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Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 58632-95-4 * Storage: {[proInfo.prStorage]}
* 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] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 878 - 881
10
[ 56-84-8 ]
[ 58632-95-4 ]
[ 13726-67-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1977, vol. 50, p. 718 - 721
11
[ 1155-64-2 ]
[ 58632-95-4 ]
[ 2389-45-9 ]
Reference：
[1] Patent: US4432971, 1984, A,
12
[ 58632-95-4 ]
[ 1155-64-2 ]
[ 2389-45-9 ]
Reference：
[1] Tetrahedron Letters, 1975, p. 4393 - 4394
13
[ 58632-95-4 ]
[ 110-60-1 ]
[ 68076-36-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 13, p. 2535 - 2545
[2] Carbohydrate Research, 2010, vol. 345, # 1, p. 33 - 40
14
[ 58632-95-4 ]
[ 62-57-7 ]
[ 30992-29-1 ]
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] Journal of Medicinal Chemistry, 1997, vol. 40, # 3, p. 342 - 349
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7388 - 7392
[3] Steroids, 2012, vol. 77, # 5, p. 403 - 412
17
[ 70-47-3 ]
[ 58632-95-4 ]
[ 7536-55-2 ]
Reference：
[1] Tetrahedron Letters, 1975, p. 4393 - 4394
18
[ 3054-01-1 ]
[ 58632-95-4 ]
[ 5068-28-0 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1977, vol. 50, p. 718 - 721
19
[ 139-13-9 ]
[ 58632-95-4 ]
[ 28320-73-2 ]
Yield
Reaction Conditions
Operation in experiment
82.3%
With triethylamine In 1,4-dioxane; water; ethyl acetate
N-Boc-triglycine. To a suspension of 18.92 g (100 mmole) of triglycine (available from Sigma Chemical Company) in 100 ml dioxane and 100 ml water was added 27.88 ml (200 mmole, 2.0 equivalents) of triethylamine and 27.1 g (110 mmole, 1.1 equivalents) of 2-[tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (available from Fluka, N.Y.). The reaction mixture was stirred at room temperature overnight. Water (65 ml) was added to the mixture, and the resultant mixture was extracted with ether (4*65 ml) ant EtoAc (1*70 ml). The aqueous layer was adjusted to pH 1.5 with 6M HCl at 0° C. and then extracted with EtOAc (25*100 ml) by the salt-out technique. A substantial amount of product precipitated out of the EtOAc extraction and was collected by filtration. The EtOAc filtrate was reduced to 1/5 of its original volume under vacuum to produce additional precipitate. The precipitate was collected by filtration and the above procedure (reduction of volume to 1/5) was repeated. The precipitates were combined and dried under vacuum to give 23.82 g of product. (82.3percent yield) 1 H-NMR (CD3 CN, δ): 7.05 (bs, 2H, NH), 5.70 (bs, 1H, NH), 3.82 (dd, 4H, CH2), 3.64 (d, 2H, CH2) and 1.92 (s, 9H, t-butyl).
Reference：
[1] Patent: US5541287, 1996, A,
[2] Patent: US6022966, 2000, A,
20
[ 76-84-6 ]
[ 58632-95-4 ]
[ 52-89-1 ]
[ 21947-98-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1979, vol. 57, p. 1388 - 1396
21
[ 107-97-1 ]
[ 58632-95-4 ]
[ 13734-36-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 19, p. 5133 - 5140
22
[ 58632-95-4 ]
[ 60-32-2 ]
[ 6404-29-1 ]
Yield
Reaction Conditions
Operation in experiment
97%
With triethylamine In 1,4-dioxane; water at 20℃; for 23 h; Inert atmosphere
Step A. Synthesis of jY-Boc-amino acid alkyl chains (Boc-aa, m = 5 or 10)[0092] A solution of a commercially available aminoacid alkyl chain (7.77 mmol) in water and dioxane was stirred at room temperature. Trielthyamine (11.65 mmol) was added slowly followed by Boc-ON (8.54 mmol). The solution was kept for 23 h under nitrogen. Afterwards, the mixture was diluted with diethyl ether and water and then washed with water (6x). The aqueous layers were then combined and a few drops of 10percent aqueous HCl solution were slowly added in order to reach pH 2.5. The resulting solution was then washed with dichloromethane (3x). The organic layers were washed with saturated sodium chloride salt solution. The organic phase was dried with magnesium sulfate, filtered and evaporated. Flash chromatography (hexanes: acetone, 4:1) was performed to yield a colorless yellow viscous oil in 97percent yield.6-Boc-amino-hexanoic acid (Boc-aa, m = 5)IR (NaCl, vmax, cm"1) : 3339 (N-H), 2860-3100 (O-H), 1711 (2x C=O), 1527 and 1250 (C-N-H), 1173 (C-O-C).1H-NMR (CDCl3, Jppm) : 8.91 (IH, br s, COOH), 4.74 (IH, s, NH), 3.02 (2H, m, CH2NH), 2.27 (2H, t, J = 7.4 Hz, CH2COOH), 1.24-1.68 (6H, No.m, 3 x CH2), 1.37 (s, 9H, 3 x CH3).13C-NMR (CDCl3, .pound.ppm) : 178.7 (COOH), 156.4 (OCONH), 79.4 ((CH3)3C), 40.5 (NHCH2), 34.1 (CH2COOH), 29.8 (NHCH2CH2), 28.6 (3 x CH3), 26.4 (CH2CH2CH2CH2CH2), 24.5 (CH2CH2COOH).ESI+ HRMS: [M + Na]+ calculated for C11H2JNNaO4 = 254.1363; found = 254.1360.
Reference：
[1] Patent: WO2011/11865, 2011, A1, . Location in patent: Page/Page column 32-33
[2] Journal of Molecular Structure, 2001, vol. 562, # 1-3, p. 205 - 213
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7388 - 7392
[4] Steroids, 2012, vol. 77, # 5, p. 403 - 412
Reference：
[1] Journal of medicinal chemistry, 1992, vol. 35, # 13, p. 2414 - 2418
[2] European Journal of Organic Chemistry, 2001, # 13, p. 2535 - 2545
[3] Synthetic Communications, 1999, vol. 29, # 10, p. 1785 - 1799
43
[ 58632-95-4 ]
[ 109-76-2 ]
[ 75178-96-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1994, vol. 131, p. 854 - 864
44
[ 58632-95-4 ]
[ 1476-39-7 ]
[ 51644-96-3 ]
Yield
Reaction Conditions
Operation in experiment
55%
With triethylamine In 1,4-dioxane; water at 20℃; for 12 h; Inert atmosphere
A solution of 2-(Boc-oxyimino)-2-phenylacetonitrile (226 mg, 0.92 mmol) in 1,4-dioxane (30 mL) was added via syringe pump (rate=8 mL/hr) to a stirred solution of 1,5 diaminopentane dihydrochloride (1 g, 5.52 mmol) and TEA (1 ml, 7.12 mmol) in 1:1 1,4-dioxane:water (40 mL) under inert atmosphere at room temperature. The reaction was stirred for 12 h and DCM (20 mL) was added to the reaction mixture. The organic phase was extracted and concentrated in vacuo. The yellow residue was dissolved in diethyl ether (15 mL) and 5percent HCl solution added. The acidic solution was washed with diethyl ether and then the pH of the aqueous layer adjusted to pH 14 with 2.5M NaOH solution. Ethyl acetate (20 mL) was added and the organic layer was washed with brine (2×50 mL), and dried (MgSO4). The solvents were evaporated in vacua to yield N-Boc-cadaverine as a yellow oil (100 mg, 55percent). HPLC/MS (Hydrophilic/TFA) Rt=6.17 min; ESI MS (+ve) m/z=203 [M+1H); calc. m/z for C10H22N2O2: 202.3 g/mol,
55 (15.861 g, 105.58 mmol) was dissolved in eOH at rt. To this stirred solution was added 2-(tert- butoxycarbonyloxyimino)-2-phenylacetonitrile (26.00g, 105.58 mmol, 1 eq), in portions, allowing dissolution before next addition. The resulting yellow solution was stirred at rt for 3 days (over weekend) before removal of all volatiles under reduced pressure. The crude residue was dissolved in EtOAc (300 mL) before washing with aq. 1 NaOH (2 x 100 mL). The combined aqueous layers were again washed with EtOAc (100 mL). Combining and concentrating the organic portions gave 29.8g of crude product. This was further purified by FCC (eluent DCIWPE 1 :1 to load column, continued until impurities wash off, then 100percent DC , followed eOH/DC 1 :1 0). This gave 25.3g (96percent) of pale yellow oil.
EXAMPLE 1 Preparation of N-(tert-Butoxycarbonyl)-3-chloro-L-ala-nine To a solution of 1.0 g (6.25 mmol) of 3-chloro-L-alanine and 1.3 mL of triethylamine in 50percent aqueous 1,4-dioxane were added 1.69 g (6.90 mmol) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile with stirring at room temperature. After 2 hours, the reaction mixture was poured into 20 mL of water and extracted twice with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to give 0.66 g (40.5percent) of white solid. Recrystallization from a mixture of ethyl acetate and n-hexane afforded 0.58 g of the pure product (35.6percent) melting at 123-124° C., with decomposition, and having the structural formula: STR72 The identity of the product was confirmed by IR and NMR analyses.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 3, p. 826 - 828
60
[ 58632-95-4 ]
[ 19883-78-4 ]
[ 114873-00-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 3, p. 826 - 828
61
[ 1197-55-3 ]
[ 58632-95-4 ]
[ 81196-09-0 ]
Reference：
[1] Journal of the American Chemical Society, 1992, vol. 114, # 9, p. 3528 - 3534
62
[ 58632-95-4 ]
[ 7689-50-1 ]
[ 76315-01-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 1983, vol. 26, # 2, p. 167 - 174
63
[ 58632-95-4 ]
[ 344-25-2 ]
[ 37784-17-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 20, p. 3792 - 3798
64
[ 58632-95-4 ]
[ 95-54-5 ]
[ 146651-75-4 ]
Reference：
[1] Journal of the American Chemical Society, 1993, vol. 115, # 4, p. 1321 - 1329
65
[ 58632-95-4 ]
[ 109-07-9 ]
[ 120737-59-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 6, p. 690 - 698
66
[ 58632-95-4 ]
[ 101385-93-7 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 10, p. 3902 - 3911
67
[ 58632-95-4 ]
[ 63399-73-5 ]
[ 103336-06-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 3, p. 536 - 541
68
[ 58632-95-4 ]
[ 111-40-0 ]
[ 117499-16-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0℃; for 2 h; Inert atmosphere
Synthesis of DiBoc-DETA: (0245) DETA (1) (1.03 g, 10 mmol) was dissolved in 10 mL anhydrous THF and bubbled with nitrogen for 20 min. At 0° C., a 3× excess of Boc-ON (2), dissolved in 15 mL anhydrous THF, was added drop-wise into the DETA solution. The mixture was stirred at this temperature for another 2 h. The solvent was removed under vacuum and the product DiBoc-DETA (3) was purified using column chromatography with an ethyl acetate:hexane mobile phase at a 1:15 ratio (yield=90percent).
88%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere
Synthesis of compound 12 was accomplished by closely following a procedure reported previously. [71] Specifically, diethylenetriamine (2.003 g, 19.415 mmol) and triethylamine (8.1 mL, 58.245 mmol) were dissolved in 100 mL of THF, and the resulting solutions was cooled to 0° C. in an ice bath and placed under an atmosphere of N2(g). Next, a solution of 2-(boc-oxyimino)-2-phenylacetonitrile (Boc-ON) (9.563 g, 38.832 mmol) in 40 mL of THF was added dropwise. The reaction mixture was stirred for 1 h on ice and then for another 1 h at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in 200 mL of dichloromethane and washed with 5percent w/v NaOH. The organic extract was then dried with MgSO4(s), filtered, concentrated under reduced pressure, and the product was purified by column chromatography (silica, 10percent v/v methanol in dichloromethane, 1percent ammonium hydroxide), yielding 12 as a colorless oil (5.184 g, 88percent). 1H NMR (400 MHz, CDCl3) δ=4.95 (br, s, 2H), 3.22 (q, J=5.9 Hz, 4H), 2.73 (t, J=5.9 Hz, 4 H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ=156.3, 79.4, 49.0, 40.5, 28.6; HRMS (ESI) calculated for [C14H30N3O4]+ (M+H+) requires m/z=304.2231, found 304.2230.
60.7%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 4 h;
To a mixture of compound 12 (0.45 g, 4.2 mol) and Et3N (8 mE, 0.06 mol) in THF (15 mE), a solution of 2-(tert-l3utoxycarbonyloxyimino)-2-phenylacetonitrile (2.1 g, 8.3 mol) in THF (30 mE) was added dropwise at 0° C. Following complete addition, the solution was allowed to warm to room temperature and lefi to stir for 4 hours. The reaction mixture was concentrated to oil under reduced pressure and CH2C12 (50 mE) was added. The mixture was washed with sodium hydroxide (5percent, 30 mE) and brine (30 mE). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOR:CH2C12=1:10, v/v) to give compound 13 as a yellow oil (803.1 mg, 60.7percent). EC-MS mlz (ESj, 304.22 (M+H).
20 g
With triethylamine In tetrahydrofuran at 0 - 20℃;
Diethylene triamine (10.8 mL, 100 mmol) and triethylamine (42 mL, 300 mmol, 3 eq.) were dissolved in tetrahydrofuran (500 mL) and cooled in ice-bath. A solution of Boc-ON (49.5 g, 200 mmol, 2 eq.) in tetrahydrofuran (190 mL) was then added drop-wise over 2.5 h. The reaction mixture was stirred at 0° C. for an additional 1 h, before it was allowed to reach ambient temperature over night. The reaction mixture was then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1 M aq. NaOH. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography, giving 20.0 g (66percent) di-tert-butyl (iminodiethane-2,1-diyl)biscarbamate (5) as a yellow viscous oil. (0151)MS (APCI pos) m/z 304.3 [M+H]+
Reference：
[1] Macromolecules, 2012, vol. 45, # 17, p. 7157 - 7162
[2] Patent: US2007/82867, 2007, A1,
[3] Inorganic Chemistry, 2014, vol. 53, # 2, p. 1144 - 1155
[4] Patent: US2016/279084, 2016, A1, . Location in patent: Paragraph 0244; 0245
[5] Organic and Biomolecular Chemistry, 2014, vol. 12, # 43, p. 8598 - 8602
[6] Patent: US2016/52878, 2016, A1, . Location in patent: Paragraph 0148-0150
[7] Journal of Organic Chemistry, 2007, vol. 72, # 26, p. 9866 - 9874
[8] Patent: US2018/55948, 2018, A1, . Location in patent: Paragraph 0199; 0201
[9] Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 236 - 243
[10] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2901 - 2910
[11] Patent: WO2009/5364, 2009, A1, . Location in patent: Page/Page column 21-22
[12] Chemical Communications, 2013, vol. 49, # 54, p. 6048 - 6050
[13] Patent: WO2016/146813, 2016, A1, . Location in patent: Page/Page column 68; 70; 71
[14] Patent: CN106946926, 2017, A, . Location in patent: Paragraph 0098-0101
[15] Patent: US9724436, 2017, B2, . Location in patent: Page/Page column 26
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 21, p. 3443 - 3451
76
[ 58632-95-4 ]
[ 127199-44-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352
77
[ 15336-72-8 ]
[ 58632-95-4 ]
[ 171049-35-7 ]
Yield
Reaction Conditions
Operation in experiment
45%
for 8 h;
To 4,4'-bipiperidine (5.48 g, 32.6 mmol) in THF (160 mL) and CHCl3 (160 mL) was added BOC-On (4.01 g) in THF (90 mL) dropwise over a 8 h period. The reaction was then concentrated and purified by flash chromatography. The residue was taken up in 1M KHSO4 (250 mL) and washed with diethyl ether (three times). K2CO3 (38.0 g, 275 mmol) was added to the aqueous layer which was subsequently extracted with CHCl3 (3.x.), dried (MgSO4) and concentrated to provide the title compound of step A (1.98 g, 7.40 mmol, 45percent). 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.18 (m, 5H), 1.42 (s, 9H), 1.58-1.69 (m, 6H), 2.50-2.61 (m, 4H), 3.06 (d, J=12.1 Hz, 2H), 4.08 (br. s., 2H).
45%
Stage #1: for 8 h; Stage #2: With potassium hydrogensulfate In water Stage #3: With potassium carbonate In water
Intermediate B114: 2-(methyloxy)-4-{1'-[2-(methylsulfonyl)ethyl]-4,4'- bipiperidin-1-yl}aniline; Step A/Intermediate B1 15: 1 ,1-dimethylethyl 4,4'-bipiperidine-1-carboxylate; To 4,4'-bipiperidine (5.48 g, 32.6 mmol) in tetrahydrofuran (160 ml.) and chloroform (160 ml.) was added BOC-ON (4.01 g, 16.2 mmol) in tetrahydrofuran (90 ml.) dropwise over an 8 hour period. The reaction was then concentrated and purified by chromatograpy on Siψ2. The residue was taken up in 1 M KHSO4 (250 ml.) and washed with diethyl ether (three times). Potassium carbonate (38.0 g, 275 mmol) was added to the aqueous layer which was subsequently extracted with chloroform (three times), dried (MgSO4), and concentrated to provide 1 ,1-dimethylethyl 4,4'- bipiperidine-1-carboxylate (1.98 g, 7.40 mmol, 45percent). 1 H NMR (400 MHz, CDCI3) δ ppm 1.06 - 1.18 (m, 6 H), 1.42 (s, 9 H), 1.58 - 1.69 (m, 6 H), 2.50 - 2.61 (m, 4 H), 3.06 (d, J=12.1 Hz, 2 H), 4.08 (br s, 1 H).
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 24, p. 4035 - 4038
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 20, p. 6491 - 6503
[3] Patent: US2008/300242, 2008, A1, . Location in patent: Page/Page column 105
[4] Patent: WO2009/20990, 2009, A1, . Location in patent: Page/Page column 144
78
[ 58632-95-4 ]
[ 78619-84-8 ]
[ 171049-35-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2224 - 2229
79
[ 58632-95-4 ]
[ 1436-59-5 ]
[ 184954-75-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 4, p. 721 - 724
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 4, p. 721 - 724
82
[ 58632-95-4 ]
[ 616-29-5 ]
[ 144912-84-5 ]
Yield
Reaction Conditions
Operation in experiment
42%
for 3 h;
Compound 22A (/.3 g, 81 mmol) was treated with BOC-ON(21.9 g, 89 rnmol) in dichloromethane for 3 hr. Solvent was removed and thecrude material was purified via sgc (10percent NH3oi\\/leOH/CH2Cl2) to give 6.5(42percent) of compound 22B.
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 20℃; for 0.75 h; Stage #2: at 20℃; for 17 h; Stage #3: With hydrogenchloride In 1,4-dioxane; water
54a. 4-((Benzyloxy)carbonyl)-1 -(tert-butoxycarbonyl)piperazine-2- carboxylic acidThe tile compound was prepared according to the procedure of [Kempf, D. J.; Norbeck, D. W.; Sham, H. L U.S. Patent 5,455,351 , Oct 3, 1995]. Piperazine-2-carboxylic acid (10.0 g, 77.0 mmol) was dissolved in a 1 :1 solution of 1 ,4-dioxane:water (100 mL) at room temperature with vigorous stirring. The clear solution was adjusted to pH 11 by the addition of an aqueous solution of sodium hydroxide (80 mL of a 1Λ/ solution). The pH was monitored in situ with a pH meter throughout the reaction. The reaction flask was fitted with an addition funnel that contained a solution of Λ/-α- (benzyloxycarbonyloxy) succinamide (13.6 g, 55 mmol) in 1 ,4-dioxane (50 mL). The Λ/-α-(benzyloxycarbonyloxy) succinamide solution was added over 45 minutes at room temperature and the pH was kept above 10 by the periodic addition of 1 Λ/ sodium hydroxide. The pH of the solution was adjusted to 9.5 and 2-(teAf-butoxycarbonyloxyimino)-2-phenylacetonitrile (13.4 g, 55 mmol) was added as a solution in 1 ,4-dioxane (50 mL) over 10 minutes. The pH was maintained at 9.5 and the solution was stirred at room temperature for 17 hours. The solution was then acidified to pH 2 and the aqueous solution was washed with diethyl ether (3 x 150 mL). The aqueous solution was cooled to O0C and acidified by adding of concentrated hydrochloric acid. The acidic solution was extracted with ethyl acetate (5 x 150 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a 1 :1 solution of dichloromethane: hexanes (150 mL) and the solvent was removed in vacuo to provide the product as a viscous yellow oil (15.7 g, 43 mmol, 80percent). Rf = 0.60 (66:34 dichloromethane: ethyl acetate + 0.1percent (v/v acetic acid); 1H-NMR (400 MHz, DMSO) δ 13.0 (br s, 1 H), 7.37-7.36 (m, 5H), 5.05 (s, 2H), 4.54-4.33 (m, 2H), 3.90-3.66 (m, 2H), 3.07-2.81 (m, 4H), 1.38 (s, 9H); Mass spectrum (ESI +ve) m/z 365.1 (MH+).
To a solution of spermidine (3.0 g, 20.6 mmol) in THF ( 100 mL) was slowly added a solution of 2-(Boc-oxyimino)-2-phenylacetonitrile (10.14 g, 20.6 mmol) in THF (20 mL) at 0 0C. The reaction mixture was stirred at 0 C for 1 hour and then the solvent was evaporated under vacuum. The residue was filtrated on silica gel and eluted with CH2CI2: EtOAc 7:3 and then with CH2Cl2:MeOH 1 : 1 to afford tert-butyl 4-(3-(tert-butyl carbamate) propyl) butylcarbamate 16 (5.3 g, > 100%) as a colourless oil. 1H NMR (300 MHz, CD3OD) delta 3.15 (t, J= 6.8 Hz, 2H), 3.08 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 6.8 Hz, 4H), 1.83 (m, 2H), 1.69 (m, 2H), 1.55 (m, 2H), 1.44 (bs, 18H). MS (APCI): 346 (M+ l)+. Rf= 0.18 (CH2Cl2:MeOH, 8:2).
With triethylamine; In 1,4-dioxane; water; at 22℃; for 23h;Inert atmosphere;
General procedure: A solution of a commercially available aminoacid alkyl chain 9 (7.77 mmol, 1.00 eq.) in water (10.0 mL) and dioxane (15.0 mL) was stirred at room temperature. Trielthyamine (11.65 mmol, 1.50 eq.) was added slowly followed by Boc-ON (8.54 mmol, 1.10 eq.). The solution was kept for 23 h under nitrogen. Afterwards, the mixture was diluted with diethyl ether (75 mL) and water (50 mL) and then washed with water (6x 50 mL). The aqueous layers were then combined and a few drops of 10% aqueous HCl solution were slowly added in order to reach pH 2.5. The resulting solution was then washed with dichloromethane (3x 60 mL). The organic layers were washed with saturated sodium chloride salt solution (1x 50 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated. Flash chromatography (hexanes:acetone, 4:1) was performed to yield a colorless yellow viscous oil in 63-97% yield.
With triethylamine; In chloroform; at 20℃; for 7h;Cooling with ice;
In a round-bottom flask, the white powder of 20 (1,4,7- triazacyclononane; TACN; 1.0 eq.) together with triethylamine (TEA; 3.0 eq.) was dissolved in chloroform and cooled in an ice bath. [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] (2.0 eq.) dissolved in chloroform was added dropwise over the course of 5 hours. After the addition was complete, the mixture was stirred at room temperature for additional 2 hours. Afterwards the solvent was evaporated and remaining yellow oily residue was washed with 5% aqueous solution of sodium carbonate, brine and 10% aqueous solution of citric acid. The acidic aqueous phase was alkalized with 1M sodium hydroxide to pH 11 and then extracted with chloroform. The chloroform was evaporated and the pure product collected as a clear oil (92% yield).
EXAMPLE 72 1- [3- (4-Phenoxy-phenyl)-ureido]-cyclopentanecarboxylic acid (2-pyrrolidin-1-yl- ethyl)-amide. A. 1-tert-Butoxvcarbonvlamino-cvcloaentanecarboxvlic acid. TEA (1.52 g, 15 mmol) was added dropwise to a solution of 1-amino-cyclopentanecarboxylic acid (1.24 g, 10 mmol) and 2- (tert-butoxycarbonyloxyimino)-2- phenylacetonitrile in acetone/water (40 mL, 1: 1). After the reaction mixture was stirred for 4 h, the acetone was evaporated and the remaining aqueous layer was extracted with ether (3 X 40 mL). The aqueous layer was acidified to pH3 with 10% HCI, and extracted with CH2CI2 (3 X 70 mL). The combined organic layers were washed with brine (40 mL), and dried (Na2SO4). Removal of the solvent under reduced pressure yielded the desired crude product. MS (electrospray) : mass calculated for C11H19NO4, 229.13 ; m7/zfound, 228.1 [M- H]-. 1 H NMR (400 MHz, DMSO-d6) : 12.45 (br s, 1 H), 7.16 (br s, 1 H), 1.94-1. 85 (br m, 4H), 1.60-1. 46 (br s, 4H), 1.36 (s, 9H).
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 2h;pH 11;
Example 61 (4-Fluoro-phenyl)-f 3- [3- (4-fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl]-4-methyl-piperazin- l-yl}-methanone; 61 (A) Piperazine-1,3-dicarboxylic acid-1-tert-butyl ester To a solution of 2-piperazine-carboxylic acid dihydrochloride (1.0 g, 4.92 mmol) in 20 mL of water/dioxane 1 : 1, NaOH 6N was added to adjust the pH to 11. A solution of BOC-ONS (1.34 g, 5.41 mmol) in dioxane (5 mL) was then added dropwise, while maintaining the pH=l 1 during the addition and the resulting solution was stirred overnight at room temperature. Another 0.134 g of BOC-ONW were added and the reaction mixture was stirred for 2h. The solvent was evaporated under reduced pressure and the residue was diluted with diethyl ether/water (60 mL). The phases were separated and the pH of the aqueous layer was adjusted to 7 by slow addition of HC1 1N. Evaporation of water under reduced pressure afforded the title compound as a white solid which was dried in a vacuum oven at 50C and used without further purification for the next step. LCMS (Tr): 3.3 min (Method B); MS (ES+) gave m/z: 231. 0.
<strong>[3022-15-9]<strong>[3022-15-9]piperazine-2-carboxylic acid dihydrochlorid</strong>e</strong> (10.0 g, 49.23 mmol) is dissolved in 1:1 dioxane/water (320 ml). 50% Aqueous sodium hydroxide is added to bring the pH to 11. BOC-ON (2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile), (15.59 g, 63.32 mmol) is dissolved in dioxane (80 ml) and added dropwise while maintaining the pH at 11 with 50% aqueous sodium hydroxide. The reaction is stirred overnight at ambient temperature. The reaction mixture is then extracted with diethyl ether (5×250 ml) and acidified to pH 2 with concentrated hydrochloric acid. The di-Boc compound is then extracted out with ethyl acetate (4×200 ml) and the acidic aqueous solution containing the desired mono-Boc product is then taken on in the synthesis.
EXAMPLE IX; Synthesis of Piperazine derivatives; Chemical Formula: C16H2iN3Oe Chemical Formula: C12H15N304 Molecular Weight: 130.15 Molecular Weight: 351.35 Molecular Weight: 265.27a: Boc-ON, NaOH, Dioxaneb: 2-flouronitrobenzene, K2C03, DMSOc: SOCI2, methanol, reflux, 2hrsd: Fmoc-NCS, CH2CI2/DMF; 20% piperidine in methanole: appropriate bromoacetophenonef: 1 N NaOH, Dioxane, reflux, 0.5hrs4-(feri-butoxycarbonyl)piperazine-2-carboxylic acid; [191] 4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid : To a solution of 2-piperazine- carboxylic acid dihydrochloride (1.0 g, 4.92 mmol) in 20 mL of water/dioxane 1 : 1, NaOH 6N was added to adjust the pH to 11. A solution of BOC-ON (1.34 g, 5.41 mmol) in dioxane (5 mL) was then added dropwise, while maintaining the pH=l 1 during the addition and the resulting solution was stirred overnight at room temperature. Another 0.134 g of BOC-ON were added and the reaction mixture was stirred for 2h. The solvent was evaporated under reduced pressure and the residue was diluted with diethyl ether/water (60 mL). The phases were separated and the pH of the aqueous layer was adjusted to 7 by slow addition of HC1 IN. Evaporation of water under reduced pressure afforded the title compound as a white solid which was dried in a vacuum oven at 50 C and used without further purification for the next step.
With triethylamine; In 1,4-dioxane; water; at 20℃;
To a solution of (S)-(4-hydroxyphenyl)glycine (Sigma Chemical) (6.5 g, 39 mmol) in dioxane/water (1:1, 120 mL) was added triethylamine (5,9 g, 8.2 mL, 58 mmol) and [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] (BOC-ON; 11 g, 45 mmol). After stirring overnight at room temperature, 300 mL of brine was added to the solution and the mixture was extracted with ether. (3.x.100 mL). The aqueous layer was acidified with HCl (pH=2) and extracted with 3.x.100 mL of ethyl acetate. The ethyl acetate layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was chromatographed with 98/2 to 95/5 methylene chloride/methanol. Recovered 12 g of crude product. The impurity was removed following esterification of the product in the next step. 400 MHz 1H NMR (CDCl3): delta1.37 (s, 9), 5.1 (1H, br s), 6.7 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz).
With hydrogenchloride; sodium hydroxide; potassium carbonate; dimethyl sulfate; In 1,4-dioxane; dioxane-water; diethyl ether; acetone;
Step A: Methyl 1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)piperazine-2-carboxylate To a solution of 3.00 g of <strong>[2762-32-5]piperazine-2-carboxylic acid</strong> in 100 mL of 1:1 dioxane-water at pH 11 was added dropwise a solution of 4.0 g of 2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile in 25 mL of dioxane, maintaining the pH of the solution at 11 during the addition with the use of 5 N NaOH. The mixture was stirred for 6 h at room temperature, then cooled to 0 C. The pH was adjusted to 9.5 with the use of 1 N HCl. Benzyl chloroformate (2.8 g) was added dropwise, maintaining the pH of the solution at 9.5 during the addition with the use of 5 N NaOH. The mixture was allowed to warm to room temperature and stirred for 20 h, then extracted with 2*75 mL of Et2O, acidified to pH<=2 with 1 N HCl, and extracted with 4*50 mL of EtOAc. The combined EtOAc extracts were washed with 50 mL of brine, dried over MgSO4, and concentrated to a pale yellow oil. This oil was dissolved in 150 mL of acetone. Dimethyl sulfate (2.25 g) and potassium carbonate (2.89 g) were added. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 6.06 g of the title compound, which was used without further purification.
Step A 1-(Benzyloxycarbonyl)-2-hydroxymethyl-4-(tert-butyloxycarbonyl)-piperazine To a solution of 3.00 g of <strong>[2762-32-5]piperazine-2-carboxylic acid</strong> in 100 mL of 1:1 dioxane-water at pH 11 was added dropwise a solution of 4.0 g of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile in 25 nL of dioxane, maintaining the pH of the solution at 11 during the addition with the use of 5N NaOH. The mixture was stirred for 6 h at room temperature, then cooled to 0 C. The pH was adjusted to 9.5 with the use of 1N HCl. Benzyl chloroformate (2.8 g) was added dropwise, maintaining the pH of the solution at 9.5 during the addition with the use of 5N NaOH. The mixture was allowed to warm to room temperature and stirred for 20 h, then extracted with 2*75 mL of Et2O, acidified to pH<=2 with 1N HCl, and extracted with 4*50 mL of EtOAc. The combined EtOAc extracts were washed with 50 mL of brine, dried over MgSO4, and concentrated to a pale yellow oil. This oil was dissolved in 150 mL of acetone. Dimethyl sulfate (2.25 g) and potassium carbonate (2.89 g) were added. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 6.06 g of the methyl ester. This methyl ester (5.32 g) was dissolved in 30 mL of THF and 834 mg of lithium chloride, 744 mg of sodium borohydride, and 30 mL of ethanol were added. The mixture was stirred overnight at room temperature, concentrated, and redissolved in 200 mL of CH2Cl2. This CH2Cl2 solution was washed with 100 mL of water and 100 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluding with a gradient system of 2:1 hexanes-EtOAc to 1:1 hexanes-EtOAc, to yield 2.65 g of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3): delta7.30-7.40 (m, 5H), 5.15 (ABq, J=12.4 Hz, 2H), 3.80-4.34 (m, 4H), 3.48-3.75 (m, 2H), 2.80-3.20 (m, 3H), 1.47 (br s, 9H).
Step A 2-(N-Tert-butyloxycarbonyl-N-ethyl)aminoethanol To a solution of 2-(ethylamino)ethanol (3 g, 33.65 mmol) in 1:1 dioxane:water at 0 C. was added triethylamine(7.04 ml, 50.48 mmol) followed by addition of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (9.9 g, 40.38 mmol). The reaction mixture was stirred at 0 C. for 10 min and then at room temperature for 2 h. The mixture was extracted with ethyl acetate (2*150 ml); the ethyl acetate layers were then combined, washed with brine and dried over sodium sulfate. Removal of the solvent and subsequent purification by column chromatography eluding with 1:2 ethyl acetate:hexane system to obtain 3.69 g of the title compound. 1H NMR (500 MHz, CDCl3): delta3.753 (t, J=5.0 Hz, 2H); 3.39 (t, J=4.8 Hz, 2H); 3.24 (brs, 2H); 1.48 (s, 9H); 1.13 (t, J=7.1 Hz, 3H).
With triethylamine; In 1,4-dioxane; water; ethyl acetate;
N-Boc-triglycine. To a suspension of 18.92 g (100 mmole) of triglycine (available from Sigma Chemical Company) in 100 ml dioxane and 100 ml water was added 27.88 ml (200 mmole, 2.0 equivalents) of triethylamine and 27.1 g (110 mmole, 1.1 equivalents) of 2-[tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (available from Fluka, N.Y.). The reaction mixture was stirred at room temperature overnight. Water (65 ml) was added to the mixture, and the resultant mixture was extracted with ether (4*65 ml) ant EtoAc (1*70 ml). The aqueous layer was adjusted to pH 1.5 with 6M HCl at 0 C. and then extracted with EtOAc (25*100 ml) by the salt-out technique. A substantial amount of product precipitated out of the EtOAc extraction and was collected by filtration. The EtOAc filtrate was reduced to 1/5 of its original volume under vacuum to produce additional precipitate. The precipitate was collected by filtration and the above procedure (reduction of volume to 1/5) was repeated. The precipitates were combined and dried under vacuum to give 23.82 g of product. (82.3% yield) 1 H-NMR (CD3 CN, delta): 7.05 (bs, 2H, NH), 5.70 (bs, 1H, NH), 3.82 (dd, 4H, CH2), 3.64 (d, 2H, CH2) and 1.92 (s, 9H, t-butyl).
With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;
Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.
With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;
Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.
With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;
Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.
With triethylamine; In bis-tetrahydropyran ether; water; ethyl acetate;
Dissolve 4,5-(dicarboethoxy)imidazole (1.06 g, 5 mmol) and triethylamine (1.5 mL, 7.5 mmol) in 50/50 dioxane water (25 mL). Add [2-(tert-butyloxycarbonyloxyimino)-2phenylacetonitrile](1.36 g, 5.5 mmol) and stir at room temperature for 2 hours. Add water (7.5 mL) and ethyl acetate (10 mL), separate the aqueous phase and wash with ethyl acetate (10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give N-(carbo-t-butyloxy)-4,5-(dicarboethoxy)imidazole.
Compound 22A (/.3 g, 81 mmol) was treated with BOC-ON(21.9 g, 89 rnmol) in dichloromethane for 3 hr. Solvent was removed and thecrude material was purified via sgc (10% NH3oi/leOH/CH2Cl2) to give 6.5(42%) of compound 22B.
With hydrogenchloride; sodium hydroxide; In ethyl acetate;
Synthesis of 1-cyclopropyl-4-(1,1-dimethylethoxycarbonyl)piperazine STR31 Solid 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (3.2 g, 0.013 mole) was added in one portion to a solution of 1.5 g (0.012 mole) <strong>[20327-23-5]1-cyclopropylpiperazine</strong> in 30 ml ethyl acetate. The solution was stirred at room temperature for 3 hours and then treated with 100 ml dilute aqueous HCl. The aqueous phase was separated, extracted with additional ethyl acetate (discarded), treated with excess 10% NaOH, and extracted with ether. The ether extracts were dried (MgSO4), filtered, and evaporated in vacuo to yield a semi-solid residue. Recrystallization from hexane at -70 C. gave 1.9 g white, crystalline solid, m.p. 65-67 C. Calculated for C12 H22 N2 O2 (226.32): C, 63.98; H, 9.80; N, 12.38; O, 14.14. Found: C, 63.82; H, 9.82; N, 12.60; O, 13.90.
Preparation 9 A mixture of DL-homoserine (50 g), triethylamine (140 ml), 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (103.3 g), water (500 ml) and dioxane (500 ml) was stirred at ambient temperature for 24 hours. After removal of the dioxane, the remained aqueous solution was adjusted to pH 8.5-9.0 with 10percent aqueous sodium hydroxide and then washed with ethyl acetate (500 ml*5). The resultant aqueous solution was adjusted to pH 2.0 with conc. hydrochloric acid and then extracted with ethyl acetate, followed by washing with an aqueous sodium chloride and drying over anhydrous magnesium sulfate. To this solution was added dropwise a solution of diazodiphenylmethane is ethyl acetate till the starting compound was disappeared on thin layer chromatography. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain N-tert-butoxycarbonyl-DL-homoserine benzhydryl ester (117.0 g), mp 125°-129° C. IR (Nujol): 3500, 3320, 1735, 1687 cm-1 NMR deltappm (CDCl3): 1.43 (9H, s), 1.8-2.5 (2H, m), 3.6 (2H, m), 4.58 (1H, m), 5.5 (1H, d, J=8 Hz), 6.92 (1H, s), 7.3 (10H, s)
With triethylamine; In 1,4-dioxane; water; ethyl acetate;
Preparation 9 A mixture of DL-homoserine (50 g), triethylamine (140 ml), 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (103.3 g), water (500 ml) and dioxane (500 ml) was stirred at ambient temperature for 24 hours. After removal of the dioxane, the remained aqueous solution was adjusted to pH 8.5-9.0 with 10percent aqueous sodium hydroxide and then washed with ethyl acetate (500 ml*5). The resultant aqueous solution was adjusted to pH 2.0 with conc. hydrochloric acid and then extracted with ethyl acetate, followed by washing with an aqueous sodium chloride and drying over anhydrous magnesium sulfate. To this solution was added dropwise a solution of diazodiphenylmethane in ethyl acetate till the starting compound was disappeared on thin layer chromatography. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain N-tert-butoxycarbonyl-DL-homoserine benzhydryl ester (117.0 g), mp 125°-129° C. IR (Nujol): 3500, 3320, 1735, 1687 cm-1. NMR deltappm (CDCl3): 1.43 (9H, s), 1.8-2.5 (2H, m), 3.6 (2H, m), 4.58 (1H, m), 5.5 (1H, d, J=8 Hz), 6.92 (1H, s), 7.3 (10H, s).
Step 2: The preparation of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester: Piperazine-2-carboxylic acid (37.5 g, 185 mmol) was dissolved in H2O (600 mL) and dioxane (600 mL). The solution was adjusted to pH 11 by the addition of 50% NaOH. 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (51.0 g, 210 mmol) in dioxane (300 mL) was added portionwise. The reaction was maintained at pH 11 by the addition of 50% NaOH over 3 hours, then cooled to 0 C. in an ice bath and adjusted to pH 9.5 with 6 N HCl. To the cooled solution was added benzylchloroformate dropwise while maintaining the pH at 9.5. The reaction was allowed to warm to room temperature and stir for 2.5 days. The reaction was extracted with Et2O (4*250 mL), then the aqueous layer was acidified to pH 2 with concentrated HCl and extracted with EtOAc (4*250 mL). The EtOAc layer was dried over MgSO4 and concentrated to give 64.2 g (95%) of the desired product. MS: 365 (M+1 for C18H24N2O6).
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
Dissolved (S)-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine tartrate trihydrate (80.0 g, 214.25 mmol) in 50 mL of 2 M HCl, giving a dark gray solution. To this was added decolorizing charcoal (20 g). The mixture stirred for 30 min. Filtered the mixture and washed with 20 mL H2O. The filtrate was heated at 50 0C with stirring. Solid NaOH was added slowly until the pH was basic. Cooing to room temperature followed by <n="145"/>refrigeration for 2h gave a white ppt. Filtered the white ppt and placed it in a vacuum drying oven overnight at 40 0C. Collected the material giving 25.19 g of (S)-4, 5,6,7- tetrahydro-benzothiazole-2,6-diamine. 1H NMR showed pure freebase.Suspended (S)-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine (20.0 g, 118.2 mmol) in 200 mL of CH2Cl2 and DIPEA (36.9 mL, 200.0 mmol) was added. The mixture remained heterogeneous and BOC-ON ( 29.2 g, 118.7 mmol) was added. The mixture stirred overnight. LC-MS analysis indicated the desired product along with one major DAD peaks. Diluted with 200 mL CH2Cl2. Quenched with 100 mL of saturated NH4Cl. Washed with 2x100 mL of H2O and 1x100 mL of brine. Dried organic phase with MgSO4, filtered and concentrated. Applied to a SiO2 column and purified (50% EtOAC/hexanes then 0-5% MeOH/CH2C12) to give mixed fractions and pure product. Repurifed the mixed fractions to give 32.6 ((S)-2-Amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester.Dissolved ((S)-2-Amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyi ester (32.6 g, 121.02 mmol) in 300 mL Of CH2Cl2. To this was added DIPEA (41.8 mL, 240 mmol). The mixture was cooled to 4 0C. To this was added the benzyl chloro formate (17.8 mL, 125 mmol). The mixture stirred overnight. TLC analysis indicated some starting material remaining. Added 0.3 eq more of chloroformate and 0.3 eq. more of DIPEA. Stirred for 4 h. TLC indicated remaining starting material Quenched with 200 mL of saturated NH4Cl. Washed with 2x200 mL Of H2O, 200 mL OfNa2CO3 and 1x200 mL of brine. Dried organic phase with MgSO4, filtered and concentrated. Applied to a SiO2 column and purified (5:5 CH2Cl2/hexanes to 9:1 CH2Cl2/Me0H) to give two main fractions. 1H NMR analysis indicated that both fractions were acceptable and they were combined to give 44.5 g of ((S)-6-tert-butoxycarbonylamino-4,5,6,7-tetrahydro- benzothiazol-2-yl)-carbamic acid benzyl ester. 3.06 g of S. M recovered 9%.Dissolved ((S)-6-tert-butoxycarbonylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)- carbamic acid benzyl ester in 20 mL Of CH2Cl2. Added 20 mL of TFA. Stirred for 1 h. LC- MS analysis indicated complete deprotection of BOC group. Concentrated to give 46.0 g <n="146"/>of ((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester trifluoroacetate as pale yellow solid.Dissolved sodium periodate (47.1 g, 220 mmol) in 400 mL of H2O. The mixture was placed in an ice bath at 4 0C and (3S,4R)-tetrahydro-furan-3,4-diol (18.4 mL, 224.5 mmol) was added. Over a period of a few minutes, a thick white ppt. formed. The mixture stirred for 20 h. Added 200 mL of CH3CN. The mixture was filtered and the ppt. rinsed with 200 mL Of CH3CN. The filtrate containing (2-oxo-ethoxy)-acetaldehyde was used directly in the next reaction.Dissolved ((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester trifluoroacetate ( 10.0 g, 23.9 mmol) in crude dialdehyde solution. The mixture stirred for 30 min. To this was added NaBH3CN (18.8 g, 299.16 mmol). The mixture was sealed and stirred for 36 h. LC-MS analysis indicated the desired morpholine product. Filtered the heterogeneous mixture and concentrated the filtrate. Dissolved residue in 5% HCl/MeOH and passed through pre-rinsed 50X2-200 Dowex acidic ion exchange resin. The column was rinsed with 1x150 mL of 5% HCl, 2x150 mL H2O, 2x125 mL of MeOH. The compound was liberated with 4x150 mL elutions of 10%NH4thetaH/MeOH and concentrated. Dissolved ppt. from initial reaction, in 5% HCl/MeOH and passed through Dowex acidic ion exchange resin. The column was rinsed with 1x150 mL of 5% HCl, 2x150 mL H2O, 2x125 mL of MeOH. The compound was liberated with 4x150 mL elutions of10%NH4thetaH/MeOH. Concentrated with previous batch to give 4.62 g. Observed white residue ion exchange medium. Rinsed with 4x100 mL Of CH2Cl2 to give an additional 3.4 g. Combined to give 8.02 g of ((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2- yl)-carbamic acid benzyl ester.Dissolved ((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester (7.46 g, 20.00 mmol) in 25 mL of 33% HBr/AcOH. Stirred mixture for 48 h. LC-MS indicated complete deprotection. Added 200 mL OfEt2O resulting in a pale orange ppt. Filtered to give 7.46 mg of (S)-6-Morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2- ylaminedihydrobromide a light brown solid. <n="147"/>[187] 3,4-Dimethoxy-N-[3-((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2- ylcarbamoyl)-benzyl]-benzamide Prepared by the method described in Ex...
Method P R4[0466] The amino acid (1 equiv) in acetone (20 vol) and water (20 vol) was treated withBoc-ON (1.1 equiv) followed by TEA (1.5 equiv) and the reaction stirred at rt for 16 h. Reaction progress was monitored by TLC (20% MeOH in DCM). On completion the acetone was removed in vacuo and the aqueous solution washed with Et2O (2 x 20 vol). The aqueous phase was then acidified to pH <2 with 1.2 M HCl and extracted into DCM <n="175"/>(3 x 40 vol). The combined organic phases were dried (Na2SO4), filtered and evaporated to give the desired product.; Example 91. (2R)-2-[[(l,l-Dimethylethoxy)carbonyl]amino]butanoic Acid (91); [0477] L-(+)-2-Aminobutyric acid (0.50 g, 4.85 mmol) was treated with Boc-ON (1.30 g,5.40 mmol) and TEA (1.0 mL, 7.28 mmol, d 0.726) using Method P to give the title compound as a pale yellow oil: 1H NMR deltaH (250 MHz, DMSO-cfe) 7.02 (IH, d), 3.78 (IH, m), 1.61 (2H, m), 1.37 (9H, s), 0.87 (3H, t).
EXAMPLE 1; 7V-Biphenyl-2-yl- 1 ,3-dioxo-2- [^r°ws-2-phenylcyclopr opyll hexahydr oimidazo [ 1 ,5-al pyrazine- 7qH)-carboxamide (A6); Step 1 : l-[(benzyloxy)carbonyll-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Al); A solution 0.164 M of <strong>[3022-15-9]2-piperazinecarboxylic acid dihydrochloride</strong> in a 1 :1 dioxane-water mixture was made basic (pH 11) with 50% aqueous NaOH. A 0.68 M solution of Boc-ON (1.1 eq) in dioxane was added dropwise at RT to the above mixture and the reaction mixture was stirred at RT overnight. The mixture was extracted with Et2O (x3) and acidified with cone. HCl to pH 2. The aqueous layer was extracted with EtOAc (x3). The aqueous solution was basified to pH 10 with 50% NaOH. A 0.59 M solution Lambda/-(benzyloxycarbonyloxy)succinimide (1.1 eq.) in dioxane was added to the mixture at 00C. The reaction mixture was stirred 3 h at RT. Dioxane was removed under reduced pressure. The basic solution was extracted with Et2O (x2) then acidified to pH 1 with cone. HCl, and extracted with EtOAc (x3). The combined organic layers were dried and evaporated. The residue was used as such in next step.
S-(-)-piperazine-2-carboxylic acid dihydrochloride[ No CAS ]
[ 150407-69-5 ]
Yield
Reaction Conditions
Operation in experiment
PREPARATIVE EXAMPLE 1; (1-tert-Butyl 3-methyl (3S)-l,3-piperazinedicarboxylate (AA3); Step 1 : (261-l-[(Benzyloxy)carbonyll-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid(AAl); It was prepared from (25)-2-piperazinecarboxylic acid dihydrochloride with slight modifications as described in Molecular Discovery 1998, 4, 221-232. A solution of (25)-2-piperazinecarboxylic acid dihydrochloride in a dioxane-water mixture (1 :1, 0.164 M) was made basic (pH 11) with 50% aqueous NaOH. A 0.68 M solution of BOC-ON (1.1 eq.) in dioxane was added dropwise at RT to the above mixture and the reaction mixture was stirred at RT overnight. The mixture was extracted with Et2O (x3) and acidified with cone. HCl to pH 2. The aqueous layer was extracted with EtOAc (x3). The aqueous solution was basified to pH 10 with 50% NaOH. A solution Lambda/-(benzyloxycarbonyloxy)succinimide in dioxane (0.59 M) was added to the mixture at 00C. The reaction mixture was stirred 3 h at RT. Dioxane was removed under reduced pressure. The basic solution was extracted with Et2O (x2) then acidified to pH 1 with cone. HCl, and extracted with EtOAc (x3). The combined organic layers were dried and evaporated. The residue was used as such in next step.
54a. 4-((Benzyloxy)carbonyl)-1 -(tert-butoxycarbonyl)piperazine-2- carboxylic acidThe tile compound was prepared according to the procedure of [Kempf, D. J.; Norbeck, D. W.; Sham, H. L U.S. Patent 5,455,351 , Oct 3, 1995]. Piperazine-2-carboxylic acid (10.0 g, 77.0 mmol) was dissolved in a 1 :1 solution of 1 ,4-dioxane:water (100 mL) at room temperature with vigorous stirring. The clear solution was adjusted to pH 11 by the addition of an aqueous solution of sodium hydroxide (80 mL of a 1Lambda/ solution). The pH was monitored in situ with a pH meter throughout the reaction. The reaction flask was fitted with an addition funnel that contained a solution of Lambda/-alpha- (benzyloxycarbonyloxy) succinamide (13.6 g, 55 mmol) in 1 ,4-dioxane (50 mL). The Lambda/-alpha-(benzyloxycarbonyloxy) succinamide solution was added over 45 minutes at room temperature and the pH was kept above 10 by the periodic addition of 1 Lambda/ sodium hydroxide. The pH of the solution was adjusted to 9.5 and 2-(teAf-butoxycarbonyloxyimino)-2-phenylacetonitrile (13.4 g, 55 mmol) was added as a solution in 1 ,4-dioxane (50 mL) over 10 minutes. The pH was maintained at 9.5 and the solution was stirred at room temperature for 17 hours. The solution was then acidified to pH 2 and the aqueous solution was washed with diethyl ether (3 x 150 mL). The aqueous solution was cooled to O0C and acidified by adding of concentrated hydrochloric acid. The acidic solution was extracted with ethyl acetate (5 x 150 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a 1 :1 solution of dichloromethane: hexanes (150 mL) and the solvent was removed in vacuo to provide the product as a viscous yellow oil (15.7 g, 43 mmol, 80%). Rf = 0.60 (66:34 dichloromethane: ethyl acetate + 0.1% (v/v acetic acid); 1H-NMR (400 MHz, DMSO) delta 13.0 (br s, 1 H), 7.37-7.36 (m, 5H), 5.05 (s, 2H), 4.54-4.33 (m, 2H), 3.90-3.66 (m, 2H), 3.07-2.81 (m, 4H), 1.38 (s, 9H); Mass spectrum (ESI +ve) m/z 365.1 (MH+).
55 (15.861 g, 105.58 mmol) was dissolved in eOH at rt. To this stirred solution was added 2-(tert- butoxycarbonyloxyimino)-2-phenylacetonitrile (26.00g, 105.58 mmol, 1 eq), in portions, allowing dissolution before next addition. The resulting yellow solution was stirred at rt for 3 days (over weekend) before removal of all volatiles under reduced pressure. The crude residue was dissolved in EtOAc (300 mL) before washing with aq. 1 NaOH (2 x 100 mL). The combined aqueous layers were again washed with EtOAc (100 mL). Combining and concentrating the organic portions gave 29.8g of crude product. This was further purified by FCC (eluent DCIWPE 1 :1 to load column, continued until impurities wash off, then 100% DC , followed eOH/DC 1 :1 0). This gave 25.3g (96%) of pale yellow oil.
With N-ethyl-N,N-diisopropylamine; In chloroform; for 120h;
To a solution of 1,4,7-triazonane trihydrogenchloride (TACN 3HC1, 1.85 g, 7.7 mmol, M.W.:238.6) in CHCl3 (25 mL) was added DIPEA (4.0 mL, 3.0 g, 23.1 mmol, M.W.: 129.24, d: 0.742) and BOC-ON (3.77 g, 15.3 mmol, M.W.: 246.26) in portions. The resulting mixture was stirred for 5 days and the solvent evaporated under vacuum. The residue was partitioned between 10% NaOH solution (10 mL) and diethyl ether (30 mL). The ether layer was separated and washed with 10% NaOH solution (10 mL) and water (10 mL) several times. The ether layer was dried (MgS04), filtered, and concentrated under vacuum to provide QC04001 (2.53 g, quantitative), which was used without furher purification.
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