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US 5,064,961 AGranted
Process for preparing an optically active cyclobutane nucleoside
AssigneeE. R. Squibb & Sons, Inc.
InventorsGregory S. Bisacchi, Toomas Mitt
Life of this patent
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Abstract
A process for the preparation of the optically active compound [IR-(1.alpha., 2.beta., 3.alpha.)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one, represented by the formula: ##STR1## and novel intermediates are described.
Claims14
A process for the preparation of the optically active compound [1R-(1.alpha.,2.beta.,3.alpha.)]-2-amino-9-[2,3-bis(hydroxymethyl) cyclobutyl]-1,9-dihydro-6H-purin -6-one, represented by the formula ##STR4## which comprises (1) reacting a racemic compound of the formula ##STR5## wherein R.sup.1 and R.sup.2 are lower alkyl with alkali to yield the racemic compound of the formula ##STR6## wherein R.sup.1 is as defined above;
- (2) reacting a compound of formula 3 with a chiral primary amine of the formula
- R.sup.3 NH.sub.2
- wherein R.sup.3 NH.sub.2 is a chiral hydroxy substituted alkylamine, a chiral alkylamine substituted with both hydroxy and phenyl, (+)- or (-)- threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol, (+)- or (-)-norepinephrine, (+)-2-amino-3-methoxy -1-phenylpropanol, L-tyrosinol, and lower alkyl esters of (+)- or (-)-tyrosine and (+)- or (-)-threonine in the presence of a coupling agent selected from the group consisting of 1,3-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to yield a mixture of compounds having the formulae ##STR7## (3) separating the diastereomeric compounds of formulae 4 and 5;
- (4) protecting the hydroxy groups substituted on the moiety R.sup.3 in a compound of formula 4to afford a compound having the formula ##STR8## wherein the hydroxy protecting group is a hindered silyl group selected from the group consisting of t-butyldimethylsilyl, t-butyldiphenylsilyl, and triisopropylsilyl, an acyl group, an aroyl group, or trityl;
- (5) reacting a compound of formula 6 with a nitrosating agent to yield a compound having the formula ##STR9## (6) treating a compound of formula 7 with a reducing agent selected from the group consisting of lithium aluminum hydride, sodium borohydride, and lithium borohydride to yield a compound of the formula ##STR10## (7) reacting a compound of formula 9 with a protecting agent selected from the group consisting of t-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, acyl, and aroyl to yield a compound of the formula ##STR11## wherein R.sup.4 is a protecting group and R.sup.1 is as defined above;
- (8) reacting a compound of formula 10 with an acid catalyst selected from the group consisting of sulfuric acid, hydrochloric acid, and p-toluenesulfonic acid to yield a compound of the formula ##STR12## wherein R.sup.4 is as defined above;
- (9) reacting a compound of formula 11 with a reducing agent selected from the group consisting of lithium trisec-butylborohydride, lithium trisiamylborohydride, diisobutylaluminum hydride, dicyclohexylborane, and disiamylborane to yield a compound of the formula ##STR13## wherein R.sup.4 is as defined above;
- (10) reacting a compound of formula 12 with a sulfonylating reagent to yield a compound of the formula ##STR14## wherein X is an alkanesulfonyloxy group, a substituted alkanesulfonyloxy group, an arenesulfonyloxy group, or a substituted arenesulfonyloxy group and the sulfonylating reagent is the corresponding sulfonic anhydride or sulfonyl chloride;
- (11) reacting a compound of formula 13 with guanine or a protected guanine to yield a compound of the formula ##STR15## wherein W is a 9-guanyl residue or a protected 9-guanyl residue and R.sup.4 is as defined above;
- and
- (12) deprotecting a compound of formula 14 to yield the compound of formula 1.
8 more elements
A process for the preparation of the optically active compound [1R-(1.alpha.,2.beta.,3.alpha.)]-2-amino-9-[2,3-bis(hydroxymethyl) cyclobutyl]-1,9-dihydro-6H-purin-6-one, represented by the formula ##STR16## which comprises (1) reacting a racemic compound of the formula ##STR17## wherein R.sup.1 and R.sup.2 are lower alkyl with alkali to yield the racemic compound of the formula ##STR18## wherein R.sup.1 is as defined above;
- (2) reacting a compound of formula 3 with a chiral primary amine of the formula
- R.sup.3 NH.sub.2
- wherein R.sup.3 NH.sub.2 is a chiral alkyl amine, a chiral phenyl or naphthyl-substituted alkyl amine, (+)- or (-)-.alpha.-methyl-p-nitrobenzylamine, (+)-dehydroabietylamine, or a lower alkyl ester of an .alpha.-amino acid selected from the group consisting of (+)-alanine, (-)-alanine, (+)-valine, (-)-valine, (+)-leucine, (-)-leucine, (+)-isoleucine, (-)-isoleucine, (+)-phenylalanine, (-)-phenylalanine, (+)-serine, and (-)-serine in the presence of a coupling agent selected from the group consisting of 1,3-dicyclohexylcarbodiimide and 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to yield a mixture of compounds having the formulae ##STR19## (3) separating the diastereomeric compounds of formulae 4 and 5;
- (4) reacting of compound of formula 4 with a nitrosating agent to yield a compound having the formula ##STR20## (5) treating a compound of formula 8 with a reducing agent selected from the group consisting of lithium aluminum hydride, sodium borohydride, and lithium borohydride to yield a compound of the formula ##STR21## (6) reacting a compound of formula 9 with a protecting agent selected from the group consisting of t-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, acyl and aroyl to yield a compound of the formula ##STR22## wherein R.sup.4 is a protecting group and R.sup.1 is as defined above;
- (7) reacting a compound of formula 10 with an acid catalyst selected from the group consisting of sulfuric acid, hydrochloric acid, and p-toluenesulfonic acid to yield a compound of the formula ##STR23## wherein R.sup.4 is as defined above;
- (8) reacting a compound of formula 11 with a reducing agent selected from the group consisting of lithium tri-sec-butylborohydride, lithium trisiamylborohydride, diisobutylaluminum hydride, dicyclohexylborane, and disiamylborane to yield a compound of the formula ##STR24## wherein R.sup.4 is as defined above;
- (9) reacting a compound of formula 12 with a sulfonylating reagent to yield a compound of the formula ##STR25## wherein X is an alkanesulfonyloxy group, a substituted alkanesulfonyloxy group, an arenesulfonyloxy group, or a substituted arenesulfonyloxy group and the sulfonylating reagent is the corresponding sulfonic anhydride or sulfonyl chloride;
- (10) reacting a compound of formula 13 with guanine or a protected guanine to yield a compound of the formula ##STR26## wherein W is a guanyl residue or a protected 9-guanyl residue and R.sup.4 is as defined above;
- and
- (11) deprotecting a compound of formula 14 to yield the compound of formula 1.
7 more elements
Dependencies are inferred from the claim text.