* 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 formic acid; palladium 10% on activated carbon In tetrahydrofuran; water
16.8 g of (S)-phenylethyl-(S)-cyclopropyl glycine obtained in the previous step, 200 mL of THE, 100 mL of water, and 4.76 g of Pd/C having a concentration of 10percent were mixed, then 17 mL of formic acid was added, then stir was performed overnight. After reacting, filtering was performed to remove a catalyst to obtain a filtrate, the filtrate was concentrated, and then methanol was added, then concentration was performed over again, operate repeatedly for several times, and vacuum drying was performed to obtain 4.75 g of a solid product.
Reference:
[1] Organic Process Research and Development, 2012, vol. 16, # 3, p. 464 - 469
3
[ 155976-13-9 ]
[ 49606-99-7 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 9, p. 1071 - 1078
4
[ 121703-92-2 ]
[ 49606-99-7 ]
[ 49607-01-4 ]
[ 121703-92-2 ]
[ 121786-35-4 ]
Reference:
[1] Journal of the American Chemical Society, 1989, vol. 111, # 16, p. 6354 - 6364
[2] Journal of the American Chemical Society, 1989, vol. 111, # 16, p. 6354 - 6364
5
[ 936097-37-9 ]
[ 49606-99-7 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 9, p. 1071 - 1078
6
[ 15785-26-9 ]
[ 49606-99-7 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 9, p. 1071 - 1078
7
[ 768356-83-8 ]
[ 49606-99-7 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 9, p. 1071 - 1078
8
[ 638207-62-2 ]
[ 49606-99-7 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 9, p. 1071 - 1078
9
[ 638207-64-4 ]
[ 49606-99-7 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 9, p. 1071 - 1078
10
[ 121703-92-2 ]
[ 49606-99-7 ]
[ 121786-35-4 ]
Reference:
[1] Journal of the American Chemical Society, 1989, vol. 111, # 16, p. 6354 - 6364
11
[ 765-43-5 ]
[ 49606-99-7 ]
Reference:
[1] Organic Process Research and Development, 2012, vol. 16, # 3, p. 464 - 469
[2] Patent: US2016/319312, 2016, A1,
12
[ 24424-99-5 ]
[ 49606-99-7 ]
[ 155976-13-9 ]
Reference:
[1] Organic Process Research and Development, 2012, vol. 16, # 3, p. 464 - 469
13
[ 67-56-1 ]
[ 49606-99-7 ]
[ 138326-68-8 ]
Yield
Reaction Conditions
Operation in experiment
62%
at 0 - 20℃; for 4 h; Heating / reflux
To a 0° C. solution of thionyl chloride (7.6 mL, 104 mmol) in anhydrous methanol (750 mL) was added (S)-cyclopropylglycine (10.0 g, 86.9 mmol, Eastman Chemical Company, Kingsport, Tenn.). The reaction mixture was allowed to warm to room temperature and then refluxed for 4 hrs, then cooled to room temperature and concentrated in vacuo to give a crude solid. The solids were washed with acetone to give 8.94 g of the product as a white solid. Yield: 62percent, MS: 130 (M+H+), mp=134.0-135.9° C.
62%
With thionyl chloride In methanol at 0 - 20℃; for 4 h; Heating / reflux
To a 0° C. solution of thionyl chloride (7.6 mL, 104 mmol) in anhydrous methanol (750 mL) was added (S)-cyclopropylglycine (10.0 g, 86.9 mmol, Eastman Chemical Company, Kingsport, Tenn.). The reaction mixture was allowed to warm to room temperature and then refluxed for 4 hrs, then cooled to room temperature and concentrated in vacuo to give a crude solid. The solids were washed with acetone to give 8.94 g of (S)-cyclopropylglycine methyl ester HCl as a white solid. Yield: 62percent, MS: 130 (M+H+), mp=134.0-135.9° C.
Reference:
[1] Patent: US2004/77646, 2004, A1, . Location in patent: Page 88
[2] Patent: US2004/248949, 2004, A1, . Location in patent: Page 33
[3] Journal of the American Chemical Society, 2015, vol. 137, # 5, p. 2042 - 2046
[4] Patent: US2018/110824, 2018, A1, . Location in patent: Paragraph 0642; 0643; 0644
14
[ 49606-99-7 ]
[ 75-36-5 ]
[ 138326-68-8 ]
Reference:
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8305 - 8320
15
[ 28920-43-6 ]
[ 49606-99-7 ]
[ 1212257-18-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium carbonate In 1,4-dioxane; water at 0 - 25℃; for 8.17 h;
Reference:
[1] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1698 - 1708
[2] Patent: WO2016/138288, 2016, A1, . Location in patent: Page/Page column 124
The (S)-2-amino-2-cyclopropylethanol required for Example 109 in the Table is prepared as follows: 500 mg (4.3 mmol) L-cyclopropylglycine are dissolved in 5 ml of tetrahydrofuran. The solution is cooled to 0 C. and 8.69 ml (8.69 mmol) of a 1 molar solution of lithium aluminium hydride in tetrahydrofuran is cautiously added so that the temperature of the reaction mixture does not exceed 10 C. The resulting suspension is stirred for approx. 16 hours at ambient temperature. Then a little water is cautiously added, Celite 545 is added and the mixture is suction filtered through Celite 545. It is washed with tetrahydrofuran, the filtrate is freed from the solvent in vacuo. The residue is used without further purification for the next stage of the synthesis.
(ii) The material from the previous step (4.75 g, 41 mmol) is dissolved in 130 mL of 1 N NaOH and treated with benzyl chloroformate (5.92 g, 49.5 mmol) with vigorous stirring. The reaction is stirred overnight and then extracted with dichloromethane twice. The organics are discarded and the aqueous phase is acidified with conc. HCl and extracted with dichloromethane three times. The combined organics are dried over MgS04 and the solvent is removed to afford 7.38 g (72% yield) of (S)-benzyloxycarbonylamino-cyclopropyl-acetic acid as a white solid.
72%
With sodium hydroxide; In water;
The material from the previous step (4.75 g, 41 mmol) was dissolved in 130 mL of 1 N NAOH and treated with benzyl CHLOROFORMATE (5.92 g, 49.5 mmol) with vigorous stirring. The reaction was stirred overnight and then extracted with dichloromethane twice. The organics were discarded and the aqueous phase was acidified with conc. HC1 and extracted with dichloromethane three times. The combined organics were dried over MGS04 and the solvent was removed to afford 7.38 g (72% yield) of the (S)-BENZYLOXYCARBONYLAMINO-CYCLOPROPYL- acetic acid as a white solid.
With sodium carbonate; In water; at 0 - 25℃; for 16h;
Step 1. To a mixture of 66-1 (5.0 g, 43.43 mmol) and Na2C03 (6.9 g, 65.15 mmol) in H20 (50 mL) was added CbzCl (8.89 g, 52.12 mmol) dropwise at 0C. After the reaction mixture was stirred at 25C for 16 h, it was washed with EtOAc (30 mL x 2). The aqueous phase was acidified to pH 2 with cone. HCl, and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to give 66-2 (11 g, crude). NMR (400 MHz, CDC13) delta 7.38-7.29 (m, 5 H), 5.13-5.08 (m, 2 H), 4.72-4.68 (m, 1 H), 1.12- 1.09 (m, 1 H), 0.61-0.43 (m, 4 H).
With formic acid;palladium 10% on activated carbon; In tetrahydrofuran; water;
( S)-(1-cyclopropyl-2-hydroxy-ethyl)-carbamic acid benzyl ester (5) used in Scheme 7 is prepared as follows; (i) A sample of (S) -phenethyl-(S)-cyclopropyl glycine (16.8 g, 76.7 mmol, prepared from cyclopropanecarboxaldehyde, potassium cyanide and (S)-(-)-a-methylbenzylamine using a modified procedure reported in Daniel J. Bayson et al. US Patent 6191306) is treated with THF (200 mL), water (100 mL) and 10% Pd/C (4.76 g). To the stirring mixture is added formic acid (17 mL) and the reaction mixture is stirred overnight. The catalyst is then removed by filtration through a pad of Celite and the solvent is removed by rotary evaporation. The material is coevaporated with methanol several times and dried under vacuum to afford 4.75 g (54% yield) of (S)-amino-cyclopropyl-acetic acid as a solid which is used without further purification.
4.75 g
With formic acid; palladium 10% on activated carbon; In tetrahydrofuran; water;
16.8 g of (S)-phenylethyl-(S)-cyclopropyl glycine obtained in the previous step, 200 mL of THE, 100 mL of water, and 4.76 g of Pd/C having a concentration of 10% were mixed, then 17 mL of formic acid was added, then stir was performed overnight. After reacting, filtering was performed to remove a catalyst to obtain a filtrate, the filtrate was concentrated, and then methanol was added, then concentration was performed over again, operate repeatedly for several times, and vacuum drying was performed to obtain 4.75 g of a solid product.
With formic acid;palladium 10% on activated carbon; In tetrahydrofuran; water;
(S) -cyclopropyl glycine was prepared according to a modified procedure from that reported in D. J. Bayston et AL. US 6191306. A sample of (R)-phenethyl- (S)-cyclopropyl glycine (16.8 g, 76.7 mmol) was treated with THF (200 mL), water (100 mL) and 10% Pd/C (4.76 g). To the stirring mixture was added formic acid (17 mL) and the reaction was stirred overnight. The catalyst was then removed by filtration through a pad of celite and the solvent was removed by rotary evaporation. The material was co-evaporated with methanol several times and dried under vacuum to afford 4.75 g (54% yield) of the desired material as a solid which was used without further purification.
With sodium hydroxide; In water; at 0 - 20℃; for 16h;
To the stirred solution of compound 33 (300 mg, 2.60 mmol) in 2 (M) aqueous NaOH [8 mLj wus added hoc anhydride (0.72 mL, 3.1 mmol) under 0-5 C. Then reaction mixture wus gradually warmed to room temperature and stirred for 16 h. After completi on pH of the reaction mixture was adjusted to 3-4 using 1 (N) aqueous HC1 and reaction mixture wus immediately extracted with EtOAc [3x50 mL j. Organic layer w as separated; dried [MgS04] and concentrated to afford compound 34 [280 mg, 49.9%] as off white solid. [ NMR complies].
With thionyl chloride; at 0℃; for 16h;Inert atmosphere; Reflux;
To a stirred solution of <strong>[49606-99-7](S)-2-amino-2-cyclopropylacetic acid</strong> (4 g, 34.78 mmol) in MeOH (40 mL) under an argon atmosphere was added thionylchloride (12.5 mL, 173.91 mmol) at 0 oC. The reaction mixture was refluxed for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo to obtain methyl (S)-2-amino-2-cyclopropylacetate (4.2 g, crude) as a pale yellow solid used without further purification. 1H-NMR (DMSO-d6, 500 MHz): delta 8.62 (br s, 2H), 3.79-3.72 (m, 4H), 1.13-1.05 (m, 1H), 0.67-0.50 (m, 4H); TLC: 10% MeOH/ CH2Cl2 (Rf: 0.7).
With thionyl chloride; at 0 - 20℃; for 16h;Inert atmosphere;
[0732] To a stirred solution of <strong>[49606-99-7](S)-2-amino-2-cyclopropylacetic acid</strong> (750 mg, 6 mmol) in MeOH (7.5 mL) at 0 C under an argon atmosphere was added thionyl chloride (2.36 mL, 32 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of starting material (by TLC), the volatiles were evaporated in vacuo to obtain methyl (S)-2-amino-2-cyclopropylacetate (800 mg, crude) as brown syrup used in the next step without further purification. ?H NMR (CD3OD, 400 MHz): 3.83 (s, 3H), 3.36-3.32 (m, 1H), 1.20-1.10 (m, 1H), 0.81-0.65 (m, 3H), 0.57-0.50 (m, 1H); TLC: 10% EtOAc Hexane (Rj: 0.7).
With thionyl chloride; at 0℃; for 16h;Inert atmosphere; Reflux;
Synthesis of methyl (S)-2-amino-2-cyclopropylacetate To a stirred solution of <strong>[49606-99-7](S)-2-amino-2-cyclopropylacetic acid</strong> (4 g, 34.78 mmol) in MeOH (40 mL) under an argon atmosphere was added thionylchloride (12.5 mL, 173.91 mmol) at 0 C. The reaction mixture was refluxed for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo to obtain methyl (S)-2-amino-2-cyclopropylacetate (4.2 g, crude) as a pale yellow solid used without further purification. 1H-NMR (DMSO-d6, 500 MHz): delta 8.62 (br s, 2H), 3.79-3.72 (m, 4H), 1.13-1.05 (m, 1H), 0.67-0.50 (m, 4H); TLC: 10% MeOH/CH2Cl2 (Rf: 0.7).
180 mg
With acetyl chloride; at 0 - 50℃; for 16.75h;
To the stirred solution of compound 30 (400 mg, 3 47 mmol) in MeOH [10 mL] was added acetyl chloride [3.72 mL, 52.1 mmol] at 0-5 C and stirred for 45 minutes. Then temperature was raised to 50 C and reaction mixture was allowed to stir for 16 h. After completion [monitored with TLC] reaction mixture was partitioned basified with saturated sodium carbonate [100 mL] and extracted with EtOAe [3x100 mL] Combined organic part was separated, dried [MgSCL] and concentrated under reduced pressure to afford 180 mg compound 31 as yellow solid. H NMR complies] .
methyl (2S,4R)-4-(2-((5S,8R,10R)-5-cyclopropyl-1-(9H-fluoren-9-yl)-8-isopropyl-7-methyl-3,6,12-trioxo-2,11-dioxa-4,7-diazatridecan-10-yl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate[ No CAS ]
methyl (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpiperidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate[ No CAS ]
methyl (2S,4R)-4-(2-((6S,9R,11R)-6-cyclopropyl-9-isopropyl-2,8-dimethyl-4,7,13-trioxo-12-oxa-2,5,8-triazatetradecan-11-yl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate[ No CAS ]
methyl (2S,4R)-4-(2-((1R,3R)-3-((S)-2-(3-acetamidobicyclo[1.1.1]pentane-1-carboxamido)-2-cyclopropyl-N-methylacetamido)-1-acetoxy-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate[ No CAS ]
methyl (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-(4-(methylamino)cubane-1-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate[ No CAS ]
methyl (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpyrrolidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate[ No CAS ]
(2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpiperidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic acid[ No CAS ]
methyl (2-((1R,3R)-3-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-cyclopropyl-N-methylacetamido)-1-acetoxy-4-methylpentyl)thiazole-4-carbonyl)-L-phenylalaninate[ No CAS ]
methyl (2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpiperidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carbonyl)-L-phenylalaninate[ No CAS ]
methyl (2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpyrrolidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carbonyl)-L-phenylalaninate[ No CAS ]
methyl 2-((5S,8R,10R)-5-cyclopropyl-1-(9H-fluoren-9-yl)-8-isopropyl-7-methyl-3,6,12-trioxo-2,11-dioxa-4,7-diazatridecan-10-yl)thiazole-4-carboxylate[ No CAS ]
methyl 2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpiperidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxylate[ No CAS ]
2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpiperidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxylic acid[ No CAS ]
methyl (2-((1R,3R)-1-acetoxy-3-((S)-2-cyclopropyl-N-methyl-2-((R)-1-methylpiperidine-2-carboxamido)acetamido)-4-methylpentyl)thiazole-4-carboxamido)-L-phenylalaninate[ No CAS ]
methyl (2S,4R)-4-(6-((5S,8R,10R)-5-cyclopropyl-1-(9H-fluoren-9-yl)-8-isopropyl-7-methyl-3,6,12-trioxo-2,11-dioxa-4,7-diazatridecan-10-yl)picolinamido)-2-methyl-5-phenylpentanoate[ No CAS ]