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CAS No. : | 103189-63-5 | MDL No. : | MFCD08058803 |
Formula : | C5H11NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SJQZRROQIBFBPS-SCSAIBSYSA-N |
M.W : | 117.15 | Pubchem ID : | 9118388 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 30.14 |
TPSA : | 52.32 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.34 cm/s |
Log Po/w (iLOGP) : | 1.56 |
Log Po/w (XLOGP3) : | -0.46 |
Log Po/w (WLOGP) : | -0.1 |
Log Po/w (MLOGP) : | 0.01 |
Log Po/w (SILICOS-IT) : | -0.22 |
Consensus Log Po/w : | 0.16 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.08 |
Solubility : | 97.8 mg/ml ; 0.835 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.17 |
Solubility : | 78.7 mg/ml ; 0.672 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.39 |
Solubility : | 48.3 mg/ml ; 0.412 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.44 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3 g | With dmap; triethylamine; In tetrahydrofuran; at 25℃;Inert atmosphere; | NHBoc To a solution of (R)-methyl 3-aminobutanoate (1.3 g, 1 1.10 mmol), TEA (4.64 mL, 33.3 mmol) and N,N-dimethylpyridin-4-amine (0.136 g, 1.1 10 mmol) in tetrahydrofuran (THF) (40 mL) was added di-tert-butyl dicarbonate (3.63 g, 16.65 mmol), stirred at stirred at 25 C for overnight under nitrogen. The organic phase was washed with brine, dried over sodium sulphate to afford the title compound (3.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen In ethyl acetate at 50℃; for 25h; | |
With hydrogen In methanol; water; acetic acid Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogen In ethyl acetate at 50℃; for 25h; | |
With hydrogen In methanol for 24h; | ||
With palladium 10% on activated carbon; hydrogen In methanol for 96h; |
With 10 wt% Pd(OH)2 on carbon; hydrogen In methanol at 20℃; for 96h; | 2 (R)-methyl 3-aminobutanoate (A3) Into a 40L pressure tank reactor (10 arm) was placed a solution of methyl (3R)-3- [benzyl[(lR)-l-phenylethyl]amino]butanoate A2 (2080 g, 6.68 mol, 1.00 equiv) in methanol (17 L), Pd(OH)2/C (208 g). The resulting solution was stirred for 4 days at room temperature under a hydrogen atmosphere. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in A3 as an oil | |
With 10 wt% Pd(OH)2 on carbon; hydrogen In methanol for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; water at 0℃; for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-[(trifluoroacetoxy)iodo]benzene In acetonitrile at 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (R)-methyl 3-aminobutanoate hydrochloride With lithium hexamethyldisilazane In tetrahydrofuran; toluene Stage #2: benzyl bromide In tetrahydrofuran; toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane In tetrahydrofuran; toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (R)-methyl 3-aminobutanoate hydrochloride With acetic acid In methanol at 20℃; for 0.0833333h; Stage #2: ethyl acetoacetate With acetic acid In benzene Heating; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 2: H2 / 5percent Pd/C / methanol | ||
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -40 °C / Inert atmosphere 1.2: 2 h / -78 °C / Inert atmosphere 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol / 96 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.2% | In acetic acid methyl ester at 20 - 50℃; for 1.5h; | 1; 20 Ru (OCOCH3) 2 ((R)-DM-BINAP) (164.3 mg, 0. 1722 mmol), methyl acetoacetate (10.00 g, 86.12 mmol), ammonium acetate (6.64 g, 86.12 mmol) and methanol (50 mL) were placed in a stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80°C under A hydrogen pressure of 3 MPa for 15 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R) -3-aminobutanoate acetate as a crude material (16.29 g). The crude product was treated with 7N ammonia/methanol and analyzed by GLC analysis USINGACAPILLARYCOLUMNTC-5HT (AVAILABLEFROMGLSCIENCESCO.), indicating THAT THE YIELD OF METHYL 3-AMINOBUTANOATE WAS 86. 4%, that of the by-produced methyl 3-hydroxybutanoate was 0. 7%, that of the by-produced methyl 3-aminocrotonate was 1.4% and that of the by-produced methyl 3- (2-methoxycarbonyl-l- methyl-ethylamino) -2-butenoate was 6. 2%. The enantiomeric excess of methyl (3R) -3-aminobutanoate in the crude product was found to be 81. 9% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate. The resulting crude material (16.29 g) was dissolved in methyl acetate (25 mL), and to the solution was added dropwise a solution of p-toluenesulfonic acid monohydrate (16.38 g; 86. 12 MMOL) IN METHYL ACETATE (100 ML) at room temperature over a period of 30 minutes. The mixture was stirred at room temperature for one hour and cooled down TO-10°C TO PRECIPITATE a solid. The solid was collected by filtration to give methyl (3R) -3-aminobutanoate p-toluenesulfonate (18.25 g, white crystal) in 73. 2% yield. The enantiomeric excess of the product obtained above was determined to be 91. 7% ee after conversion into methyl (3R)-3- (4-NITROBENZOYLAMINO) butanoate in a similar manner to the crude product. 1H-NMR (DMSO-d6): 8 ; 1.20 (d, J=6.6Hz, 3H), 2.28 (s, 3H), 2.56 (dd, J= 7.4, 16. 8HZ, LH), 2.68 (dd, J=6.3, 16.8Hz, lH), 3.40-3. 60 (m, LH), 3.6 3 (s, 3H), 7.12 (D, J=8. 0HZ, 2H), 7.49 (d, J=8. 0HZ, 2H), 7.83 (brs, 3H).; Under a nitrogen atmosphere, a mixture of [RuCl2 (P-CYMENE)] 2 (0. 527g, 0. 861MMOL), (R) -DM-SEGPHOS (1.276 g, 1.77 mmol), and ammonium acetate (0.664 g, 8.61 mmol) was stirred in 1,4-dioxane (10 ML) at 120 °C for 5 hours and then cooled to room temperature. The resultant mixture was added to a mixture of methyl acetoacetate (100.00 g, 861 mmol), ammonium acetate (66.38 g, 861 mmol) and methanol (500 mL) in a 1 L stainless steel autoclave. The reaction mixture was stirred under a hydrogen pressure of 3 MPa at 85 ° C for 8 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R) -3-aminobutanoate acetate as a crude material (161.20 g). The crude product was treated with 7N AMMONIA/METHANOL AND ANALYZED BY GLC USING A CAPILLARY COLUMN TC-5HT, indicating that the yield of methyl 3-aminobutanoate was 87. 2%, that of the by-produced methyl 3-hydroxybutanoate was 0. 3%, that of the by-produced methyl 3-aminocrotonate was 0. 4% and that of the by-produced methyl 3- (2-methoxycarbonyl-l-methyl-l-ethylamino)-2-butenoate was 6. 6%. THEENANTIOMERICEXCESS OFMETHYL (3R)-3-AMINOBUTANOATE in the crude product was determined to be 94.4% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4-NITROBENZOYLAMINO) butanoate. The resulting crude material (161.20 g) was dissolved in methyl acetate (250 mL), and to the solution was added dropwise a solution of p-toluenesulfonic acid monohydrate (137. 05 g, 0.721 mol) in methyl acetate (500 mL) at 50 °C over a period of 30 minutes. The mixture was stirred at room temperature for 1 hour and cooled down to-10 °C to precipitate a solid. The solid was collected by filtration to give methyl (3R) -3-aminobutanoate p-toluenesulfonate (185.12 g, white crystal) IN 74. 2% yield. The enantiomeric excess of the product obtained above was determined to be 97. 9% ee after conversion into methyl (3R)-3- (4-NITROBENZOYLAMINO) butanoate in a similar manner to the crude product. mp: 112-113 °C [A] D20-10. 1 (c = 1. 19, MeOH) H-NMR (CD30D) : B ; 1.32 (d, J = 6.8 Hz, 3H), 2.36 (s, 3H), 2.68 (d, J = 6.6 Hz, 2H), 3.58-3. 70 (m, 1H), 3.71 (s, 3H), 7.23 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 6.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.8 % ee | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 14 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
66.0 % ee | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 19 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
47.6 % ee | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 8 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
51.6 % ee | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen; acetic acid In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 11 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.3 - 76.7 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 2; 3 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
37.2 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen; magnesium sulfate In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 12 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
7.5 %Chromat. | Stage #1: acetoacetic acid methyl ester With hydrogen; ammonium formate In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 7 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
74.6 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 7h; Stage #2: With ammonia In methanol | 16 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
11.2 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 15 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
26.7 - 30.1 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 6; 9 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
94.2 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen; acetic acid In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 4 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
92.6 - 94.6 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen; acetic acid In methanol at 90℃; for 8h; Stage #2: With ammonia In methanol | 17; 18 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
36.2 %Chromat. | Stage #1: acetoacetic acid methyl ester With ammonium acetate; hydrogen; acetic acid In methanol at 80℃; for 15h; Stage #2: With ammonia In methanol | 10 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
44.8 - 87.3 %Chromat. | Stage #1: acetoacetic acid methyl ester With 2,2,2-trifluoroethanol; ammonium acetate; hydrogen In methanol at 80 - 90℃; for 7 - 15h; Stage #2: With ammonia In methanol | 5; 13 Except for changes of the catalyst, the amount of methanol, the reaction temperature, the reaction time, the molar ratio of the metal in the catalyst and the molar ratio of the additive used in Example 1, the same reaction as in Example 1 was carried out using methyl acetoacetate as a starting material, as shown in Table 1. The yield of methyl 3-aminobutanoate was analyzed by GLC analysis using a capillary column TC-5HT after treatment of the crude product with 7N ammonia/methanol obtained in the same way as in Example 1. The enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate in a similar manner to Example 1. The reaction results are shown in Table 1. |
95 %Chromat. | Stage #1: acetoacetic acid methyl ester With Ru(OAc)<SUB>2</SUB>((R)-dm-segphos); hydrogen; ammonium salicylate In methanol at 85℃; for 7h; Autoclave; Stage #2: With sodium carbonate In water; ethyl acetate for 0.5h; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.9 - 94.4 % ee | With ammonia In methanol | 1; 20 Ru (OCOCH3) 2 ((R)-DM-BINAP) (164.3 mg, 0. 1722 mmol), methyl acetoacetate (10.00 g, 86.12 mmol), ammonium acetate (6.64 g, 86.12 mmol) and methanol (50 mL) were placed in a stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80°C under A hydrogen pressure of 3 MPa for 15 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R) -3-aminobutanoate acetate as a crude material (16.29 g). The crude product was treated with 7N ammonia/methanol and analyzed by GLC analysis USINGACAPILLARYCOLUMNTC-5HT (AVAILABLEFROMGLSCIENCESCO.), indicating THAT THE YIELD OF METHYL 3-AMINOBUTANOATE WAS 86. 4%, that of the by-produced methyl 3-hydroxybutanoate was 0. 7%, that of the by-produced methyl 3-aminocrotonate was 1.4% and that of the by-produced methyl 3- (2-methoxycarbonyl-l- methyl-ethylamino) -2-butenoate was 6. 2%. The enantiomeric excess of methyl (3R) -3-aminobutanoate in the crude product was found to be 81. 9% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4- nitrobenzoylamino) butanoate. The resulting crude material (16.29 g) was dissolved in methyl acetate (25 mL), and to the solution was added dropwise a solution of p-toluenesulfonic acid monohydrate (16.38 g; 86. 12 MMOL) IN METHYL ACETATE (100 ML) at room temperature over a period of 30 minutes. The mixture was stirred at room temperature for one hour and cooled down TO-10°C TO PRECIPITATE a solid. The solid was collected by filtration to give methyl (3R) -3-aminobutanoate p-toluenesulfonate (18.25 g, white crystal) in 73. 2% yield. The enantiomeric excess of the product obtained above was determined to be 91. 7% ee after conversion into methyl (3R)-3- (4-NITROBENZOYLAMINO) butanoate in a similar manner to the crude product. 1H-NMR (DMSO-d6): 8 ; 1.20 (d, J=6.6Hz, 3H), 2.28 (s, 3H), 2.56 (dd, J= 7.4, 16. 8HZ, LH), 2.68 (dd, J=6.3, 16.8Hz, lH), 3.40-3. 60 (m, LH), 3.6 3 (s, 3H), 7.12 (D, J=8. 0HZ, 2H), 7.49 (d, J=8. 0HZ, 2H), 7.83 (brs, 3H).; Under a nitrogen atmosphere, a mixture of [RuCl2 (P-CYMENE)] 2 (0. 527g, 0. 861MMOL), (R) -DM-SEGPHOS (1.276 g, 1.77 mmol), and ammonium acetate (0.664 g, 8.61 mmol) was stirred in 1,4-dioxane (10 ML) at 120 °C for 5 hours and then cooled to room temperature. The resultant mixture was added to a mixture of methyl acetoacetate (100.00 g, 861 mmol), ammonium acetate (66.38 g, 861 mmol) and methanol (500 mL) in a 1 L stainless steel autoclave. The reaction mixture was stirred under a hydrogen pressure of 3 MPa at 85 ° C for 8 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R) -3-aminobutanoate acetate as a crude material (161.20 g). The crude product was treated with 7N AMMONIA/METHANOL AND ANALYZED BY GLC USING A CAPILLARY COLUMN TC-5HT, indicating that the yield of methyl 3-aminobutanoate was 87. 2%, that of the by-produced methyl 3-hydroxybutanoate was 0. 3%, that of the by-produced methyl 3-aminocrotonate was 0. 4% and that of the by-produced methyl 3- (2-methoxycarbonyl-l-methyl-l-ethylamino)-2-butenoate was 6. 6%. THEENANTIOMERICEXCESS OFMETHYL (3R)-3-AMINOBUTANOATE in the crude product was determined to be 94.4% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3- (4-NITROBENZOYLAMINO) butanoate. The resulting crude material (161.20 g) was dissolved in methyl acetate (250 mL), and to the solution was added dropwise a solution of p-toluenesulfonic acid monohydrate (137. 05 g, 0.721 mol) in methyl acetate (500 mL) at 50 °C over a period of 30 minutes. The mixture was stirred at room temperature for 1 hour and cooled down to-10 °C to precipitate a solid. The solid was collected by filtration to give methyl (3R) -3-aminobutanoate p-toluenesulfonate (185.12 g, white crystal) IN 74. 2% yield. The enantiomeric excess of the product obtained above was determined to be 97. 9% ee after conversion into methyl (3R)-3- (4-NITROBENZOYLAMINO) butanoate in a similar manner to the crude product. mp: 112-113 °C [A] D20-10. 1 (c = 1. 19, MeOH) H-NMR (CD30D) : B ; 1.32 (d, J = 6.8 Hz, 3H), 2.36 (s, 3H), 2.68 (d, J = 6.6 Hz, 2H), 3.58-3. 70 (m, 1H), 3.71 (s, 3H), 7.23 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 6.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In diethyl ether at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;C40H39BN2P2Ru; In tetrahydrofuran; at 80℃; under 26252.6 - 37503.8 Torr; for 14h;Product distribution / selectivity; | Example 9Hydrogenation of Methyl (R)-3-aminobutanoate A ruthenium complex 1 (0.333 mmol) was charged into a 100-mL autoclave equipped with a stirrer, and air inside the autoclave was replaced with nitrogen. Tetrahydrofuran (40 mL) and methyl (R)-3-aminobutanoate (100 mmol, 99% ee or more) were charged thereinto. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 3.5 MPa to 5 MPa at 80 C. for 14 hours. The reaction liquid was concentrated, and the obtained residue was distilled. Thus, (R)-3-aminobutanol (7.39 g; boiling point of 84 to 86 C./14 Torr) was obtained. The obtained alcohol had an optical purity of 99% ee or more. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-<(S)-1-(N-t-butoxycarbonyl)aminoethyl>thiazole-4-carboxylic acid; (R)-methyl 3-aminobutanoate hydrochloride In dichloromethane at 0℃; for 0.25h; Stage #2: With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 °C / Inert atmosphere 2.1: hydrogen; palladium 10% on activated carbon / methanol / 96 h / 3102.97 Torr | ||
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -78 - 0 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; hydrogen / methanol / 96 h / 3102.97 Torr | ||
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / 0 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 96 h / 3102.97 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium carbonate In dichloromethane; water at 20℃; for 3h; | |
15.6 g | With sodium carbonate In dichloromethane; water at 20℃; | |
21.4 g | With sodium carbonate In dichloromethane; water at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With palladium 10% on activated carbon; hydrogen In methanol for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium carbonate In dichloromethane; water at 20℃; for 3h; | |
10.8 g | With sodium carbonate In dichloromethane; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (2-cyano-1(R)-methylethyl)carbamic acid, 1,1-dimethylethyl ester With hydrogenchloride; water Reflux; Stage #2: methanol With thionyl chloride at 90℃; | D14 (R)-methyl 3-aminobutanoate A solution of (R)-tert-butyl (l-cyanopropan-2-yl)carbamate (2.6 g, 14.1 1 mmol) in concentrated HC1 was heated to reflux overnight, and concentrated. The residue was dissolved in methanol (100 mL), added dropwise SOCl2 (3.09 ml, 42.3 mmol) at r.t. The reaction mixture was stirred at 90 °C overnight, and concentrated to afford the title compound (1.4g) as a crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloropyridine With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene Sealed tube; Inert atmosphere; Stage #2: (R)-methyl 3-aminobutanoate hydrochloride In toluene at 100℃; Inert atmosphere; Sealed tube; | Synthesis of Compound 223 Synthesis of Compound 223 2-chloro-pyridine (25 mmol), palladium (II) acetate (2.5 mmol), racemic 2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl (2.5 mmol) and cesium carbonate (65 mmol) are dissolved in toluene (75 m l_) in a previously degassed sealed vessel. The mixture is flushed with nitrogen gas. Methyl-(fi)-3-aminobutyrate SM01 (20 mmol) is added to the solution under nitrogen and the sealed mixture is heated overnight at 100 °C. The reaction is cooled to room temperature, diluted with diethyl ether and washed with pH 7 buffer and water. The organic layer is concentrated and purified by silica gel column chromatography (10:90 methanol-dichloromethane) to afford (3R)-3-[(pyridin-2-yl)amino]butanoic acid (223). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | With thionyl chloride; at 0 - 10℃;Reflux; | Put 240g methanol, 50g (R) -3-aminobutyric acid in the clean reaction bottle, cool with ice water, the temperature drops to 0 10 , and slowly add 66.4g sulfoxide chloride dropwise. After the dropwise addition, the temperature was raised to reflux reaction until the raw materials disappeared.The reaction solution is directly concentrated under reduced pressure to obtain the product.Yield: 98.5%, purity: 99.7%, ee: 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With trifluoroacetic acid In tetrahydrofuran for 16h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine In tetrahydrofuran at 60℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride In methanol at 0 - 20℃; for 2.5h; Inert atmosphere; | 3 (R)-methyl 3-(benzylamino)butanoate (A4) Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed benzaldehyde (638 g, 6.01 mol, 0.90 equiv), and a solution of (R)-methyl-3-aminobutanoate (782.5 g, 6.68 mol, 1.00 equiv) in methanol (18 L). This was followed by the addition of Na(AcO)3BH (2550 g, 12.03 mol, 1.80 equiv), in portions. The resulting solution was stirred for 0.5 h at 0°C and 2 h at room temperature. The pH value of the solution was adjusted to 10 with aq. potassium carbonate (sat.). The resulting solution was extracted with 3 x 20L of ethyl acetate. The organic layers were combined, washed with 1 x 10L of saturated brine, dried over magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50). This resulted in A4 as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.71% | Stage #1: (R)-methyl 3-aminobutanoate hydrochloride; ethyl bromoacetate With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 80℃; for 19h; Stage #2: benzyl chloroformate In 1,4-dioxane at 25℃; for 16h; | 5.65. (R)-Methyl 3-(((benzyloxy)carbonyl)(2-ethoxy-2-oxoethyl)amino)butanoate 15b N,N-Diisopropylethylamine (11.5 mL, 65.6 mmol) was added to (R)-methyl 3-aminobutanoate hydrochloride 14b (2.52 g, 16.41 mmol)in 1,4-dioxane (38.9 mL). Then, ethyl 2-bromoacetate (2.0 mL,18.05 mmol) was added and the reaction mixture was stirred at 80 °C for ninety hours. Then, benzyl chloroformate (2.3 mL, 16.41mmol) was added and the reaction mixture was stirred for sixteen hours at room temperature, poured into 10% citric acid, extracted with diethyl ether, washed with saturated aqueous sodium bicarbonate,dried over magnesium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography, eluting withethyl acetate:hexanes (1:4), followed by RP HPLC eluting with acetonitrile:water with 0.1% trifluoroacetic acid (5:95:100:0) to give(R)-methyl 3-(((benzyloxy)carbonyl)(2-ethoxy-2-oxoethyl)amino)butanoate 15b (1.09 g, 3.07 mmol, 18.71% yield). 1H NMR (400MHz, CD3SOCD3) d 7.40-7.24 (m, 5H), 5.09 & 5.01 (s, 2H), 4.-7 (h,1H, J = 7 Hz), 4.12-3.86 (m, 4H), 3.55 & 3.52 (s, 3H), 2.66-2.50 (m,2H), 1.17 & 1.08 (t, 3H, J = 7 Hz), 1.12 (d, 3H, J = 7 Hz); LC-MS(LC-ES) M+H = 338. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0℃; | Methyl (S)-3-((4-nitrophenyl)sulfonamido)butanoate [(S)-4] NaN3 (5.26 g, 80.8 mmol, 1.1 equiv) wasadded to a mixture of (R)-1 (20 g, 73.5 mmol) in DMF (70 mL). The mixture was stirred at 48° C for 14 h.The mixture was cooled down to room temperature and filtered to remove insoluble solid. The filtratewas diluted with water (150 mL) and the product was extracted with 5% EtOAc in diethyl ether(2 200 mL). The organics were washed with brine (200 mL), dried over Na2SO4 and concentratedunder reduced pressure to afford the crude intermediate methyl (S)-3-azidobutanoate [(S)-2], 8.2 g],which was used for the next step without further purification (caution: product is volatile). The crudematerial (S)-2 (8.2 g) was dissolved in MeOH/CH2Cl2 (9:1, 120 mL) and then hydrogenated with catalytic Pd/C 10% (0.82 g) at 30 psi for 4 h. The catalyst was removed by filtration through Celite,and the filtrates were evaporated to afford crude methyl (S)-3-aminobutanoate [(S)-3, 6.7 g], which was used for the next step without further purification. (caution: product is volatile). The concentrated product (S)-3 (6.7 g) was dissolved in CH2Cl2 (130 mL), and Et3N (15.9 mL, 114.6 mmol, 2 equiv) was added. To the solution, cooled to 0 °C, was slowly added p-nitrobenzenesulfonyl chloride (12.6 g,57.3 mmol, 1 equiv). The mixture was stirred for 30 min to complete the reaction. Then, the reactionmixture was washed with water (3 150 mL) and the combined organic phase was dried overNa2SO4 and concentrated under reduced pressure. The crude residue was purified by flash columnchromatography to afford a title compound (S)-4 (8.5 g, 38% overall yield for 3 steps) as yellowish powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; pyridine / toluene / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 14 h / 48 °C 3: hydrogen; palladium 10% on activated carbon / methanol; dichloromethane / 20 °C / 1551.49 Torr | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 °C 2: sodium azide / formamide / 2 h / 20 - 55 °C 3: palladium 10% on activated carbon; hydrogen / ethyl acetate / 14 h / 20 °C / 2844.39 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; for 14h; | |
With palladium 10% on activated carbon; hydrogen In methanol; dichloromethane at 20℃; | Methyl (S)-3-((4-nitrophenyl)sulfonamido)butanoate [(S)-4] NaN3 (5.26 g, 80.8 mmol, 1.1 equiv) wasadded to a mixture of (R)-1 (20 g, 73.5 mmol) in DMF (70 mL). The mixture was stirred at 48° C for 14 h.The mixture was cooled down to room temperature and filtered to remove insoluble solid. The filtratewas diluted with water (150 mL) and the product was extracted with 5% EtOAc in diethyl ether(2 200 mL). The organics were washed with brine (200 mL), dried over Na2SO4 and concentratedunder reduced pressure to afford the crude intermediate methyl (S)-3-azidobutanoate [(S)-2], 8.2 g],which was used for the next step without further purification (caution: product is volatile). The crudematerial (S)-2 (8.2 g) was dissolved in MeOH/CH2Cl2 (9:1, 120 mL) and then hydrogenated with catalytic Pd/C 10% (0.82 g) at 30 psi for 4 h. The catalyst was removed by filtration through Celite,and the filtrates were evaporated to afford crude methyl (S)-3-aminobutanoate [(S)-3, 6.7 g], which was used for the next step without further purification. (caution: product is volatile). The concentrated product (S)-3 (6.7 g) was dissolved in CH2Cl2 (130 mL), and Et3N (15.9 mL, 114.6 mmol, 2 equiv) was added. To the solution, cooled to 0 °C, was slowly added p-nitrobenzenesulfonyl chloride (12.6 g,57.3 mmol, 1 equiv). The mixture was stirred for 30 min to complete the reaction. Then, the reactionmixture was washed with water (3 150 mL) and the combined organic phase was dried overNa2SO4 and concentrated under reduced pressure. The crude residue was purified by flash columnchromatography to afford a title compound (S)-4 (8.5 g, 38% overall yield for 3 steps) as yellowish powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 °C 2: caesium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With triethylamine In tetrahydrofuran at 20 - 50℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine In tetrahydrofuran at 20 - 50℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine In tetrahydrofuran at 20 - 50℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium azide / formamide / 2 h / 20 - 55 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate / 14 h / 20 °C / 2844.39 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In tetrahydrofuran at 20 - 50℃; for 8h; | |
67% | With triethylamine In tetrahydrofuran at 20 - 50℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | at 65℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 14 h / 65 °C 2: triethylamine; triphenylphosphine; carbon tetrabromide / dichloromethane / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9 g | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 2.2 Methyl (R)-3-((5-bromo-3-fluoro-2-nitrophenyl)amino)butanoate 203 1,3-Difluoro-5-bromo-2-nitrobenzene (6.8 g, 29 mmol) and methyl (R)-3-aminobutanoate 202 (4.0 g, 29 mmol) were dissolved in 50 mL of DMF, followed by the addition of DIEA (11.2 g, 87 mmol). The reaction solution was stirred at room temperature overnight. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, 100 mL of water was added, and the raction solution was extracted with ethyl acetate (3 * 25 mL). The organic phases were combined, washed with water, dried and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain the title compound as a yellow solid (9 g, yield: 90.3%). MS (ESI):335.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With transaminase; pyridoxal 5'-phosphate In dimethyl sulfoxide at 30℃; for 72h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With transaminase; pyridoxal 5'-phosphate In dimethyl sulfoxide at 30℃; for 72h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With transaminase; pyridoxal 5'-phosphate In dimethyl sulfoxide at 30℃; for 72h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With transaminase; pyridoxal 5'-phosphate In dimethyl sulfoxide at 30℃; for 72h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With transaminase; pyridoxal 5'-phosphate In dimethyl sulfoxide at 30℃; for 72h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With transaminase; pyridoxal 5'-phosphate In dimethyl sulfoxide at 30℃; for 72h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With Sodium sulfate [anhydrous] In dichloromethane; toluene at 20℃; for 18h; |
A133136[ 139243-54-2 ]
(R)-Methyl 3-aminobutanoate hydrochloride
Reason: Free-salt
[ 139243-54-2 ]
(R)-Methyl 3-aminobutanoate hydrochloride
Similarity: 0.97
[ 139243-55-3 ]
(S)-Methyl 3-aminobutanoate hydrochloride
Similarity: 0.97
[ 1236525-13-5 ]
(S)-Methyl 3-aminopentanoate hydrochloride
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