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Structure of 36239-09-5 * 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, 2007, vol. 17, # 2, p. 410 - 413
[2] Tetrahedron, 1993, vol. 49, # 23, p. 5133 - 5146
[3] Organic and Biomolecular Chemistry, 2014, vol. 12, # 48, p. 9822 - 9830
[4] Bulletin de la Societe Chimique de France, 1905, vol. <3> 33, p. 550
[5] Gazzetta Chimica Italiana, 1927, vol. 57, p. 827,830
[6] Bulletin de la Societe Chimique de France, 1905, vol. <3> 33, p. 550
[7] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1975, p. 1302 - 1308
[8] Journal of Organic Chemistry, 1975, vol. 40, p. 1927 - 1932
[9] Bulletin des Societes Chimiques Belges, 1970, vol. 79, p. 631 - 637
[10] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 1, p. 61 - 66
[11] Journal of Organic Chemistry, 1985, vol. 50, # 25, p. 5223 - 5230
[12] Heterocycles, 2000, vol. 52, # 3, p. 1371 - 1383
[13] Journal of Organic Chemistry, 2010, vol. 75, # 24, p. 8604 - 8614
[14] Tetrahedron, 2015, vol. 71, # 43, p. 8333 - 8349
[15] Patent: WO2015/164161, 2015, A1, . Location in patent: Paragraph 0242; 0256
[16] Patent: KR2016/13149, 2016, A, . Location in patent: Paragraph 0430
[17] Patent: CN105339350, 2016, A, . Location in patent: Paragraph 0465; 0466; 0467
[18] Patent: WO2017/40757, 2017, A1, . Location in patent: Paragraph 00843-00844
[19] Patent: WO2017/46606, 2017, A1, . Location in patent: Page/Page column 110; 111
[20] Patent: CN104086527, 2016, B, . Location in patent: Paragraph 0052; 0054-0056
[21] Patent: CN104974162, 2018, B, . Location in patent: Paragraph 0342; 0343; 0413; 0414
7
[ 6148-64-7 ]
[ 36239-09-5 ]
Reference：
[1] Heterocycles, 1991, vol. 32, # 2, p. 245 - 251
[2] Advanced Synthesis and Catalysis, 2015, vol. 357, # 18, p. 3943 - 3948
[3] Angewandte Chemie - International Edition, 2008, vol. 47, # 52, p. 10155 - 10158
8
[ 105-53-3 ]
[ 36239-09-5 ]
Reference：
[1] Journal of the American Chemical Society, 1969, vol. 91, p. 2993 - 3002
[2] Heterocycles, 1991, vol. 32, # 2, p. 245 - 251
[3] Journal of Organic Chemistry, 2010, vol. 75, # 24, p. 8604 - 8614
9
[ 7719-09-7 ]
[ 1071-46-1 ]
[ 36239-09-5 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1905, vol. <3> 33, p. 550
10
[ 36239-09-5 ]
[ 75-65-0 ]
[ 32864-38-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474
[2] Synthetic Communications, 1990, vol. 20, # 13, p. 2033 - 2040
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1286
11
[ 36239-09-5 ]
[ 100-46-9 ]
[ 29689-63-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In dichloromethane at 20℃; for 1 h;
16a) Ethyl 3-oxo-3-[(phenylmethyl)amino]propanoate A solution of benzylamine (1.10 g, 10.3 mmol) and ethyl malonyl chloride (1.29 mL, 10.3 mmol) in dichloromethane (10 mL) was treated with triethylamine (1.44 mL, 10.3 mmol). The solution was stirred at ambient temperature for 1 h and then diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3*20 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a yellow oil (2.27 g, 100percent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (br. s., 1 H), 7.24-7.36 (m, 5 H), 4.45 (d, J=5.6 Hz, 2 H), 4.17 (q, J=7.2 Hz, 2 H), 3.31 (s, 2 H), 1.27 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 222 [M+H]+.
Reference：
[1] Patent: US2007/213335, 2007, A1, . Location in patent: Page/Page column 14
[2] Patent: US4663319, 1987, A,
[3] Journal of Organic Chemistry, 1985, vol. 50, # 25, p. 5223 - 5230
12
[ 36239-09-5 ]
[ 103181-68-6 ]
[ 119637-67-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 3, p. 508 - 525
With triethylamine; In dichloromethane; at 0 - 20℃;
Example 22 Amide 35 was prepared in 3 steps from ethyl 3-chloro-3-oxopropanate according to the following procedures: To a stirred solution of morpholine (479 mg, 5.5 mmol, 1.1 eq) and triethylamine (1.01 g, 10 mmol, 10 eq) in DCM (20 mL) at 0 C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 mmol, 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the product ethyl 3-morpholino-3-oxopropanoate 33.
In a 20 L reaction flask,2.5 kg of 2-nitro-5-chlorodiphenylamine was added,16L anhydrous acetonitrile,1.8 kg of malonic acid monoethyl ester chloride,The reaction was heated to reflux for 12 hours.60 vacuum distillation in addition to acetonitrile,Add 8L ethanol stirring dissolved,0 ~ 5 cooling crystallization, pumping filter, dried at 60 yellow crystal weight 3.3kg.Melting point 85-87 C, yield 91%.
With triethylamine; In dichloromethane; at 20℃; for 1h;
16a) Ethyl 3-oxo-3-[(phenylmethyl)amino]propanoate A solution of benzylamine (1.10 g, 10.3 mmol) and ethyl malonyl chloride (1.29 mL, 10.3 mmol) in dichloromethane (10 mL) was treated with triethylamine (1.44 mL, 10.3 mmol). The solution was stirred at ambient temperature for 1 h and then diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3*20 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a yellow oil (2.27 g, 100%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.55 (br. s., 1 H), 7.24-7.36 (m, 5 H), 4.45 (d, J=5.6 Hz, 2 H), 4.17 (q, J=7.2 Hz, 2 H), 3.31 (s, 2 H), 1.27 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 222 [M+H]+.
96.8%
In hexane; dichloromethane;
(1) A mixture of benzylamine (43.24 g) and methylene chloride (300 ml) is cooled with ice-water, and a solution of ethoxycarbonylacetyl chloride (29.63 g) in methylene chloride (150 ml) is added dropwise thereto. The mixture is stirred at the same temperature for 2 hours. The mixture is filtered to remove precipitates (benzylamine hydrochloride). The filtrate is washed with 2% hydrochloric acid and a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby ethyl (N-benzylcarbamoyl)acetate (42.15 g) is obtained as colorless needles. Yield: 96.8%. M.p. 50-52 C. IRnumaxKBr (cm-1): 1735, 1650. NMR (CDCl3)delta: 3.34 (s, 2H, --COCH2 CO--), 4.47(d, J=5.7 Hz, 2H, STR27 Mass (m/e): 221 (M+).
With triethylamine; In dichloromethane; at 0 - 20℃; for 18.25h;
To a stirred solution of Example 30A (100 mg, 0.62 mmol) and triethylamine (75 mg, 0.74 mmol) at0 C in dichloromethane (5 ml) is added ethyl malonyl chloride (108 mg, 0.65 mmol) dropwise over 15 minutes. The solution is allowed to warm to room temperature, and stirring is continued overnight (18 h). The crude reaction solution is concentrated in vacuo and the residue is purified by preparativeRP-HPLC (acetonitrile/water 1: 9 to 9: 1 gradient) to afford a colourless oil. Yield: 144.4 mg(85% of th.)HPLC (method 5): Rt = 3.80 min. , max 196 nm, 244 nm MS (ESIpos):m/z = 277[M+H] +H-NMR (300MHz, CDC13) :8 = 9.74 (s, 1H); 8.81 (s, 1H); 8.64 (s, 1H) ; 8.47 (s,1H) ; 4.30 (q, 2H); 3.53 (s, 2H);1. 35 (t, 3H) ppm.
ethyl 4-[N'-(2-ethoxycarbonyl-acetyl)-hydrazino]-benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at -10 - 20℃;
(4-Hydrazino) ethylbenzoate hydrochoride (12 g, 551.4 mmol, prepared according to Coquet G. et AL., Tetrahedron 2000, 56,2975-2984) was stirred for 15 min at room temperature in a mixture of 10% aqueous NA2CO3 solution (100 ml) and CH2CL2 (200 ml). The separated aqueous solution was extracted with CH2CL2 (3 x 200 ml). The combined organic phases were dried over NA2SO4, filtered and concentrated. The residue was dissolved in anhydrous THF (100 ml) and ET3N (8.11 mL, 58.3 mmol) was added. The reaction mixture was cooled to-10C and a solution of ethyl malonyl chloride (7.12 ml, 56.6 mmol) in anhydrous THF (50 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with H20 (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with H20 (100 ml), brine (100 ml), dried over NA2SO4, filtered and concentrated to yield crude title compound as a brown residue (16.3 g): tR = 5.34 min, MS (POS.) : m/z 295.1 [M+H] + ; MS (NEG. ) : m/z 293.3 [M-H] +.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Ethyl 3-amino-3-methylbutanoate hydrochloride (0.87 g, 4.79 MMOL) was suspended on methylene chloride (12 mL) and triethylamine (1.4 mL, 2.1 eq. ). The mixture was cooled to 0C and treated dropwise with ETHYL 3-CHLORO-3-OXOPROPANOATE (0.64 mL, 1.05 eq. ). The reaction was kept at room temperature for 2 hours, diluted with methylene chloride, washed with 1 N HCI and then with 5% NAHC03, dried over NA2SO4 and evaporated to dryness to obtain ethyl 3- [ (3-ethoxy-3-oxopropanoyl) amino]-3-methylbutanoate (1. 2G, Y=97%) as a red oil. TH NMR (DMSO-d6/300 MHz) 5 ppm 1.11-1. 21 (m, 6H), 1. 29. (s, 6H), 2.71 (s, 2H), 3.14 (s, 2H), 3.95-4. 15 (m, 4H), 7.75 (BS, 1H).
97%
Ethyl 3-amino-3-methylbutanoate hydrochloride (0.87 g, 4.79 MMOL) was suspended on methylene chloride (12 mL) and triethylamine (1.4 mL, 2.1 EQ.). The mixture was cooled to 0C and treated dropwise with ethyl 3-chloro-3-oxopropanoate (0.64 mL, 1.05 eq. ). The reaction was kept at room temperature for 2 hours, diluted with methylene chloride, washed with 1 N HCI and then with 5% NAHCO3, dried over NA2SO4 and evaporated to dryness to obtain ethyl 3- [ (3-ethoxy-3-oxopropanoyl) amino]-3-methylbutanoate (1.2g, Y=97%) as a red oil.
97%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Ethyl 3-amino-3-methylbutanoate hydrochloride (0.87 g, 4.79 mmol) was suspended on methylene chloride (12 mL) and triethylamine (1.4 mL, 2.1 eq.). The mixture was cooled to 0 C. and treated dropwise with ethyl 3-chloro-3-oxopropanoate (0.64 mL, 1.05 eq.). The reaction was kept at room temperature for 2 hours, diluted with methylene chloride, washed with 1 N HCl and then with 5% NaHCO3, dried over Na2SO4 and evaporated to dryness to obtain ethyl 3-[(3-ethoxy-3-oxopropanoyl)amino]-3-methylbutanoate (1.2 g, Y=97%) as a red oil. 1H NMR (DMSO-d6/400 MHz) delta ppm 1.11-1.21 (m, 6 H), 1.29 (s, 6 H), 2.71 (s, 2 H), 3.14 (s, 2 H), 3.95-4.15 (m, 4 H), 7.75 (bs, 1 H).
71%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
INTERMEDIATE 2Ethyl 3 -[(3 -ethoxy-3 -oxopropanov0amino]-3 -methylbutanoateTo a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40 mL) was added NEt3 (11.1 g, 15.3 mL, 109.6 mmol). The reaction mixture was then cooled to O0C and ethyl malonyl chloride (4.4 g, 3.7 mL, 28.8 mmol) was added dropwise. The suspension was stirred at r.t. for 2 h before it was diluted with DCM (50 mL) and washed with aqueous IM HCl (50 mL) and water (2 x 50 mL). The organics were dried over <n="24"/>MgSO4, filtered and concentrated in vacuo to give the title compound (5.0 g, 71%) as an orange oil that was used without further purification. 6H (DMSOd6) 7.75 (IH, br. s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21-1.11 (6H, m).
71%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
INTERMEDIATE 2Ethyl 3 -f (3 -ethox v-3 -oxopropano vDamino] -3 -methylbutanoate To a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40 mL) was added triethylamine (15.3 mL, 109.6 mmol). The reaction mixture was then cooled to O0C and ethyl malonyl chloride (3.7 mL, 28.8 mmol) added dropwise. The suspension was stirred at r.t. for 2 h before being diluted with DCM (50 mL) and washed with aqueous IM HCl (50 mL) and water (2 x 50 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (5.0 g, 71 %) as an orange oil. deltaH (DMSO-d6) 7.75 (IH, br s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21 -1.11 (6H, m).
71%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
To a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40 mL) was added NEt3 (11.1 g, 15.3 mL, 109.6 mmol). The reaction mixture was then cooled to 00C and ethyl malonyl chloride (4.4 g, 3.7 mL, 28.8 mmol) was added dropwise. The suspension was stirred at r.t. for 2 h before it was diluted with DCM (50 mL) and washed with aqueous IM HCl (50 mL) and water (2 x 50 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange oil (5.0 g, 71%) that was used without further purification. deltaH (DMSO-d6) 7.75 (IH, br. s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21-1.11 (6H, m).
62%
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
Step 11-I-b: Ethyl 3-(ethyl 2-carbamoylacetyl)-3-methylbutanoate (11-I-b)To a solution of compound 11-I-a (11 g, 68.9 mmol) in DCM (150 mL) was added TEA (38.1 mL, 275 mmol) and ethyl malanoyl chloride (8.8 mL, 68.9 mmol) at 0 C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction was quenched water and extracted with DCM (2×200 mL). The combined organic layer was washed with 1N HCl (100 mL), saturated NaHCO3 (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford 11-I-b (11 g, 62%) as brown syrup. TLC: 30% EtOAc/Hexane (Rf: 0.3); 1H-NMR (CDCl3, 200 MHz): delta 4.28-4.07 (m, 4H), 3.24 (s, 2H), 2.74 (s, 2H), 1.45 (s, 6H), 1.35-1.20 (m, 6H); Mass: 260 [M++1].
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
INTERMEDIATE 50Ethyl 3 -[(3 -ethoxy-3 -oxopropanoypamino] -3 -methylbutanoate; To a stirred suspension of Intermediate 49 (5.0 g, 27.4 mmol) in DCM (40 mL) was added triethylamine (11.1 g, 15.3 mL, 109.6 mmol). The reaction mixture was then cooled to O0C and ethyl malonyl chloride (4.4 g, 3.7 mL, 28.8 mmol) was added dropwise. The suspension was stirred at r.t. for 2 h before it was diluted with DCM (50 mL) and washed with aqueous IM HCl (50 mL) and water (2 x 50 mL). The organics <n="52"/>were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.0 g, 71%) as an orange oil that was used without further purification. 8H (DMSOd6) 7.75 (IH, br s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21-1.11 (6H, m).
With triethylamine; In dichloromethane; at 0 - 20℃;
To a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40 mL) was added NEt3 (11.1 g, 15.3 mL, 109.6 mmol). The reaction mixture was then cooled to 0 C. and ethyl malonyl chloride (4.4 g, 3.7 mL, 28.8 mmol) was added dropwise. The suspension was stirred at r.t. for 2 h before it was diluted with DCM (50 mL) and washed with aqueous 1M HCl (50 mL) and water (2×50 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.0 g, 71%) as an orange oil that was used without further purification. deltaH (DMSO-d6) 7.75 (1H, br. s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21-1.11 (6H, m).
3.8 g
With triethylamine; In dichloromethane; at 0 - 20℃; for 24h;
To a solution of <strong>[85532-40-7]ethyl 3-amino-3-methylbutanoate hydrochloride</strong> (2.8 g, 15.41 mmol) in DCM (40 mL) was added triethylamine (4.68 g, 46.23 mmol) and ethyl 3-chloro-3-oxopropanoate (3.48 g, 23.12 mmol) at 0 C. The reaction was stirred at ambient temperature for 24 h. Water (100 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organics were washed with 1 N HCl (70 mL) and sat. Na2CO3 (100 mL). The organic was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide ethyl 3-(3-ethoxy-3- oxopropanamido)-3-methylbutanoate (3.8 g, 14.65 mmol) as a brown oil
This scheme depicts the introduction of functionality to the 5 position of the quinoxaline ring system. The preparation of these compounds is analogous to those of U. S. Patent 4,264, 600 and preparations described herein. The nitro group may be reduced at selected steps along the way to the amino compound, which may be further diversified by diazotization and subsequent replacement of the diazonium salt.
With hydrogenchloride; sodium hydrogencarbonate;triethylamine; In N-methyl-acetamide; dichloromethane; water;
The residue obtained is taken up in dimethylformamide (30 cc) and the insoluble product formed is filtered off and washed with dimethylformamide (5 cc) and then with methylene chloride (2*5 cc). After drying, a further batch of 5-morpholino-1,2-dithiol-3-thione (2 g), melting at 248-250 C., is obtained. Ethyl 3-morpholino-3-oxopropionate can be prepared by reacting morpholine (17.4 g) with ethyl chloroformylacetate (30.1 g), in the presence of triethylamine (20.2 g), in methylene chloride (200 cc) at a temperature of about 20 C. for 2 hours 30 minutes. After hydrolysis with distilled water (200 cc), the organic phase is washed successively with distilled water (200 cc), with a 1 N aqueous solution of hydrochloric acid (200 cc), with distilled water (2*200 cc), with a 2% aqueous solution of sodium bicarbonate (200 cc) and then with distilled water (200 cc), dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40 C. This gives ethyl 3-morpholino-3-oxopropionate (30 g), melting at 60 C.
PREPARATION 19; 2,4-Dihydroxy-6-trifluoromethyl-nicotinic acid ethyl ester; Pyridine (53 mls/660 mmols) was added to dissolve 3-Amino-4,4,4-trifluorocrotonic acid ethyl ester (100 g/546 mmols) in DCM(6000 mls). The mixture was then placed under nitrogen and cooled to 5 C. by suspending in an ice-bath. Ethyl malonyl chloride was added dropwise over approx 1 hr such that temperature did not exceed 20 C. The resulting pale brown solution was stirred at 5 C. for 3 hrs then allowed to warm to room temperature overnight to give a dark green solution. The mixture was then washed with 1M HCl(aq) (200 mls) then sat.NaHCO3(aq) (250 mls). Aqueous washings were sequentially re-extraced with further DCM (2×250 mls). The Organic layers were combined, dried over Na2SO4, filtered and concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g). A portion of the crude material (120 g) was dissolved in EtOH (300 mls) and placed under nitrogen. Potassium tert-butoxide (54 g/480 mmols) was then added in several portions such that temperature did not exceed 60 C. resulting in a purple solution. The mixture was then heated at 70 C. for 3 hrs. EtOH (100 mls) was then added to reduce viscosity and heated at 80 C. for a further hour. The mixture was then allowed to cool and then concentrated in vacuo to a red solid. The mixture was dissolved in water (500 mls) and citric acid (180 g) then added, causing precipitation. EtOAc (600 mls) was then added and the mixture poured into a separating funnel and the aqueous layer run off. The organic layer containing much undissolved solid was filtered to give the title compound (46.5 g) as a white solid. Concentration of the organic filtrate and trituration with MeOH afforded further title compound (15.3 g) as a white solid.1H NMR (d6-DMSO, 400 MHz) 1.20-1.25 (t, 3H), 4.20-4.25 (q, 2H), 6.8 (s, 1H)
N-[(4-hydroxy-2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)carbonyl]glycine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
EXAMPLE 7 N-[(4-hydroxy-2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)carbonyl]glycine A solution of ethyl 3-aminoisonicotinate (0.071 g, 0.43 mmol) in methylene chloride (2.0 mL) was treated with triethylamine (1.00 mL, 7.17 mmol) followed by ethyl malonyl chloride (0.060 mL, 0.47 mmol). The mixture was stirred overnight at ambient temperature, followed by concentration in vacuo. The residue was dissolved in ethanol (2.0 mL), treated with sodium ethoxide (0.158 mL, 0.43 mmol, 21% solution in ethanol) at ambient temperature, and stirred overnight. The solution was concentrated in vacuo, and the resulting residue was dissolved in ethanol (2.0 mL) and treated with <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.030 g, 0.43 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.060 mL, 0.43 mmol) and heated to 180 C. for 30 min. in a Biotage Initiator microwave synthesizer. The reaction was diluted with water, acidified with 1 N aqueous hydrochloric acid, and the resulting precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as a light brown solid (0.034 g, 30%). 1H NMR (400 MHz, DMSO-d6 delta ppm 12.4 (s, 2 H), 10.4 (s, 2 H), 8.88 (s, 1 H), 7.89 (s, 1 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 264 [M+H]+.
A mixture of <strong>[20570-96-1]benzylhydrazine dihydrochloride</strong> (2.50 g, 12.8 mmol), potassium carbonate (1.77 g, 12.8 mmol), acetone (6.0 mL, 82 mmol) and ethyl acetate (30 mL) was stirred at room temperature while a solution of IM aqueous sodium hydroxide (6.0 mL, 6.0 mmol) was added dropwise. After the addition, the mixture was stirred 0.5 h, then excess magnesium sulfate added and the mixture filtered. The filtrate was evaporated under reduced pressure and the residue azeotroped with toluene three times, then dissolved in tetrahydrofuran (50 mL). l,8-Diazabicyclo[5.4.0]undec-7-ene (1.84 mL, 12.3 mmol) was added to the stirred solution under nitrogen at 0 0C, followed by ethyl 3-chloro-3- oxopropionate (1.57 mL, 12.3 mmol) dropwise. The mixture was stirred at 0 0C for 5 min, and at room temperature for 3 h, then IM aqueous hydrochloric acid (50 mL) added. After stirring a further 0.5 h, water (100 mL) was added and the mixture extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and the residue chromatographed (silica gel, 1-5% methanol/dichloromethane) to give the title compound (1.60 g) as an oil. IH NMR (400 MHz, DMSO-^6) delta ppm 1.18 (t, J=7.08 Hz, 3 H) 3.56 (s, 2 H) 4.08 (q, J=7.16 Hz, 2 H) 4.58 (s, 2 H) 4.65 (s, 2 H) 7.25 - 7.36 (m, 5 H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h;
5.1.43 Ethyl 3-[(3-ethoxy-3-oxo-propyl)amino]-3-oxo-propanoate (33) To a solution of beta-alanine ethyl ester hydrochloride (9.29 g, 60.5 mmol) and N,N-diisopropylethylamine (21.6 mL, 124 mmol) in CH2Cl2 (100 mL) was added ethyl malonyl chloride (7.90 mL, 61.7 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. 1 N HCl aqueous solution (100 mL) was added to the reaction mixture and resultant mixture extracted 3 times with CH2Cl2 (50 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was chromatographed (NH silica gel, EtOAc/CH2Cl2 = 0-20percent) to give the title compound (11.56 g, 50.0 mmol, 83percent) as a pale yellow oil. 1H NMR (CDCl3) delta: 1.29-1.33 (6H, m), 2.58 (2H, t, J = 6.3 Hz), 3.32 (2H, s), 3.60 (2H, q, J = 6.3 Hz), 4.18-4.25 (4H, m), 7.54 (1H, s).
72%
EXAMPLE 6; Preparation of piperidine-2,4-dione; A solution of mu-alanine ethylester hydrochloride (13.8 g, 90mmol) in dichloromethane (90 mL) and TEA (13.8 mL, 99 mmol) was stirred at RT for one hour. More TEA (13.8 mL, 99 mmol) was added, the solution was cooled to 0° C. under stirring and ethylmalonylchloride (12.6 mL, 99 mmol) was added dropwise. After one hour at 0° C., the reaction mixture was stirred one hour at RT. A 15percent aqueous solution of K2CO3 (90 mL) was added and the layers were separated. The organic phase was washed with 10percent HCl (90 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed on flash silica gel (450 g, eluant: ethyl acetate/n-hexane 2:1) to give N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester as a yellow oil (15 g, 64.9 mmol, 72percent yield). TLC: DCM/MeOH 20:1, iodine vapours. Sodium metal (610 mg, 26.6 mmol) was dissolved in dry MeOH (25 mL) at RT under stirring and inert atmosphere. After complete dissolution the mixture was stirred 10' longer, then N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (6.15 g, 26.6 mmol) in dry toluene (150 mL) is added dropwise. After addition the reaction mixture was stirred at 90° C. for 6 hours, cooled to RT, water (30 mL) was added and the layers were separated. The organic phase was washed with water (2.x.10 mL), the joined aqueous phases were acidified with 37percent HCl and extracted thoroughly (.x.20 or more) with a mixture of DCM/MeOH (5:1). After drying over Na2SO4 and concentration, 3-methoxycarbonylpiperidin-2,4-dione as a pink solid was obtained (4 g, 23.4 mmol, 88percent yield). 3-Methoxycarbonylpiperidin-2,4-dione (4 g, 23.4 mmol) is dissolved in acetonitrile containing 1percent of water (250 mL) and refluxed 4 hours. The reaction mixture is concentrated to give piperidine-2,4-dione, as a yellow solid (2.4 g, 21.2 mmol, 90percent yield). 1H NMR (400 MHz, DMSO-D6) delta ppm 2.43-2.49 (m, 2 H) 3.24 (s, 2 H) 3.28-3.45 (m, 2 H) 8.07 (s, 1 H).
72%
A solution of beta-alanine ethylester hydrochloride (13.8 g, 90 mmol) in dichloromethane (90 ml.) and triethylamine (TEA, 13.8 ml_, 99 mmol) was stirred at room temperature for 1 hour. More TEA (13.8 ml_, 99 mmol) was added, the solution was cooled to 00C under stirring and ethylmalonylchloride (12.6 ml_, 99 mmol) was added dropwise. After 1 hour at 00C, the reaction mixture was stirred 1 hour at room temperature. A 15percent aqueous solution of K2CO3 (90 ml.) was added and the layers were separated. The organic phase was washed with 10percent HCI (90 ml_), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed on flash silica gel (450 g, eluant: ethyl acetate/n-hexane 2:1 ) to give N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester as a yellow oil (15 g, 64.9 mmol, 72percent yield). Sodium metal (610 mg, 26.6 mmol) was dissolved in dry MeOH (25 ml.) at room temperature under stirring and inert atmosphere. After complete dissolution the mixture was stirred 10' longer, then N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (6.15 g, 26.6 mmol) in dry toluene (150 ml.) was added dropwise. After addition, the reaction mixture was stirred at 900C for 6 hours, cooled to room temperature, water (30 ml.) was added and the layers were separated. The organic phase was washed with water (2x10 ml_), the combined aqueous phases were acidified with 37percent HCI and extracted thoroughly with a mixture of DCM/MeOH (5:1 ). After drying over Na2SO4 and concentration, 3-methoxycarbonylpiperidin-2,4-dione as a pink solid was obtained (4 g, 88percent yield). 3-Methoxycarbonylpiperidin-2,4-dione (4 g, 23.4 mmol) was dissolved in acetonitrile containing 1percent of water (250 ml.) and refluxed for 4 hours. The reaction mixture was concentrated to give the title compound, as a yellow solid (2.4 g, 90percent yield). 1 H NMR (400 MHz, DMSO-D6) delta ppm 2.43 - 2.49 (m, 2 H) 3.24 (s, 2 H) 3.28 - 3.45 (m,2 H) 8.07 (s, 1 H).
39%
EXAMPLE 1; 5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-pyrido[4,3-b]indol-1(5H)-one hydrochloride; Step 1 N-(2-ethoxycarbonyl-ethyl)-malonamicacid ethyl ester:; Triethylamine (22.2 g, 0.22 mol, 2.2 equiv) was added to a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (15.4 g, 100.26 mmol, 1.0 equiv) and dichloromethane (100 mL). The resulting mixture was stirred for about 1 hour, and then ethyl 3-chloro-3-oxopropanoate (16.6 g, 110.23 mmol, 1.1 equiv) was added dropwise at about 0° C. After stirring at ambient temperature for about 2 hours, the mixture was washed sequentially with a 19percent potassium carbonate solution (50 mL) and a 10percent hydrochloric acid solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:3-1:1)) to give the title product as yellow liquid (9 g, yield=39percent). LC-MS: m/z=232 (MH)+.
To a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (20 g, 0.13 mol) dissolved in dichloromethane (400 mL) at 0° C. was added triethylamine (37.2 mL, 0.272 mol) dropwise. The mixture was stirred for 1 hour at 0° C., and then ethyl malonyl chloride (16.8 mL, 0.13 mol) was added dropwise. The mixture was stirred for 1 hour, then poured into 75 mL of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×50 mL), washed with water (50 mL), dried with Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluted with petroleum ether/ethyl acetate (50:1) to give the titled compound. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (s, 1H), 4.14-4.22 (m, 4H), 3.54-3.59 (m, 2H), 3.29 (s, 2H), 2.55 (t, J=6.2 Hz, 2H), 1.25-1.30 (m, 6H)
Example 1A ethyl 3-(3-ethoxy-3-oxopropylamino)-3-oxopropanoate To a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (20 g, 0.13 mol) dissolved in dichloromethane (400 mL) at 0° C. was added triethylamine (37.2 mL, 0.272 mol) dropwise. The mixture was stirred for 1 hour at 0° C., and then ethyl malonyl chloride (16.8 mL, 0.13 mol) was added dropwise. The mixture was stirred for 1 hour, then poured into 75 mL of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane (3*50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2*50 mL), washed with water (50 mL), dried with Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluted with petroleum ether/ethyl acetate (50:1) to give the titled compound. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (s, 1H), 4.14-4.22 (m, 4H), 3.54-3.59 (m, 2H), 3.29 (s, 2H), 2.55 (t, J=6.2 Hz, 2H), 1.25-1.30 (m, 6H).
With triethylamine; In acetonitrile; at 5 - 20℃; for 1.75h;
To a solution of triazole base 1 (0.75g, 3.3mmol) in acetonitrile (15mL) at 5AC was added triethylamine (0.96mL, 6.9mmol) followed by ethylmalonyl chloride (0.45mL, 3.5mmol) over 5min. After being stirred for lOmin the reaction mixture was allowed to self warm to EPO <DP n="27"/>room temperature and stirred for a further 90min. The reaction mixture was diluted with ethyl acetate and washed with IN HCl(aq). The aqueous phase was back extracted with ethyl acetate and the organic phases combined, dried over MgSO4 and evaporated. The residue was purified on silica, eluting with ethyl acetate to give amide 2 (0.76g, 76%) as a yellow oil.
Synthesis of N-(3-Phenyl-isoxazol-5-yl)-malonamic acid ethyl ester A solution of <strong>[4369-55-5]3-phenyl-isoxazol-5-ylamine</strong> (500 mg, 0.31 mmol) and mono-ethyl malonyl chloride (56 mg, 0.37 mmol) in dichloromethane (2 mL) was stirred at ambient temperature overnight. The mixture was diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with saturated sodium bicarbonate solution, followed by brine, dried over Na2SO4, concentrated to afford 78 mg (92.85percent Yield) of N-(3-phenyl-isoxazol-5-yl)-malonamic acid ethyl ester.
Synthesis of N-[4-(2-Oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid ethyl ester Mono ethyl malonyl chloride (182 mg, 1.2 mmol) was added drop wise to a stirred solution of <strong>[13143-47-0]1-(4-amino-phenyl)-1H-pyridin-2-one</strong> (200 mg, 1.1 mmol) in CHCl3 (10 mL) at 0 C. was and the resulting mixture was stirred for 1 hour. The mixture was then diluted with water and the product extracted with CHCl3. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine, dried over Na2SO4 and concentrated to afford 226 mg (68%) of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid ethyl ester. 1H NMR: (DMSO-d6): delta 10.4 (s, 1H), 7.8-7.6 (m, 3H), 7.5 (t, 1H), 7.4 (d, 2H), 6.5 (d, 1H), 6.3 (t, 1H), 4.2 (q, 2H), 1.3 (t, 3H).
With N-ethyl-N,N-diisopropylamine; In chloroform; at 0 - 20℃; for 0.333333h;
Intermediate 59-Synthesis of N-(5-Phenyl-thiazol-2-yl)-malonamic acid To a stirred solution of <strong>[39136-63-5]5-phenyl-thiazol-2-ylamine</strong> (0.4 g, 0.0022 mol) and DIEA (0.73 g, 0.0056 mol) in chloroform (4 mL) was added mono-ethylmalonyl chloride (0.375 g, 0.0024 mol) dropwise at 0 C. and the resulting mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was then diluted with cold water and the product was extracted with chloroform. The chloroform was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.3 g (46%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester. To a solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester (0.292 g, 0.001 mol) in the mixture of methanol (1 mL), THF (1.5 mL) and H2O (1 mL) was added LiOH.H2O (0.084 g, 0.002 mol) and the resulting mixture was stirred for 1 hour. The reaction mixture was then concentrated. The residue was diluted with water, acidified with concentrated HCl and the product was extracted with ethylacetate. The ethyl acetate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.23 g (87%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid.
Example 6Preparation of 4-amino-6-((2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)methoxy)-5-pyrimidinecarbonitrile; Methyl 3-(3-ethoxy-3-oxopropanamido)picolinate To a stirred solution of <strong>[36052-27-4]methyl 3-aminopicolinate</strong> (1.8 mL, 13.80 mmol) in dichloroethane (60 mL) was added ethyl 3-chloro-3-oxopropanoate (2.08 g, 13.80 mmol). The reaction was heated at reflux for 45 min. After this time the reaction was cooled to rt and partitioned between DCM (60 mL) and NaHCO3 (satd aq. solution, 30 mL). The separated aq. layer was extracted with DCM (40 mL) and the combined organic layer were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give methyl 3-(3-ethoxy-3-oxopropanamido)picolinate: LC-MS (ESI) m/z 267.1 [M+H]+.
With pyridine; In tetrahydrofuran; at 65℃; for 2h;
To a solution of <strong>[36052-27-4]methyl 3-aminopicolinate</strong> (3.04 g, 20 mmol) and pyridine (4.74 g, 60 mmol) in THF (120 mL). Then ethyl 3-chloro-3-oxopropanoate (4.5 g, 30 mmol) was added dropwise under 65C. Then the mixture was stirred at 65C for 2 hours. Then the solvent was removed under reduce and the residue was purified by flash column chromatography to afford desired compound. Isolated weight: 2.6 g, yield: 48.87%, as a yellow oil.
(1-i) To a solution of <strong>[17809-36-8]2-fluoro-6-nitroaniline</strong> (20.0 g, 128 mmol) in toluene (250 mL) was added ethyl malonyl chloride (21.3 g, 141 mmol) at 0 C. After being refluxed for 3 hour, the reaction mixture was cooled to ambient temperature and diisopropyl ether was added. The precipitate was collected and washed with diisopropyl ether to give ethyl 3-[(2-fluoro-6-nitrophenyl)amino]-3-oxopropanoate as a pale brown powder (29.2 g, 84%). mp 99-102 C. MS (APCI): m/z 381 (M+H).
General procedure: Amides 2a-2j were prepared using a modified procedure as previously described.21 Ethyl malonyl chloride (11 mmol) was added to a solution of aniline (10 mmol) in acetone. The reaction mixture was stirred for 4 h at room temperature and the solvent was removed in vacuo. Water was added to the residue and acidified with HCl to pH 3.
A 1.0M potassium tert-butoxide/tetrahydrofuran solution (24 mL, 24 mM) was added to 18-crown-6 (0.52 g, 2.0 mM), followed by the stirring of the mixture, the addition of acetonitrile (1.2 mL, 22 mM) and the subsequent stirring of the mixture for 5 minutes. Ethyl-5-pyrimidine carboxylate (3.0 g, 20 mM) was added to the mixture, the reaction liquid was then stirred for one hour, while raising the temperature thereof to 60 C., it was then cooled to room temperature, the precipitated solid was recovered through filtration and then washed with tetrahydrofuran and diethyl ether. The resulting solid was dried in vacuo, suspended in ethanol (40 mL) and concentrated hydrochloric acid (2.2 mL) was added to the suspension with ice-cooling. Then methyl carbazinate (2.8 g, 32 mM) was added to the suspension at room temperature and then the mixture was stirred for 18 hours. The reaction liquid was concentrated under reduced pressure followed by the addition of water to the concentrate and the extraction of the mixture with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid was dried in vacuo, suspended in dichloromethane (30 mL), then ethyl malonyl chloride (0.87 mL, 6.8 mM) and triethylamine (0.94 mL, 6.8 mM) were added to the suspension with ice-cooling and then the mixture was stirred at room temperature for 3 hours. After the reaction liquid was concentrated, ethyl acetate and water were added to the resulting residue, the precipitated solid was recovered through filtration and then washed with diethyl ether. After the resulting solid was dried in vacuo, it was suspended in ethanol (20 mL), a 5.0M sodium methoxide/methanol solution (1.9 mL, 9.6 mM) was added to the suspension, the mixture was stirred at 50 C. for 2 hours and then concentrated under reduced pressure. The resulting solid was dried under a vacuum, suspended in toluene (20 mL), followed by the addition of phosphorus oxychloride (20 mL) and the stirring of the mixture at 90 C. To this solution, there was dropwise added pyridine (1.2 mL, 14 mM) and the mixture was further stirred at 90 C. for 5 hours. After the reaction liquid was cooled to room temperature, it was concentrated under reduced pressure, then the concentrate was suspended in 1,2-dichloroethane (20 mL), followed by the filtration of the suspension and the concentration of the residue under reduced pressure. The resulting concentrate was diluted with water and then extracted with dichloromethane. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting solid was suspended in ethanol (10 mL), morpholine (0.31 mL, 3.6 mM) was added to the suspension and the mixture was stirred at room temperature for 20 hours. The reaction liquid was concentrated under reduced pressure, the resulting residue was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and then the solvent was distilled off to thus give a crude product of the title compound (20 mg, overall yield of these six steps: %). MS (ESI) m/z 317 (M+H)+
To a suspension of 2-(7-methoxy-naphthalen-1-yl)ethylamine hydrochloride (compound A) (5.0 g, 21.0 mmol) in 100 mL of a mixture of water-ethyl acetate (1/1), potassium carbonate (8.7 g, 63.0 mmol) was added and the reaction mixture was cooled at 0 °C in an ice-bath. Ethyl malonyl chloride (3.58 mL, 27.8 mmol) was added and the mixture stirred for 1 h at room temperature. The organic phase was then washed respectively with an aqueous solution of HCl (1 M) and water, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.09 g (92percent yield) of the desired product after recrystallization from isopropyl ether as a white solid; m.p. 90-92 °C; 1H NMR (300 MHz, CDCl3): deltaH 1.29 (t, J = 7.2, 3H, CH3), 3.20-3.40 (m, 4H, CH2-a,c), 3.70 (m, 2H, CH2-b), 4.00 (s, 3H, OCH3), 4.18 (quintet, J = 7.2, 2H, CH2-d), 7.18 (dd, J = 9.0, J = 2.4, 1H, H-6), 7.25-7.35 (m, 3H, H-2,3 and NH), 7.50 (d, J = 2.4, 1H, H-8), 7.70 (d, J = 7.6, 1H, H-4), 7.76 (d, J = 9.0, 1H, H-5); IR (neat, cm-1): 3230 (NH), 1738 (CO), 1641 (CO); LC/MS m/z 316.4 (M + 1); Anal. calcd for C18H21NO4: C 68.65percent, H 6.71percent, N 4.44percent; Found: C 68.66percent, H 6.68percent, N 4.41percent.
Intermediate 55 : Methyl 4-chloro-2-[3-(ethyloxy)-3-oxopropanoyl1amino)-5-iodobenzoateTo a solution of <strong>[199850-56-1]methyl 2-amino-4-chloro-5-iodobenzoate</strong> (Intermediate 2) (8 g, 25.7 mmol) and pyridine (2.18 mL, 27 mmol) in dichloromethane (200 mL) was added ethyl 3-chloro-3- oxopropanoate (Aldrich, 3.45 mL, 27 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness, diluted with ethyl acetate, washed successively with water and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in pentane, filtered and dried to give the title compound methyl 4-chloro-2-[3-(ethyloxy)-3- oxopropanoyl]amino}-5-iodobenzoate (8.24 g, 19.36 mmol, 75 % yield) as beige solid. LCMS: (M+H)+ = 426 ; Rt= 3.78 min.
1 ,2-Benzoxazol-3-amine (802 mg, 5.98 mmol) was dissolved in a mixture of anhydrous dichloromethane (4 ml_) and anhydrous pyridine (1 .5 ml_, 19 mmol). To this mixture was added, drop-wise, a solution of ethyl malonyl chloride (1.00 g, 6.64 mmol) in anhydrous dichloromethane (4 ml_). The resulting warm mixture (from slight exotherm) was stirred at ambient temperature for 30 min and quenched with the addition of cold water (20 ml_). Solid sodium carbonate was added until a pH of 10 was reached, and the mixture was stirred at ambient temperature for 1 hour. The organic layer was separated and the aqueous layer back-extracted withdichloromethane (4 x 30 ml_). The combined organic layers were passed through a phase separator column and concentrated under reduced pressured to yield crude ethyl 3-(1 ,2-benzoxazol-3-ylamino)-3- oxopropanoate.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
To a stirred solution of ethyl 3-(N-benzylamino)propionate 9 (414 mg, 2.00 mmol) and ethyldiisopropylamine (342 muL, 2.00 mmol) in 4 mL of CH2Cl2 at 0 C, was added ethyl malonyl chloride (303 muL, 2.40 mmol). The reaction mixture was warmed to ambient temperature and stirred for 10 min. H2O was added at 0 C and the separated aqueous layer was extracted with CHCl3. The combined organic layers were washed with a saturated aqueous NaHCO3 solution and with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to give the titled compound (598 mg, 93%) as a viscous colorless oil. 1H NMR (CDCl3, delta); 7.32-7.27 (m, 5H), 4.65 (s, 2H), 4.61* (s, 2H), 4.25-4.08 (m, 4H), 3.65 (t, 2H, J=6.9 Hz), 3.56* (t, 2H, J=6.9 Hz), 3.44 (s, 2H), 2.65 (t, 2H, J=6.9 Hz), 2.54* (t, 2H, J=6.9 Hz), 1.31-1.22 (m, 6H); 13C NMR (CDCl3, delta) 171.9, 170.9*, 167.6*, 167.4, 166.7, 166.5*, 136.7*, 136.2, 129.0, 128.6*, 127.81, 127.77*, 127.4*, 126.3, 61.5*, 61.4, 61.0*, 60.5, 52.7, 47.9*, 43.1*, 43.0, 41.4, 41.1*, 33.1*, 32.5, 14.09*, 14.06, 14.0; IR (ATR) 1736, 1654 cm-1; Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.68; H, 7.29; N, 4.39. HRMS (MH+) calcd for C17H24NO5: 322.1654. Found: 322.1654 (major:minor=57:43, *peaks of minor conformer).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 1h;
To a solution of <strong>[67567-26-4]4-bromo-2,6-difluoroaniline</strong> (10 g, 48 mmol) in DCM (15mL) was added ethyl 3-chloro-3-oxopropanoate (6.8 mL, 53 mmol) and DIEA (9.2 mL,53 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was partitioned between H20 and DCM and the layers separated. The DCM portion was washed with satd. NH4C1 and H20 then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to give Compound 90a(10 g, 65percent yield). LCMS = 1.60 mmusing analytical method (Q), 321.9 (M+H). 1HNMR(500MHz, CDC13) oe 8.89 (br. s.,1H), 7.20 - 7.15 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 1.36 - 1.31 (m, 3H).
65%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;
To a solution of <strong>[67567-26-4]4-bromo-2,6-difluoroaniline</strong> (10 g, 48 mmol) in DCM (15mL) was added ethyl3-chloro-3-oxopropanoate (6.8 mL, 53 mmol) and DIEA (9.2 mL,53 mmol) at room temperature. After 1 hour, the reaction mixture was partitioned10 between H20 and DCM. The organic phase was washed with saturated NH4Cl, H20,dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure togive Compound B26a (10 g, 65percent yield). HPLC: RT = 1.6 (LCMS Method Q). MS(ES): m/z = 321.9 [M+H( 1H NMR (500MHz, CHLOROFORM-d) 8 8.89 (br. s.,1H), 7.20-7.15 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 1.36- 1.31 (m, 3H).
ethyl 3-((4-bromo-2,5-difluorophenyl)amino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With pyridine; In dichloromethane; at 0℃; for 1h;
To a solution of <strong>[112279-60-4]4-bromo-2,5-difluoroaniline</strong> 11 g, 24 mmol) in DCM (30 mL) were added pyridine (6.4 mL, 36 mmol) and ethyl 3-chloro-3-oxopropanoate (6.9 mL, 24 mmol) at 0 C. After 1 h, the reaction mixture was concentrated under reduced pressure,diluted with EtOAc, washed with 1 M HC1 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO, silica gel, 80 g column, eluting with ethyl acetate/hexane 0% to 50% gradient) to give Compound la (17 g, 97%). HPLC RT = 1.78 mm (LCMS Method B). MS(ES): m/z = 323.9 [M+H]. ?H NMR (400MHz,chloroform-d) oe 8.60 (m, 1H), 6.97 (dd, J=10.6, 7.9 Hz, 1H), 4.28 (m, 2H), 3.50 (m, 2H),1.33 (t, J=7.2 Hz, 3H).
97%
With pyridine; In dichloromethane; at 0℃; for 1h;
To a solution of <strong>[112279-60-4]4-bromo-2,5-difluoroaniline</strong> 11 g, 24 mmol) in DCM (30 mL) were added pyridine (6.4 mL, 36 mmol) and ethyl 3-chloro-3-oxopropanoate (6.9 mL, 24 mmol) at 0 C. After 1 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with 1 M HCl and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO, silica gel, 80 g column, eluting with ethyl acetate/hexane 0% to 50% gradient) to give Compound 1a (17 g, 97%). HPLC RT=1.78 min (LCMS Method B). MS(ES): m/z=323.9 [M+H]+. 1H NMR (400 MHz, chloroform-d) delta 8.60 (m, 1H), 6.97 (dd, J=10.6, 7.9 Hz, 1H), 4.28 (m, 2H), 3.50 (m, 2H), 1.33 (t, J=7.2 Hz, 3H).
ethyl 2-(3,5-dichlorobenzylcarbamoyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;
To a solution of 3,5-diehlorobenzylamine (133 mg, 0.756 mmol) and DIPEA (0.756 mmol) in 10 ml of DCM was added ethyl malonyi chloride (0.756 mmol) in 3 ml of DCM at 0 C with stirring. The reation was performed at 0 C for 2h. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to give ethyl 2~(3,5~ dichlorobenzylcarbamoyi)acetate.
methyl 2-bromo-5-(3-ethoxy-3-oxopropanamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In tetrahydrofuran; at 0 - 25℃;
To a solution of <strong>[6942-37-6]methyl 5-amino-2-bromobenzoate</strong> (1 1 .5 g, 50 mmol) and TEA (20.5 mL, 150 mmol) in THF (150 mL) was added ethyl 3-chloro-3-oxopropanoate (1 1 .3 g, 75 mmol) at 0C. After stirred at room temperature overnight, the reaction mixture was quenched with sat.NaHC03, the layers were separated and the aqueous layer was extracted with ethylacetate (50 mL X3). The combined organic layers were washed with brine, dried over Na2S04. Solvents were removed under vacuum and the obtained crude product methyl 2-bromo-5-(3- ethoxy-3-oxopropanamido)benzoate (2) (12.9 g, 75 %) was used in the next step without purification. LC-MS (ESI): m/z (M/M+1 ) 344.0/346.0.
ethyl 3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
In a 500 ml three-necked flask, 20 g (0.122 mol, leq.) Of the (s) -4-phenyl-2-oxazolone raw material and tolueneWas cooled to between 0 and 10 C, and 22 g (0.146 piomicron1, 1.2 eq.) Of t-butyldimethylchlorosilane was added and maintained at 0 toL0 C for 30 minutes under stirring, diisopropylethylamine 19.6g (0.152mall, 1.25eq.), Dropping the process to control the material temperatureAfter 0-10 C, the mixture was stirred at 0-10 C for 2 hours until the (S) -4-phenyl-2-oxazolone was subjected to TLCThe reaction was completed (TLC conditions: petroleum ether / ethyl acetate = 2/1). Then 36.7 g monoethyl malonate chloride was added(0.244piomicron1,2 eq.), Dropping process control the material temperature between 0 ~ 10 C, after the completion of the drop by adding 0.32g anhydrous fourButyl ammonium fluoride (TBAF, 1.2 O1, O. Oleq.) Was added and the reaction was stirred at room temperature for 2-5 hours. After completion of the reaction, the reaction solution was addedPoured into 200 ml of ice water and stirred at room temperature for 30 minutes. The organic phase was separated and the organic phase was washed with 10% sodium carbonate solution,The organic phase was evaporated to dryness to give a crude product. To the crude product isopropyl alcohol l0ml, stirring at 10 ~ 15 C 2 small, And dried to obtain 31.4 g of a product compound in a yield of 93%.
90%
(S) -3-oxo-3- (2-oxo-4-phenyloxazolin-3-yl)Propionic acidEthyl ester,The structure is as follows:In a 500 ml three-necked flask,Join(S) -4-phenyl-2-oxazolone(0.122 mol, 1 eq.) AndDichloromethane 200 ml,Cooling to between 0 and 10 C,16 g (0.146 mol, 1.2 eq.) Of the TMSCl starting material was added,The mixture was stirred at 0 to 10 C for 30 minutes,15.4 g (0.152 mol, 1.25 eq.) Of triethylamine was added dropwise,Dropping process control material temperature between 0 ~ 10 ,After completion of the dropwise addition,Stirring was continued at 0 to 10 C for 2 hours((S) -4-phenyl-2-oxazolone TLC detection reaction was completed (TLC detection conditions:Petroleum ether / ethyl acetate = 2/1).Then 36.8 g was addedMalonic acidMonoethyl ester chloride (0.245 mol, 2 eq.) Was added dropwiseProcess control of material temperature at0 to 10 C,After completion of the dropwise addition,0.2 g of anhydrous tetrabutylammonium fluoride (TBAF,Gt; mmol, 0.005 eq.),The reaction solution was stirred at room temperature for 2 to 5 hours.After completion of the reaction,The reaction solution was poured into 200 mlIce-water, and the mixture was stirred at room temperature for 30 minutes,The organic phase was separated and the organic phase was washed with 10% sodium carbonate solution,The organic phase was separated and the organic phase was evaporated to dryness to give a crude product. To the crude product was added 100 ml of isopropanolStirred at 20 to 25C for 2 hours, and suction-filtered to obtain a white solid powder, which was dried to obtain 30.4 g of the product compound,Yield 90%,
With dmap; triethylamine; aniline; In dichloromethane; for 0.5h;
Aniline (3.1 g), 4-dimethylaminopyridine (0.61 g), triethylamine (5.1 mL), and dichloromethane (25 mL) wereadded into a 300-mL 3-diameter eggplant flask, and, then, a dichloromethane solution (25 mL) of ethyl malonyl chloride(5.0 g) was dropped over 20 minutes. The resulting solution was stirred as it is for 30 minutes, and then water was addedthereto, and dichloromethane removed by evaporation under reduced pressure. The residue was extracted with ethylacetate, and then washed with 1N hydrochloric acid and saturated saline solution sequentially in this order, and driedover anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation under reduced pressure. Theobtained residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 7:3 ? 1:1) to obtain thetitle compound (5.8 g) having the following physical property values.TLC: Rf 0.50 (hexane : ethyl acetate =1:1);1H-NMR (CDCl3): delta 1.32, 3.47, 4.26, 7.13, 7.35, 7.55, 9.22
N-(1-pyridin-2-ylethyl)malonamic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
To a stirred solution of 1-(pyridin-2-yl)ethanamine (46-1) (1 g, 8.18 mmol) in Dichloromethane (20 mL ) at 0C was added Triethyl amine (1.13 mL, 8.18 mmol) and ethyl 3- chloro-3-oxopropanoate (1.00 mL, 8.18 mmol). The reaction was stirred at room temperature for 4 hours and then diluted with DCM, washed with saturated sodium bicarbonate solution, water, brine and dried over sodium sulfate. The organics were concentrated under reduced pressure and purified by column chromatography using (silica, gradient, 0%-2% methanol in DCM) to afford ethyl 3-oxo-3-((1-(pyridin-2-yl)ethyl)amino)propanoate (46-2) (1 g) as a gum. Yield-52%; LC MS: ES+ 237.3.
ethyl 3-((2-methyl-4-(perfluoropropan-2-yl)phenyl)amino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.5%
With triethylamine; In dichloromethane; at 0 - 25℃;
General procedure: A solution of intermediate 2 (60 mmol) and triethylamine (60 mmol) dissolved in dichloromethane(100 mL) was cooled to 0-5 C. Ethyl malonyl chloride (60 mmol) was added dropwise over ten minutes,and the mixture was stirred for a further thirty minutes at this temperature. The reaction mixture was then stirred at room temperature until the reaction was complete as indicated by TLC. At the end ofthe reaction, the reaction mixture was successively washed with diluted hydrochloric acid (30 mL,5% vol) and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using petroleum ether (60-90 C) and ethyl acetate(v/v = 15:1) as the eluent to give intermediate 3, with yields ranging from 89.4% to 93.5%. Physical,spectral data, and 1H-NMR spectra of intermediate 3 were provided in the Supplementary Materials.
92%
With triethylamine; In dichloromethane; at 0 - 25℃; for 2h;
250mL three-neck bottle,Add <strong>[238098-26-5]2-methyl-4-heptafluoroisopropylaniline</strong> (16.5 g, 60 mmol),Triethylamine (6.06 g, 60 mmol) and 100 mL of dichloromethane,0 C stirring downSlow dropMalonyl chloride monoethyl ester(9.0g, 60mmol),After the addition is completed,Transfer to room temperature 25 C for 2 h.After the reaction is completed, the reaction liquid is washed successively with a dilute hydrochloric acid solution.Wash with saturated sodium bicarbonate solution and wash with saturated sodium chloride solution.The organic phase was collected and dried over anhydrous sodium sulfate, and evaporated to dissolve.Residue column chromatographyEthyl 3-((2-methyl-4-heptafluoroisopropylphenyl)amino)-3-oxopropionate(21.5 g, 55.2 mmol), yield 92%.
With potassium hydroxide; In tetrahydrofuran; at 0 - 20℃;
To a solution of methanamine hydrochloride (2.24 g, 33.2 mmol) in THF (50 mL) was added KOH (4.09 g, 73.1 mmol). The reaction was cooled to 0 C and added ethyl 3-chloro- 3-oxo-propanoate (5.00 g, 33.2 mmol) slowly. The reaction was warmed to rt and stirred overnight. The reaction was quenched with water (20 mL), then extracted with EtOAc (100 mL x 4). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtO Ac/PE (v/v) = 1/2) to give the title compound as yellow liquid (0.89 g, 18.6%).MS (ESI, pos. ion) m/z: 146.1 [M+H]+;1H NMR (400 MHz, DMSO-76) d (ppm): 7.98 (s, 1H), 4.07 (q, j = 7.1 Hz, 2H), 3.19 (s, 2H), 2.59 (d, J= 4.6 Hz, 3H), 1.18 (t, J= 7.1 Hz, 3H).
With potassium hydroxide; In tetrahydrofuran; at 0 - 20℃;
To methylamine hydrochloride (2.24 g, 33.2 mmol)KOH (4.09 g, 73.1 mmol) was added to a solution of THF (50 mL).The reaction was cooled to 0 C.Ethyl 3-chloro-3-oxo-propionate (5.00 g, 33.2 mmol) was added slowly.The reaction was allowed to warm to room temperature and stirred overnight.The reaction was then quenched with water (20 mL).It was extracted with EtOAc (100 mL×4).The combined organic phases were washed with saturated brine.Dry over anhydrous sodium sulfate,Filter and concentrate under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc /EtOAcThe title compound was obtained as a yellow oil (0.89 g, 18.6%).
With triethylamine; In dichloromethane; at 20℃; for 5h;
The appropriate amount of melatonin was dissolved in dichloromethane, and 3 times equivalent of triethylamine was added, and then 1.5 times equivalent of malonic acid monoethyl ester chloride was added to the reaction solution. The reaction was stirred at room temperature for 5 hours, and then the reaction was carried out. The organic phase was extracted by liquid extraction and purified by column to obtain M5. M5 was dissolved in a mixture of MeOH/H2O = 2/1, and 2 times equivalent of sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 30 minutes, and the reaction liquid was spin-dried to obtain the desired product molecule 11. Its reaction formula is as follows:
O,O'-(2-(((3-ethoxy-3-oxopropanoyl)oxy)methyl)-2-ethylpropane-1,3-diyl) diethyl dimalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With pyridine; In tetrahydrofuran; dichloromethane; at 20℃; for 12h;
2-ethyl-2-(hydroxymethyl)propane-1,3-diol (4.45 g, 33.2 mmol), ethyl malonyl monochloride (21.23 ml, 166 mmol), and pyridine (13.41 ml, 166 mmol) were mixed in dichloromethane (491 ml, 7628 mmol)/ tetrahydrofuran (82 ml, 995 mmol) and the solution was stirred for 12 h at 20C. The mixture was washed with saturated aqueous NH4Cl solution (2 x ), dried (Na2S04), and evaporated to dryness. Column chromatography (Si02;CH2Cl2/Ac0Et 3:1) yielded the desired product O,O'-(2-(((3-ethoxy-3-oxopropanoyl)oxy)methyl)-2-ethylpropane-1,3-diyl) diethyl dimalonate (15.5 g, 31.9 mmol, 96 % yield) as a colorless oil.
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