Claims
- 1. A process for the preparation of a compound of the formula (V) or (VI) wherein R is aryl, C3-8 cycloalkyl, C1-10 alkyl, (aryl)C1-10 alkylene, (C3-8 cycloalkyl)C1-10 alkylene, heterocyclyl, (heterocyclyl)C1-10 alkylene, (aryl)C3-8 cycloalkylene, (C3-8 cycloalkyl)arylene or (C1-10 alkylaryl)C1-10 alkylene, wherein aryl is a mono- or bicyclic partially or fully unsaturated carbocyclic ring system containing from 4 to 10 atoms, wherein aryl is a mono- or bicyclic partially or fully unsaturated carbocyclic ring system is phenyl or naphthyl, or a partially or fully unsaturated mono- or bicyclic heterocyclic moiety having up to 10 atoms in the ring system and with up to 4 hetero-atoms in the said ring system each independently selected from N, O and S, said carbocyclic ring system and heterocyclic moiety being optionally substituted by one or more substituents each independently selected from halogen, NO2, NH2, CO2R9, phenyl, C1-6 alkyl(optionally substituted by one or more halogen), and C1-6 alkoxy(optionally substituted by one or more halogen), and wherein heterocyclyl is a 3- to 8-membered mono or bicyclic saturated heterocyclic group having from 1 to 4 ring hetero-atoms each independently selected from N, O and S, optionally substituted by one or more substituents each independently selected from halogen, NO2, NH2, CO2R9, phenyl, C1-6 alkyl(optionally substituted by one or more halogen), and C1-6 alkoxy(optionally substituted by one or more halogen); R1 is C1-6 alkoxy; R2 is OH or O−M+, wherein M+ is a metal cation is sodium, lithium, potassium or a protonated amine moiety selected from the group consisting of mono(C1-10 alkyl)ammonium, di(C1-10 alkyl)ammonium, tri(C1-10 alkyl)ammonium, mono(C3-10 cycloalkyl)ammonium, di(C3-10 cycloalkyl)ammonium, tri(C3-10 cycloalkyl)ammonium, (C1-10 alkyl)n1 (C3-10 cycloalkyl)n2ammonium, anilinium, benzylammonium, triethanolammonium, and (S)-α-methylbenzylammonium, where n1 and n2 are each independently selected from 1 or 2 with the proviso that the sum of n1 and n2 is not greater than 3; R9 is H or C1-6 alkyl; comprising (A) reacting an aldehyde of formula RCHO, or a protected derivative thereof selected from the group consisting of a hemiacetal or adduct thereof wherein said adduct is a bisulphite, wherein R is as defined above, with a phosphorus compound of formula (IX) or a metal carboxylate salt thereof, selected from the group consisting of a sodium, lithium or potassium carboxylate salt thereof,wherein R1 is as defined above, and wherein P is a phosphonate moiety of formula —P(O)(OR3)(OR4), wherein R3 and R4 are each independently selected from H, C1-6 alkyl, benzyl and phenyl (optionally substituted by one or more C1-6 alkyl), or R3 and R4 taken together are C2-5 alkylene, or P is a phosphorane moiety of formula —(PR5R6R7)+X− wherein R5, R6 and R7 are each independently selected from C1-6 alkyl and phenyl, and X is bromine, chlorine or iodine, in the presence of a sodium, lithium or potassium C1-C6 alkoxide base, in an inert solvent, and at a temperature of from −80° C. to 20° C. to form a compound of the formula (IV) and (B) asymmetric reduction of the compound of formula (IV) to form the compound of formula (V) or (VI).
- 2. The process according to claim 1, wherein said asymmetric reduction comprises hydrogenation.
- 3. The process according to claim 1, wherein the catalyst used for reduction of compounds of formula (IV) where R2 is O−M+, is ruthenium based.
- 4. The process according to claim 3, wherein the catalyst used is a ruthenium complex of BINAP or a derivative thereof.
- 5. The process according to claim 4, wherein the catalyst is [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride.
- 6. The process according to claim 1, wherein the catalyst for reduction of compounds of formula (IV) where R2 is OH is rhodium-based.
- 7. The process according to claim 6, wherein the catalyst is Rh-DUPHOS (1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene-(1,5-cyclooctadien)-rhodium (I) tetrafluoroborate), or Rh-Ferrotane (1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate).
- 8. The process according to claim 2, wherein the hydrogenation of the compound of formula IV when R2 is OH is carried out in the presence of a base.
- 9. The process according to claim 8, wherein the base is selected from the group consisting of sodium bicarbonate, cyclohexylamine, isopropylamine, t-butylamine, adamantanamine and (S)-α-methylbenzylamine.
- 10. The process according to claim 2, wherein hydrogenation is carried out on the preformed salt of formula IV wherein R2 is O− M+.
- 11. The process according to claim 3, wherein the hydrogenation is carried out in an inert solvent and under a positive pressure of hydrogen.
- 12. The process according to claim 11, wherein the solvent is an aqueous C1-3 alcohol or a C1-3 alcohol.
- 13. The process according to claim 3, where the reaction is carried out with a ruthenium-based catalyst and the reaction temperature is approximately 60° C.
- 14. The process according to claim 6, where the reaction is carried out with a rhodium-based catalyst and the reaction temperature is approximately 20° C.
Priority Claims (1)
Number |
Date |
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0025310 |
Oct 2000 |
GB |
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Parent Case Info
This is a divisional application of U.S. application Ser. No. 09/977,822, now U.S. Pat. No. 6,452,041, filed Oct. 15, 2001, which claims the benefit of U.S. Provisional Patent Application No. 60/253,434, filed Nov. 28, 2000 and U.K. Patent Application No. 0025310.4, filed Oct. 16, 2000, all of the aforementioned applications are hereby incorporated by reference in their entirety.
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Provisional Applications (1)
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Number |
Date |
Country |
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60/253434 |
Nov 2000 |
US |