Processes for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof
OwnerDaniel R. Henton, Frederick J. McCarty +2inventors
InventorsDaniel R. Henton, Frederick J. McCarty, Susan I. Tripp, Jill E. DeWitt
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Abstract
The present invention is related to novel processes for preparing anhydrous and hydrated forms of piperidine derivatives, polymorphs and pseudomorphs thereof of the formulas 1 2 which are useful as antihistamines, antiallergic agents and bronchodilators.
Claims47
A process for preparing a compound of the formula 9
- wherein
- R1 represents hydrogen or hydroxy;
- R2 represents hydrogen;
- or
- R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
- n is an integer of from 1 to 5;
- R3 is —CH2OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
- W is —CH(OH)− or —C(═O)—;
- A is hydrogen or hydroxy;
- Y is a pharmaceutically acceptable acid;
- and
- the individual optical isomers thereof, comprising subjecting a compound of the formula 10
- and the individual optical isomers thereof, wherein R1, R2, R3, n, W, A and Y are defined above and X is a number ranging essentially from 0.10 to 5 to an azeotropic distillation.
A process for preparing a compound of the formula 11
- wherein
- R1 represents hydrogen or hydroxy;
- R2 represents hydrogen;
- or
- R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
- n is an integer of from 1 to 5;
- R3 is —CH2OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
- W is —CH(OH)— or —C(═O)—;
- A is hydrogen or hydroxy;
- Y is a pharmaceutically acceptable acid;
- and
- the individual optical isomers thereof, comprising subjecting a compound of the formula 12
- and the individual optical isomers thereof, wherein R1, R2, R3, n, W, A and Y are defined above and X is a number ranging essentially from 0.10 to 5 to a water-minimizing recrystallization.
A process for preparing a compound of the formula 13
- wherein
- R1 represents hydrogen or hydroxy;
- R2 represents hydrogen;
- or
- R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
- n is an integer of from 1 to 5;
- R3 is —CH2OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
- W is —CH(OH)— or —C(═O)—;
- A is hydrogen or hydroxy;
- Y is a pharmaceutically acceptable acid;
- X is a number ranging essentially from 0.1 to 5;
- and
- the individual optical isomers thereof,
- comprising subjecting a compound of the formula 14
- and the individual optical isomers thereof wherein R1, R2, R3, n, A, W and Y are as defined above, to an aqueous recrystallization.
A process for preparing a compound of the formula 15
- and the individual optical isomers thereof, wherein Y is a pharmaceutically acceptable acid, comprising subjecting a compound of the formula 16
- wherein Y is as defined above and X is a number ranging essentially from 0.10 to 5 to an azeotropic distillation.
A process for preparing a compound of the formula 17
- and the individual optical isomers thereof, wherein Y is a pharmaceutically acceptable acid, comprising subjecting a compound of the formula 18
- wherein Y is as defined above and x is a number ranging essentially from 0.10 to 5 to a water-minimizing recrystallization.
A process for preparing a compound of the formula 19
- and the individual optical isomers thereof, wherein Y is a pharmaceutically acceptable acid and X is a number ranging essentially from 0.10 to 5, comprising subjecting a compound of the formula 20
- wherein Y is as defined above to an aqueous recrystallization.
A compound of the formula 21
- and the individual optical isomers thereof, formed by the process comprising the steps of:
- a) treating a compound of the formula 22
- wherein X is a number ranging from 0.1 to 5 and the individual optical isomers thereof,-with a suitable solvent or solvent mixture;
- b) heating the mixture to a suitable temperature;
- and
- c) cooling the mixture to complete crystallization.
A compound of the formula 23
- and the individual optical isomers thereof, formed by the process comprising the steps of:
- a) treating a compound of the formula 24
- wherein X is a number ranging from 0.1 to 5 and the individual optical isomers thereof, with a suitable anhydrous solvent or solvent mixture in an amount sufficient to cause dissolution;
- b) heating the mixture to a suitable temperature.
- c) adding an additional volume of a suitable anhydrous solvent or solvent mixture in a quantity sufficient to initiate crystallization;
- and
- d) cooling the reaction mixture to complete crystallization.
A compound of the formula 25
- wherein X is a number ranging from 0.1 to 5 and the individual optical isomers thereof, formed by the process comprising the steps of:
- a) treating a compound of the formula 26
- and the individual optical isomers thereof with a suitable solvent;
- b) heating the mixture to a suitable temperature;
- and
- c) cooling the mixture to initiate crystallization.
Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.
Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.
Form III anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.
Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.
A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a water-minimizing recrystallization.
A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to an azeotropic distillation.
A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form III anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a crystal digestion.
A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a water-minimizing recrystallization.
A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to an azeotropic distillation.
A process for preparing the Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises:
- a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride with an appropriate reducing agent in a suitable solvent;
- b) acidifying with hydrochloric acid;
- and
- c) adding water over a period of time ranging from 1 minute to 45 minutes at a temperature range of about −20° C. to 50° C.
A process for preparing the Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises:
- a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate with an appropriate reducing agent in a suitable solvent;
- b) acidifying with hydrochloric acid;
- and
- c) adding water over a period of time ranging from 1 minute to 45 minutes at a temperature range of about −20° C. to 50° C.
A process for preparing the Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to an aqueous recrystallization.
A process for preparing the Form III anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-α,α-dimethylbenzeneacetic acid hydrochloride to a water-minimizing recrystallization.
A process for preparing the Form IV hydrated 4-[4-(4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises:
- a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride with an appropriate reducing agent in a suitable solvent;
- b) acidifying with hydrochloric acid;
- and
- c) adding water over a period of time ranging from 30 minutes to 24 hours at a temperature range of about 0° C. to 50° C.
A process for preparing the Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises:
- a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate with an appropriate reducing agent in a suitable solvent;
- b) acidifying with hydrochloric acid;
- and
- c) adding water over a period of time ranging from 30 minutes to 24 hours at a temperature range of about 0° C. to 50° C.
Dependencies are inferred from the claim text.