Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2001-02-26
2002-06-11
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
active
06403817
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for preparing a prostaglandin E-type compound, and a novel intermediate generated during producing the same.
2. Related Prior Art
Prostaglandin is a group of compounds with different pharmaceutical activities, wherein the prostaglandin E-type compounds (PGEs) and cyclopentanone substituted derivatives thereof own multiple curative effects, such as loosing the vascular smooth muscle, curing impotence, being a parturifacient, or an inducing medicine. It can also be used to treat the gastric ulcer caused by non-steroid anti-inflammatory drugs (NSAID). Accordingly, the synthesis of prostaglandin E-type compounds and the derivatives thereof are always one of the most important subjects to chemists and pharmacologists.
In the early days, the prostaglandin E-type compounds were directly extracted from bionts, but only few amounts were obtained. Therefore, varied chemical synthesis methods are developed in order to mass-produce the prostaglandin E-type compounds. Among these methods, the most common one is to couple ethylene compounds to the cycle of cyclopentanone, which is disclosed in U.S. Pat. No. 5,618,959, and WO 9,626,891. Another method disclosed in Japanese patent No. 01,074,995 is to cyclize an arachidonic acid by utilizing a catalyst. In addition to the methods aforementioned, it is pretty common to convert other type prostaglandin into prostaglandin E-type compounds, wherein converting the prostaglandin A-type into E-type is the most often as described in U.S. Pat. No. 3,912,725. Additionally, U.S. Pat. No. 3,892,792 (Yankee E. W. etc.,) and J. Chem. Commun., 1972, 1120 have mentioned that PGE
2
can be obtained by using trimethylsilyl group for silylating the 11-,15-hydroxyl group of PGF
2&agr;
with esterified carboxylic group, and then oxidizing the 9-hydoxyl group thereof, and finally carrying out desilylation and hydrolysis reactions. Czech patent No. 265,733 B1 indicates that PGE
2
can be produced by oxidizing and desilylating PGF
2&agr;
. which has a silylated 11,15-tert-butyldimethylsilyl group.
In the methods of U.S. Pat. No. 3,892,792 (Yankee E. W. etc.) and J. Chem. Commun., 1972, 1120, esterification of the carboxylic group of PGF
2&agr;
is necessary before a silylation reaction of the hydroxyl group, by which the acidity can be reduced and desilylation of the protective trimethylsilyl group on the 11-, 15- position can be prevented. However, this method includes at least five steps to produce PGE
2
. In the prior arts of Corey E. J. etc. (Tetrahedron Lett., 1986, 2199) and Czech patent No. 265,733B1, tert-butyldimethylsilyl group is selected as a protective group according to its excellent stability and uneasily desilylation, so that the esterification of the carboxylic group can be neglected. On the other hand, the excellent stability may result in a demand for the strong corrosive acid, i.e., hydrofluoric acid, in order to remove the tert-butyldimethylsilyl group, which is just disadvantage of operation and scaling-up.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a method for preparing prostaglandin E-type compounds, in which a more stable intermediate is generated, and the desilylation reaction is easily carried out.
The present invention provides a method of preparing prostaglandin E-type compounds of the formula (I),
wherein A is
X is trans —CH═CH—or —CH
2
—CH
2
—; Y and Z each independently is trans —CH═CH—, cis —CH═CH— or —CH
2
—CH
2
—; and pharmaceutically acceptable salts thereof which comprises reacting a compound of the formula (II)
wherein X, Y and Z are defined as above; R is H or —Si(C
2
H
5
)
3
; B is
with a Cr(VI)-based reagent or an activated dimethyl sulfoxide reagent in a halogen-containing solvent to proceed an oxidation reaction, and then reacting with an acidic aqueous solution having pH=4~6 in the presence of a water soluble low-boiling-point organic solvent to proceed a desilylation reaction.
The typical compounds of formula (I) are compounds of formula (IV),
wherein A, X, Y and Z is defined as above. The more typical compound of formula (I) is PGE
2
.
The Cr(VI)-based reagent used in the present invention can be a Collins reagent, pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC). The activated dimethyl sulfoxide reagent can be a Swern reagent or a Corey-Kim reagent. The acidic aqueous solution can be a pyridinium p-toluenesulfonate (PPTS) aqueous solution or an acetic acid aqueous solution. The halogen-containing solvent is selected from the group consisting of dichloromethane, chloroform and dichloroethane. The water-soluble low-boiling-point organic solvent is selected from the group consisting of acetone, acetonitrile, iso-propanol and tetrahydrafuran.
The compound of the formula (II) aforementioned can be obtained by reacting a prostaglandin F-type compound of the formula (III),
wherein A, X, Y and Z are defined as above; and a pharmaceutically acceptable salt thereof with N-triethylsilyldiethylamine (TESiD) in a polar organic solvent. The polar organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane, dichloroethane, chloroform, tetrahydrafuran, diethyl ether, methyl tert-butyl ether, and methyl ethyl ketone. The compound of the formula (III) can be PGF
2&agr;.
During the reaction, a novel intermediate of the formula (V) is further generated,
wherein R is H or —Si(C
2
H
5
)
3
.
The method of the present invention can be additionally applied to producing correspondent prostaglandin E-type compounds by converting other prostaglandin F-type compounds.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is related to the method for prostaglandin E-type compounds of formula (I), so that a reaction of PGE
2
converting from PGF
2&agr;
can be used to clearly explain the procedures, and scheme (A) shows such a reaction.
The scheme (A) indicates that a regioselectively silylated compound, i.e., bis-triethylsilyl-PGF
2&agr;
, triethylsilyl ester, can be obtained by reacting PGF
2&agr;
, with TESiD under 15~35° C. for 18~36 hours. Next, the oxidation of the 9-hydroxy group into ketone group is carried out by reacting with a Cr (VI)-based reagent under 15~35° C. for 10~15 minutes or activated dimethyl sulfoxide reagent under −78° C. for 2~3 hours. Last, PGE
2
is obtained via a desilylation reaction performed in an acidic aqueous solution reagent having pH=4~6 under 15~35° C. for 12~24 hours.
The examples described below are used for well understanding, but not used to limit the scope of the present invention.
Liu Yu-Liang
Suen Rung-Tian
Yao Chi-Hsiang
Bacon & Thomas PLLC
Carr Deborah D.
Everlight USA, Inc.
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