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US 5,856,492 AGranted
Efficient synthesis of a chiral mediator
AssigneeMerck & Co., Inc.
InventorsCheng Yi Chen, Feng Xu, Richard D. Tillyer, Dalian Zhao
Life of this patent
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Abstract
An efficient method for the quantitative preparation and isolation of a compound of formula I ##STR1## or its enantiomer, a chiral mediator used in enantioselective synthesis.
Claims32
A process for the preparation of a hydrochloride salt of a compound of Formula I:
- ##STR45## wherein A represents:
- ##STR46## ##STR47## represents a six-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with C.sub.1 -C.sub.6 -alkyl;
- ##STR48## represents:
- a five-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with C.sub.1 -C.sub.6 -alkyl;
- n is 1, 2, or 3;
- m is 0, or 1;
- t is 0, 1, or 2;
- s is 1 or 2;
- R.sup.1 is:
- H, phenyl, or C.sub.1 -C.sub.6 -alkyl, unsubstituted or substituted with C.sub.1 -C.sub.6 -alkoxy;
- R.sup.2 is:
- H, C.sub.1 -C.sub.6 -alkyl, or ##STR49## R.sup.3 is:
- H, C.sub.1 -C.sub.6 -alkyl, or phenyl;
- R.sup.4 is:
- H, except that R.sup.1 and R.sup.4 can represent a carbon carbon bond, when t is 1 or 2, or --(CH.sub.2).sub.s --, when t is 0;
- comprising the steps of:
- (a) refluxing the 1,2-amino alcohol compound, ##STR50## with an alkylating agent ##STR51## wherein X is Cl, Br, I, OTf, OTs or OMs;
- in the presence of a base and a solvent, at a reaction temperature of about 65.degree. C. to about 120.degree. C. for reaction time of about 12 to about 36 hours, while removing the water formed to give a solution of crude compound of Formula I;
- (b) adding hydrogen chloride in solution or as a gas to a solution of the crude compound of Formula I at about 10.degree. to about 15.degree. C. and maintaining a reaction temperature of about 10.degree. to about 25.degree. C. to form a slurry of the hydrochloride salt of the compound of Formula I;
- (c) azeotropically distilling the solvents leaving a concentrated slurry-solution of the hydrochloride salt of the compound of Formula I;
- (d) crystallizing the concentrated solution of the hydrochloride salt of the compound of Formula I at about 0.degree. C. to about 20.degree. C. to give a slurry of crystalline hydrochloride salt of the compound of Formula I;
- and
- (e) filtering the slurry of crystalline hydrochloride salt of the compound of Formula I to isolate crystalline hydrochloride salt of the compound of Formula I.
20 more elements
A process for the preparation of R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer, ##STR53## comprising the steps of:
- (a) refluxing (1R,2S)-(-)-norephedrine or its enantiomer, ##STR54## with 1,4-dibromobutane in the presence of a base, sodium bicarbonate and a solvent, toluene, at a reaction temperature of about 100.degree. to about 120.degree. C. for reaction time of about 12 to about 24 hours, while removing the water formed to give a toluene solution of crude R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol or its enantiomer;
- (b) adding a solution of hydrogen chloride in isopropanol to a toluene solution of R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol or its enantiomer at about 10.degree. to about 15.degree. C. and maintaining a reaction temperature of about 10.degree. to about 25.degree. C. to form R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer;
- (c) azeotropically distilling the isopropanol-toluene leaving a concentrated toluene slurry of R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer;
- (d) crystallizing the concentrated toluene slurry of (R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer at about 0.degree. C. to about 20.degree. C. to give a toluene slurry of crystalline R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer;
- and
- (e) filtering the toluene slurry of crystalline R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer to isolate crystalline R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol hydrochloride or its enantiomer.
3 more elements
A compound of Formula I:
- ##STR55## or its enantiomer, wherein A represents:
- ##STR56## ##STR57## represents a six-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with C.sub.1 -C.sub.6 -alkyl;
- ##STR58## represents:
- a five-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with C.sub.1 -C.sub.6 -alkyl;
- n is 1, 2, or 3;
- m is 0, or 1;
- t is 0, 1, or 2;
- s is 1 or 2;
- R.sup.1 is:
- H, phenyl, or C.sub.1 -C.sub.6 -alkyl, unsubstituted or substituted with C.sub.1 -C.sub.6 -alkoxy;
- R.sup.2 is:
- H, C.sub.1 -C.sub.6 -alkyl, or ##STR59## R.sup.3 is:
- H, C.sub.1 -C.sub.6 -alkyl, or phenyl;
- and R.sup.4 is:
- H, except that R.sup.1 and R.sup.4 can represent a carbon carbon bond, when t is 1 or 2, or --(CH.sub.2).sub.s --, when t is 0,
- with the proviso that:
- (a) when the compound of structural formula I ##STR60## or its enantiomer is defined as R.sup.1 is H or CH.sub.3, that A cannot represent --(CHR.sup.3).sub.n --, or ##STR61## when n is 2, or 3, R.sup.3 is H and m is 0;
- and (b) when the compound of structural formula I or its enantiomer is defined as ##STR62## that A cannot represent --(CHR.sup.3).sub.n --, when n is 2, and R.sup.3 is H, as a free base or an acid salt thereof.
15 more elements
A process for the preparation of a compound of Formula I:
- ##STR63## wherein A represents:
- ##STR64## ##STR65## represents a six-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with C.sub.1 -C.sub.6 -alkyl;
- ##STR66## represents:
- a five-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with C.sub.1 -C.sub.6 -alkyl;
- n is 1, 2, or 3;
- m is 0, or 1;
- t is 0, 1, or 2,
- s is 1 or 2;
- R.sup.1 is:
- H, phenyl, or C.sub.1 -C.sub.6 -alkyl, unsubstituted or substituted with C.sub.1 -C.sub.6 -alkoxy;
- R.sup.2 is:
- H, C.sub.-C.sub.6 -alkyl, or ##STR67## R.sup.3 is:
- H, C.sub.1 -C.sub.6 -alkyl, or phenyl;
- R.sup.4 is:
- H, except that R.sup.1 and R.sup.4 can represent a carbon carbon bond, when t is 1 or 2, or --(CH.sub.2).sub.s --, when t is 0;
- comprising the steps of:
- (a) refluxing the 1,2-amino alcohol compound, ##STR68## with an alkylating agent ##STR69## wherein X is Cl, Br, I, OTf, OTs or OMs;
- in the presence of a base and a solvent at a reaction temperature of about 100.degree. to about 120.degree. C. for reaction time of about 12 to about 36 hours, while removing the water formed to give a solution of crude compound of Formula I;
- (b) filtering the solvent solution containing the crude compound of Formula I to remove the sodium bromide salt, once the solution reaches room temperature;
- (c) washing the sodium bromide wet cake with a solvent;
- (d) extracting the filtrate-solvent solution containing the crude compound of Formula I with water to remove any additional sodium bromide salt;
- (e) mixing the washed filtrate-solvent solution containing the crude compound of Formula I with an aqueous acid solution to form the acid salt of the compound of Formula I;
- (f) isolating the aqueous layer containing the acid salt of a compound of Formula I;
- (g) neutralizing a biphasic solution of the aqueous layer containing the acid salt of a compound of Formula I and solvent with a base while maintaining the temperature below about 30.degree. C.;
- (h) extracting the compound of Formula I from the biphasic solution into the solvent after mixing for less than about one hour;
- and
- (i) isolating the solvent layer containing the compound of Formula I.
24 more elements
Dependencies are inferred from the claim text.