# US 6,294,688 B1 · Process useful to produce vitamin D analogs

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- Number: US 6,294,688 B1
- Document ID: US6294688B1
- Status: Granted
- Kind: B1
- Application number: 09/633,672
- Filed: 2000-08-07
- Granted: 2001-09-25
- Earliest claimed: 1999-08-23
- Assignees: Hoffman-La Roche Inc.
- Inventors: Andrzej Robert Daniewski; Marek Michal Kabat; Masami Okabe; Roumen Nikolaev Radinov
- Web page: https://patentgrep.com/patent/US6294688B1

## CPC

- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07D 303/32: by aldehydo- or ketonic radicals
- C07D 303/40: by ester radicals
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C07F 7/1892: {by reactions not provided for in C07F7/1876 - C07F7/1888}
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A stereospecific method for accomplishing the below reaction: results in the compound of formula 2 having the same stereochemistry at both carbon 1 and carbon 3 as that in the compound of formula 1. Thus, if carbon 3 is in the R-configuration in the compound of formula 1, then carbon 3 will be in the R-configuration in the compound of resulting formula 2. In the above process, R1 is C1-C6 alkyl that can be straight-chain or branched. The process functions using a fluorinated alcohol having a pKa less than about 9, in the presence of a palladium catalyst. The compounds of formula 1, as well as novel intermediates in this process, are useful in manufacturing vitamin D analogs.

## Claims

### Claim 1

A method of stereospecifically producing a compound of formula:
or its enantiomer
wherein R1 is C1-C6 alkyl and R2 is a hydroxy protective group, which comprises reacting a compound of formula:
or its enantiomer, respectively,
wherein R1 and R2 are as above and the stereochemistry of both the compound of formula 1AA and the compound of formula 2AA is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula 1AA* and the compound of formula 2AA* is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pKa lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2AA or 2AA*, respectively.

### Claim 2 (depends on 1)

The method of claim 1, wherein the reacting is in the presence of a palladium catalyst that is palladium-phosphine catalyst.

### Claim 3 (depends on 2)

The method of claim 2, wherein the reacting is in the presence of a palladium-phosphine catalyst that is a palladium-triarylphosphine.

### Claim 4 (depends on 3)

The method of claim 3, wherein the reacting is in the presence of a palladium-triarylphosphine catalyst selected from the group consisting of palladium-triphenylphosphine, palladium-tris(2-methoxyphenyl)phosphine, palladium-tris(3-methoxyphenyl)phosphine, palladium-tris(4-methoxyphenyl)phosphine, palladium-tris(o-tolyl)phosphine, palladium-tris(m-tolyl)phosphine, palladium-tris(p-tolyl)phosphine, palladium-tris(4-fluorophenyl)phosphine, palladium-tris(p-trifluoromethylphenyl)phosphine, and palladium-tris(2-furyl)phosphine.

### Claim 5 (depends on 1)

The method of claim 1, wherein the reacting is in the presence of a palladium catalyst that is palladium-1,2-bis(diphenylphosphino) ethane.

### Claim 6 (depends on 1)

The method of claim 1, wherein the reacting is with a fluorinated alcohol selected from the group consisting of:
wherein X is phenyl or CF3.

### Claim 7 (depends on 6)

The method of claim 6, wherein the reacting is with a fluorinated alcohol which is

### Claim 8 (depends on 6)

The method of claim 6, wherein the reacting is with a fluorinated alcohol which is

### Claim 9 (depends on 6)

The method of claim 6, wherein the reacting is with a fluorinated alcohol which is: