was added, maintaining the temperature at <40C. The mixture was heated to reflux and stirred for 6 hours. The contents were distilled under atmospheric pressure to a residual volume of approximately 200L over a period of 14 hours. The mixture was cooled to 45-50C and methyl fert-butyl ether (395L) was added. The mixture was cooled to 0-5C and stirred for 1 hour. Material was isolated by filtration and washed with methyl fert-butyl ether (160L) pre-cooled to 0-5C, then dried in vacuo at 30-40C to give ethyl 2-aminoisobutyrate hydrochloride (105.5Kg) with 86.2% purity in 71 % yield (based on active).= The amine has 3 protons rather than 2 because it is protonated in the HCI in the solution.
With thionyl chloride; at 20℃; for 6h;Reflux; Large scale;
2A. 2-aminoisobutyric acid ethyl ester hydrochloride Ethanol (395 L) was added to 2-aminoisobutyric acid (79 Kg) and the mixture stirred at 20 C. Thionyl chloride (91.2 Kg) was added, maintaining the temperature at 540 C. The mixture was heated to reflux and stirred for 6 hours. The contents were distilled under atmospheric pressure to a residual volume of approximately 200 L over a period of 14 hours. The mixture was cooled to 45-50 C. and methyl tert-butyl ether (395 L) was added. The mixture was cooled to 0-5 C. and stirred for 1 hour. Material was isolated by filtration and washed with methyl tert-butyl ether (160 L) pre-cooled to 0-5 C., then dried in vacuo at 30-40 C. to give ethyl-2-aminoisobutyrate hydrochloride (105.5 Kg) with 86.2% purity in 71% yield (based on active).
With thionyl chloride; In ethanol; at 0 - 90℃; for 16h;
General procedure: Thionyl Chloride (3.87 mL, 53.3 mmol) was added dropwise to a stirred solution of 2-amino-2-methylpropanoic acid (5 g, 48.5 mmol) in cyclopentanol (26.4 ml, 291 mmol) at 0C. The mixture was stirred at 80 C for 16 hours. The reaction mixture was cooled, diluted with water (60 mL) and washed with DCM (2x80 mL). The aqueous layer was concentrated under reduced pressure to afford the title compound: 1 H NMR (400MHz, dMSO-<=) delta 8.61 (brs, 3H), 5.19-5.15 (m, 1H), 1.87- 1.81 (m, 2H), 1.72-1.55 (m, 6H), 1.45 (s, 6H).
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h;
Preparation 56 N-[(Benzyloxy)carbonyl1-2-methylalanine To a solution of 2-methylalanine (50 g, 0.49 mmol) and Na2CO3 (156 g, 1 .47 mol) in water (1 L) was added a solution of CbzCI (91 g, 0.54 mmol) in dioxane (500 mL) at 0C over 15 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction was extracted with Et2O (2 x 500 mL), and the aqueous layer collected, acidified to pH=1 with cHCI and extracted with EtOAc (2 x 500 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford a white solid as the title compound that was used directly in the next step (1 1 1 g, 97%).
72%
With sodium carbonate; In 1,4-dioxane; water; at 23℃; for 24h;
A mixture containing sodium carbonate (3 equiv.), 2-amino-2-methylpropanoic acid (1.0 equiv.) and benzyl chloroformate (1.1 equiv.) in water and 1 ,4-dioxane (2:1) was stirred at 23 C for 24 h. The mixture was diluted in ethyl acetate and washed with IN HC1 solution. The organic layer was dried, filtered and evaporated to deliver the desired intermediate 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (825 mg, 72% yield) as a clear oil. 'H NMR (500 MHz, CD3OD) delta ppm 7.32 - 7.38 (m, 5 H), 5.03 - 5.09 (m, 2 H), 1.43 - 1.50 (m, 6 H).
To a solution of acid 1 (0.49 mol) and K2CO3 (1.46 mol) in H2O (1 L) and 1,4-dioxane (0.5 L) was added dropwise the solution of Cbz-Cl (0.73 mol) in 1,4-dioxane (50 mL) at 0 C. The mixture was stirred at room temperature for 10 h, then washed with diethyl ether (0.5 L) and acidified to a pH of 2 with 10% HCl at 0 C, then extracted with ethyl acetate (3 × 0.5 L). The combined organic extracts were dried with anhydrous MgSO4 and concentrated in vacuo to give crude 2-(benzyloxycarbonylamino)-2-methylpropanoic acid as a colorless oil, which was directly dissolved with THF (1.6 L) and Et3N (0.63 mol). To the stirred mixture was added dropwise ethyl chloroformate (0.58 mol) at -15 C and reacted for 1 h at this temperature, then 25% NH3·H2O (99 g) was added. The mixture was allowed to warm to room temperature for 10 h and 60 C for 1 h, then concentrated in vacuo, brine (200 mL) was added, and stayed at 0 C for 1 h, filtered to give compound 2 (107 g, 93.5% yield for two steps).
To a solution of 2-methylalanine (CAN 62-57-7, 30.9 g, 0.3 mol) and sodium hydroxide (20 g, 0.5 mol) in water (500 mL) was added benzyl chloroformate (61.4 g, 0.36 mol) at ice-water bath temperature. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting solution was washed with ethyl acetate (2×80 mL), then the aqueous layer was adjusted to pH=2 with conc. hydrochloric acid and the solution was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude target compound (26 g, 36%) which was used directly for the next step without further purification; MS: m/e 238.0 [M+H]+.
To a solution of 2-methylalanine (CAN 62-57-7, 30.9 g, 0.3 mol) and sodium hydroxide (20 g, 0.5 mol) in water (500 mL) was added benzyl chloro formate (61.4 g, 0.36 mol) at ice-water bath temperature. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The resulting solution was washed with ethyl acetate (2 x 80 mL), then the aqueous layer was adjusted to pH = 2 with cone, hydrochloric acid and the solution was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude target compound (26 g, 36%) which was used directly for the next step without further purification; MS: m/e 238.0 [M+H] +
With sodium carbonate; In 1,4-dioxane; water; at 10 - 20℃;
Reference Example 9: Preparation of intermediate (I)[Chem. 36][0122] 2-Aminoisobutyric acid (150 g, 1.45 mol) was dissolved in water (2.2 L), and sodium carbonate (465 g, 4.39 mol) was added thereto. The reaction mixture was cooled on ice, to which a solution of benzyl chloroformate (227 mL, 1.60 mol) in 1,4-dioxane (0.63 L) was then added dropwise over 45 minutes such that the internal temperature did not exceed 100C. After stirring overnight at room temperature, water (3.5 L) and toluene (1.0 L) were added to the reaction mixture. The aqueous layer was separated, to which concentrated hydrochloric acid (700 mL) was then added dropwise until the pH reached 1. Ethyl acetate (1.0 L) was added and stirred for 1 hour. The organic layer was separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure.[0123] The resulting residue (338 g) was dissolved in chloroform (1.7 L). To this solution, N5N' -carbon yldiimidazole (CDI) (253 g, 1.56 mol) was added portionwise under ice cooling such that the internal temperature did not exceed 200C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled again on ice and l,2-diamino-2- methylpropane (138 g, 1.56 mol) was added dropwise thereto over 25 minutes. After stirring overnight at room temperature, 10% aqueous potassium carbonate (1.7 L) was added. The organic layer was separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. [0124] The resulting residue (417 g) was dissolved in THF (2.0 L). To this solution, Boc2O (355 g, 1.63 mol) was added and stirred at room temperature for 1.5 hours. Then, saturated aqueous sodium bicarbonate (1.0 L) was added to the reaction mixture, and the organic layer was separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure.[0125] The resulting residue (549 g) was dissolved in methanol (2.75 L). To this solution, 10% palladium hydroxide (27.5 g) was added and stirred under a hydrogen atmosphere at room temperature for 4.5 hours. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure and the resulting residue was crystallized from a 2:1 heptane:ethyl acetate mixture (1.75 L). The resulting precipitate was filtered to give intermediate (I) (193 g, 53%; 4 steps) as a colorless powder. [0126] 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.27 (s, 6 H) 1.37 (s, 6 H) 1.43 (s, 9 H) 1.53 (br. s, 2 H) 3.39 (d, J=6.53 Hz, 2 H) 4.78 (br. s, 1 H) 8.04 (br. s, 1 H).MS ESVAPCI Dual posi: 274[M+H]+, 296[M+Na]+.MS ESI/APCI Dual nega: 3O8[M+C1]
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 16h;Cooling with ice;
General procedure: To a stirred solution of 2-(1-(aminomethyl) cyclohexyl)acetic acid 2a (2g, 11.68 mmol, 1equiv.) in 1, 4-dioxane (20 mL) atice temperature, aq. NaOH (560.57mg, 14.02 mmol, 1.2 equiv,dissolved in 10 mL water) was added followed by addition of ditert-butyl dicarbonate (5.10 gm, 23.36mmol, 2 equiv.) in 1,4-dioxane (5mL). The reaction mixture was stirred at room temperature for 16 h. The resulting suspension was concentrated in vacuo and the residuewas dissolved in water (10-15mL) and washed by ethyl acetate (15mL x 2). The resultingaqueous layer was acidified using dilute KHSO4 solution, followed by extraction withethyl acetate (30 mL x 3), dried (Na2SO4) and concentrated in vacuo to afford 3a as awhite solid, which was carried forward for the next reaction. Yield: 3.04g, 95%.
80%
With sodium hydroxide; In 1,4-dioxane; at 20℃; for 16h;
Preparational Example 26 Preparation of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid 200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80%). 1H NMR (400 MHz, CDCl3) delta 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
80%
With sodium hydroxide; In 1,4-dioxane; at 20℃; for 16h;
200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80%). 1H NMR (400 MHz, CDCl3) delta 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
67%
With sodium hydroxide; water; In 1,4-dioxane; at 20℃; for 15h;
alpha-Aminoisobutyric acid (1.0 g, 9.70 mmol) was dissolved in a mixture of dioxane (15.0 mL) and 0.5 M NaOH (15.0 mL). To this solution was added di-tert-butyl dicarbonate (2.5 g, 11.64 mmol, 1.2 equiv.) and the resulting mixture stirred at RT for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL) and 1 M HCl (30 mL). The aqueous solution was extracted with EtOAc (2*30 mL) and the combined organic phases were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (1.3 g, 67%) as a white solid: mp 122-123 C.; 1H NMR (CDCl3+methanol-d4) delta 1.44 (s, 9H), 1.51 (s, 6H), 3.99 (br s, NH).
66%
With sodium hydroxide; In 1,4-dioxane; at 0 - 20℃;
To a stirred solution of 2-Amino-2-methylpropanoic acid (50 g, 484.87 mmol, 1.0 eq)in 1,4-dioxane (500 mL) at 0 oc was added 2N NaOH solution (500 mL) followed by di-tertbutyldicarbonate(158.55 g, 727.30 mmol, 1.5 eq). The reaction mixture was allowed to stir atroom temperature for overnight. After completion of the reaction (monitored by TLC), the organic phase was evaporated under reduced pressure, reaction mixture was diluted withwater (100 mL), cooled to 0 C, pH adjusted to 5 with IN HCI and then extracted with DCM(3x500 mL). The combined organic extracts were washed with water (500 mL) and brinesolution (200 mL). The organic layer was dried over Na2S04, filtered and evaporated underreduced pressure. The residue was stirred with n-hexane (500 mL) at room temperature for about 30 minutes. The solid was filtered and dried under vacuum to obtain the title compound(65 g, yield: 66%) as a white solid. 1H NMR (300 MHz, CDCh): 8 ppm 9.50 (brs, IH), 1.53(s, 6H), 1.44 (s, 9H); ESI-MS: m/z 226.03 (M+Nat
64.4%
With sodium hydroxide; In 1,4-dioxane; water; at 20℃;
Method 1 : To a stirred solution of 2-Amino-2-methylpropanoic acid (30 g, 290.92 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 C was added 2N NaOH solution (300 ml) followed by (Boc)20 (95.13 g, 436.38 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml), cooled to 0 C, pH adjusted to 5 with IN HC1 and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room temperature for about 30 minutes. The obtained solid was filtered and dried under vacuum to obtain the desired product (38.0 g, yield: 64.4%) as a white solid.
61%
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 16h;Inert atmosphere;
A solution of compound 14 (10.0 grams, 97.0 mmol) in dioxane (150 ml) and NaOH (5%, 150 ml) was cooled to 0 C., then Boc2O was added dropwised. The mixture was stirred for 16 hours at room temperature under N2 atmosphere, then added HCl (concentrated) to make PH to 3, and the mixture was extracted with EtOAc (100 ml×3), washed with brine (50 ml), dried over Na2SO4, concentrated in vacuo and purified on silica gel column (PE/EtOAc=5:1) to give the product as white solid (12.1 grams, 61% yield).
49%
With triethylamine; In methanol; at 60℃; for 0.5h;
The starting materials N1, 2-dimetliylalaninamide and 2-methylalaninamide used in Examples 95 and 97 were prepared from 2-aminoisobutyric acid (ex. Aldrich) following the procedure below: Di-tert-butlydicarbonate (6.98 g, 32.0 mmol) was added to a stirred solution of the 2- aminoisobutyric acid (3 g, 29.13 mmol) in methanol/triethylmine (10/90) (100 ml). The reaction mixture was heated at 60C/30 minutes, cooled to room temperature and concentrated to dryness. The residue was taken up in dichloromethane (100 ml), washed with 10% aqueous potassium hydrogensulfate, water, dried over magnesium sulfate, filtered and evaporated to dryness to give N-(tert-butoxycarbonyl)-2-methylalanine (2.87 g, 49%) as a white solid ; 1H NMR Spectrum : (CDC13) 1.45 (s, 6H), 1.53 (s, 9H), 5.2 (br s, 1H).
45.44%
With hydrogenchloride; sodium hydroxide; In tetrahydrofuran;
E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid <strong>[62-57-7]2-Aminoisobutyric acid</strong> (140 g, 1.36 mol), 1 N NaOH (1620 mL, 1.63 mol), (Boc)2O (375 mL, 1.63 mol) and THF 420 mL were mixed together and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (700 mL) and adjusted to about pH 3.0 by adding 6 N HCl. The organic phase separated was washed with saturated NaCl solution and concentrated to approximately 1/4 of the original volume. After treatment with hexane a white solid product was isolated and collected (125.8 g, yield 45.44 %). An additional 7.8 g of product was recovered from the mother liquor.
44%
With sodium hydroxide; In tetrahydrofuran; at 20℃;
Step 1To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and Tiff (30 mL) was added (Boc)20 (26 g, 0.12 rnol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2), The organic phases were combined, washed with brine, dried over Na2SC>4. concentrated to give 9 g (44%) of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid
44%
With sodium hydroxide; In tetrahydrofuran; at 20℃;
Step 1. To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and THF (30 mL) was added (Boc)2O (26 g, 0.12 mol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2). The organic phases were combined, washed with brine, dried over Na2SO4, concentrated to give 9 g (44%)of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid.
40.7%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃;
To a solution of 2-amino-2-methylpropanoic acid (4.0 g, 39 mmol) , NaOH (1.55 g, 38.8 mmol) , water (50 mL) , and THF (20 mL) was added (Boc)2O (10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirred overnight at rt, then concentrated to dryness, and extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound as a white solid (3.21 g, 40.7yield) .
With sodium hydroxide; In tetrahydrofuran; water; for 4h;
To a solution of 2-aminoisobutyric acid (10 g, 97 mmol) in 1M aqueous NAOH (100ml) was added tert-butyloxycarbonyl anhydride (26 g, 120 mmol) in THF (30 ml). The reaction mixture was stirred for 4 h, diluted with ethyl acetate (250 ml), washed with 0. 5M aqueous HCl (200 ml), and finally with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo yielding crude N-BOC-2-AMINOISOBUTYRIC acid (7.3 g).
With triethylamine; sodium hydroxide; In methanol; water; at 20℃;
2-Amino-2-methyl-propionic acid (50.0 g) was suspended in a mixture of methanol and triethylamine (9:1, 1.2 L) (Scheme 11). 1M aqueous NaOH (450 mL) was added with stirring until all solid was dissolved. Di-tert-butyl dicarbonate (Boc2O; 214.0 g) was added, and the mixture was stirred at ambient temperature overnight. The organic volatiles were removed in vacuo. EtOAc (500 mL) was added. The organic layer was washed with brine and dried over Na2SO4, filtered, then concentrated to afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 90 g) as a white solid which was used directly in next step directly.
With water; sodium hydroxide; In tetrahydrofuran; at 20℃;Inert atmosphere;
To a solution of 2-amino-2- methylpropanoic acid (4.0 g, 39 mmol), NaOH (1.55 g, 38.8 mmol), water (50 mL), and THF (20 mL) was added (Boc)20 (10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirred overnight at rt, then concentrated to dryness, and extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over anhydrous Na2S04, and concentrated to dryness to give the title compound as a white solid (3.21 g, 40.7% yield).
50 g (0.48 mol) of 2-methylalanine were added to a cooled solution (water/ice) OF NAOH (19. 6 g) in water (100 ml). Once the solution had turned clear, 34 ml (0.50 mol) of acrylonitrile were dropped on cooling. The mixture was left overnight. After 18 hours, 28 ml of acetic acid were added on cooling (water/ice); a white solid precipitated; 200 ML of 95% ethanol were dropped in the flask, stirring was continued for 1 hour, then the mixture was allowed to stand in a fridge for 2-3 hours. After filtration, the solid was collected and dried in an oven at 80C. The filtrates were evaporated and taken up with ethanol (160 ml). On cooling a further amount of product was obtained, which was filtered and dried. 72 g of the title compound were obtained from the first filtration. Total yield: 95%. ESI MS : M/Z 157 (MH+) ; 1H NMR (400 MHz, DMSO-D6) : 8 7.47 (s, 1H), 2.70 (T, 2H), 2.48 (t, 2H), 1.18 (s, 6H).
80%
Acrylonitrile (5.13 g, 96.9 mmol) was added to a cold (0C) solution of 2-amino-2- methylpropanoic acid (10 g, 96.9 mmol) and sodium hydroxide (3.9 g, 96.9 mmol) in water (40 mL) and the resulting mixture was stirred at room temperature for 16 hours. AcOH (6 mL) was added and the precipitate filtered off. The solid was taken up in 95% EtOH (50 mL) and cooled down to 0C for 1 hour. The precipitate was filtered off, washed with EtOH (25 mL) and dried to afford the title compound (12 g, 80%) as a white solid. 1H NMR (DMSO-d6) delta 3.37 (s, 1H), 2.70 (t, J = 6.3 Hz, 2H), 2.58 (t, J = 7.3 Hz, 2H), 1.16 (s, 6H).
With sodium carbonate; In tetrahydrofuran; water; at 20℃; for 16h;
Step 1. Cbz-OSu (57 g, 0.23 mol) in THF (150 mL) was added a mixture of aq Na2C03 (82 g, 0.78 mol) and 80-1 (20 g, 0.19 mol). After it was stirred at r.t. for 16 h, it was adjusted to pH > 10 and washed with EtOAc (400 mL x 2). The aqueous layer was pooled and acidified to pH < 1 with cone. HC1. It was extracted with EtOAc (500 mL x 2). The organic layer was dried over Na2S04 and evaporated to give 80-2 (45 g, 97.8%).
72%
Synthesis of Compound S.2. To S.1 (10 g, 0.0969 mol) in THF (60 ml) and water (60 mL) at 0 C. was added sodium bicarbonate (16.27 g, 0.193 mole) followed by N-(benzyloxy carbonyloxy) succinimide (60.37 g, 0.242 mol). The reaction mixture was stirred at RT for 12 hr. The THF was removed under vacuum and the aqueous phase was washed with ether (2×100 mL). The aqueous phase was cooled to 0 C. and acidified to pH=2 with 5N HCL (50 mL). The reaction mixture was extracted with ethyl acetate (2×100 mL); the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (1% MeOH in dichloromethane) to give S.2 (16 g, 72%). 1H NMR (CDCl3, 200 MHz) delta 7.45-7.32 (m, 5H), 5.40 (bs, 1H,) 5.12 (s, 2H), 1.82 (s, 6H); MS: m/z 238 [M+1]+.
72%
To S.1 (10 g, 0.0969 mol) in THF (60 ml) and water (60 mL) at 0 C. was added sodium bicarbonate (16.27 g, 0.193 mole) followed by N-(benzyloxy carbonyloxy) succinimide (60.37 g, 0.242 mol). The reaction mixture was stirred at RT for 12 hr. The THF was removed under vacuum and the aqueous phase was washed with ether (2×100 mL). The aqueous phase was cooled to 0 C. and acidified to pH=2 with 5N HCL (50 mL). The reaction mixture was extracted with ethyl acetate (2×100 mL); the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (1% MeOH in dichloromethane) to give S.2 (16 g, 72%). 1H NMR (CDCl3, 200 MHz) delta 7.45-7.32 (m, 5H), 5.40 (bs, 1H,) 5.12 (s, 2H), 1.82 (s, 6H); LCMS: m/z 238 [M+1]+.
With hydrogenchloride In 1,4-dioxane; methanol; ammonium hydroxide
2.b 2-(4-(3,4-Methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide
b) 2-Amino-2,2-dimethylethanamide A solution of HCl in dioxane (4.0 M), methanol (54 ml) and aminoisobutyric acid (11.7 g, 0.114 mol) was refluxed for 6 h. Once at rt, the solution was concentrated to a white solid. NMR of the solid showed that the solid was a mixture of aminoisobutyric acid and methyl 2-amino-2,2-dimethylacetate. This crude intermediate was heated to 50 degree Celsius in aqueous ammonium hydroxide (29%, 140 ml) in a sealed tube for 24 hours. The solution was cooled to room temperature, then evaporated under reduced pressure to give a white solid. 1H NMR of the solid showed that the white solid contained 40% of the title product. 1H NMR (CDCl3) δ7.80 (s, 2 H), 7.48 (s, 2 H), 1.27 (s, 6 H).
With triethylamine; methyl trifluoromethanesulfonate In N,N-dimethyl-formamide
93 Example 93
Example 93 Methyl triflate (0.80 mL, 7.11 mmol) was added to a suspension of resin bound (tert-alkoxycarbonyl)imidazole (5.06 g, Loading 0.70 mmol/g) in dry 1,2-DCE (30 mL), cooled at 10° C. The mixture was stirred for 15 min at this temperature and for 10 min while being warmed to rt. After addition of Et3N (2.40 mL, 17.2 mmol), stirring was continued for an additional 10 min. A suspension of methyl 2-aminoisobutyrate (1.14 g, 7.42 mmol) and Et3N (0.98 mL, 7.04 mmol) in DMF (13 mL) was filtered and transferred via syringe to the stirred resin suspension. The mixture was shaken for 5.5 h at rt and filtered. The resin bound Part A compound was washed with THF (3 times), 1/1 THF/MeOH, THF (3 times), and CH2Cl2 (3 times) and dried: IR 1728 cm-1; Anal. Found C, 82.02; H, 7.96; N, 0.89. Loading on N content: 0.64 mmol/g. A 3/2 dioxane/0.25 M KOH solution (40 mL) was added to the Part A compound (2.63 g, Loading 0.64 mmol/g) and the suspension was heated at 75° C. for 4.5 h. After filtration, the polymer was washed with DMF (3 times), 5% AcOH/DMF (3 times, 50 mL total), MeOH (3 times), THF (3 times)and CH2Cl2 (3 times) and dried to provide the Part B compound (2.50 g). A portion of the resin (53 mg) was treated with 10% TFA/CH2Cl2 (1.5 mL) for 5 h and filtered. The resin was rinsed with CH2Cl2 (3 times) and MeOH (2 times) and the filtrates were evaporated and dried (vacuum, overnight) to give pure 2-aminoisobutyric acid, as its TFA salt (6.3 mg): 1H NMR δ(CD3OD, ppm) 1.55 (s, 6H).
With triethylamine; methyl trifluoromethanesulfonate In N,N-dimethyl-formamide
93 EXAMPLE 93
EXAMPLE 93 Methyl triflate (0.80 mL, 7.11 mmol) was added to a suspension of resin bound (tert-alkoxycarbonyl)imidazole (5.06 g, Loading 0.70 mmol/g) in dry 1,2-DCE (30 mL), cooled at 10° C. The mixture was stirred for 15 min at this temperature and for 10 min while being warmed to rt. After addition of Et3N (2.40 mL, 17.2 mmol), stirring was continued for an additional 10 min. A suspension of methyl 2-aminoisobutyrate (1.14 g, 7.42 mmol) and Et3N (0.98 mL, 7.04 mmol) in DMF (13 mL) was filtered and transferred via syringe to the stirred resin suspension. The mixture was shaken for 5.5 h at rt and filtered. The resin bound Part A compound was washed with THF (3 times), 1/1 THF/MeOH, THF (3 times), and CH2Cl2 (3 times) and dried: IR 1728 cm-1; Anal. Found C, 82.02; H, 7.96; N, 0.89. Loading on N content: 0.64 mmol/g. A 3/2 dioxane/0.25 M KOH solution (40 mL) was added to the Part A compound (2.63 g, Loading 0.64 mmol/g) and the suspension was heated at 75° C. for 4.5 h. After filtration, the polymer was washed with DMF (3 times), 5% AcOH/DMF (3 times, 50 mL total), MeOH (3 times), THF (3 times) and CH2Cl2 (3 times) and dried to provide the Part B compound (2.50 g). A portion of the resin (53 mg) was treated with 10% TFA/CH2Cl2 (1.5 mL) for 5 h and filtered. The resin was rinsed with CH2Cl2 (3 times) and MeOH (2 times) and the filtrates were evaporated and dried (vacuum, overnight) to give pure 2-aminoisobutyric acid, as its TFA salt (6.3 mg): 1H NMR 5 (CD3OD, ppm) 1.55 (s, 6H).
2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
In 1,4-dioxane; sodium hydroxide
13.A N-Hydroxy-2-methyl-2-(5pyridin-2-ylthlophene-2-sulfonylamino)propionamide
(A) To a solution of 2-amino-2-methylpropionic acid (2.0 grams, 19.4 mmole) in 1 N aqueous sodium hydroxide solution (45 mL) and dioxane (45 mL) was added 5-pyridin-2-ylthiophene-2-sulfonyl chloride (8.41 grams, 32.4 mmole). The resulting mixture was stirred at room temperature for 16 hours. Additional 1 N aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture which was then extracted with diethyl ether. The organic extracts were discarded. The aqueous layer was acidified with 1 N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine, dried over magnesium sulfate and concentrated to afford 2-methyl-2-(5pyridin-2-ylthiophene-2-sulfonylamino)propionic acid as a white solid (2.18 grams, 34%).
(B) General Procedure for Preparing amino acid ester hydrochloric Salts Thionyl chloride (2.0 mol. equivalents) was added dropwise to a stirred solution of the appropriate anhydrous alcohol (10.0 mol equivalents) under argon atmosphere and cooled to 0 C. The mixture was stirred at 0 C. for 1 h and then slowly allowed to warm to RT. The appropriate amino acid (1.0 mol. equivalents) was added and the mixture was heated at reflux overnight. The solvent was removed under reduced pressure (last traces of solvent were removed by co-evaporation with increasingly more volatile solvents). The crude product was then triturated with Et2O to afford the pure amino acid ester hydrochloric salt. EXAMPLE 14 2-[(2R,3S,4R,5R)-5-(4-Amino-2-oxo-2H-pyrimidin- 1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-2-methyl-propionic acid ethyl ester (I-10) and 2-[(2R,3S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylamino}-2-methyl-propionic acid; compound with ammonia (I-69) step 1-Ethyl 2-amino-2-methylpropanoate hydrochloride salt The title compound was prepared according to Example 1 (A) utilizing 2-amino-isobutyric acid (8.0 g, 77.6 mmol), thionyl chloride (11.3 mL, 155.2 mmol) and anhydrous EtOH (45.5 mL, 776.0 mmol). The product 14n was isolated as a white solid (9.12 g, yield 70%). 1H-NMR (CDCl3; 300 MHz): delta 8.93 (3H, bs, NH3Cl), 4.25 (2H, q, J=7.1 Hz, OCH2CH3), 1.72 (6H, s, [CH3]2C), 1.30 (3H, t, J=7.1 Hz, OCH2CH3); 13C-NMR (CDCl3; 75 MHz): delta 14.4 (OCH2CH3), 24.3 ([CH3]2C), 57.8 (C[CH3]2), 63.0 (OCH2CH3), 171.5 (CO).
In ethanol;
REFERENCE EXAMPLE 4 A stirred suspension of 2-amino-2-methylpropanoic acid (165 g) in ethanol at 0 C. was saturated with hydrogen chloride gas. The mixture was heated at reflux for 4 hours and the solvent was evaporated under reduced pressure to give ethyl 2-amino-2-methylpropanoate hydrochloride as a white solid.
With hydrogenchloride; potassium hydroxide In water
S.9.1 Preparation of S-sec-butyl O-ethyl (5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl)phosphonothiolate
(1) 2.75 g of potassium hydroxide was dissolved in 50 ml of water, and 5.0 g of 2-aminoisobutyric acid and 3.6 g of methyl isothiocyanate were sequentially added thereto. The mixture was stirred at 40° C. for 15 minutes. Then, the reaction mixture was acidified by an addition of concentrated hydrochloric acid, and refluxed for 10 minutes to complete the reaction. After completion of the reaction, the reaction mixture was cooled with ice, whereby crystals precipitated. The crystals were collected by filtration to obtain 3.0 g of 5,5-dimethyl-4-oxo-2-thioxoimidazolidine having a melting point of from 138 to 140° C.
Stage #1: 2-Aminoisobutyric acid; benzyl alcohol With toluene-4-sulfonic acid In toluene for 6 - 24h; Heating / reflux;
Stage #2: With potassium carbonate In dichloromethane; water
Stage #3: With hydrogenchloride In water; acetone
1.A; 12.1
EXAMPLE 1 (A) General Procedure for Preparing amino acid benzyl ester hydrochloride Salts The amino acid (1.0 mol eq.) was suspended in toluene (10 mol eq.), p-TsOH (1.1 mol eq.) and anhydrous benzyl alcohol (4.0 mol eq.) was added and the resulting mixture was heated at reflux with Dean-Stark trap for 6-24 h (the reaction was quenched when the appropriate amount of water was collected from the Dean-Stark trap). On cooling to RT, Et2O was added and the mixture was left in ice bath for 1 h then filtered and washed with Et2O. The solid was dissolved in DCM and washed with 10% K2CO3 and water. The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting product was dissolved in acetone and the mixture was neutralized with 1 M HCl. The solvent was then evaporated and the solid was triturated with Et2O to afford the amino benzyl ester hydrochloride salt as a white solid. EXAMPLE 12 2-[(2R,3S,4R,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-2-methyl-propionic acid benzyl ester (I-3) step 1-Benzyl 2-amino-2-methylpropanoate hydrochloride salt (14p). The title compound was prepared as described in Example 1 utilizing 2-amino-isobutyric acid (10.0 g, 0.097 mmol),p-TsOH (20.3 g, 0.107 mmol), benzyl alcohol (40.0 mL, 0.388 mmol) and toluene (200 mL). The benzyl ester (14p) was isolated as a white solid (13.0 g, yield 59%). 1H-NMR (CDCl3; 300 MHz): δ 9.04 (3H, bs, NH3Cl), 7.42-7.38 (5H, m, Ph), 5.27 (2H, s, CH2Ph), 1.76 (6H, s, [CH31]2C); 13C-NMR (CDCl3; 75 MHz): δ 24.3 ([CH3]2C), 58.0 (C[CH3]2), 68.5 (CH2Ph), 128.6, 129.0, 129.1 (C-Ph), 135.2 (‘ipso’, C-Ph), 171.65 (CO).
Stage #1: 2-Aminoisobutyric acid; benzyl alcohol With toluene-4-sulfonic acid In toluene at 115℃; for 16h; Dean-Stark;
Stage #2: With hydrogenchloride In 1,4-dioxane; diethyl ether
Benzyl 2-amino-2-methylpropanoate hydrochloride:
A mixture of 2-amino-2- methylpropanoic acid (3 g, 29.1 mmol), benzyl alcohol (12 mL, 115 mmol) and p- toluenesulfonic acid monohydrate (5.53 g, 29.1 mmol) in toluene (40 mL) was heated under reflux overnight. Additional benzyl alcohol (12 mL, 115 mmol) was added and the reaction mixture was heated with a Dean Starck overnight. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether. Diethyl ether was removed, and then the residue was dissolved in ethyl acetate and washed with a saturated aqueous NaHC03 solution. The organic layer was dried over a2S04 and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether and HCI in dioxane. The resulting solid was filtered, washed with diethyl ether and dried under reduced pressure to afford the title compound: 1 H NMR (400MHz, dMSO-d6) δ 8.54 (brs, 3H), 7.42-7.35 (m, 5H), 5.25 (s, 2H), 1.49 (s, 6H).
With thionyl chloride at 5 - 90℃; for 16.6667h; Inert atmosphere; Sealed tube;
3 Synthesis of benzyl 2-amino-2-methylpropanoate hydrochloride (3a)
To a suspension of 2-amino-2-methyl-propanoic acid (2 g, 19.4 mmol) in benzyl alcohol (10.4 g, 97.0 mmol) was added thionyl chloride (2.83 mL, 38.8 mmol) over 10 min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature and the reaction was quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL x 2) and concentrated. The residue was taken up in water (20 mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 3a.1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 3H), 7.46 - 7.33 (m, 5H), 5.26 (s, 2H), 1.49 (s, 6H).
With thionyl chloride at 5 - 90℃; for 16.6667h; Inert atmosphere; Sealed tube;
3 Synthesis of benzyl 2-amino-2-methylpropanoate hydrochloride (3a)
To a suspension of 2-amino-2-methyl-propanoic acid (2 g, 19.4 mmol) in benzyl alcohol (10.4 g, 97.0 mmol) was added thionyl chloride (2.83 mL, 38.8 mmol) over 10 min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature and the reaction was quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL x 2) and concentrated. The residue was taken up in water (20 mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 3a.1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 3H), 7.46 - 7.33 (m, 5H), 5.26 (s, 2H), 1.49 (s, 6H).
With sodium acetate In water-d2 olefin and K2PtCl4 reacted in 1:1 mole ratio in D2O, amino acid and acetate in 1:1 ratio was dissolved in D2O, then evapd. to dryness, to this solid Pt(allylsulfonate)Cl3(2-) dissolved in D2O was added; complexes were monitored by NMR;
Stage #1: 2-Aminoisobutyric acid With N,O-Bis(trimethylsilyl)trifluoroacetamide In acetonitrile for 3.5h; Reflux;
Stage #2: 5-chlorothiophene-2-carbonyl chloride With triethylamine In acetonitrile for 0.25h; Reflux;
4.a
4.5 g (27.7 mmol) 5-chloro-thiophene-2-carboxylic acid are combined with 8.0 ml (110.7 mmol) thionyl chloride in 250 ml dichloromethane with stirring at room temperature and stirred for 3 h at reflux temperature. Then the reaction mixture is evaporated to dryness.2.9 g (27.7 mmol) 2-amino-isobutyric acid are combined with 8.0 ml (30.4 mmol) N,O-bis-(trimethylsilyl)-trifluoro-acetamide in 300 ml acetonitrile with stirring and stirred for 3.5 h at reflux temperature. The reaction mixture is combined with 8.5 ml (60.9 mmol) TEA and the solution of the prepared acid chloride in 75 ml acetonitrile, stirred for 15 min at reflux temperature and then slowly cooled to room temperature. The reaction mixture is evaporated to dryness i. vac., the residue is mixed with water and 2-molar sodium carbonate solution and washed with diethyl ether. The aqueous phase is adjusted to pH 1 with 20 ml conc. Hydrochloric acid, the precipitate is suction filtered and dried at 50° C. in the vacuum drying cupboard.Yield: 5.9 g (86%)C9H10ClNO3S (247.70) Mass spectrum: (M+H)+=248/250 (chlorine isotopes)
With toluene-4-sulfonic acid; In cyclohexane; at 100℃; for 72.0h;
Intermediate 35 ;3-Methylcyclopentyl 2-methylalaninate2-Aminoisobutyric acid (1g,9.7mmol), <strong>[18729-48-1]3-methylcyclopentanol</strong> (3.2mL, 29.1 mmol) and para-toluenesulphonic acid (2.03, 10.67mmol) were heated to 100oC in cyclohexane (10OmL) in Dean-Stark apparatus for 72h. The reaction was then cooled to room temperature. The reaction was filtered and the filtrate concentrated under reduced pressure to a brown oil (1 ,29g). The oil was determined to be a 1 :1 mixture of Intermediate 35 and <strong>[18729-48-1]3-methylcyclopentanol</strong> by 1H NMR and was used without further purification.
With potassium carbonate In water; N,N-dimethyl-formamide at 95 - 100℃; for 48h;
6b
4-Bromo-2-fluorobenzamide (0.5 g, 2.29 mmol), 2 aminoisobutyric acid (0.354 g,3.54 mmol), CuI (87 mg, 0.458 mmol), and K2CO3 (0.790 g, 5.72 mmol) were mixed in DMF (5 mL). H2O (0.5 mL) and TEA (11 mg, 0.1 mmol) were added followed by 2-acetyl cyclohexanone (60 mg, 0.428 mmol). The reaction mixture was heated to 95-100 °C for 48 h. The reaction mixture was diluted with H2O (20 mL) and the aqueous layer was washed with ethyl acetate (20 mL). The aqueous layer was acidified with IM citric acid to pH 4 and the product was extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the product. 1H NMR (DMSO, Freebase): δ (ppm) 7.55-7.45 (t, IH), 7.20 (bs, IH), 7.05 (bs, IH), 6.80 (bs, IH), 6.35-6.30 (d, IH), 6.18-6.10 (d, IH), 1.42 (s, 6H).
With hydrogen;20% palladium hydroxide on carbon; In ethanol; at 100℃; under 20686.5 Torr; for 27.5h;
A high pressure vessel on the HEL 100 system containing compound 12 (2.5 g; 24.244 mmol) and tetrahydro-pyran-4-carbaldehyde (5.05 mL; 48.487 mmol) is added palladium hydroxide, 20% on carbon, wet (3.405 g; 10 mol%; 2.424 mmol) and 50 mL of ethanol. The reaction is subjected to 400 psi H2 at 50 C for 40 h. After this time, the reaction is cooled to room temperature and filtered through Celite. The CeIi te is rinsed with methanol and water.The combined filtrates are concentrated and slurried in dichloromethane, then filtered to afford compound 13 as a white solid (3.95g; 81%), LC-MS (LC Method h): retention time 0.32 min, m/z 202 [M+H]+
70%
With hydrogen; palladium(II) hydroxide; In methanol; at 50℃; under 20679.6 Torr; for 18h;
To 0.90 g (8.76 mmol) of 2-amino-2-methyl-propionic in 10 mL MeOH is added at RT1.00 g (8.76 mmol) of tetrahydro-pyran-4-carbaldehyde. After 25 min Pd(OH)2 (310 mg, w=20%) is added. The reaction is stirred at 50 C. and 2757 kPa hydrogen pressure for 18 h. 10 mL of acetonitrile and 20 mL of water are added, filtered through celite to remove the catalyst and washed with water. The solvent is removed under reduced pressure to give 1.62 g of crude product, which is recrystallized from MeOH and water to afford 1.24 g of 2-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid. Yield: 70%; ESI-MS: 202 [M+H]+
70%
To 0.90 g (8.76 mmol) of 2-amino-2-methyl-propionic in 10 mL MeOH is added at RT 1 .00 g (8.76 mmol) of tetrahydro-pyran-4-carbaldehyde. After 25 min Pd(OH)2 (310 mg, w=20%) is added. The reaction is stirred at 50 C and 2757 kPa hydrogen pressure for 18 h. 10 mL of acetonitrile and 20 mL of water are added, filtered through celite to remove the catalyst and washed with water. The solvent is removed under reduced pressure to give 1.62 g of crude product, which is recrystallized from MeOH and water to afford 1.24 g of 2-methyl-2- [(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid. Yield: 70%; ESI-MS: 202 [M+H]+
With potassium carbonate;copper(l) iodide; N,N-dimethylglycine hydrochoride; In dimethyl sulfoxide; at 120℃; for 12h;
Example 392- [3- (6-Methanesulfonylaminocarbonyl-3, 3 -dimethyl- 1,2,3 ,4-tetrahydro-quinolin-2- yl)-phenylamino]-2,N-dimethyl-propionamideA mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (388 mg, 1 mmol), 2-amino-2-methyl-propionic acid (516 mg, 5 mmol), copper(I) iodide (114 mg, 0.6 mmol), N, N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120C for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2 x 150 mL), washed with water (2 x 50 mL) and saturated aqueous ammonium chloride solution (2 x 50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[3-(l-carboxy-l- methyl-ethylamino)-phenyl] -3,3-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (410 mg, 100%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C24H30N2O4 (M+H)+: 411.52, observed: 411.1.
With potassium carbonate;copper(l) iodide; N,N-dimethylglycine hydrochoride; In dimethyl sulfoxide; at 120℃; for 12h;
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (388 mg, 1 mmol), 2-amino-2-methyl-propionic acid (516 mg, 5 mmol), copper(I) iodide (114 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120 C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (410 mg, 100%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C24H30N2O4 (M+H)+: 411.52, observed: 411.1.
With water; potassium carbonate; L-proline; copper(l) chloride; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere;
4-bromo-2-fluoro -N- methylbenzamide, 2-amino - isobutyric acid molar ratio, catalyst, co-catalyst, acid binding agent, followed by water 1:1.5:0.1:0.1:4:2.3 In a single-neck flask was added4-bromo-2-fluoro -N- methylbenzamide (10g, 43.1mmol), 2- amino - isobutyric acid (6.7g, 64.7mmol), potassium carbonate (23.8g, 172.4mmol), proline (0.7g, 4.31mmol), water (1.8ml, 100mmol) was dissolved in DMF (60ml), andStirring under nitrogen replacementAfter addition of CuCl (0.45g, 4.31mmol), was heated to 100 , reaction 24h.After completion of the reaction first added water (120ml) the mixture was diluted, added and extracted with dichloromethane, the organic phase was removed, the aqueous phase was adjusted pH = 4 with 1mol / L citric acid solution, and the precipitated solid was filtered. The solid washed with water and ethanol (100: 1) mixed solution was washed three times to give pure white solid 9.5g. Yield 87%
75.4%
The bromobenzamide A-2 (10 g, 43.1 mmol), aminoisobutyric acid B-l (6.7 g, 64.6 mmol, 1.5 equiv), K2C03 (15 g, 2.5 equiv), 99% CuCl (0.8 g, 8.1 mmol, 0.2 equiv), DMF (60 mL, 6 vol) and water (1.8 mL) were added to the flask and the reaction slurry was heated to 30 C. 2-Acetylcyclohexanone (1.14 mL, 8.1 mmol, 0.2 equiv) was added to the reaction slurry followed by stirring at 105 C under nitrogen for 12-14 h. HPLC analysis showed 96.6% conversion to the desired product. The reaction mixture was then cooled to RT and extracted with water (120 mL) and IP Ac (60 mL). The lower aqueous layer was re-extracted with IP Ac (60 mL) and acidified with 180 mL of 1M citric acid to a pH of 4.0. The product began to crystallize at RT and the batch was further cooled to 5-7 C, filtered, washed with water (40 mL) and dried under vacuum at 50 C for 12 h. The reaction yielded 8.3 g of product C-1 (75.4% yield) as a tan solid with HPLC purity of 99.6%.
75%
With potassium carbonate; acetylacetone; copper dichloride; In water; at 110℃; for 110h;
S3:Dissolving 9.2 g of 4-bromo-2-fluoro-N-methylbenzamide and 6.18 g of 2-aminoisobutyric acid in an organic solvent.Then, 792 mg of cuprous chloride, 1.6 g of acetylacetone, 13.8 g of potassium carbonate and 1 ml of water were added.The nitrogen strip was reacted for 110 hours at 110 degrees Celsius. S4:TLC detection, after the reaction is completed, the organic solvent is evaporated to dryness, and then, under ice bath conditions,Slowly add 0.1 mol/L citric acid to adjust the pH = 1 to 2, filter, dry the filter cake as the target product, and wash the solid water three times with ethanol (100:1).Then wash it again with ethyl acetate.Obtaining 8g of solid,The yield was 75% and the HPLC purity was 99%.
26 g
4-bromo-2-fluoro-N-methyl benzamide (48.0 gm, 0.21mol) and K2C03 (52.8 gm, 0.38 mol) was charged in to reaction flask containing DMF (67.2 mL), 1,4-dioxane (268mL) and DM water (8.6mL). The reaction mixture was purged with nitrogen gas for 20 min and then charged CuCl (6.24 gm, 0.06 mol),L-proline(9.6 gm, 0.08 mol) and 2-aminoisobutyric acid (31.6 gm, 0.31mol). Continue purging nitrogen gas for 20 min followed by refluxed for 24 hrs. Solvent is distilled off completely from the obtained reaction mixture under vacuum at 70C. The reaction mass was cooled to 10 to 15 C and then charged DM water (20 mL). The pH of the reaction mass adjusted to 3-5 with 1 M citric acid solution to obtain the title product. Yield: 26.0 gm Chromatographic Purity (By HPLC): 95.38 %
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;Inert atmosphere;
A mixture of 278.4 g of N-methyl-4-bromo-2-fluoro-benzamide,103 g of 2-methylalanine, 276 g of potassium carbonate and 9.5 g of cuprous iodide were dissolved in 2.3 L of dimethylsulfoxide (DMSO)The reaction was stirred under heating at 120 C for 16 h under nitrogen, followed by cooling the reaction solution to 30 to 40 C,218 g of benzyl iodide was added, and after the reaction for 60 min, 342 g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile was added in portions,The reaction was carried out at 80 C overnight and the reaction progress was measured by LC-MS. 100 mL of methanol was added,After stirring at 80 C for 45 minutes, the reaction solution was cooled to 20 to 30 C, 4 L of isopropyl acetate, 2 L of water,1L isopropanol, the aqueous layer was extracted with isopropyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate,Filtered, concentrated, adding 1L isopropanol, heated to 80 C dissolved completely, cooled to 0 C precipitation of solid,Filtered, isopropanol and dried to give 309 g of product, yield 66.6%.
135 g
Copper chloride (12.8 gm) was charged to N,N?-dimethyl Formamide (600 ml) under argon atmosphere at 75-80C. 4-Bromo-2-fluoro-N-methylbenzamide obtained in example 1 (100 g) was charged to the mixture followed by addition of N,N-dimethylaniline (8.35 gm). The reaction mixture was stirred for 15-20 minutes. 2-aminoisobutyric acid (67 gm) was added and again the mixture was stirred for 15-20 minutes at 75-80C. Powdered potassium carbonate (148 gm) was added and stirred for 15 minutes. Water (10 ml) was added and the temperature of the mass was raised to 1 l0C and the mass was stirred for 4- 5 hours at 4-5 hours. The mass was cooled to 30-35C and filtered. The mass was filtered and washed with dimethyl formamide. Dimethyl formamide was distilled out under vacuum and the mass was cooled. Water (700 ml) was added to the mass and pH was adjusted to 13.5 - 14 by using 10% sodium hydroxide solution. MDC (300 ml) was added to the reaction mass and stirred. The layers were separated and aqueous layer was extracted with MDC (300 ml). MDC layer was separated and washed with water (300 ml). All the aqueous layers were combined and pH was adjusted to 2.5-3 by HC1 to precipitate out the product. The mass was stirred and filtered under vacuum. The precipitate was washed with water (100 ml) and suck dried well. The material was dried under vacuum at 55-60C.The dried product 2-[3-fluoro-4-(methylcarbamoyl) anilino]-2-methyl-propanoic acid (135 g) was isolated. Thereafter, the product is tested for HPLC purity which was observed to be 99.4%.
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 2-amino-2-methyl-propionic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120 C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 373.0.
60%
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 2-amino-2-methyl-propionic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL x 2), washed with water (50 mL x 2) and saturated aqueous ammonium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-chloro-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2- methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+)[(M+H)+] 373.0.
A solution of <strong>[1373546-23-6]2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile</strong> (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120 C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (120.1 mg, 33.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 364.1.
33.1%
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL x 2), washed with water (50 mL x 2) and saturated aqueous ammonium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-2-yl)- phenylamino]-2-methyl-propionic acid (120.1 mg, 33.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 364.1.
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (135 mg, 1.3 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120 C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{3-[4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl]-phenylamino}-2-methyl-propionic acid (90 mg, 56.0%) as a white solid: MS (ESI) M+1=488.0.
56%
Example 82 2-{3-[4,4-Dimethyl-6-(morpholine-4-sulfonyl)-l,2,3,4-tetrahydro-quinolin-2-yl]- phenylamino}-2-methyl-propionic acidTo a stirred solution of morpholine (5.2 mL, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0 C. The mixture was stirred at room temperature for 4 h and then washed with brine (50 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 4-(4-nitro- benzenesulfonyl)-morpholine (10.0 g, 92.5%) as a white powder: MS(ESI) M+l = 273.0.To a stirred solution of 4-(4-nitro-benzenesulfonyl)-morpholine (5.0 g, 18.4 mmol) ethanol (400 mL) was added iron powder (5.2 g, 92.0 mmol) and the solution of ammonium chloride (10 g, 184.0 mmol) in water (100 mL). After the reaction mixture was refluxed for 3 h, the iron was filtered off and the filtrate was basified to pH 9 by addition of sodium carbonate. The reaction mixture was extracted with ethyl acetate (300 mL x 2). The extract was washed with water (130 mL x 2) and brine (130 mL x 2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi- flash chromatography (gradient elution, 20 - 60% ethyl acetate in petroleum ether) to afford 4-(morpholine-4-sulfonyl)-phenylamine (4.2 g, 95%) as a yellow powder: MS(ESI) M+l = 243.1.To a stirred solution of 4-(morpholine-4-sulfonyl)-phenylamine (3 g, 12.4 mmol) and 3- bromo-benzaldehyde (2.52 g, 13.6 mmol) in acetonitrile (150 mL) were added isobutene (2.7 mL, 37.2 mmoll) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.54 g, 2.5 mmol). The resulting mixture was stirred at 80 C for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10- 40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-6- (morpholine-4-sulfonyl)-l,2,3,4-tetrahydro-quinoline (2.7 g, 47.4%) as a light yellow solid: MS(ESI) M+l = 465.0 & 467.0. A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)- 1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2- amino-2-methyl-propionic acid (135 mg, 1.3 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL x 2), washed with water (30 mL x 3) and saturated aqueous ammonium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{3-[4,4-dimethyl-6-(morpholine-4-sulfonyl)- l,2,3,4-tetrahydro-quinolin-2-yl]-phenylamino}-2-methyl-propionic acid (90 mg, 56.0%) as a white solid: MS(ESI) M+l = 488.0.
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.34 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (138 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120 C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (112.1 mg, 70.0%) as a white solid: MS (ESI) M+1=472.1.
70%
Example 852- [3- (6- Cyclobutylsulf amoyl-4,4-dimethyl- 1 ,2,3,4-tetrahydro- quinolin-2-yl)- phenylamino] -2-methyl-propionic acidA mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- sulfonic acid cyclobutylamide (150 mg, 0.34 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (138 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL x 2), washed with water (30 mL x 3) and saturated aqueous ammonium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl- l,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (112.1 mg, 70.0%) as a white solid: MS(ESI) M+l = 472.1.
With copper(l) iodide; 2-acetylcyclohexanone; potassium carbonate; triethylamine In water; N,N-dimethyl-formamide at 100℃; for 18h;
7 Preparation of 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic Acid
4-Bromo-2-fluoro-N-propylbenzamide (620 mg, 2.39 mmol), 2-aminoisobutyric acid (422 mg, 4.09 mmol), CuI (100 mg, 0.6 mmol), TEA (catalytic amount) and K2CO3 (1.13 g, 8.1 mmol) were dissolved in DMF (8 mL) and water (2 mL) stirred at RT for 5 min. 2-Acetylcyclohexanone (0.13 g, 0.3 mmol) was added and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was acidified with 1 M citric acid (pH 4) and extracted with ethyl acetate (100 mL, 2 times). The combined organic layer was dried over Na2SO4 and concentrated to obtain 1.0 g of 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.
Stage #1: 2-Aminoisobutyric acid With sodium hydroxide In 1,4-dioxane; water at 20℃; for 0.333333h;
Stage #2: 2,4-dichlorophenyl isocyanate In 1,4-dioxane; water at 20℃; for 1h;
5; 3.1
Scheme 3, Step 1. A solution of NaOH (0.028 g, 0.698 mmol) in Water (1 ml) was added to a suspension of 1 -aminocyclohexanecarboxylic acid (0.1 g, 0.698 mmol) in 1 ,4- dioxane (3 ml) at RT. The mixture was stirred at RT for 20 min (clear solution). A solution of 2,4-dichloro- l -isocyanatobenzene (0.131 g, 0.698 mmol) in dioxane (2 ml) was added dropwise to the reaction mixture at RT. The resulting solution was stirred at RT for 1 hr, and then evaporated to dryness under reduced pressure to give the title compound.
Fmoc-8-amino-3,6-dioxaoctyl succinamic acid[ No CAS ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-38-3 ]
[ 71989-26-9 ]
[ 71989-35-0 ]
[ 132327-80-1 ]
[ 62-57-7 ]
[ 109425-51-6 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
[ 166108-71-0 ]
Fmoc-Try(pg)-OH[ No CAS ]
HAibEGTFTSDVSSYLEEQAARK(N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])FIAWLVRGRGGGSK(N{Epsilon}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Method: SPPS_P; SPPS_P was performed on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, Ariz. 85714 U.S.A.) at 250-mumol scale using six fold excess of Fmoc-amino acids (300 mM in NMP with 300 mM HOAt or Oxyma Pure) relative to resin loading, e.g. low load Fmoc-Gly-Wang (0.35 mmol/g). Fmoc-deprotection was performed using 20% piperidine in NMP. Coupling was performed using 3:3:3:4 amino acid/(HOAt or Oxyma Pure)/DIC/collidine in NMP. NMP and DCM top washes (7 ml, 0.5 min, 2×2 each) were performed between deprotection and coupling steps. Coupling times were generally 60 minutes. Some amino acids including, but not limited to Fmoc-Arg(Pbf)-OH, Fmoc-Aib-OH or Boc-His(Trt)-OH were ?double coupled?, meaning that after the first coupling (e.g. 60 min), the resin is drained and more reagents are added (amino acid, (HOAt or Oxyma Pure), DIC, and collidine), and the mixture allowed to react again (e.g. 60 min).; Method: SC_P; The N-epsilon-lysine protection group was removed as described above and the chemical modification of the lysine was performed by one or more automated steps on the Prelude peptide synthesiser using suitably protected building blocks as described above. Double couplings were performed as described in SPPS_P with 3 hours per coupling.; Method: CP_M1; After synthesis the resin was washed with DCM, and the peptide was cleaved from the resin by a 2-3 hour treatment with TFA/TIS/water (95/2.5/2.5 or 92.5/5/2.5) followed by precipitation with diethylether. The peptide was dissolved in a suitable solvent (such as, e.g., 30% acetic acid) and purified by standard RP-HPLC on a C18, 5 mum column, using acetonitrile/water/TFA. The fractions were analysed by a combination of UPLC, MALDI and LCMS methods, and the appropriate fractions were pooled and lyophilised.; If desired the peptide counter ion can be exchanged to sodium using methods known in the art. As an example approx. 2 g peptide was dissolved in 250 ml acetonitrile/water (50/50) and loaded onto a Waters X-Bridge C8, 5 muM, 50×250 mm column on a preparative RP-HPLC system. Following loading, the column was washed with water for 8 min at a flow rate of 60 ml/min and 0.01 N NaOH pH 11 at a flow rate of 60 ml/min for 2×8 min. The sodium salt of the peptide was eluted using an isocratic flow of water at 60 ml/min for 10 min followed by a linear gradient of 5% to 85% acetonitrile over 30 min.
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
Fmoc-Try(pg)-OH[ No CAS ]
HAibEGTFTSDVSSYLEEQAAREFIAWLVRGRGK(N{Epsilon}-3-[2-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl)GGSK(N{Epsilon}-3-[2-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Method: SPPS_P; SPPS_P was performed on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, Ariz. 85714 U.S.A.) at 250-mumol scale using six fold excess of Fmoc-amino acids (300 mM in NMP with 300 mM HOAt or Oxyma Pure) relative to resin loading, e.g. low load Fmoc-Gly-Wang (0.35 mmol/g). Fmoc-deprotection was performed using 20% piperidine in NMP. Coupling was performed using 3:3:3:4 amino acid/(HOAt or Oxyma Pure)/DIC/collidine in NMP. NMP and DCM top washes (7 ml, 0.5 min, 2×2 each) were performed between deprotection and coupling steps. Coupling times were generally 60 minutes. Some amino acids including, but not limited to Fmoc-Arg(Pbf)-OH, Fmoc-Aib-OH or Boc-His(Trt)-OH were ?double coupled?, meaning that after the first coupling (e.g. 60 min), the resin is drained and more reagents are added (amino acid, (HOAt or Oxyma Pure), DIC, and collidine), and the mixture allowed to react again (e.g. 60 min).; Method: SC_P; The N-epsilon-lysine protection group was removed as described above and the chemical modification of the lysine was performed by one or more automated steps on the Prelude peptide synthesiser using suitably protected building blocks as described above. Double couplings were performed as described in SPPS_P with 3 hours per coupling.; Method: CP_M2; After synthesis the resin was washed with DCM, and the peptide was cleaved from the resin by a 2-3 hour treatment with TFA/TIS/water (95/2.5/2.5 or 92.5/5/2.5) followed by precipitation with diethylether. The peptide was dissolved in a suitable solvent (such as, e.g., 30% acetic acid) and purified by standard RP-HPLC on a Kinetex C18, 5 mum column, eluting with a binary mixture of 0.09M diammoniumhydrogenphosphate in water/acetonitrile (90:10, pH 3.0) and acetonitrile/2-propanol/water (60:20:20). The peptide was then further purified by standard RP-HPLC on a C18, 5 mum column, using acetonitrile/water/TFA. The fractions were analysed by a combination of UPLC, MALDI and LCMS methods, and the appropriate fractions were pooled and lyophilised.; If desired the peptide counter ion can be exchanged to sodium using the methods known in the art. As an example approx. 2 g peptide was dissolved in 250 ml acetonitrile/water (50/50) and loaded onto a Waters X-Bridge C8, 5 muM, 50×250 mm column on a preparative RP-HPLC system. Following loading, the column was washed with water for 8 min at a flow rate of 60 ml/min and 0.01 N NaOH pH 11 at a flow rate of 60 ml/min for 2×8 min. The sodium salt of the peptide was eluted using an isocratic flow of water at 60 ml/min for 10 min followed by a linear gradient of 5% to 85% acetonitrile over 30 min.
2-methyl-2-((3-trifluoromethyl)phenyl)aminopropanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: 3-bromo-1-trifluoromethylbenzene; 2-Aminoisobutyric acid With potassium carbonate; copper(l) chloride In water; N,N-dimethyl-formamide at 30℃; Inert atmosphere;
Stage #2: With 2-acetylcyclohexanone In water; N,N-dimethyl-formamide at 105℃; for 14h; Inert atmosphere;
1.1.18 Synthesis of 2-methyl-2-((3-trifluoromethyl)phenyl)aminopropanoic acid (67)
K2CO3 (16.5 mmol), CuCl (1.32 mmol) and 2-aminoisobutyric acid (9.9 mmol) were added to a round bottom flask. DMF (8.2 mL) and H2O (0.8 mL) were added followed by 66 (6.6 mmol). The reaction slurry was heated to 30 C and 2-acetylcycloheanone (1.32 mmol) was added. The reaction slurry was stirred at 105Cfor 14 h. After cooling down to r.t., the reaction mixture was extracted with water (30mL) and ethyl acetate (30 mL). The aqueous layer was re-extracted with ethyl acetate(30 mL) and acidified with 1 M citric acid to pH 4. The aqueous layer was then extract with ethyl acetate (2 x 30 mL) and the organic phase was dried under MgSO4 and concentrated under vacuum. The residue was purified by flash columnchromatography eluting with n-hexane 100 % then DCM 100% to give a white solidin quantitative yield. 1H-NMR (DMSO-d6): 12.08 (bs, 1H), 7.28-7.22 (m, 1H), 6.84-6.79 (m, 1H), 6.78-6.75 (m, 1H), 6.67-6.63 (m, 1H), 1.45 (s, 6H). 19F-NMR (DMSOd6): -61.48 (s, 3F). 13C-NMR (DMSO-d6): 176.8, 147.1, 129.5, 129.3 (q, J= 30.6Hz), 125.4 (q, J= 270.2 Hz), 116.5, 111.6 (q, J= 3.9 Hz), 109.1 (q, J= 4.0 Hz), 55.9,25.4.
3-(9-carboxy-nonyloxy)benzoic acid tert-butyl ester[ No CAS ]
[ 84793-07-7 ]
[ 35661-40-6 ]
[ 71989-23-6 ]
[ 62-57-7 ]
[ 32926-43-5 ]
[ 166108-71-0 ]
Fmoc-Arg(pg)-OH[ No CAS ]
Fmoc-Trp(pg)-OH[ No CAS ]
Fmoc-Gln(pg)-OH[ No CAS ]
Fmoc-Tyr(pg)-OH[ No CAS ]
Fmoc-Ser(pg)-OH[ No CAS ]
Fmoc-Asp(pg)-OH[ No CAS ]
Fmoc-Thr(pg)-OH[ No CAS ]
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{2-[2-(2-{4-carboxy-4-[10-(3-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{4-carboxy-4-[10-(3-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation method: SPPS Method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin. Fmoc-Lys(Mtt)-OH was used in position 26, and Boc-His(trt)-OH was used in position 7. The Mtt was removedwith HFIP, and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commercially available from Iris Biotech),Fmoc-Glu-OtBu, and 3-(9-carboxy-nonyloxy)-benzoic acid tert-butyl ester were coupled using a double couplingmethod on the Liberty Peptide synthesiser.UPLC (method 04_A4_1): 10.01 minUPLC (method 08_B4_1): 8.81 minLCMS4: m/z = 978.5 (M+5H)5+, 1222.8 (M+4H)4+, 1630.1 (M+3H)3+
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-[2-(2-{2-[10-(4-carboxyphenoxy)decanoylamino]ethoxy}ethoxy)acetyl])-EFIAWLVRGRK(Nε-[2-(2-{2-[10-(4-carboxyphenoxy)decanoylamino]ethoxy}ethoxy)acetyl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling.Preparation method: SPPS method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin.Fmoc-Lys(Mtt)-OH was used in position 26, and Boc-His(trt)-OH was used in position 7. The Mtt was removed withHFIP, and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commercially available from Iris Biotech)and 4-(9-carboxy-nonyloxy)-benzoic acid tert-butyl ester (prepared as described in Example 25, step 2 of WO2006/082204) were coupled using a double coupling method on the Liberty Peptide synthesiserUPLC (method 04_A3_1): 10.51 minLCMS4: m/z = 1085.2 (M+4H)4+, 1447.3 (M+3H)3+
H-Aib-EGTFTSDVSSYLEGQAAK(Nε{2-[2-(2-{2-[2-(2-{(S)-4-Carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acet yl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation method: SPPS method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin. Fmoc-Lys(Mtt)-OHwas used in position 26, and Boc-His(Trt)-OH was used in position 7. The Mtt was removed with HFIP, and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commercially available from Iris Biotech), Fmoc-Glu-OtBu,and 4-(9-carboxy-nonyloxy)-benzoic acid tert-butyl ester (prepared as described in Example 25, step 2 of WO2006/082204) were coupled using a double coupling method on the Liberty Peptide synthesiser.UPLC (method 04_A3_1): 7.19 minLCMS4: m/z = 978.5 (M+5H)5+, 1222.8 (M+4H)4+ 1630.1 (M+3H)3+
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation method: SPPS method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin. Fmoc-Lys(Mtt)-OHwas used in position 26, and Boc-His(Trt)-OH was used in position 7. The Mtt was removed with HFIP, and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commercially available from Iris Biotech), Fmoc-Glu-OtBuand 4-(9-carboxy-nonyloxy)-benzoic acid tert-butyl ester (prepared as described in Example 25, step 2 of WO2006/082204) were coupled using SPPS method D.UPLC (method 08_B4_1): Rt = 8.8 minUPLC (method 04_A3_1): Rt = 9.6 minLCMS4: 4598.0Calculated MW = 4598.2
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRK(Nε-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation method: SPPS method BLCMS4: Rt = 2.12 min, m/z: 4916.0UPLC (method: 08_B2_1): Rt = 12.59 minUPLC (method: 04_A3_1): Rt = 10.57 min
H-Aib-GGTFTSDVSSYLEGQAAK(Nε-[2-[2-[2-[[2-[2-[2-[[(2S)-4-carboxy-2-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRK(Nε-[2-[2-[2-[[2-[2-[2-[[(2S)-4-carboxy-2-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation method: SSPS method BUPLC (method:08_B2_1): Rt = 13.193 minUPLC (method:05_B5_1): Rt = 6.685 minLCMS4: m/z: 4887; m/3:1630; m/4:1222; m/5:978
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-((S)-4-carboxy-4-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}butyryl))-EFIAWLVRGRK(Nε-((S)-4-carboxy-4-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}butyryl))-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation: SPPS method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin. Fmoc-Lys(Mtt)-OH was usedin position 26, and Boc-His(Trt)-OH was used in position 7. The Mtt was removed with HFIP, and Fmoc-Glu-OtBu and4-(9-carboxy-nonyloxy)-benzoic acid tert-butyl ester (prepared as described in Example 25, step 2 of WO 2006/082204)were coupled using SPPS method D.UPLC (method 08_B4_1): Rt = 8.6 minUPLC (method 04_A3_1): Rt = 7.9 minLCMS4: 4565.0Calculated MW = 4566.1
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[4-(4-iodophenyl)butyrylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[4-(4-iodophenyl)butyrylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual couplingPreparation method: SPPS method B, 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commerciallyavailable from Iris Biotech), <strong>[27913-58-2]4-(4-iodophenyl)butyric acid</strong> (commercially available from Aldrich) and Fmoc-Glu-OtBu were coupled using SPPS method D.UPLC (method 04_A4_1): Rt = 8.54 minUPLC (method 01_A4_2): Rt = 10.23 minLCMS4: Rt = 2.4 min, m/z = 971 (m/5) 1213 (m/44) 1617 (m/3)
3-(11-carboxy-undecyloxy)benzoic acid tert-butyl ester[ No CAS ]
[ 84793-07-7 ]
[ 35661-40-6 ]
[ 71989-23-6 ]
[ 62-57-7 ]
[ 32926-43-5 ]
[ 166108-71-0 ]
Fmoc-Arg(pg)-OH[ No CAS ]
Fmoc-Trp(pg)-OH[ No CAS ]
Fmoc-Gln(pg)-OH[ No CAS ]
Fmoc-Tyr(pg)-OH[ No CAS ]
Fmoc-Ser(pg)-OH[ No CAS ]
Fmoc-Asp(pg)-OH[ No CAS ]
Fmoc-Thr(pg)-OH[ No CAS ]
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[12-(3-carboxyphenoxy)dodecanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[12-(3-carboxyphenoxy)dodecanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[4-(4-methylphenyl)butyrylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[4-(4-methylphenyl)butyrylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation: SPPS method B, 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commerciallyavailable from Iris Biotech), <strong>[4521-22-6]4-(4-methylphenyl)butyric acid</strong> (commercially available from ABCR) and Fmoc-Glu-OtBuwere coupled using SPPS method D.UPLC (method 01_B4_1): Rt = 9.93 minLCMS4: Rt = 2.44 min, m/z = 926(m/5) 1157(m/4) 1543(m/3)
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{(S)-4-carboxy-4-[2-(2-{2-[(13-carboxytridecanoylamino)]ethoxy}ethoxy)acetylamino]butyrylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{(S)-4-carboxy-4-[2-(2-{2-[(13-carboxytridecanoylamino)]ethoxy}ethoxy)acetylamino]butyrylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation: SPPS method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin. Fmoc-Lys(Mtt)-OH was usedin position 26, and Boc-His(trt)-OH was used in position 7. The Mtt was removed with HFIP manually, and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commercially available from Iris Biotech), Fmoc-Glu-OtBu andtetradecanedioc were coupled using a double coupling method on the Liberty Peptide synthesiser. The theoreticalmolecular mass was confirmed by MALDI-MS.UPLC (method 08_B4_1): Rt = 8.6 minUPLC (method 04_A3_1): Rt = 9.7 minMALDI-MS: 4788
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-[(S)-4-carboxy-4-{2-[2-(2-[2-(2-{2-[(13-carboxytridecanoylamino)]ethoxy}ethoxy)acetylamino]ethoxy)ethoxy] acetylamino}butyryl])-EFIAWLVRGRK(Nε-[(S)-4-carboxy-4-{2-[2-(2-[2-(2-{2-[(13-carboxytridecanoylamino)]ethoxy}ethoxy)acetylamino]ethoxy)ethoxy]acetylamino}butyryl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation: SPPS method B, starting with low-load Fmoc-Lys(Mtt)-Wang resin. Fmoc-Lys(Mtt)-OH was used in position 26, and Boc-His(trt)-OH was used in position 7. The Mtt was removed with HFIP manually, and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commercially available from Iris Biotech), Fmoc-Glu-OtBu andtetradecanedioc were coupled using a double coupling method on the Liberty Peptide synthesiser. The theoreticalmolecular mass was confirmed by MALDI-MS.UPLC (method 08_B4_1): Rt = 8.8 minUPLC (method 04_A3_1): Rt = 10 minMALDI-MS: 4787
4-(7-carboxyheptyloxy)benzoic acid tert-butyl ester[ No CAS ]
[ 84793-07-7 ]
[ 35661-40-6 ]
[ 71989-23-6 ]
[ 62-57-7 ]
[ 32926-43-5 ]
[ 166108-71-0 ]
Fmoc-Arg(pg)-OH[ No CAS ]
Fmoc-Trp(pg)-OH[ No CAS ]
Fmoc-Gln(pg)-OH[ No CAS ]
Fmoc-Tyr(pg)-OH[ No CAS ]
Fmoc-Ser(pg)-OH[ No CAS ]
Fmoc-Asp(pg)-OH[ No CAS ]
Fmoc-Thr(pg)-OH[ No CAS ]
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[8-(4-carboxyphenoxy)octanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRK(Nε-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[8-(4-carboxyphenoxy)octanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation method: SPPS method BLCMS4: Rt: 1.93 min, m/z: 4832.4; M/4: 1208.5; M/3: 1611.0UPLC (method 09_B4_1): Rt = 8.10 minUPLC (method 04_A3_1): Rt = 8.15 minUPLC (method 05_B5_1): Rt = 5.30 min
5-(12-carboxydodecyl)thiophene-2-carboxylic acid tertbutyl ester[ No CAS ]
[ 84793-07-7 ]
[ 35661-40-6 ]
[ 71989-23-6 ]
[ 62-57-7 ]
[ 32926-43-5 ]
[ 166108-71-0 ]
Fmoc-Arg(pg)-OH[ No CAS ]
Fmoc-Trp(pg)-OH[ No CAS ]
Fmoc-Gln(pg)-OH[ No CAS ]
Fmoc-Tyr(pg)-OH[ No CAS ]
Fmoc-Ser(pg)-OH[ No CAS ]
Fmoc-Asp(pg)-OH[ No CAS ]
Fmoc-Thr(pg)-OH[ No CAS ]
H-Aib-EGTFTSDVSSYLEGQAAK(Nε[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[13-(5-carboxythiophene-2-yl)tridecanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRK(Nε-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[13-(5-carboxythiophene-2-yl)tridecanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preperation method: SSPS method B. 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commerciallyavailable from Iris Biotech), Fmoc-Glu-OtBu, and 5-(12-Carboxy-dodecyl)-thiophene-2-carboxylic acid tertbutylester (prepared as described in Example 6 of WO07128815) were coupled using SSPS method D method on theLiberty synthesiser.UPLC (method 08_B4_1): Rt = 9.87 minLCMS4: m/z =1651 (m/3), 1239 (m/4), 991 (m/5)
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[16-(4-carboxyphenoxy)hexadecanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[16-(4-carboxyphenoxy)hexadecanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-[4-(4-tert-butylphenyl)butyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-EFIAWLVRGRK(Nε-{2-[2-(2-{2-[2-(2-{(S)-4-[4-(4-tert-butylphenyl)butyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl})-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
SPPS method B refers to the synthesis of a protected peptidyl resin using Fmoc chemistry on a microwave based Liberty peptide synthesiser (CEM Corp., North Carolina). A suitable resin is a pre-loaded, low-load Wang resinavailable from Novabiochem (e.g. low load Fmoc-Lys(Mtt)-Wang resin, 0.35 mmol/g). Fmoc-deprotection was with 5percentpiperidine in NMP at up to 70 or 75°C. The coupling chemistry was DIC/HOAt in NMP. Amino acid/HOAt solutions (0.3M in NMP at a molar excess of 3-10 fold) were added to the resin followed by the same molar equivalent of DIC (0.75Min NMP). For example, the following amounts of 0.3M amino acid/HOAt solution were used per coupling for the followingscale reactions: Scale/ml, 0.10 mmol/2.5 ml, 0.25 mmol/5 ml, 1 mmol/15 ml. Coupling times and temperatures weregenerally 5 minutes at up to 70 or 75°C. Longer coupling times were used for larger scale reactions, for example 10min. Histidine amino acids were double coupled at 50°C, or quadruple coupled if the previous amino acid was stericallyhindered (e.g. Aib). Arginine amino acids were coupled at RT for 25 min then heated to 70 or 75°C for 5 min. Someamino acids such as but not limited to Aib, were "double coupled", meaning that after the first coupling (e.g. 5 min at75°C), the resin is drained and more reagents are added (amino acid, HOAt and DIC), and the mixture in heated again(e.g. 5 min at 75°C). When a chemical modification of a lysine side chain was desired, the lysine was incorporated asLys(Mtt). The Mtt group was removed by washing the resin with DCM and suspending the resin in neat (undiluted)hexafluoroisopropanol for 20 minutes followed by washing with DCM and NMP. The chemical modification of the lysinewas performed either by manual synthesis (see SPPS method D) or by one or more automated steps on the Libertypeptide synthesiser as described above, using suitably protected building blocks (see General methods), optionallyincluding a manual coupling. Preparation: SPPS method B, 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (commerciallyavailable from Iris Biotech), 4-(4-t-butylphenyl)butyric acid and Fmoc-Glu-OtBu were coupled using SPPS method D.UPLC (method 08_B4_1): Rt = 9.07 minLCMS4: Rt = 2.29 min, m/z = 943 (m/5) 1179 (m/4) 1571 (m/3)
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl])-EFIAWLVRGRK(Nε-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl])-NH2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Preparation method: The peptide was synthesised on Lys(Mtt)-Wang resin with a loading of 0.35 mmol/g. Thesynthesis was performed on a Liberty synthesiser under microwave conditions using 5 minute single couplings withDIC/HOAt at up to 70C, except for histidine which was coupled for 20 minutes at up to 50C. All amino acids wereprotected with standard protecting groups, except for lysines to be acylated (in this case Lys26) which was protectedwith Mtt. Deprotection was with 5% piperidine in NMP at 50C for 3 minutes. After the synthesis was completed, the Nterminuswas blocked with 10 equivalents of Boc-carbonate and 10 equivalents of DIPEA for 30 minutes. The Mtt groupswere removed by treatment with neat (undiluted) hexafluoroisopropanol for 20 minutes and the side chains were builtstepwise on the Liberty using the same protocol as above using Fmoc-8-amino-3,6-dioxaoctanoic acid, Fmoc-Glu-OBut,and <strong>[843666-27-3]hexadecanedioic acid mono-t-butyl ester</strong>. The peptide was cleaved with TFA/water/TIS (95:2.5:2.5) for 2 hours andisolated by precipitation with diethylether. The crude peptide was purified by preparative HPLC on a 20 mm x 250 mmcolumn packed with either 5u or 7u C18 silica. The peptide was dissolved in 5 ml 50% acetic acid and diluted to 20 mlwith H2O and injected on the column which then was eluted with a gradient of 40-60 % CH3CN in 0.1% TFA 10 ml/minduring 50 min at 40C. The peptide containing fractions were collected and purity assessed by MALDI and UPLC. Thepurified peptide was lyophilised after dilution of the eluate with water.Preparation method: As in Example 3, except that the resin used was Tentagel S RAM with a loading of 0.24mmol/g and the Fmoc-Lys(Mtt) was used both on positions 26 and 37.The theoretical molecular mass of 4843.6 was confirmed by MALDI-MS.UPLC (method 08_B4_1): Rt 9.43 minUPLC (method 04_A3_1): Rt 11.88 min
H-Aib-EGTFTSDVSSYLEGQAAK(Nε-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl])-EFIAWLVRGRK(Nε-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl])-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The peptide was synthesised on Lys(Mtt)-Wang resin with a loading of 0.35 mmol/g. Thesynthesis was performed on a Liberty synthesiser under microwave conditions using 5 minute single couplings withDIC/HOAt at up to 70C, except for histidine which was coupled for 20 minutes at up to 50C. All amino acids wereprotected with standard protecting groups, except for lysines to be acylated (in this case Lys26) which was protectedwith Mtt. Deprotection was with 5% piperidine in NMP at 50C for 3 minutes. After the synthesis was completed, the Nterminuswas blocked with 10 equivalents of Boc-carbonate and 10 equivalents of DIPEA for 30 minutes. The Mtt groupswere removed by treatment with neat (undiluted) hexafluoroisopropanol for 20 minutes and the side chains were builtstepwise on the Liberty using the same protocol as above using Fmoc-8-amino-3,6-dioxaoctanoic acid, Fmoc-Glu-OBut,and <strong>[843666-27-3]hexadecanedioic acid mono-t-butyl ester</strong>. The peptide was cleaved with TFA/water/TIS (95:2.5:2.5) for 2 hours andisolated by precipitation with diethylether. The crude peptide was purified by preparative HPLC on a 20 mm x 250 mmcolumn packed with either 5u or 7u C18 silica. The peptide was dissolved in 5 ml 50% acetic acid and diluted to 20 mlwith H2O and injected on the column which then was eluted with a gradient of 40-60 % CH3CN in 0.1% TFA 10 ml/minduring 50 min at 40C. The peptide containing fractions were collected and purity assessed by MALDI and UPLC. Thepurified peptide was lyophilised after dilution of the eluate with water.The theoretical molecular mass of 4844.6 was confirmed by MALDI-MS.UPLC (method 08_B4_1): Rt 9.50 minUPLC (method 04_A3_1): Rt 11.23 min
With copper(l) iodide; 2-(2-methyl-1-oxopropane)cyclohexanone; potassium carbonate In water at 90℃; for 0.833333h; Microwave irradiation; Green chemistry;
2-[2-(1-carboxy-1-methyl-ethylcarbamoyl)-2-methyl-propionylamino]-2-methyl-propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With pyridine at 20 - 65℃; for 12h; Inert atmosphere;
1 Example 1
In a 250 mL three-necked flask equipped with a constant pressure dropping funnel and argon, add the magnet and connect the argon to 2-aminoisobutyric acid (10 g, 97 mmol), anhydrous pyridine (150 mL) was added, and the mixture was stirred slowly at room temperature Add freshly prepared dimethyl malonyl chloride (8.2mL, 63mmol), 1h after the drop is completed, heated to 65 , the reaction 12h rotation Evaporation on the removal of pyridine, the oil, by adding 3M hydrochloric acid (30mL) adjusted to pH2 ~ 3, precipitation of large amounts of solid, low temperature for 1hAfter the filter, filter cake with a small amount of acetonitrile washed three times to obtain a white solid powder after drying weighing 11.6g, the yield of 75%
In the stainless steel pressure reactor (50 ml) in, adding magneton, 2 - amino isobutyric acid (1g, 9.7mmol), anhydrous pyridine (15 ml), two fluorine third acid diethyl ester (1.6 ml, 9 . 7mmol), argon replacement system 3 to turn off the reaction kettle, in oil bath heated to 200 C and maintain 2h, out of the reaction solution after cooling, in the rotary evaporator to remove the pyridine, obtaining oil objects, adding 3 mol/L hydrochloric acid (5 ml) adjusted to pH2 - 3, separating out a large quantity of solid, low warm settlement 1h after filtering, a small amount of b the nitrile washes cake three times, to obtain white solid powder after drying weighing 2.5g, yield 83%.
With triethylamine; In water; at 0 - 20℃; for 12.5h;Sealed tube;
The reactions were carried out in a one-neck round bottomask. The corresponding 2-amino-2-methylpropanoic acid (0.88 g,8.5 mmol) and triethylamine (3.4 g, 34 mmol) were added to avigorously stirred mixture of water (5 mL) at 0C. When solidcompletely dissolved in water, 4-chlorosulfonyl benzoic acidmethyl ester (1 g, 4.3 mmol) was added dropwise over 30 min. Thenthe reaction was stirred at rt for 12 h, the product was extractedwith EtOAc (3 50 mL). Combined organic layers were dried overNa2SO4, concentrated in vacuo. The residue was puried by silicagel column chromatography (DCM/MeOH 30/1) to afford thedesired product. Yellow solid, m.p. 170.2e173.6C.1H NMR(400 MHz, DMSO) d 8.24 (s, 1H), 8.10 (d, J 8.4 Hz, 2H), 7.93 (d,J 8.4 Hz, 2H), 3.88 (s, 3H), 1.28 (s, 6H).13C NMR (100 MHz, DMSO)d 175.5, 165.7, 148.0, 132.9, 130.2, 127.0, 58.4, 53.0, 26.2. HRMS (ESI-TOF) m/z Calcd for C12H15NO6S [MNa]324.0518, found 324.0504.
6-bromo-5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With copper(l) iodide; 1,8-diazabicyclo[5.4.0]undec-7-ene In 1,4-dioxane; N,N-dimethyl acetamide at 140℃; for 16h; Inert atmosphere; Sealed tube;
2 Step 2
A solution of 2,4-dibromo-3-chloro-6-methylaniline (7.5 g, 25.08 mmol, 1 eq), 2-amino-2-methylpropanoic acid (5.16 g 50.16 mol, 2 eq) 1,4-dioxan ad DBU (9.54 g, 44.94 mmol, 2 eq) in dry DMA (112 ml) in a sealed tube were deoxygenated by Ar for 10 min. Cuprous iodide (0.479 g, 2.5 m ol, 0.1 eq) was added to the reaction mixture and again deoxygenated by Ar for 10 min. Reaction mixture was then stirred at 140° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to RT and diluted with EtOAc (1000 m) and washed with water (4*150 ml), brine (200 ml), dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 20% EtOAc/hexane; Rf-value-0.4) to afford 6-bromo-5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (2.2 g, 29%) light brown solid.
6-fluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium phosphate; copper(l) iodide In dimethyl sulfoxide at 140℃; for 16h; Inert atmosphere;
Step2: To the stirred suspension of 2-bromo-4-fluoro-6-trifluoromethyl-phenylamine (25 g, 0.097 mol) in dry DMSO (375 mL) was added 2-amino-2-methylpropionic acid (20 g, 0.194 mol) followed by K3PO4 (41.1 g, 0.194 mol) at RT. Resulting reaction mixture was degassed with nitrogen for 30 min, then CuCl (0.96 g, 0.0097 mol) was added and the reaction mixture was stirred at 140°C for 16 h. The reaction mixture was cooled to RT and filtered through celite. Celite bed was washed with EtOAc (500 mL). Resulting filtrate was poured into ice cold water (1000 mL). Resulting aqueous layer was extracted with EtOAc (2 x 250 mL). Total organic part was washed with water (2 x 500 mL), brine (250 mL), dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure to afford crude product which was purified by column chromatography to afford 6-fluoro-3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one (16 g, 63%) as brown solid.
63%
Stage #1: 2-bromo-4-fluoro-6-trifluoromethyl-phenylamine; 2-Aminoisobutyric acid With potassium phosphate In dimethyl sulfoxide at 20℃; for 0.5h;
Stage #2: With copper(l) chloride In dimethyl sulfoxide at 140℃; for 16h;
Step2
To the stirred suspension of 2-bromo-4-fluoro-6-trifluoromethyl-phenylamine (25 g, 0.097 mol) in dry DMSO (375 mL) was added 2-amino-2-methyl-propionic acid (20 g, 0.194 mol) followed by K3PO4 (41.1 g, 0.194 mol) at RT. Resulting reaction mixture was degassed with nitrogen for 30 min, then CuCl (0.96 g, 0.0097 mol) was added and the reaction mixture was stirred at 140°C for 16 h. The reaction mixture was cooled to RT and filtered through celite. Celite bed was washed with EtOAc (500 mL). Resulting filtrate was poured into ice cold water (1000 mL). Resulting aqueous layer was extracted with EtOAc (2 x 250 mL). Total organic part was washed with water (2 x 500 mL), brine (250 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to afford cmde product which was purified by column chromatography to afford 6-fluoro-3, 3 -dimethyl-8-trifluoromethyl-3 ,4- dihydro- 1H-quinoxalin-2 -one (16 g, 63%) as brown solid.
49%
With potassium phosphate; copper(l) chloride In dimethyl sulfoxide for 6h;
1 Step 1:
To a stirred solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (9.0 g, 35.02 mmol, 1.0 eq) and 2- aminoisobutyric acid (7.22 g, 70.04 mmol, 2.0 eq) in DMSO was added K3PO4(14.86 g, 70.04 mmol, 2.0 eq) under nitrogen atmosphere. The mixture was degassed for 10 minutes (N2) and then CuCI (0.346 g, 3.502 mmol, O.leq) was added. The mixture was heated to 130 °C for 6 h (monitored by TLC). The reaction mixture was then cooled to room temperature and filtered through a celite pad. The filtrate was diluted with EtOAc and was washed with water and brine. The organic layer was dried over Na3SO4and concentrated, the obtained crude resdue was purified by column chromatography (100-200 mesh silica gel, TLC system: EtOAc / hexane (3:7); Rf= 0.2) to give 6-fluoro-3,3-dimethyl- 8-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (4.5 g, 49%).
6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere;
Step1: A suspension of <strong>[444-14-4]2-bromo-4,6-difluoroaniline</strong> (25 g, 120.19 mmol, 1 eq.), 2-amino-2-methylpropanoic acid (24.75 g, 240.38 mmol, 2 eq.), K3PO4 (50.96 g, 240.38 mmol, 2 eq.) and Cul (2.29 g, 12.02 mmol, 0.1 eq.) in dry DMSO (375 mL) in a sealed tube were deoxygenated with Ar for 20 min. Reaction mixture was then stirred at 125C for 16 h. After completion of the reaction, it was filtered through celite bed and washed by EtOAc (100 mL). The filtrate was diluted with EtOAc (500 mL) and washed with water (3 x 150 mL), brine (200 mL), dried over anhydrous Na2S04 and evaporated under reduced pressure. Crude product was purified by column chromatography to afford 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (34.0 g, 67%) as brown solid.
6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; Sealed tube;
Step1: A suspension of <strong>[202865-77-8]2-bromo-4-fluoro-6-methylaniline</strong> (5 g, 24.5 mmol, 1 eq.), 2-aminoisobutaric acid (5.05 g, 49 mmol, 2 eq.), CS2CO3 (15.92 g, 49 mmol, 2 eq.) and cuprous iodide (0.466 g, 2.45 mmol, 0.1 eq.) in dry DMSO (75 mL) in a sealed tube were deoxygenated with Ar for 20 min. Reaction mixture was then stirred at 125C for 16 h. The reaction mixture was filtered through celite bed and washed with EtOAc (100 mL). The filtrate was diluted with EtOAc (200 mL) and washed with water (3 x 100 mL), brine (100 mL), dried over anhydrous Na2S04 and evaporated under reduced pressure to get the crude product which was purified by column chromatography to afford 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (3.0 g, 59%) as brown solid.
3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 140℃; for 16h;Inert atmosphere; Sealed tube;
Step 1: A suspension of <strong>[53848-17-2]2-bromo-6-methylaniline</strong> (1.0 g, 54.0 mmol, 1.0 eq) and 2-aminobutyric acid (1.1 g, 10.8 mmol, 2.0 eq) in DMSO (10 ml) in a sealed tube was deoxygenated with Ar for 20 minutes. K3PO4 (2.3 g, 10.8 mmol, 2.0 eq) and CuCl (53.0 mg, 5.4 mmol, 0.1 eq) were then added. The reaction mixture was then stirred at 140 C for 16 h. After completion of the reaction, the reaction mixture was filtered through a celite bed and the celite bed was washed with EtOAc (100 ml). The filtrate was diluted with EtOAc (100 ml) and was washed with water (3 x 150 ml) and brine (200 ml), dried over anhydrous Na2SC>4 and was then evaporated under reduced pressure to obtain the crude compound, which was purified by column chromatography (100-200 mesh silica gel; 30% EtO Ac/hexane; R^ value-0.4) to afford 3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.6 g, 60%).
3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium phosphate; copper(l) chloride; In dimethyl sulfoxide; at 140.0℃; for 6.0h;Inert atmosphere;
Step 1: To a stirred suspension of <strong>[58458-13-2]2-bromo-6-trifluoromethylphenylamine</strong> (25.0 g, 0.104 mol) in dry DMSO (375 ml) was added 2-amino-2-methyl-propionic acid (21.5 g, 0.208 mol) followed by K3PO4 (44.2 g, 0.208 mol) at ambient temperature. The resulting reaction mixture was degassed with nitrogen for 30 minutes, then cuprous chloride (1.03 g, 0.010 mol) was added and reaction mixture was heated to 140 C for 6 h. After completion of the starting material (monitored by TLC, 20% EA-Hexane, Rf 0.4) the reaction mixture was cooled to ambient temperature and was filtered through celite. The celite bed was washed with EtOAc (2 x 250 ml). The resulting filtrate was poured into ice cold water (800 ml). The resulting aqueous layer was extracted with EtOAc (2 x 500 ml). The combined organic layers were washed with water (2 x 650 ml) and brine (650 ml), were dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure to afford the crude material. The obtained crude material was triturated with MTBE-Hexane to afford 3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one (17.0 g, 66%) as a brown solid.
Stage #1: 2-Aminoisobutyric acid; 2-fluoro-4-bromobenzoic acid With potassium carbonate; copper(l) chloride In water; N,N-dimethyl-formamide at 140℃; for 17h; Inert atmosphere;
Stage #2: dimethyl sulfate In N,N-dimethyl-formamide at 40℃; for 2.5h;
1-4; 1-4 Example 4
At room temperature, put 2-fluoro-4-bromobenzoic acid (500g), 2-aminoisobutyric acid (370g), N,N-dimethylformamide (2300g) into the reaction flask in sequence, and add carbonic acid with stirring Potassium (825g) and water (400mL), vacuumed and replaced with nitrogen, added cuprous chloride (50g), maintained under nitrogen protection, heated to 140°C for 17h, after the reaction, the material was cooled to 90°C and filtered, and the filtrate was stirred Cool down to 40°C for crystallization for 1 hour, after filtering, put the obtained intermediate into the reaction flask again, add N,N-dimethylformamide (1150g), add dimethyl sulfate (575g) dropwise, and keep at this temperature React for 2.5h. After the reaction is over, add water (6L) and stir to crystallize for 1.5h, filter to obtain the crude product, then add the crude product to methanol (650mL), raise the temperature to reflux for 1.5h, cool to 5 to crystallize, filter and dry to obtain the target Compound 559g, the molar yield was 91.0%, and the purity determined by HPLC method was 99.90%.
3,3-dimethylcyclobutyl 2-amino-2-methylpropanoate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In 1,4-dioxane at 65℃; for 120h;
42 Synthesis of 3,3-dimethylcyclobutyl 2-amino-2-methylpropanoate hydrochloride (42a)
2-Amino-2-methylpropanoic acid (250 mg, 2.42 mmol) was suspended in 3,3-dimethylcyclobutanol (0.671 mL, 5.43 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4N, 3.03 mL, 12.1 mmol). The mixture was heated at 65 oC for 5 days. The reaction was cooled and any solid was removed by filtration. The 1,4-dioxane was removed under reduced pressure. The mixture was diluted with ethyl acetate / hexanes (1:1, 25 mL) and water (25 mL). The organic phase was extracted with water (2 x 25 mL). The combined aqueous phases were washed with ethyl acetate / hexanes (1:1, 3 x 25 mL), diethyl ether (3 x 25 mL) and dichloromethane (3 x 25 mL). Any residual solvent in the aqueous phase was removed and the volume was reduced to 20 mL, under reduced pressure. The aqueous phase was diluted with acetonitrile (20 mL) and subjected to lyophilization, providing intermediate 42a.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 3H), 5.04 (p, J = 7.1 Hz, 1H), 2.22 (m, 2H), 1.94 - 1.79 (m, 2H), 1.47 (m, 6H), 1.15 (s, 3H), 1.13 (s, 3H).
With hydrogenchloride In 1,4-dioxane at 65℃; for 120h;
42 Synthesis of 3,3-dimethylcyclobutyl 2-amino-2-methylpropanoate hydrochloride (42a)
2-Amino-2-methylpropanoic acid (250 mg, 2.42 mmol) was suspended in 3,3-dimethylcyclobutanol (0.671 mL, 5.43 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4N, 3.03 mL, 12.1 mmol). The mixture was heated at 65 oC for 5 days. The reaction was cooled and any solid was removed by filtration. The 1,4-dioxane was removed under reduced pressure. The mixture was diluted with ethyl acetate / hexanes (1:1, 25 mL) and water (25 mL). The organic phase was extracted with water (2 x 25 mL). The combined aqueous phases were washed with ethyl acetate / hexanes (1:1, 3 x 25 mL), diethyl ether (3 x 25 mL) and dichloromethane (3 x 25 mL). Any residual solvent in the aqueous phase was removed and the volume was reduced to 20 mL, under reduced pressure. The aqueous phase was diluted with acetonitrile (20 mL) and subjected to lyophilization, providing intermediate 42a.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 3H), 5.04 (p, J = 7.1 Hz, 1H), 2.22 (m, 2H), 1.94 - 1.79 (m, 2H), 1.47 (m, 6H), 1.15 (s, 3H), 1.13 (s, 3H).
4-methylpentyl 2-amino-2-methylpropanoate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; Sealed tube;
67 Synthesis of 4-methylpentyl 2-amino-2-methylpropanoate hydrochloride (67a)
2-Amino-2-methylpropanoic acid (1.5 g, 10.7 mmol) and 4-methylpentan-1-ol (5.49 g, 53.7 mmol) were taken up in 4N HCl in 1,4-dioxane (13.4 mL, 53.7 mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, solids were filtered off and the solution was concentrated down under reduced pressure. The residue was taken up in water (40 mL) and concentrated down under reduced pressure, taken up in water (40 mL) and concentrated down under reduced pressure. That residue was taken up in toluene and concentrated down under reduced pressure. The residue was taken up in water and lyophilized over the weekend to afford intermediate 67a. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (bs, 3H), 4.15 (t, J = 6.5 Hz, 2H), 1.67 - 1.48 (m, 3H), 1.48 (s, 6H), 1.27 - 1.14 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H). LCMS: MS m/z = 188.2 [M+1], tR = 0.61 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.
With hydrogenchloride In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; Sealed tube;
67 Synthesis of 4-methylpentyl 2-amino-2-methylpropanoate hydrochloride (67a)
2-Amino-2-methylpropanoic acid (1.5 g, 10.7 mmol) and 4-methylpentan-1-ol (5.49 g, 53.7 mmol) were taken up in 4N HCl in 1,4-dioxane (13.4 mL, 53.7 mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, solids were filtered off and the solution was concentrated down under reduced pressure. The residue was taken up in water (40 mL) and concentrated down under reduced pressure, taken up in water (40 mL) and concentrated down under reduced pressure. That residue was taken up in toluene and concentrated down under reduced pressure. The residue was taken up in water and lyophilized over the weekend to afford intermediate 67a. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (bs, 3H), 4.15 (t, J = 6.5 Hz, 2H), 1.67 - 1.48 (m, 3H), 1.48 (s, 6H), 1.27 - 1.14 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H). LCMS: MS m/z = 188.2 [M+1], tR = 0.61 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.
5-methylhexyl 2-amino-2-methylpropanoate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; Sealed tube;
68 Synthesis of 5-methylhexyl 2-amino-2-methylpropanoate hydrochloride (68a)
2-Amino-2-methylpropanoic acid (1.5 g, 10.7 mmol) and 5-methylhexan-1-ol (6.24 g, 53.7 mmol) were taken up in 4N HCl in 1,4-dioxane (13.4 mL, 53.7 mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, solids were filtered off and the solution was concentrated down under reduced pressure. The residue was taken up in water (40 mL) and concentrated down under reduced pressure, taken up in water (40 mL) and concentrated down under reduced pressure. That residue was taken up in toluene and concentrated down under reduced pressure. The residue was taken up in water and lyophilized over the weekend to afford intermediate 68a. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (bs, 3H), 4.16 (t, J = 6.5 Hz, 2H), 1.65 - 1.49 (m, 3H), 1.48 (s, 6H), 1.38 - 1.26 (m, 2H), 1.22 - 1.11 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H). LCMS: MS m/z = 202.2 [M+1], tR = 0.63 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.
With hydrogenchloride In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; Sealed tube;
68 Synthesis of 5-methylhexyl 2-amino-2-methylpropanoate hydrochloride (68a)
2-Amino-2-methylpropanoic acid (1.5 g, 10.7 mmol) and 5-methylhexan-1-ol (6.24 g, 53.7 mmol) were taken up in 4N HCl in 1,4-dioxane (13.4 mL, 53.7 mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, solids were filtered off and the solution was concentrated down under reduced pressure. The residue was taken up in water (40 mL) and concentrated down under reduced pressure, taken up in water (40 mL) and concentrated down under reduced pressure. That residue was taken up in toluene and concentrated down under reduced pressure. The residue was taken up in water and lyophilized over the weekend to afford intermediate 68a. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (bs, 3H), 4.16 (t, J = 6.5 Hz, 2H), 1.65 - 1.49 (m, 3H), 1.48 (s, 6H), 1.38 - 1.26 (m, 2H), 1.22 - 1.11 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H). LCMS: MS m/z = 202.2 [M+1], tR = 0.63 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.
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