Preparation of deazaguanine analog

Details Preparation of deazaguanine analog Preparation of deazaguanine analog

2003-02-19

2004-08-24

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06780993

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
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STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
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REFERENCE TO A COMPACT DISK APPENDIX
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BACKGROUND OF THE INVENTION
The present invention relates to a method for producing certain deazaguanine analogs. The compounds, as disclosed in U.S. Pat. No. 6,458,799, disclosure of which is incorporated herein by reference are useful as inhibitors for 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP)and in treating cancers.
5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorolysis of 5′-deoxy-5′-methylthioadenosine (MTA) to adenine and 5-methylthio-D-ribose-1-phosphate. MTA is a by-product of polyamine biosynthesis, which is essential for cell growth and proliferation. This salvage reaction is the principal source of free adenine in human cells. Because of its importance in coupling the purine salvage pathway to polyamine biosynthesis, MTAP is a potential chemotherapeutic target. The overall quaternary structure and subunit topology of MTAP are somewhat similar to mammalian purine nucleoside phosphorylase (PNP) (see Appleby, T. C., Erion, M. D., Ealick, S. E.,
Structure
, 1999, 7, 629-641 for the crystal structure and a comparison to mammalian PNP).
Cancer cell lines lacking MTAP do display increased sensitivity towards known chemotherapeutic drugs such as methotrexate and azaserine in the presence of MTA, whereas cancer cell lines with MTAP activity are not as severely affected. In view of these observations, the treatment of MTAP
+
tumors could be enhanced by the co-administration of a potent MTAP inhibitor together with traditional chemotherapeutic compounds that specifically target the de novo purine biosynthetic machinery.
As disclosed in U.S. Pat. No. 6,458,799, certain derivatives of 9-deazaadenine and more particularly 1-C-(9-deazaaden-9-yl)-1,4-imino-D-5′-deoxy-5′-methylthioribitol and pharmaceutically acceptable salts thereof suppress 5′-deoxy-5′-methylthioadenosine phosphorylase.
However, the method for preparing the compounds disclosed in U.S. Pat. No. 6,458,799 is somewhat tedious to perform and does not result in especially good yields of high purity product.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to an improved process for producing 1-C-(9-deazaaden-9-yl)-1,4-imino-D-5′-deoxy-5′-methylthioribitol and salts thereof.
The process comprises:
a) converting a 4-cyanomethyl-6-substituted-methyl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester to the corresponding methyl sulfanyl compound, 4-cyanomethyl-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester by reaction with toluenesulfonylchloride in the presence of a base;
b) the product from a) is methylated to form the corresponding methylsulfanyl derivative;
c) the methylsulfanyl derivative from b) is reacted with tert-butoxy-bis(N,N-dimethylamino)methane to provide the corresponding 4-(1-cyano-2 dimethylamino-vinyl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester;
d) the product from c) is converted to the corresponding 4-(1-cyano-2-hydroxy-vinyl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester by reacting with a hydrolyzing agent;
e) the product from d) is converted to the corresponding cyanomethylamino compound by reacting with amino acetonitrile.
f) the product from e) is converted to the ester form by reaction with an esterification agent;
g) the product from f) is cyclized to the corresponding pyrrol compound, 4-(4-amino-5-cyano-1-ethoxycarbonyl-1H-pyrrol-3-yl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-arboxylic acid tert-butyl ester;
h) the product from g) is converted to the corresponding amino derivative by removal of the ethoxycarbonyl substituent to produce 4-4-amino-5-cyano-1H-pyrrol-3-yl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester
i) the product from h) is reacted with formamidine acetate to form the target compound.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for producing 1-C-9-deazaaden-9-yl)-1,4-imino-D-5′-deoxy-5′-methylthioribitol which can be represented by the following formula:
and salts thereof.
Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonie, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic acids.
The method the present invention is shown below in the Scheme. In this method, the starting material, a 4-cyanomethyl-6-substututed-methyl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester, such as 4-cyanomethyl-6-hydroxymethyl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester; 4-cyanomethyl-6-tert-butyldimethoxysilyl-methyl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester and 4-cyanomethyl-6-fluoromethyl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester, can be prepared the method described by Evans et al,
Tetrahedron
56, 2000, pages 3053-3062, disclosure of which is incorporated herein by reference. This starting material is then converted to the corresponding methyl sulfanyl compound, 4-cyanomethyl-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester by reaction with toluenesulfonylchloride in the presence of a base such as pyridine and trimethylamine followed by methylating such as using sodium thiomethoxide. This methylsulfanyl derivative is then reacted with tert-butoxy-bis(N,N-dimethylamino)methane to provide the corresponding 4-(1-cyano-2 dimethylamino-vinyl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester, which in turn is converted to the corresponding 4-(1-cyano-2-hydroxy-vinyl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester by reacting with a hydrolyzing agent such as a weak acid such as acetic acid.
The corresponding cyanomethylamino compound is then obtained by reaction, for example, with amino acctonitrile. This intermediate is then converted to the ester form by reaction with an esterification agent such as ethyl chloroformate. This intermediate is then cyclized to the corresponding pyrrol compound, 4-(4-amino-5-cyano-1-ethoxycarbonyl-1H-pyrrol-3-yl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester using, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene. This compound w

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