* 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.
With potassium carbonate In methanol; water at 10 - 20℃;
(1) A mixture of (R)-2-amino-2-phenylacetic acid (200 g, 1.32 mol), potassium carbonate (218 g, 1.58 mol) was dissolved in water (2.0 L) and methanol (0.5 L), cooling to T <10 deg. C, di-tert-butyl dicarbonate (288 g, 1.32 mol) was added dropwise, room temperature reaction overnight, pH 4 to 5 with 1 N HCl, extraction with ethyl acetate (1.0 L * 3), was washed with saturated brine (1.0 L * 1), concentrated to give 315 g of a white solid, yield 95percent.
76%
With water; sodium hydroxide In methanol at 20℃; for 2 h;
The raw material 2 was dissolved in 10 ml of methanol,Then slowly add 20 ml of 1 N NaOH aqueous solutionAnd (Boc) 2O (2.18 g, 10 mmol).After 2 hours of reaction at room temperature,The pH was adjusted to 4-5 with 1N HCl solution.Followed by extraction with chloroform (3 x 30 ml) and the combined organic phases were dried over anhydrous magnesium sulfate to give the crude product. The crude product was purified by silica gel column chromatography,CH2Cl2 / MeOH (10: 1) as the mobile phase to afford intermediate 3 (955 mg, 76percent),
72%
With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24 h;
Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooledto 0°C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0°C for 10 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 24 hours. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0N aqueous potassium hydrogen sulphate solution (pH 2.5) and subsequently washed with ethyl acetate (2 x 40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72percent) as a clear oil, which solidified on standing. 1H NMR (400 MHz, CDC13): ö 8.08 (s, 1 H), 7.47-7.27 (m, 5 H), 5.48* OT+ (dd, J = 72.0 Hz, 6.5 Hz, 1 H), 5.13*0T+ (d, J = 5.6 Hz, 1 H), 3.71 (s, 1 H), 1.43 (s, 3 H), 1.21 (s, 6 H). * and refer to different isomers.
72%
With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.17 h; Cooling with ice
Intermediate 4. (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (I4) Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0° C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0° C. for 10 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 24 hours. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulphate solution (pH 2.5) and subsequently washed with ethyl acetate (2*40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72percent) as a clear oil, which solidified on standing. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.47-7.27 (m, 5H), 5.48*or + (dd, J=72.0 Hz, 6.5 Hz, 1H), 5.13*or + (d, J=5.6 Hz, 1H), 3.71 (s, 1H), 1.43 (s, 3H), 1.21 (s, 6H). * and † refer to different isomers.
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8049 - 8065
[2] Journal of Medicinal Chemistry, 1991, vol. 34, # 3, p. 968 - 978
[3] Tetrahedron Letters, 1995, vol. 36, # 29, p. 5227 - 5230
[4] Patent: CN104592163, 2016, B, . Location in patent: Paragraph 0041; 0042
[5] Patent: CN106748892, 2017, A, . Location in patent: Paragraph 0051; 0053; 0054; 0055
[6] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2776 - 2792
[7] Patent: WO2014/86849, 2014, A1, . Location in patent: Page/Page column 69; 70
[8] Patent: US2014/155428, 2014, A1, . Location in patent: Paragraph 0431 - 0433
[9] Archiv der Pharmazie, 1994, vol. 327, # 4, p. 215 - 219
[10] Journal of the American Chemical Society, 2004, vol. 126, # 48, p. 15666 - 15667
[11] Chemistry - A European Journal, 2003, vol. 9, # 17, p. 4031 - 4045
[12] Chemical Research in Toxicology, 2011, vol. 24, # 5, p. 706 - 717
[13] Molecules, 2014, vol. 19, # 11, p. 19050 - 19065
[14] Tetrahedron Letters, 2015, vol. 56, # 48, p. 6742 - 6746
[15] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 47 - 63
[16] Journal of Organic Chemistry, 2018,
2
[ 875-74-1 ]
[ 33125-05-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium carbonate In 1,4-dioxane; water at 25℃; for 12 h;
General procedure: L-Phenylalanine (1.0 g, 6.05 mmol) and sodium carbonate (0.71 g, 6.70 mmol) in water (10 mL) was reacted with a solution of 2 (1.89 g, 6.36 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature till the reaction completes, as monitored by TLC. The resulting solution was concentrated, to the residue was added water (10 mL) and ethyl acetate (10 mL), pH adjusted to 6.0 with 10percent KHSO4 and stirred for 5 minutes. The organic layer was removed and the aqueous layer was acidified to pH 2.0 with 10percent KHSO4 at 0-5°C and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 5percent NaHCO3 solution, water, brine and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated and the residue was crystallized from EtOAc/ n-hexane (2:8) mixture to give the product as a white solid (1.53g, 95percent yield).
With sodium hydroxide In <i>tert</i>-butyl alcohol at 20℃; for 1h; Inert atmosphere;
99%
With potassium hydrogencarbonate In tetrahydrofuran; water for 18h;
96%
With sodium hydroxide
95%
With potassium carbonate In methanol; water at 10 - 20℃;
1.1
(1) A mixture of (R)-2-amino-2-phenylacetic acid (200 g, 1.32 mol), potassium carbonate (218 g, 1.58 mol) was dissolved in water (2.0 L) and methanol (0.5 L), cooling to T <10 deg. C, di-tert-butyl dicarbonate (288 g, 1.32 mol) was added dropwise, room temperature reaction overnight, pH 4 to 5 with 1 N HCl, extraction with ethyl acetate (1.0 L * 3), was washed with saturated brine (1.0 L * 1), concentrated to give 315 g of a white solid, yield 95%.
76%
With water; sodium hydroxide In methanol at 20℃; for 2h;
1 Preparation of intermediate 3
The raw material 2 was dissolved in 10 ml of methanol,Then slowly add 20 ml of 1 N NaOH aqueous solutionAnd (Boc) 2O (2.18 g, 10 mmol).After 2 hours of reaction at room temperature,The pH was adjusted to 4-5 with 1N HCl solution.Followed by extraction with chloroform (3 x 30 ml) and the combined organic phases were dried over anhydrous magnesium sulfate to give the crude product. The crude product was purified by silica gel column chromatography,CH2Cl2 / MeOH (10: 1) as the mobile phase to afford intermediate 3 (955 mg, 76%),
76%
With sodium hydroxide In methanol at 20℃; for 2h;
76%
With sodium hydroxide In methanol; water at 20℃; for 2h;
To prepare Intermediate 1, raw material 1 was dissolved in 10 ml methanol, and then 20 ml 1 N NaOH aqueous solution and (Boc) 2 O (2.18 g, 10 mmol) were slowly added. After reacting at room temperature for 2 hours, adjust the pH to 4-5 with 1 N HCl solution. Then it was extracted with chloroform (3 x 30 ml), the organic phases were combined and dried over anhydrous magnesium sulfate to obtain a crude product. The crude product was purified by a silica gel chromatography column using CH2Cl2/MeOH (10:1) as the mobile phase to obtain Intermediate 5 (955 mg, 76%) as a white solid.
72%
With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24h;
Intermediate 4(R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (14)
Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooledto 0°C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0°C for 10 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 24 hours. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0N aqueous potassium hydrogen sulphate solution (pH 2.5) and subsequently washed with ethyl acetate (2 x 40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil, which solidified on standing. 1H NMR (400 MHz, CDC13): ö 8.08 (s, 1 H), 7.47-7.27 (m, 5 H), 5.48* OT+ (dd, J = 72.0 Hz, 6.5 Hz, 1 H), 5.13*0T+ (d, J = 5.6 Hz, 1 H), 3.71 (s, 1 H), 1.43 (s, 3 H), 1.21 (s, 6 H). * and refer to different isomers.
72%
With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.17h; Cooling with ice;
Intermediate 4. (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (I4)
Intermediate 4. (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (I4) Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0° C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0° C. for 10 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 24 hours. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulphate solution (pH 2.5) and subsequently washed with ethyl acetate (2*40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil, which solidified on standing. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.47-7.27 (m, 5H), 5.48*or + (dd, J=72.0 Hz, 6.5 Hz, 1H), 5.13*or + (d, J=5.6 Hz, 1H), 3.71 (s, 1H), 1.43 (s, 3H), 1.21 (s, 6H). * and † refer to different isomers.
60%
With triethylamine In methanol; water for 6h;
With sodium carbonate In 1,4-dioxane at 20℃;
With sodium hydroxide In tetrahydrofuran at 20℃; for 18h;
With triethylamine In water; acetone at 20℃; for 24h;
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h;
General Procedure for the Synthesis of Compounds 6a-d
General procedure: Amino acid derivative (5 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and water (20 mL). A 1 N NaOH (6 mL) was added followed by the addition of 1.1 g di-tert-butyl dicarbonate (5mmol) dropwise at room temperature. After stirring for 4 h, the tetrahydrofuran was evaporated under vacuum from the reaction mixture. To the residue was added ethyl acetate (50 mL) and 5% citric acid (30 mL). The organic layer was separated, washed with water (20 mL × 3), dried with anhydrous MgSO4 and rotary evaporated to dryness. The crude residue was used the next reaction without purification. A mixture of the above N-Boc protected amino acids (2.2 mmol), compound 4 (0.98 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g,2.2 mmol), 1-hydroxybenzotriazole (0.30 g, 2.2 mmol), triethylamine (0.30 g, 3.0 mmol) and dichloromethane (50 mL) was stirred at room temperature for 36 h. The mixture was washed with saturated aqueous NaHCO3 and water then, evaporated under vacuum and the residue was treated with a mixture of trifluoroacetic acid (TFA, 10 mL) and dichloromethane (10 mL) at room temperature for 30 min. The reaction mixture was quenched with 25% aqueous NaHCO3 (30 mL) and washed with water, dried with anhydrous Na2SO4 overnight and rotary evaporated to dryness. The crude residue thus obtained was purified by silica gel column chromatography (petroleum ether-ethyl acetate 1:2 v/v) to afford the desired compounds.
With sodium hydroxide In isopropyl alcohol
With sodium hydroxide In isopropyl alcohol at 20℃; for 2h;
2-((tert-butoxycarbonyl)amino)acetic acid (20a)
General procedure: To a solution of glycine (1g, 13.32 mmol) in 1M NaOH/iPrOH (4:3) was added Boc2O(2.9 g, 13.32 mmol). The reaction, monitored by TLC, was stirred at rtfor 2h and then washed with Et2O, acidified to pH 3.0 with 1N HCland finally extracted several time with AcOEt. The organic layer was dried overanhydrous Na2SO4 and evaporated under reduced pressure.The crude product was used for the next step without further purification (1.68g, 9.59 mmol, 72% yield).
With sodium hydroxide
With sodium hydroxide In tetrahydrofuran; water
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 72h;
2.1. General Procedure for the Synthesis of N-(tert-Butoxycarbonyl)-amino Acid (1a-d)
General procedure: Di-tert-butyl dicarbonate (1.1 equiv) dissolved in 50 mlTHF was added to a mixture of selected amino acids(1 equiv) and sodium bicarbonate (4 equiv) in 50 ml of water. The reaction mixture was stirred at room temperature for three days until completion. Upon completion, reaction products were observed by TLC (Hexane/EtOAc 1:1 by volume) followed by removal of THF from the medium through evaporation. The pH of the evaporated medium was adjusted to pH 2 by the addition of 2M HCl. The target product was extracted with EtOAc (4×20ml), dried with Na2SO4 and concentrated in vacuo to give the desired product. DPhenlyglycine,L-phenylalanine, L-isoleucine and Lmethioninewere obtained in %85, %88, %90 and %92yields.
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 1h;
Step 1: (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (115b).
The title compound (1.6 g, 96%, white solid) was synthesized starting from (R)-2-amino-2-phenylacetic acid 114b (1 g, 6.61 mmol) and Boc2O (1.68 mL, 7.34 mmol) according to the procedure described in step 1 for the preparation of intermediate 115a in the synthesis of compound 57. LCMS (ES+) m/z calculated for C13H17NO4 251.12, found 152 (M+H-Boc)+.
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 1h;
Step 1: (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (115b).
The title compound (1.6 g, 96%, white solid) was synthesized starting from (R)-2-amino-2-phenylacetic acid 114b (1 g, 6.61 mmol) and Boc2O (1.68 mL, 7.34 mmol) according to the procedure described in step 1 for the preparation of intermediate 115a in the synthesis of compound 57. LCMS (ES+) m/z calculated for C13H17NO4 251.12, found 152 (M+H-Boc)+.
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0℃; for 1.58333h;Product distribution / selectivity;
b. Preparation of (R)-[4-(2-TERT-BUTOXYVARBONYLAMINOETHYL) phenylcarbamoyl] phenyl- METHYLCARBAMIC acid tert-butyl ester; A 1 L FLASK was charged with the product of the previous step (30.0 g, 1.07 equiv), ((R)-TERT-BUTOXYCARBONYLAMINO) phenylacetic acid (30.0 g, 1.0 equiv) and a solution of L-HYDROXY-7-AZABENZOTRIAZOLE (16.3 g, 1. 01 equiv) IN N, N-DIMETHYLFORMAMIDE (240 ML). The solution was stirred until all the solids had dissolved. The solution was cooled over an ice bath for 15 minutes and 1- [3-DIMETHYLAMINOPROPYL]-3-ETHYLCARBODIIMIDE hydrochloride (26.9 g, 1. 18 equiv) was added. The reaction was stirred at 0 C for 80 minutes. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed sequentially with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate. The solids were filtered and the filtrate concentrated to give the title intermediate as a solid (57 g, quantitative yield) which was used without further purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 21.1667h;Product distribution / selectivity;
c. Preparation of (R)- [4-(2-TERT-BUTOXYCARBONYLAMINOETHYL) phenylcarbamoyl] phenyl- METHYLCARBAMIC acid tert-butyl ester; [2- (4-Aminophenyl) ethyl] carbamic acid tert-butyl ester (L g, 4.2 mmol), ((R)-TERT- butoxycarbonylamino) phenylacetic acid (920 mg, 3.7 mmol) and 1-HYDROXYBENZOTRIAZOLE (600 mg, 4.4 mmol) were dissolved in N, N-DIMETHYLFORMAMIDE (10 mL) under nitrogen and cooled to 0C. 1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE hydrochloride (850 mg, 4.4 mmol) was added and the mixture stirred at 0C for 10 minutes, then at room temperature for 21 hours. The mixture was partitioned between water and ethyl acetate, and the organics washed with 0.5 M citric acid, saturated sodium hydrogencarbonate and saturated sodium chloride. The organics were then dried over sodium sulfate and evaporated to dryness. The title intermediate was used without further purification.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 1h;
EXAMPLE 155 EPO <DP n="131"/>Preparation of (2R) 4-(l-memylpiperidin-4-yl)piperidin-l-yl-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; [0533] To a solution of (D) N-BOC phenylglycine (100 mg, 0.40 mmol), <strong>[78619-84-8]4,4'-<strong>[78619-84-8]bipiperidine dihydrochloride</strong></strong> (482 mg, 2.00 mmol) and triethylamine (0.70 mL, 5.0 mmol) in DMF (6.0 mL) and H2O (3.0 mL), BOP (355 mg, 0.80 mmol) was added. After being stirred at room temperature for 1 h, the mixture was purified by HPLC to give the amide (160 mg). MS 402.5 (M+H).[0534] To a solution of the amide (160 mg, 0.40 mmol) and HCHO (37% aq, 0.178 mL, 2.39 mmol) in MeOH (6.0 mL), NaBH3CN (151 mg, 2.39 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in TFA (6.0 mL). After being stirred for 2 h, TFA removed in vacuo. The residue was dissolved in CH3CN (6 mL). To the solution, 4-chlorophenylisocyanate (90 mg, 0.58 mmol) was added. After 30 min of stirring, the mixture was purified by HPLC to give the titled compound (32 mg). MS 469.5 and 471.5 (M+H, Cl pattern).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 1h;
EXAMPLE 37; Preparation of (2R) 4-(l-methylpiperidin-4-yl)piperidin-l-yl-2-phenyl-2-(4- chlorophenylaminothiocarbonylamino)-acetamide; EPO <DP n="52"/> [0193] To a solution of (D) N-BOC phenylglycine (100 mg, 0.40 mmol), <strong>[78619-84-8]4,4'-<strong>[78619-84-8]bipiperidine dihydrochloride</strong></strong> (482 mg, 2.00 mmol) and triethylamine (0.70 mL, 5.0 mmol) in DMF (6.0 mL) and H2O (3.0 mL), BOP (355 mg, 0.80 mmol) was added. After being stirred at room temperature for 1 h, the mixture was purified by HPLC to give the amide (160 mg). MS 402.5 (M+H).[0194] To a solution of the amide (160 mg, 0.40 mmol) and HCHO (37% aq, 0.178 mL, 2.39 mmol) in MeOH (6.0 mL), NaBH3CN (151 mg, 2.39 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in TFA (6.0 mL). After being stirred for 2 h, TFA removed in vacuo. The residue was dissolved in CH3CN (6 mL). To the solution, 4-chlorophenylisothiocyanate (110 mg, 0.64 mmol) was added. After 30 min of stirring, the mixture was purified by HPLC to give the titled compound (16 mg). MS 485.2 and 487.3 (M+H, Cl pattern).
27 Synthesis of 1ethyl-2-[2-[(S)-1-((R)-2-methylsulfonylamino-2-phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 37)
EXAMPLE 27 Synthesis of 1ethyl-2-[2-[(S)-1-((R)-2-methylsulfonylamino-2-phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 37) 1.00 g of (R)-(-)-2-phenylglycine, 10 ml of 1,4-dioxane and 10 ml of 2N aqueous NaOH solution were mixed, and 1.73 g of (BOC)2O was slowly added at 0° C. The reaction mixture was stirred overnight at room temperature and distilled under reduced pressure to remove 1,4-dioxane. To the residue were added 50 ml of water and 5 ml of aqueous NH4OH solution. The aqueous layer was washed with dichloromethane, acidified with c-HCl, and then extracted with ethyl acetate. The extract was dried over sodium sulfate and distilled under reduced pressure to obtain 1.6 g of liquid (R)-2-[(tert-butoxy)carbonylamino]-2-phenylacetic acid.
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h;
General procedure: A suspension of amino acid derivative (5 mmol) was dissolved ina mixture of tetrahydrofuran (50 mL) and water (20 mL). 1 N NaOH(6 mL) was added followed by adding 1.1 g tert-butoxycarbonyl(5 mmol) dropwise at room temperature. After stirring for 4 h,the tetrahydrofuran was evaporated in vacuum from the reaction mixture. The residue was added ethyl acetate (50 mL) and 5% citricacid (30 mL). The organic layer was separated, washed with water(20 mL), dried with anhydrous Na2SO4 and rotary evaporated to dryness. Crude residue was used into next reaction without purification.
methyl (R)-4-[(tert-butoxycarbonyl)amino]-3-oxo-4-phenylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 10h;Cooling; Inert atmosphere;
General procedure: For example 4a: A solution of N, N¢-dicyclohexylcarbodiimide (2.06 g, 10 mmol) in dried CH2Cl2 (15 mL) was dropwise added to a mixture of (1S,2S)-(+)-1,2-diaminocyclohexane (0.57 g, 5 mmol) and N-Boc-protected D-phenylalanine (2.65 g, 10 mmol) in dried CH2Cl2 (15 mL) at ice-salt bath under a nitrogen atmosphere. The mixture was stirred over 10 hours and filtered. The filtered cake was washed with CH2Cl2 for three times (5 mL × 3). The combined organic phase was dried over anhydrous Na2SO4. The solvent was removed under a vacuum and the residue was purified by column chromatography on silica gel to afford the pure 4a in 70% isolated yield as white solid.
(R)-tert-butyl (2-oxo-2-((2-oxoindolin-5-yl)amino)-1-phenylethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
General procedure: To a solution of carboxylic acid 19 (300 mg, 1.13 mmol), in dry DMF (5 mL), under N2 atmosphere and cooled to 0 °C, were added TBTU (363 mg, 1.13 mmol) and DIPEA (6.18 mL, 39.55 mmol). After 30' a 0 °C, 5-amine-2-oxindole (168 mg, 1.13 mmol) was added and the temperature was kept at 0 °C for additional 30'. Later the mixture was slowly warmed to room temperature and left under stirring at rt overnight. Once TLC verified the disappearance of the precursor, the organic solvent was evaporated under vacuum and the crude product was purified by flash chromatography over silica gel, using 0-4percent MeOH as a gradient in CHCl3, to obtain pure 1 as a white solid (210 mg, 0.53 mmol, 47percent yield).
(R)-tert-butyl (2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxo-1-phenylethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;
4.2 Synthesis of 1-(3,4-difluorobenzyl)-2-oxo-N-(2-oxoindolin-5-yl)-1,2-dihydropyridine-3-carboxamide (1)
General procedure: To a solution of carboxylic acid 19 (300 mg, 1.13 mmol), in dry DMF (5 mL), under N2 atmosphere and cooled to 0 °C, were added TBTU (363 mg, 1.13 mmol) and DIPEA (6.18 mL, 39.55 mmol). After 30' a 0 °C, 5-amine-2-oxindole (168 mg, 1.13 mmol) was added and the temperature was kept at 0 °C for additional 30'. Later the mixture was slowly warmed to room temperature and left under stirring at rt overnight. Once TLC verified the disappearance of the precursor, the organic solvent was evaporated under vacuum and the crude product was purified by flash chromatography over silica gel, using 0-4% MeOH as a gradient in CHCl3, to obtain pure 1 as a white solid (210 mg, 0.53 mmol, 47% yield).
tert-butyl (2,4-dioxo-3-azaspiro[5,5]undecan-3-yl) carbonate[ No CAS ]
[ 33125-05-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium carbonate In 1,4-dioxane; water at 25℃; for 12h;
Preparation of N-(tert-Butoxycarbonyl)-L-Phenylalanine (Table 1, entry 1).
General procedure: L-Phenylalanine (1.0 g, 6.05 mmol) and sodium carbonate (0.71 g, 6.70 mmol) in water (10 mL) was reacted with a solution of 2 (1.89 g, 6.36 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature till the reaction completes, as monitored by TLC. The resulting solution was concentrated, to the residue was added water (10 mL) and ethyl acetate (10 mL), pH adjusted to 6.0 with 10% KHSO4 and stirred for 5 minutes. The organic layer was removed and the aqueous layer was acidified to pH 2.0 with 10% KHSO4 at 0-5°C and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 5% NaHCO3 solution, water, brine and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated and the residue was crystallized from EtOAc/ n-hexane (2:8) mixture to give the product as a white solid (1.53g, 95% yield).
Stage #1: 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione; Boc-D-Phg-OH With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 30℃;
Stage #2: With hydrogenchloride In tetrahydrofuran at 50 - 60℃;
11 Example 11
In a three-necked flask, compound X (1.0 g, 2.4 mmol) was added.N- (tert-butoxycarbonyl) -D-2-phenylethanolamine (0.67 g, 2.8 mmol), triphenylphosphine (0.74 g, 2.8 mmol) and tetrahydrofuran (50 ml).Control temperature 20 30 ,Diisopropyl azodicarboxylate (0.71 g, 3.5 mmol) was added dropwise. After the reaction is complete,Further concentrated hydrochloric acid (1 mL) was added.After stirring the reaction at 50-60 ° C to complete,Concentrate to remove tetrahydrofuran.To the residue were added isopropyl acetate and an aqueous sodium hydroxide solution, and the mixture was separated after stirring. The organic phase was concentrated and separated by column chromatography (ethyl acetate: n-hexane = 20% to 100%) to obtain Compound I (0.5 g, 39%).
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