PROCESS FOR PREPARATION OF N-BOC BIPHENYL ALANINOL

Abstract

A process is provided for preparation of (R)N-Boc biphenyl alaninol. It provides a preparation process for a compound outlined as compound 4, which includes these operations: in one of the alcohol solvents, asymmetric hydrogenation of 5 in the presence of [Rh(Duanphos)(X)]Y and hydrogen to provide compound 4. Here Duanphos is (Rc,Sp)-Duanphos or (Sc,Rp)-Duanphos; X is NBD or/and COD; Y is one or more of BF4, PF6, SbF6. This process has a lot of advantages, such as low cost, safe operation, less pollution and high yield. The product was obtained in >99% purity and ee which is suitable to scale up in industrial scale.

##STR00001##

Claims

1. A process for preparing compound 4, comprising in one of the alcohol solvents, asymmetric hydrogenation of 5 in the presence of [Rh(Duanphos)(X)]Y and hydrogen to provide compound 4, wherein Duanphos is (Rc,Sp)-Duanphos or (Sc,Rp)-Duanphos, X is NBD or/and COD, Y is selected from the group consisting of BF4, PF6 and SbF6, ##STR00017## wherein, indicates that compound 5 is E or/and Z; * indicates that compound 4 has a chiral center, which is R configuration when (Rc,Sp)-Duanphos is used, otherwise it is S configuration when (Sc,Rp)-Duanphos is used.

2. The process defined as claim 1, wherein the pressure of hydrogen is in the range of 0.1-0.5 MPa; and/or in the process for preparing compound 4, the alcohol solvent is methanol; and/or in the process for preparing compound 4, the ratio of the volume of the alcohol solvent to the mole of compound 5 is in the range of 1-10 L/mol; and/or in the process for preparing compound 4, the mole ratio of [Rh(Duanphos)(X)]Y to compound 5 is in the range of 0.00001-0.01; and/or in the process for preparing compound 4, the hydrogenation temperature is in the range of 0-60 C.; and/or in the process for preparing compound 4, the reaction time for hydrogenation is 1-20 h.

3. The process defined as claim 2, wherein the pressure of hydrogen is in the range of 0.5-3.0 MPa; and/or in the process for preparing compound 4, the ratio of the volume of the alcohol solvent to the mole of compound 4 is in the range of 1.5-3 L/mol; and/or in the process for preparing compound 4, the mole ratio of [Rh(Duanphos)(X)]Y to compound 5 is in the range of 0.0001-0.0003; and/or in the process for preparing compound 4, the hydrogenation temperature is in the range of 2030 C.; and/or in the process for preparing compound 4, the reaction time for hydrogenation is 4-8 h.

4. The process defined as claim 3, wherein the pressure of hydrogen is in the range of 1.5-2.0 MPa; and/or in the process for preparing compound 4, the ratio of the alcohol solvent to the mole of compound 4 is in the range of 2.3-2.8 L/mol; and/or in the process for preparing compound 4, the mole ratio of [Rh(Duanphos)(X)]Y to compound 5 is in the range of 0.00025-0.000265.

5. The process defined as claim 1, which comprises that in an organic solvent, compound 6 condenses with compound 7 in the presence of base to afford compound 5, ##STR00018##

6. According to the process defined as claim 5, wherein in the preparation of compound 5, the reaction solvent is selected from the group consisting of haloalkanes, nitriles, alcohols, ethers and any combination thereof; and/or in the preparation of compound 5, the ratio of the volume of the solvent to the mole of compound 7 is in the range of 1.0-3.0 L/mol; and/or in the preparation of compound 5, the base is one of the common bases used for this transformation or any combination thereof, which is selected from the group consisting of tetramethylguanidine, sodium methoxide, sodium ethoxide, sodium hydroxide, sodium hydride, sodium amide and DBU; and/or in the preparation of compound 5, the mole ratio of the base to compound 7 is in the range of 1.1-2.0; and/or in the preparation of compound 5, the mole ratio of compound 6 to compound 7 is in the range of 1.0-4.0; and/or in the preparation of compound 5, the reaction temperature for condensation is in the range of 0-40 C.; and/or in the preparation of compound 5, the reaction time for condensation is 2-8 h.

7. The process defined as claim 6, wherein in the preparation of compound 5, the haloalkane solvent is dichloromethane; and/or, in the preparation of compound 5, the nitrile solvent is acetonitrile; and/or, in the preparation of compound 5, the alcohol solvent is methanol and/or ethanol; and/or, in the preparation of compound 5, the ether solvent is methyl tert-butyl ether; and/or, in the preparation of compound 5, the ratio of the volume of the solvent to the mole of compound 7 is in the range of 1.3-1.6 L/mol; and/or, in the preparation of compound 5, the base is DBU; and/or, in the preparation of compound 5, the mole ratio of the base to compound 7 is in the range of 1.2-1.6; and/or, in the preparation of compound 5, the mole ratio of compound 6 to compound 7 is in the range of 1.1-2.0; and/or, in the preparation of compound 5, the reaction temperature for condensation is in the range of 1025 C.; and/or, in the preparation of compound 5, the reaction time for condensation is 4-6 h.

8. A process for preparing compound 3, which comprises: (1). preparing compound 4 according to the process defined as claim 1, (2). in the presence of a base, reacting compound 4 with di-tert butyl dicarbonate to form compound 3; ##STR00019## wherein, * indicates that compound 4 and compound 3 have chiral centers in their molecular structure, and compound 4 and compound 3 have same configuration R or S.

9. The process defined as claim 8, wherein in step (2), a reaction solvent is selected from the group consisting of haloalkanes, nitriles, alcohols, ethers, pyridine, NMP and any combination thereof; and/or, in step (2), the ratio of the volume of the solvent to the mole of compound 4 is in the range of 1-6 L/mol; and/or, in step (2), the base is an inorganic base and/or an organic base; and/or, in step (2), the mole ratio of the base to compound 4 is in the range of 0.1-0.2; and/or, in step (2), the mole ratio of di-tert butyl dicarbonate to compound 4 is in the range of 1.2-2.0; and/or, in step (2), the reaction temperature for bocylation is in the range of 3070 C.; and/or, in step (2), the reaction time for bocylation is 3-7 h.

10. The process defined as claim 9, wherein in step (2), the haloalkane solvent is dichloromethane; and/or, in step (2), the nitrile solvent is acetonitrile; and/or, in step (2), the alcohol solvent is methanol; and/or, in step (2), the ether solvent is tetrahydrofuran; and/or, in step (2), the ratio of the volume of the organic solvent to the mole of compound 4 is in the range of 2-3 L/mol; and/or, in step (2), the inorganic base is sodium bicarbonate and/or sodium carbonate; and/or, in step (2), the organic base is selected from the group consisting of ammonia aqueous, morpholine, pyridine, triethyl amine, ethanol amine, ethylene diamine, 4-dimethylaminopyridine, diisopropyl ethyl amine and any combination thereof; and/or, in step (2), the mole ratio of the base to compound 4 is in the range of 0.12-0.18; and/or, in step (2), the mole ratio of di-tert butyl dicarbonate to compound 4 is in the range of 1.5-1.8; and/or, in step (2), the reaction temperature for bocylation is in the range of 60-66 C.; and/or, in step (2), the reaction time for bocylation is 5-6 h.

11. A process for preparing compound 2, which comprises: (a) preparing compound 3 according to the process defined as claim 8; (b) in an organic solvent, reacting compound 3 with hydrazine to afford compound 2; ##STR00020## wherein * indicates that compound 3 and compound 2 have chiral centers in their molecular structure and compound 3 and compound 2 have same configuration R or S.

12. The process defined as claim 11, wherein in step (b), the organic solvent is selected from the group consisting of haloalkanes, nitriles, alcohols, ethers, pyridine and NMP and any combination thereof; and/or, in step (b), the ratio of the volume of the solvent to the mole of compound 3 is in the range of 1-6 L/mol; and/or, in step (b) which is hydrazinolysis, the hydrazine is added in the form of hydrazine hydrate; and/or, in step (b) which is hydrazinolysis, the mole ratio of hydrazine to compound 3 is in the range of 2-4; and/or, in step (b), the reaction temperature for hydrazinolysis is in the range of 020 C.; and/or, in step (b), the reaction time for hydrazinolysis is 2-7 h.

13. The process defined as claim 12, wherein in step (b), the haloalkane solvent is dichloromethane; and/or, in step (b), the nitrile solvent is acetonitrile; and/or, in step (b), the alcohol solvent is methanol; and/or, in step (b), the ether solvent is tetrahydrofuran; and/or, in step (b), the ratio of the volume of the solvent to the mole of compound 3 is in the range of 2-3 L/mol; and/or, in step (b) which is hydrazinolysis, the mole ratio of hydrazine to compound 3 is in the range of 2.8-3.5; and/or, in step (b), the reaction temperature for hydrazinolysis is in the range of 0-10 C.; and/or, in step (b), the reaction time for hydrazinolysis is 5-6 h.

14. The process defined as claim 11, wherein compound 3 is not necessary to be isolated when step (a) is completed, which means there is no need to isolate and purify compound 3, which is used directly for step (b).

15. A process for preparing N-Boc biphenyl alaninol, which comprises: (a) preparing compound 2 according to the process defined as claim 11; (b) in methanol or/and ethanol, reacting compound 2 with metal borohydride to afford compound 1; ##STR00021## wherein, * indicates that compound 2 and compound 1 have chiral centers in their molecular structure, and compound 2 and compound 1 have same configuration R or S.

16. The process defined as claim 15, wherein in step (b) of preparing compound 1, the ratio of the volume of methanol and/or ethanol to the mole of compound 2 is in the range of 2-4 L/mol; and/or, in step (b) of preparing compound 1, the metal borohydride is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, and any combination thereof; and/or, in step (b) of preparing compound 1, the mole ratio of metal borohydride to compound 2 is in the range of 2.0-4.0; and/or, in step (b) of preparing compound 1, the reaction temperature for reduction is 15-30 C.; and/or, in step (b) of preparing compound 1, the reaction time for reduction is 4-10 h.

17. The process defined as claim 16, wherein in step (b) of preparing compound 1, the ratio of the volume of methanol and/or ethanol to the mole of compound 2 is in the range of 2.1-3.0 L/mol; and/or, in step (b) of preparing compound 1, the metal borohydride is sodium borohydride; and/or, in step (b) of preparing compound 1, the mole ratio of metal borohydride to compound 2 is in the range of 2.9-3.1; and/or, in step (b) of preparing compound 1, the reaction temperature for reduction is 25-30 C.; and/or, in step (b) of preparing compound 1, the reaction time for reduction is 5-8 h.

18. Compound 3, which is represented as: ##STR00022## wherein, * indicates that compound 3 has chiral center in their molecular structure, which is R or S.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0065] The present invention will be elucidated with reference to the following examples, without however being limited or restricted by these. If there were no detail method in any the following examples, follow regular methods and conditions.

[0066] The catalyst [Rh((Rc,Sp)-Duanphos)(NBD)]BF4 used in the example was our own product, or can be purchased from STREM.

[0067] The ee determination method in the example was: HPLC. Column: AD-H, 2504.6 mm, 5 m. Flow rate: 1.0 mL/min. Column temperature: 25 C. Mobile phase: n-hexane/isopropyl alcohol=85/15 (v/v). Run time: 20 min. Retention time for R: 11.6 min. S: 7.9 min.

Example 1: 3-(1, 1-biphen-4-yl)-2-acetylaminoacrylic acid methyl ester

[0068] To a flask were added 66.4 g of 4-phenylbenzaldehyde, 85.0 g of methyl 2-acetamido-2-(dimethoxyphosphoryl)acetate and 460 mL of dichloromethane. The mixture was cooled to 0 C. and 65.0 g of DBU was added drop wise while maintaining temperature at 05 C. After addition, the temperature was increased to 1025 C. and the mixture was stirred for additional 2 hours. When TLC showing no starting material, the mixture was then cooled to 10 C. The pH was adjusted to about 67 by adding acetic acid (9 g). The resulting mixture was then concentrated to remove solvents under reduced pressure. To the residue was added 500 mL of water and the mixture was stirred for 1 hour. The solid was collected by filtration. The wet cake was then slurried in 500 mL of water for 1 hour. The solid was further purified by being slurried in water (500 mL, 1 h) and MTBE (500 mL, at 50 C. for 2 h). It was filtered and dried at 55 C. to afford 103 g of white solid, with HPLC purity of 99.2% in 96% yield.

[0069] .sup.1H NMR (400 MHz, CDCl.sub.3), (ppm): 7.63-7.56 (m, 6H), 7.48-7.45 (m, 2H), 7.40-7.37 (m, 1H), 7.24 (s, 1H), 3.88 (s, 3H), 2.18 (s, 3H).

Example 2: (R)-3-(1, 1-biphen-4-yl)-2-acetylaminopropionic acid methyl ester

[0070] To a high pressure reactor were added 15 g of 3-(1, 1-biphen-4-yl)-2-acetylaminoacrylic acid methyl ester and 120 mL of methanol. The air in the reactor was replaced by nitrogen three times. 9 mg of catalyst Rh[(NBD)(Rc,Sp-DuanPhos)]BF4 was added under nitrogen. The reactor was charged with hydrogen and then released. Repeat this operation four times. Then the reactor was charged with hydrogen to 1.53 MPa and stirred at 2030 C. for 48 h. When the reaction is complete monitored by HPLC, hydrogen was released carefully. The mixture was concentrated to provide 15.1 g of white solid with HPLC purity of 99.1% in 100% yield. The ee was 99.2%.

[0071] .sup.1H NMR (400 MHz, CDCl.sub.3): =7.617.59 (d, 2H), 7.567.54 (d, 2H), 7.487.44 (t, 2H), 7.387.35 (t, 1H), 7.207.18 (d, 2H), 5.975.95 (d, 1H), 4.984.93 (m, 1H), 3.78 (s, 3H), 3.253.15 (m, 2H), 2.03 (s, 3H).

[0072] []D.sup.25=111.0 (c=0.011 g/mL, CHCl.sub.3).

[0073] Advanced Synthesis and Catalysis, 2013, vol. 355, 594600 reported specific rotation of []D.sup.25=+111.0 (c=0.011 g/mL, CHCl.sub.3) for (S)-3-(1, 1-biphenyl-4)-2-acetylaminopropionic methyl ester. Therefor the product from this step is R configuration.

Example 3: (R)-3-(1, 1-biphen-4-yl)-2-tert-butoxycarbonyl-aminopropionic acid methyl ester

[0074] To a flask were added 4 g of (R)-3-(1, 1-biphen-4-yl)-2-acetylaminopropionic acid methyl ester, 0.2 g DMAP, 4.4 g (Boc).sub.2O and 28 mL of anhydrous THF. The resulting mixture was then heated to reflux (60-66 C.) for 3 hours. After the reaction was completed, it was cooled to 010 C. 1.9 g of hydrazine hydrate was then added and the mixture was maintained for 5 hours under 010 C. till HPLC showing the reaction no intermediate detected. Its pH was then adjusted to 56 by adding diluted hydrochloric acid. The mixture was then concentrated and the residue was dissolved in 30 mL of DCM. The organic phase was separated and washed twice with water. Concentration of the organic phase to provide light yellow solid 4.7 g with 99.3% HPLC purity and in 98% yield.

[0075] .sup.1H NMR (400 MHz, CDCl.sub.3): =7.617.22 (m, 9H), 5.075.05 (d, 1H), 4.674.65 (m, 1H), 3.76 (s, 3H), 3.223.09 (m, 2H), 1.46 (s, 9H).

[0076] []D.sup.25=53.0 (c=0.01 g/mL, CHCl.sub.3).

Example 4: (R)-3-(1, 1-biphen-4-yl)-N-Boc-alaninol

[0077] To a flask were added 25 g of (R)-3-(1, 1-biphen-4-yl)-2-tert-butoxycarbonyl-aminopropionic acid methyl ester and 150 mL of methanol. The mixture was then cooled to 5 C. 7.7 g of sodium borohydride was then added while maintaining 515 C. After the addition, the mixture was heated to 2530 C. and stirred for 5 hours till HPLC showing no starting material. Its pH was then adjusted to 78 by adding diluted hydrochloric acid (10%). Methanol was removed. To the residue was then added 150 mL of ethyl acetate and 100 mL of water. The mixture was then stirred well and two phases were separated. The organic phase was then washed with 5% brine, dried, concentrated to provide 21.2 g white solid with 98.7% HPLC purity in 92% yield.

[0078] .sup.1H-NMR (400 MHz, CDCl.sub.3): =7.647.62 (d, 2H), 7.577.55 (d, 2H), 7.477.43 (t, 2H), 7.367.32 (t, 1H), 7.317.29 (d, 2H), 6.596.57 (d, 1H), 4.73 (s, 1H), 3.653.63 (m, 1H), 3.353.39 (m, 1H), 2.902.85 (dd, 1H), 2.652.60 (dd, 1H), 1.37 (s, 9H).

[0079] []D.sup.25=+24.1 (c=0.01 g/mL, CHCl.sub.3).

[0080] US2015/210632A1 reported specific rotation of []D.sup.25=+21.78 (c=0.01 g/mL, CHCl.sub.3) for (R)-3-(1, 1-biphen-4-yl)-N-Boc-alaninol. Therefor the product from this step is R configuration.

Example 5: 3-(1, 1-biphen-4-yl)-2-acetylaminoacrylic Acid Methyl Ester

[0081] To a flask were added 3 kg of 4-phenylbenzaldehyde, 3.9 kg of methyl 2-acetamido-2-(dimethoxyphosphoryl)acetate and 20 L of dichloromethane. The mixture was cooled to 0 C. and 3 kg of DBU was added slowly while maintaining temperature at 05 C. After addition, the temperature was increased to 1025 C. and the mixture was stirred for additional 46 hours. When HPLC showing no starting material, the mixture was then cooled to 10 C. The pH was adjusted to about 67 by adding acetic acid (0.4 kg). The resulting mixture was then concentrated to remove solvents under reduced pressure. To the residue was added 23 kg of water and the mixture was stirred for 2 hour. The solid was collected by filtration. The wet cake was then slurried in 500 mL of water for 1 hour. The solid was further purified by being slurried in water (20 kg, 1 h) and MTBE (20 L, at 50 C. for 2 h). It was filtered and dried at 55 C. to afford 4.6 of white solid, with HPLC purity of 99.1% in 95% yield. The characterization data is same as that from example 1.

Example 6: (R)-3-(1, 1-biphen-4-yl)-2-acetylaminopropionic Acid Methyl Ester

[0082] To a high pressure reactor were added 1.8 kg of 3-(1, 1-biphen-4-yl)-2-acetylaminoacrylic acid methyl ester and 14 L of methanol. The air in the reactor was replaced by nitrogen three times. 1.0 g of catalyst Rh[(NBD)(Rc,Sp-DuanPhos)]BF4 was added under nitrogen. The reactor was charged with hydrogen and then released. Repeat this operation four times. Then the reactor was charged with hydrogen to 1.53 MPa and stirred at 2030 C. for 48 h. When the reaction is complete monitored by HPLC, hydrogen was released carefully. The mixture was concentrated to provide 1.8 g of white solid with HPLC purity of 99.0% in 100% yield. The ee was 99.3%. The characterization data is same as that from example 2.

Example 7: (R)-3-(1, 1-biphen-4-yl)-2-tert-butoxycarbonyl-aminopropionic Acid Methyl Ester

[0083] To a flask were added 1.4 kg of (R)-3-(1, 1-biphen-4-yl)-2-acetylaminopropionic acid methyl ester, 0.07 kg DMAP, 1.55 kg (Boc).sub.2O and 10 L of anhydrous THF. The resulting mixture was then heated to reflux (60-66 C.) for 57 hours. After the reaction was completed, it was cooled to 010 C. 0.67 kg of hydrazine hydrate was then added and the mixture was maintained for another 57 hours under 010 C. till HPLC showing the reaction no intermediate detected. Its pH was then adjusted to 56 by adding diluted hydrochloric acid. The mixture was then concentrated and the residue was dissolved in 10 L of DCM. The organic phase was separated and washed twice with water. Concentration of the organic phase to provide light yellow solid 1.57 kg with 98.5% HPLC purity and in 94% yield. The characterization data is same as that from example 3.

Example 8: (R)-3-(1, 1-biphen-4-yl)-N-Boc-alaninol

[0084] To a flask were added 1.5 kg of (R)-3-(1, 1-biphen-4-yl)-2-tert-butoxycarbonyl-aminopropionic acid methyl ester and 9 L of methanol. The mixture was then cooled to 5 C. 0.5 kg of sodium borohydride was then added while maintaining 515 C. After the addition, the mixture was heated to 2530 C. and stirred for 58 hours till HPLC showing no starting material. Its pH was then adjusted to 78 by adding diluted hydrochloric acid. Methanol was removed. To the residue was then added 9 L of ethyl acetate and 6 L of water. The mixture was then stirred well and two phases were separated. The organic phase was then washed with 5% saturated brine, dried, concentrated to provide 1.3 kg white solid with 98.8% HPLC purity in 94% yield. The characterization data is same as that from example 4.