Synthesis of methylthiophenyl hydroxyketones

Details Synthesis of methylthiophenyl hydroxyketones Synthesis of methylthiophenyl hydroxyketones

1999-10-27

2001-08-28

Vollano, Jean F (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfur containing

C568S042000, C568S067000

Reexamination Certificate

active

06281391

ABSTRACT:

BACKGROUND OF THE INVENTION
This application is directed to an improved process for making methythiophenyl hydroxyketones such as (S)-2-hydroxy-2-methyl-1 -(4-methylthiophenyl)butan-1-one. These compounds are intermediates useful in the preparation of certain compounds that selectively inhibit cyclooxygenase-2 (COX-2). Compounds having COX-2 selectivity, for example, are found in WO 97/14691 filed on Oct. 9, 1996 and published on Apr. 24, 1997.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, COX-2 has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
A brief description of the potential utility of selective COX-2 inhibitors is given in an article by John Vane,
Nature
, Vol. 367, pp. 215-216, 1994, and in an article in
Drug News and Perspectives
, Vol. 7, pp. 501-512, 1994.
SUMMARY OF THE INVENTION
This invention encompasses a novel process for synthesizing compounds represented by formula A:
wherein R and R
1
are C
1-6
alkyl, comprising reacting a compound of formula B:
wherein the group:
represents a 5 or 6-membered non-aromatic ring wherein X is selected from the group consisting of: C, N, O and S,
with a lithiating agent and a compound of formula C:
in a substantially non-reactive solvent at reduced temperature to produce a compound of formula A.
These compounds are intermediates useful in the preparation of certain agents which are selective COX-2 inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses a process for synthesizing compounds represented by formula A:
wherein R and R
1
are C
1-6
alkyl, comprising reacting a compound of formula B:
wherein the group:
represents a 5 or 6-membered non-aromatic ring wherein X is selected from the group consisting of: C, N, O and S,
with a lithiating agent and a compound of formula C:
in a substantially non-reactive solvent at reduced temperature to produce a compound of formula A.
In a preferred embodiment of the invention the lithiating agent is selected from the group consisting of: n-butyllithium, hexyllithium and phenyllithium.
In another embodiment the substantially non-reactive solvent is selected from the group consisting of: tetrahydrofuran, toluene, ethylene glycol dimethyl ether, t-butyl methyl ether and the like. Another embodiment of the invention encompasses a mixture of two or more of the aforesaid solvents.
In another embodiment of the invention the reduced temperature ranges from about −78° C. to about 0° C. In another preferred embodiment the reduced temperature is about −40° C.
A preferred embodiment of the invention is that wherein the reaction is quenched with an aqueous acid. Examples of quenching acids include: sulfuric acid, hydrochloric acid, citric acid and acetic acid.
Another embodiment of the invention is that wherein R is methyl and R
1
is ethyl.
Typically the compound of formula A consists of two stereoisomers, one stereoisomer in enantiomeric excess with respect to the other.
Another embodiment of the invention is that wherein the product yield of the compound of formula A is greater than about 90%.
In yet another embodiment, the following group of formula B:
is selected from pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl. More particularly, the group represents pyrrolidinyl.
A preferred embodiment of the invention encompasses the process wherein the compound of formula B is produced by reacting a compound of formula D:
wherein R and R
1
are C
1-6
alkyl, with an activating agent in a substantially non-reactive solvent at reduced temperature and then with pyrrolidine at room temperature to produce a compound of formula B.
An example of an activating agent is carbonyldiimidazole.
Another embodiment is that wherein the substantially non-reactive solvent is selected from the group consisting of: tetrahydrofuran, toulene, isopropyl acetate, ethyl acetate, t-butlymethyl ether, ethylene glycol dimethyl ether and N,N-dimethylformamdide. Mixtures of two or more of the aforesaid solvents are also contemplated.
As used herein, the reduced temperature is in the range of about −25° C. to about 10° C. More particularly the reduced temperature is about 0° C.
A preferred embodiment is that wherein the product yield of the compound of formula B is greater than about 90%.
Another preferred embodiment is that wherein R is methyl and R
1
is ethyl.
A subclass of this class encompasses a process wherein the compound of formula D consists of one stereoisomer that is in enantiomeric excess with respect to the other.
A group of this subclass is a process wherein the compound of formula D is resolved by reacting the racemic mixture of the compound of formula D with a chiral amine resolving agent in a substantially non-reactive solvent.
Examples of substantially non-reactive solvent include those selected from the group consisting of: acetone, ethyl acetate, hexane and isopropyl acetate. Additionally mixtures of two or more of the aforesaid solvents are included.
A preferred embodiment is a process wherein the compound of formula D is resolved to an enantiomeric excess of about 98%.
In a more preferred embodiment the product yield for the resolution is greater than about 65%.
More particularly, the compound of formula D is resolved to about 98% enatiomeric excess and the yield is about 60-70%.
The invention is illustrated in connection with the following generic schemes A and B.
The racemic starting material is first separated into its diastereomers with a chiral amine resolving agent to provide the desired stereospecific hydroxy acid. Alternatively, the appropriate families of chiral amines

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