Claims
- 1. A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having the formula
- 2. A process according to claim 1 wherein the transition metal is ruthenium, rhodium or iridium; the bis-phosphine is a substantially enantiomerically-pure bis-phosphine selected from 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl, 1,2-bis-2,5-dialkylphospholano(benzene), 1,2-bis-2,5-dialkylphospholano(ethane), 2,3-bis-(diphenylphosphino)butane, 2-diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonyl-pyrrolidine and bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral back-bone; and the hydrogenation conditions of pressure and temperature comprise a hydrogen pressure of about 0.5 to 69 bars gauge and a temperature in the range of about −20 to 100° C.
- 3. A process according to claim 1 wherein the transition metal is ruthenium or rhodium; the bis-phosphine is a substantially enantiomerically-pure bis-phosphine having the formula
- 4. A process according to claim 1 wherein the transition metal is ruthenium or rhodium; the bis-phosphine is a substantially enantiomerically-pure N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]alkyl-amine wherein each alkyl group independently contains 1 to 6 carbon atoms or 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS) wherein each alkyl group contains 1 to 6 carbon atoms; the hydrogenation conditions of pressure and temperature comprise a hydrogen pressure of about 0.69 to 20.7 bars gauge and a temperature of about 0 to 50° C.; R1 is C1 to C6 alkyl, phenyl, tolyl, or C1 to C6 alkoxy; and R2 is C1 to C6 alkyl or benzyl.
- 5. A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5
- 6. A process according to claim 5 wherein step (1) is carried out at a temperature of about 35 to 150° C. in the presence of acetic anhydride and a base selected from the acetates, carbonates and bicarbonates of lithium, sodium, potassium, cesium, magnesium, calcium, lead and barium; step (2) is carried out at a temperature of about −10 to 100° C. in the presence of an alcohol and an alkali or alkaline earth metal alkoxide or hydroxide; and step (3) is carried out in the presence of a transition metal selected from ruthenium, rhodium or iridium; and a substantially enantiomerically-pure bis-phosphine selected from 2,3-O-isopropylidene-2,3-dihydroxy-1,4-2,3-bis-(diphenylphosphino)butane, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,2-bis-2,5-dialkylphospholano(benzene), 1,2-bis-2,5-dialkylphospholano-(ethane), 2,3-bis-(diphenylphosphino)butane, 2-diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonylpyrrolidine and bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone; under hydrogenation conditions of pressure and temperature comprising a hydrogen pressure of about 0.5 to 69 bars gauge and a temperature in the range of about −20 to 100° C.
- 7. A process according to claim 5 wherein step (1) is carried out at a temperature of about 85 to 110° C. in the presence of acetic anhydride and sodium acetate; step (2) is carried out at a temperature of about 25 to 50° C. in the presence of an alcohol and an alkali metal alkoxide or hydroxide selected from the alkoxides and hydroxides of sodium and potassium; and step (3) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium or rhodium and a substantially enantiomerically-pure bis-phosphine having the formula
- 8. A process according to claim 7 wherein, in step (3), the transition metal is ruthenium or rhodium; the bis-phosphine is a substantially enantiomerically-pure N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]alkylamine wherein each alkyl group independently contains 1 to 6 carbon atoms or 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS) wherein each alkyl group contains 1 to 6 carbon atoms; the hydrogenation conditions of pressure and temperature comprise a hydrogen pressure of about 0.69 to 20.7 bars gauge and a temperature of about 0 to 50° C.; R1 is C1 to C6 alkyl, phenyl, tolyl, or C1 to C6 alkoxy; and R2 is C1 to C6 alkyl or benzyl.
- 9. A process according to claim 7 wherein in Step (1) the base is sodium acetate; step (2) is carried out in the presence of benzyl alcohol and sodium methoxide; and step (3) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium or rhodium and a substantially enantiomerically-pure N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethylamine wherein the alkyl group contains 1 to 6 carbon atoms or 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS) wherein each alkyl group contains 1 to 6 carbon atoms; the hydrogenation conditions of pressure and temperature comprise a hydrogen pressure of about 0.69 to 20.7 bars gauge and a temperature of about 0 to 50° C.; R1 is methyl; and R2 is benzyl.
- 10. A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having the formula
- 11. A process according to claim 10 wherein step (i) is carried out at a temperature of about 35 to 150° C. in the presence of acetic anhydride and a base selected from the acetates, carbonates and bicarbonates of lithium, sodium, potassium, cesium, magnesium, calcium, lead and barium; step (ii) is carried out at a temperature of about −10 to 100° C. in the presence of an alcohol and an alkali or alkaline earth metal alkoxide or hydroxide; step (iii) is carried out in the presence of di-tert-butyl dicarbonate as the acylating agent and at a temperature of about −20 to 45° C.; step (iv) is carried out in the presence of an alkanol solvent and a nucleophile selected from hydrazine and hydrazine hydrate at a temperature of about −40 to 15° C.; and step (v) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium, rhodium or iridium and a substantially enantiomerically-pure bis-phosphine selected from 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,2-bis-(2,5-dialkylphospholano)benzene, 1,2-bis-2,5-dialkylphospholano(ethane), 2,3-bis(diphenylphosphino)butane, 2-diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonylpyrrolidine and bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone; under hydrogenation conditions of pressure and temperature comprising a hydrogen pressure of about 0.5 to 69 bars gauge and a temperature in the range of about −20 to 100° C.
- 12. A process according to claim 10 wherein step (i) is carried out at a temperature of about 85 to 110° C. in the presence of acetic anhydride and sodium acetate; step (ii) is carried out at a temperature of about 25 to 50° C. in the presence of an alcohol and an alkali metal alkoxide or hydroxide selected from the alkoxides and hydroxides of sodium and potassium; step (iii) is carried out in the presence of an inert, organic solvent and di-tert-butyl dicarbonate as the acylating agent and at a temperature of about 15 to 35° C.; step (iv) is carried out in the presence of an alkanol solvent selected from methanol and ethanol and a nucleophile selected from hydrazine and hydrazine hydrate at a temperature of about −5 to 5° C.; and step (v) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium and rhodium and a substantially enantiomerically-pure bis-phosphine having the formula
- 13. A process according to claim 12 wherein step (v) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium and rhodium and a substantially enantiomerically-pure bis-phosphine selected from substantially enantiomerically-pure N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethylamine wherein the alkyl group contains 1 to 6 carbon atoms and 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS) wherein each alkyl group contains 1 to 6 carbon atoms; the hydrogenation conditions of pressure and temperature comprise a hydrogen pressure of about 0.69 to 20.7 bars gauge and a temperature of about 0 to 50° C.
- 14. A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5
- 15. A process according to claim 14 wherein step (a) is carried out at a temperature of about −78 to 50° C. in an inert solvent selected from aliphatic hydrocarbons, cyclic and acyclic ethers, aromatic hydrocarbons, esters, and polar aprotic solvents in the presence of a base selected from alkoxides of the alkali metals and alkaline earth metals and amines; and step (b) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium, rhodium or iridium and a substantially enantiomerically-pure bis-phosphine selected from 2,3—O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,2-bis-(2,5-dialkylphospholano)benzene, 1,2-bis-2,5-dialkylphospholano(ethane), 2,3-bis-(diphenylphosphino)butane, 2-diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonyl-pyrrolidine and bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral back-bone; under hydrogenation conditions of pressure and temperature comprising a hydrogen pressure of about 0.5 to 69 bars gauge and a temperature in the range of about −20 to 100° C.
- 16. A process according to claim 14 wherein step (a) is carried out at a temperature of about −20 to 30° C. in the presence of tetramethylguanidine in tetrahydrofuran or ethyl acetate; and step (b) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium and rhodium and a substantially enantiomerically-pure bis-phosphine having the formula
- 17. A process according to claim 16 wherein step (b) is carried out in the presence of a catalyst system comprising a transition metal selected from ruthenium and rhodium and a substantially enantiomerically-pure bis-phosphine selected from substantially enantiomerically-pure N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethylamine wherein the alkyl group contains 1 to 6 carbon atoms and 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS) wherein each alkyl group contains 1 to 6 carbon atoms; the hydrogenation conditions of pressure and temperature comprise a hydrogen pressure of about 0.69 to 20.7 bars gauge and a temperature of about 0 to 50° C.
- 18. A compound having the formula
- 19. A compound according to claim 18 wherein R1 is C1 to C6 alkyl, phenyl, tolyl, C1 to C6 alkoxy, or benzyloxy; and R2 is C1 to C6 alkyl or benzyl.
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60/236,544, filed Sep. 29, 2000.
Provisional Applications (1)
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Number |
Date |
Country |
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60236544 |
Sep 2000 |
US |