Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-06-25
2004-02-10
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C514S530000
Reexamination Certificate
active
06689901
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a process, including intermediates, to produce latanoprost, a pharmaceutical agent useful in treating ophthalmic conditions.
2. Description of the Related Art
U.S. Pat. No. 5,422,368 discloses latanoprost (Example 2) and its usefulness as an ophthalmic agent. The patent discloses a process (Example 2) to prepare latanoprost and two closely related compounds.
There are very limited numbers of examples of reductions of &agr;,&bgr;-unsaturated enones with chlorodiisopinocampheylborane.
J. Am. Chem. Soc.,
110(5), 1539-46 (1988) describes a single example of reduction of an acyclic aryl enone, 4-phenyl-3-buten-2-one, with chlorodiisopinocampheylborane giving an 81% eantiomeric selectivity, and no examples of simple acyclic non-aryl conjugated enones.
Bull. Korean Chem. Soc.,
15(12), 1033-4 (1994) addresses the issue of 1,2 versus 1,4 reduction with chlorodiisopinocampheylborane but did not discuss the enantioselectivity or diastereoselectivity of the reductions.
Tetrahedron Letters
1067-1070 (1976) discloses a cyclopentane diol-acid where the side-chain did not contain any aromatic functionality.
SUMMARY OF INVENTION
Disclosed is a compound of the formula (VI)
where:
(1) R
3
is —H and R
4
is —H,
(2) R
3
is —H and R
4
is —O—CH
3
and
(3) R
3
and R
4
are taken together to form a five member ring attached to the 3- and 4-positions of the phenyl ring where the second ring from the R
3
-position to the R
4
-position is —CH═CH—O— and
where
. . .
is a single or double bond and pharmaceutically acceptable salts thereof.
Also disclosed is a process for the preparation of a 15(S)-prostaglandin intermediate selected from the group consisting of compound (IV)
where R
3
, R
4
and
. . .
are as defined above and where X
11
is phenyl or phenyl substituted with one thru three C
1
-C
4
alkyl, one thru three C
1
-C
4
alkoxy, one phenyl, one thru three —F, —Cl, —Br and —I and compound (XVIII)
where X
11
is defined above which comprises:
(1) contacting a compound selected from the group consisting of compound (III)
where R
3
, R
4
, X
11
and
. . .
are as defined above or compound (XVII), respectively,
where X
11
is defined above with (−)-chlorodiisopinocampheylborane while maintaining the reaction mixture temperature in the range of from about −50° to about 0° and
(2) contacting the reaction mixture of step (
1
) with a boron complexing agent.
DETAILED DESCRIPTION OF THE INVENTION
Latanoprost (XVI) is known, see U.S. Pat. No. 5,422,368, Example 2.
The process of the present invention is set fort in CHARTs A and B and in EXAMPLES 1-12.
The enone (III), as well as the other compounds of the invention, has three possibilities for the substitution on the phenyl ring of the bottom side chain. These are where R
3
and R
4
are:
(1) R
3
is —H and R
4
is —H which gives phenyl,
(2) R
3
is —H and R
4
is —O—CH
3
which give 4-methoxyphenyl and
(3) R
3
and R
4
are taken together to form a five member ring attached to the 3- and 4-positions of the phenyl ring where the second ring from the R
3
-position to the R
4
-position is —CH═CH—O—;
where
. . .
is a single or double bond and
where X
11
is phenyl or phenyl substituted with one thru three C
1
-C
4
alkyl, one thru three C
1
-C
4
alkoxy, one phenyl, one thru three —F, —Cl and —Br. It is preferred that R
3
and R
4
are both —H. It is preferred that X
11
is phenyl.
The enone (III) must be protected at the C-11 position as is known to those skilled in the art. It is preferred that for the protecting group —CO—X
11
, X
11
is phenyl or phenyl substituted with one thru three C
1
-C
4
alkyl, one thru three C
1
-C
4
alkoxy, one phenyl, one thru three —F, —Cl and —Br. With regard to the (−)-chlorodiisopinocampheylborane reduction of the &agr;,&bgr;-unsaturated enone (III) the reduction can be performed in any chemically inert solvent that adequately dissolves the enone (III). Suitable solvents include THF, methylene chloride and DME and mixtures thereof. MTBE and toluene alone are not operable. The use of a cosolvent, such as hexane, heptane, isooctane or similar hydrocarbons is not necessary but is preferred. This is important since (−)-chlorodiisopinocampheylborane is available commercially as a solution in these solvents. MTBE and toluene can be used as the cosolvent. The nature of the solvent has virtually no effect with regard to the 15(S)/15(R) ratio in the product. It is preferred that from about 3 to about 4 equivalents of (−)-chlorodiisopinocampheylborane be used; it is more preferred that at least 3.5 equivalents of (−)-chlorodiisopinocampheylborane be used. With fewer equivalents the reaction is incomplete; there is no improvement in rate or selectivity with more equivalents. When the (−)-chlorodiisopinocampheylborane is contacted with the &agr;,&bgr;-unsaturated enone (III), the temperature should be maintained less than 0°. It is preferred that the temperature be maintained at less than −20°; it is more preferred that the temperature be maintained in the range of from about −35 to about −45°. Above −35° the selectivity decreases and below about −45° the rate becomes too slow to be practical.
When the reaction is complete, the excess (−)-chlorodiisopinocampheylborane must be destroyed by use of a boron complexing agent which is selected from the group consisting of water, C
1
-C
6
alcohols and diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. It is preferred that the boron complexing agent be group be water and diethanolamine; it is more preferred that the complexing agent be water.
It is preferred that prior to step (2), the reaction mixture of step (1) is contacted with a readily reducible aldehyde or ketone. It is preferred that the readily reducible aldehyde or ketone is selected from the group consisting of C
1
-C
6
aldehydes and ketones and benzaldehyde; it is more preferred that the readily reducible aldehyde or ketone is acetone or methylethylketone. When adding the boron complexing agent it is preferred that a base also be added. It is preferred that the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tri-C
1
-C
6
alkylamines, pyridine and pyridine substituted with C
1
-C
4
alkyl; it is more preferred that the base be bicarbonate or carbonate. It is even more preferred that the base be bicarbonate.
Either prior to, or after, step (
2
), it is preferred to warm the reaction mixture to about 15 to about 25°. It is preferred that the reaction mixture is warmed from about 1 to about 3 hr.
Latanoprost (XVI) is known to be useful as an ophthalmic pharmaceutical agent, see U.S. Pat. Nos. 5,296,504 and 5,422,368. In addition, International Publication WO98/30900 discloses that latanoprost (XVI) is useful in treating another ophthalmic condition, myopia.
The process of CHART B (and EXAMPLEs 11 & 12) starts with a known enone (XVII) and transforms it to the 15-alcohol (XVIII) intermediate known to be useful in the production of pharmaceutically useful prostaglandins, see
Tetrahedron Letters,
1076-1070 (1976) and
J. Am. Chem. Soc.
92, 397-8 (1970). The process of the reduction of the non-aryl &agr;,&bgr;-unsaturated ketone (XVII) is analogous to the reduction of the aryl &agr;,&bgr;-unsaturated ketone (III).
The products where R
3
is —H and R
4
is —O—CH
3
and where R
3
and R
4
are taken together to form a five member ring attached to the 3- and 4-positions of the phenyl ring where the second ring from the R
3
-position to the R
4
-position is —CH—CH—O— are also known to be useful pharmaceutical agents. Those two agents can also be prepared by the process of the present invention.
Definitions and Conventions
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
Definitions
All temperatures are in degrees Celsius.
Latanoprost (XVI) refers to (5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-
Engelmann John H.
Pharmacia & Upjohn Company
Reyes Hector M.
Rotman Alan L.
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