Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-29
2002-08-20
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S553000
Reexamination Certificate
active
06437134
ABSTRACT:
BACKGROUND OF THE INVENTION
The compound phenylthiobutyl-isoquinoline of the formula
and its preparation starting from L-serine is described, e.g., in U.S. Pat. No. 5,484,926, incorporated herein by reference. This compound is a valuable intermediate for the manufacture of pharmacologically active compounds, suitable for the treatment of viral infections, especially those caused by HIV and other retroviruses, described in U.S. Pat. No. 5,484,926, e.g., at columns 16 and 17, such as represented by formula
wherein Ph is phenyl,
and pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
The present invention relates to a new method for making compounds of formula
and intermediates for making compounds of formula II.
The compounds of this invention are useful intermediates for the manufacture of pharmacologically active compounds suitable for the treatment of viral infections, particularly, those caused by HIV and other retroviruses.
The method of the present invention is characterized by less reaction steps, more convenient reaction conditions and a higher overall yield of the desired stereoisomer of formula II. Particularly, in accordance with the method of the present invention, protection of a carbamate group of an intermediate phenylthio compound by a silyl group leads to a considerable increase in yield compared to that of prior methods for making compounds of formula II.
DETAILED DESCRIPTION OF THE INVENTION
The method of the present invention comprises
(a) reacting diprotected L-serine of formula
wherein R is lower alkyl and R
1
is lower alkyl or benzyl,
with mesyl or tosyl chloride and a thiophenolate;
(b) reacting the resulting phenylthio compound of formula
with halogenated methyllithium;
(c) reducing a resulting halogen ketone of formula
wherein X is halogen,
to the corresponding halogen alcohol of formula
(d) treating the halogen alcohol of formula V with a base to form the [(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]-carbamic acid ester of formula
(e) reacting the carbamic acid ester of formula IV with N-tert.-butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide of formula
and
(f) treating the resulting compound of formula
with a base to yield the compound of formula II above.
The term “lower-alkyl” used throughout the specification and claims refers to straight- or branched-chain saturated hydrocarbon residues with 1-6, preferably 1-4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, a pentyl or a hexyl group with methyl and ethyl being preferred, especially for R
1
. Especially preferred in connection with the present invention are compounds wherein R
1
is methyl. Halogen denotes chlorine, bromine and iodine with chlorine being preferred.
The starting diprotected L-serines of formula VIII are known compounds and can easily be prepared from L-serine via reacting the corresponding L-serine lower alkyl esters with the corresponding chloroformates.
The phenylthio compounds of formula VII may be prepared using methods known in the art (e.g. Sasaki et al., Tetrahedron Letters 28, 6069 (1987)). The amino- and carboxy-protected L-serine is transformed into its tosylate or mesylate in the presence of an amine such as pyridine or triethylamine in an aprotic solvent such as methylene chloride or acetic acid ester and then reacted with a thiophenolate. The thiophenolate can be prepared in situ from thiophenol and a strong base, at low temperature, preferably a temperature from −10° C. up to 0° C..
Any conventional halomethylating agent can be used to halomethylate the phenylthio compounds of formula VII to form the halogen ketone compounds of formula VI. The halomethylation of the resulting phenylthio compound VII is preferably effected using halogenated methyllithium which is generated in situ. The latter is conveniently formed using dihalogenated methane, e.g., dichloro-, dibromo- or diiodomethane, preferably using bromochloromethane, and a lower-alkyl-lithium, such as, for example, butyllithium or hexyllithium, in an ether, preferably tetrahydrofuran, at −20° to −120° C., preferably −80° C.
In accordance with the method of the present invention, the halomethylation of the phenylthio compound VII to the halogen ketone VI is carried out by
(a) silylating a carbamate group of a compound of formula VII in the presence of a lower-alkyl-lithium to form a silyl-protected compound; and
(b) alkylating the silyl-protected compound in the presence of dihalogenated methane with a lower-alkyl-lithium to produce a halogen ketone of formula VI.
Preferred silyl-protected compounds of the present invention include compounds of the
general formula VII-A and/or VII-B formed as an intermediate
In accordance with the present invention, any conventional method for producing the silyl-protected compounds of formulas VII-A and VII-B can be used. Suitable silylating agents for use with the present invention include organochlorosilanes of the formula ClSi(R
2
, R
3
, R
4
), wherein R
2
, R
3
and R
4
are lower-alkyl or phenyl. A preferred organochlorosilane is chlorotrimethylsilane.
The method of the present invention for making the halogen ketone of formula VI provides new and unexpected results. Surprisingly, the protection of the carbamate group present in compound VII by a silyl group yielding compounds VII-A and/or VII-B as intermediates leads to a considerable increase in yield of the halogen ketone compounds of formula VI. Furthermore, this novel method for producing the halogen ketone compounds of formula VI can be used in a process for making the compounds of formula II to provide increased yields of the compounds of formula II compared to prior methods.
In accordance with the present invention, any conventional means can be used to alkylate the silyl-protected compounds of formula VII-A and VII-B. Preferred alkylating agents are lower-alkyl-lithium compounds such as butyllithium or hexyllithium. Moreover, an almost complete halomethylation of the phenylthio compounds of formula VII can be achieved using significantly less lower-alkyl-lithium and dihalogenated methane compared to amounts typically used in conventional halomethylation methods. In accordance with the present invention, the halogen ketone VI can be reduced to the corresponding alcohol of formula V with a hydride In a solvent such as toluene, tetrahydrofuran or an alcohol, preferably methanol, ethanol or isopropanol, at a temperature between −30 and 80° C., preferably between −15° C. and 50° C., optionally under reduced pressure, using sodium bis-(2-methoxy-ethoxy)-aluminium hydride, lithium aluminium hydride, lithium aluminium tri-tert.-butoxyhydride, sodium borohydride, tetramethylammonium borohydride or, preferably, using, an aluminium tri-alkoxide or lithium aluminium tri-alkoxyhydride. The term “alkoxide” means lower alkoxy with the lower-alkyl residue being as defined above, such as, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or isobutoxy, tert.-butoxy, as well as pentyloxy or hexyloxy groups. The aluminium compounds can have identical or different alkoxy groups. Aluminium tri-isopropoxide and aluminium tri-sec.-butoxide are especially preferred compounds. The reagents lithium aluminium tri-tert.-butoxyhydride, aluminium tri-isopropoxide and aluminium tri-sec.-butoxide gave unexpected high stereoselectivity in a molar ratio of at least 9:1 of the (1S,2S) and (1S, 2R) isomeric halohydrins V, which could be crystallized in >99% optical purity and with high yield.
The ring closure of the halohydrin of formula V to form the corresponding epoxide of formula IV can be carried out by conventional means, such as in a solvent, for example, ethanol or preferably, a toluene/water mixture in the presence of a base such as an alkaline or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide, at a temperature between 0° and 80° C., preferably 40-50° C. The epoxide which is formed need not be purified.
The reaction of the epoxide of formula IV with the isoqu
Convington Raymond
Hoffmann-La Roche Inc.
Johnston George W.
Rotman Alan L.
Tramaloni Dennis P.
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