Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-10-02
2002-04-09
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C549S009000, C514S211010
Reexamination Certificate
active
06369220
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides.
2. Description of Related Art
It is well established that agents which inhibit the transport of bile acids across the ileum can also cause a decrease in the level of cholesterol in blood serum. Stedronski, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,” Biochimica et
Biophysica Acta
, 1210 (1994) 255-287, discusses biochemistry, physiology, and known active agents affecting bile acids and cholesterol.
A class of ileal bile acid transport-inhibiting compounds which was recently discovered to be useful for influencing the level of blood serum cholesterol is tetrahydrobenzothiepine-1,1-dioxides (THBDO compounds). (U.S. patent application Ser. No. 08/816,065=WO96/08484).
Some classes of compounds show enhanced potency as pharmaceutical therapeutics after they have been enantiomerically-enriched (see, for example, Richard B. Silverman,
The Organic Chemistry of Drug Design and Drug Action
, Academic Press, 1992, pp. 76-82). Therefore, THBDO compounds that have been enantiomerically-enriched are of particular interest.
A class of chemistry useful as intermediates in the preparation of racemic THBDO compounds is tetrahydrobenzothiepine-1-oxides (THBO compounds). THBDO compounds and THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring. A method of preparing enantiomerically-enriched samples of another phenyl/seven-member fused ring system, the benzothiazepines, is described by Higashikawa (JP 59144777), where racemic benzothiazepine derivatives are optically resolved on a chromatographic column containing chiral crown ethers as a stationary phase. Although optical resolution is achieved, the Higashikawa method is limited to producing only small quantities of the enantiomerically-enriched benzothiazepine derivatives.
Giordano (CA 2068231) reports the cyclization of (2S,3S)-aminophenylthiopropionates in the presence of a phosphonic acid to produce (2S,3S)-benzothiazepin-4-ones. However, that preparation is constrained by the need to use enantiomerically-enriched starting materials rather than racemic starting materials. In addition, the Giordano method controls the stereochemistry of the seven-member ring of the benzothiazepin-4-one only at the 2- and 3-positions. The 4-and 5-positions of the seven-member ring of the benzothiazepin-4-one are not asymmetric centers, and the stereochemistry at these sites therefore cannot be controlled by the Giordano method.
A method by which enantiomerically-enriched 1,5-benzothiazepin-3-hydroxy-4(5H)-one compounds have been produced is through the asymmetric reduction of 1,5-benzothiazepin-3,4(2H,5H)-dione compounds, reported by Yamada, et al. (J. Org. Chem. 1996, 61 (24), 8586-8590). The product is obtained by treating the racemic 1,5-benzothiazepin-3,4(2H,5H)-dione with the reaction product of an optically active alpha-amino acid and a reducing agent, for example sodium borohydride. Although a product with high optical purity was achieved, the method is limited by the use of a relatively expensive chemical reduction step.
The microbial reduction of racemic 1,5-benzothiazepin-3,4(2H,5H)-dione compounds to produce enantiomerically-enriched 1,5-benzothiazepin-3-hydroxy-4(5H)-one compounds is reported by Patel et al., U.S. Pat. No. 5,559,017. This method is limited by the inherent problems of maintaining a viable and pure bacterial culture of the appropriate species and variety. In addition, that method is limited in scale, producing only microgram quantities of the desired product.
Until now, there have been no reported processes for preparing enantiomerically-enriched THBDO compounds or enantiomerically-enriched THBO compounds. Furthermore, there have been no reported processes for controlling the stereochemistry at the 4- and 5-positions of the seven-member rings of THBDO compounds or THBO compounds.
SUMMARY OF THE INVENTION
A convenient and cost-effective method for preparing enantiomerically-enriched THBDO compounds and intermediates in the preparation thereof is of great importance and utility. In response to the need therefor, the present inventors have developed a method for preparing enantiomerically-enriched tetrahydrobenzothiepine-1-oxides or enantiomerically-enriched tetrahydrobenzo-thiepine-1,1-dioxides with chiral centers at the 4- and 5-positions of the seven-member ring.
Accordingly, among its various aspects, the present invention provides a method of preparing an enantiomerically-enriched tetrahydrobenzothiepine-1-oxide having the formula (I):
wherein:
R
1
and R
2
are independently selected from among H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl;
R
3
is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR
24
, SR
15
, S(O)R
15
, SO
2
R
15
, and SO
3
R
15
, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR
19
, NR
19
R
20
, SR
19
, S(O)R
19
, SO
2
R
19
, SO
3
R
19
, NR
19
OR
20
, NR
19
NR
20
R
21
, NO
2
, CO
2
R
19
, CN, OM, SO
2
OM, SO
2
NR
19
R
20
, C(O)NR
19
R
20
, C(O)OM, COR
19
, P(O)R
19
R
20
, P
+
R
19
R
20
R
21
A
−
, P(OR
19
)OR
20
, S
+
R
19
R
20
A
13
, and N
+
R
15
R
17
R
18
A
−
,
wherein:
A
−
is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation;
said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR
13
, NR
13
R
14
, SR
13
, S(O)R
13
, SO
2
R
13
, SO
3
R
13
, CO
2
R
13
, CN, oxo, CONR
13
R
14
, N
+
R
13
R
14
R
15
A—, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R
13
R
14
, P
+
R
13
R
14
R
15
A
−
, and P(O)(OR
13
)OR
14
, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR
13
, N
+
R
13
R
14
A—, S, SO, SO
2
, S
+
R
13
A—, PR
13
, P(O)R
13
, P
+
R
13
R
14
A—, or phenylene;
R
19
, R
20
, and R
21
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, polyether, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclealkyl, heterocyclealkyl, heteroarylalkyl, quaternary heterocyclealkyl, alkylammoniumalkyl, carboxyalkylaminocarbonylalkyl, and quaternary heteroarylalkyl,
wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR
15
, N
+
R
15
R
16
A—, S, SO, SO
2
, S
+
R
15
A
−
, PR
15
, P
+
R
15
R
16
A—, P(O)R
15
, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
R
19
, R
20
, and R
21
are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, sulfoalkyl, carboxyalkyl, sulfoalkyl, alkyl, heterocycle, heteroaryl, quaternary heterocyclealkyl, quaternary heteroarylalkyl, guanidinyl, quaternary heterocycle, quaternary heteroaryl, OR
15
, NR
15
R
16
, N
+
R
15
R
17
R
18
A
−
, SR
15
, S(O)R
15
, SO
2
R
15
, SO
3
R
15
, oxo, CO
2
R
15
, CN, halogen, CONR
15
R
6
, S
2
OM, SO
2
NR
15
R
16
, PO(OR
22
)OR
23
, P
+
R
15
R
16
R
17
A—, S
+
R
15
R
16
A—, and C(O)OM,
wherein R
22
and R
23
are independently selected from the substituents constituting R
15
and M, or
R
20
and R
21
, together wit
Carpenter Andrew J.
Huang Horng-Chih
Li Jinglin (James T.)
Reitz David B.
Snieckus Victor
Banner & Witcoff , Ltd.
Higel Floyd D.
Sackey Ebenezer
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