U.S. patent application number 10/128926 was filed with the patent office on 2002-12-19 for process for preparing anyhdrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof.
Invention is credited to DeWitt, Jill E., Henton, Daniel R., McCarty, Frederick J., Tripp, Susan I..
Application Number | 20020193600 10/128926 |
Document ID | / |
Family ID | 26937420 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020193600 |
Kind Code |
A1 |
Henton, Daniel R. ; et
al. |
December 19, 2002 |
Process for preparing anyhdrous and hydrate forms of antihistaminic
piperidine derivatives, polymorphs and pseudomorphs thereof
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 which are
useful as antihistamines, antiallergic agents and
bronchodilators.
Inventors: |
Henton, Daniel R.; (Midland,
MI) ; McCarty, Frederick J.; (Hilton Head Island,
SC) ; Tripp, Susan I.; (Lee's Summit, MO) ;
DeWitt, Jill E.; (Kansas City, MO) |
Correspondence
Address: |
AVENTIS PHARMACEUTICALS, INC.
PATENTS DEPARTMENT
ROUTE 202-206, P.O. BOX 6800
BRIDGEWATER
NJ
08807-0800
US
|
Family ID: |
26937420 |
Appl. No.: |
10/128926 |
Filed: |
April 24, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10128926 |
Apr 24, 2002 |
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09213565 |
Dec 17, 1998 |
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09213565 |
Dec 17, 1998 |
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08815642 |
Mar 13, 1997 |
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08815642 |
Mar 13, 1997 |
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08439671 |
May 12, 1995 |
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08439671 |
May 12, 1995 |
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08417161 |
Apr 11, 1995 |
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08417161 |
Apr 11, 1995 |
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08245731 |
May 18, 1994 |
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Current U.S.
Class: |
546/217 ;
546/238 |
Current CPC
Class: |
A61P 11/08 20180101;
A61P 37/08 20180101; C07D 211/22 20130101; A61P 43/00 20180101;
A61K 31/445 20130101; A61P 11/00 20180101 |
Class at
Publication: |
546/217 ;
546/238 |
International
Class: |
C07D 211/44; C07D
211/54 |
Claims
What is claimed is:
1. A process for preparing a compound of the formula 5wherein
R.sub.1 represents hydrogen or hydroxy; R.sub.2 represents
hydrogen; or R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2; n is an
integer of from 1 to 5; R.sub.3 is --CH.sub.2OH, --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(.dbd.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 6and the individual optical isomers
thereof, wherein R.sub.1, R.sub.2, R.sub.3, n, W, A and Y are
defined above and X is a number ranging essentially from 0.10 to 5
to an azeotropic distillation.
2. A process for preparing a compound of the formula 7wherein
R.sub.1 represents hydrogen or hydroxy; R.sub.2 represents
hydrogen; or R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2; n is an
integer of from 1 to 5; R.sub.3 is --CH.sub.2OH, --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(.dbd.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 8and the individual optical isomers
thereof, wherein R.sub.1, R.sub.2, R.sub.3, 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.
3. A process for preparing a compound of the formula 9wherein
R.sub.1 represents hydrogen or hydroxy; R.sub.2 represents
hydrogen; or R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2; n is an
integer of from 1 to 5; R.sub.3 is --CH.sub.2OH, --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(.dbd.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 10and the individual optical isomers thereof wherein
R.sub.1, R.sub.2, R.sub.3, n, A, W and Y are as defined above, to
an aqueous recrystallization.
4. A process for preparing a compound of the formula 11and the
individual optical isomers thereof, wherein Y is a pharmaceutically
acceptable acid, comprising subjecting a compound of the formula
12wherein Y is as defined above and X is a number ranging
essentially from 0.10 to 5 to a azeotropic distillation.
5. A process for preparing a compound of the formula 13and the
individual optical isomers thereof, wherein Y is a pharmaceutically
acceptable acid, comprising subjecting a compound of the formula
14wherein Y is as defined above and X is a number ranging
essentially from 0.10 to 5 to a water-minimizing
recrystallization.
6. A process for preparing a compound of the formula 15and 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 16wherein Y is
as defined above to an aqueous recrystallization.
7. A process according to claim 4, claim 5 or claim 6 wherein Y is
HCl.
8. A process according to claim 7 wherein x is a number ranging
from 1 to 4.
9. A process according to claim 8 wherein x is a number ranging
from 2 to 3.
10. A compound of the formula 17and the individual optical isomers
thereof, formed by the process comprising the steps of: a) treating
a compound of the formula 18 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.
11. A compound of the formula 19and the individual optical isomers
thereof, formed by the process comprising the steps of: a) treating
a compound of the formula 20 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.
12. A compound of the formula 21wherein X is a number 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 22
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.
13. Form I anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydr-
oxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride.
14. Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydr-
oxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride.
15. Form III anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hy-
droxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride.
16. Form IV hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydr-
oxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride.
17. A pharmaceutical composition comprising an effective
antiallergic amount of a compound of claim 13 in admixture or
otherwise in association with an inert carrier.
18. A pharmaceutical composition comprising an effective
antiallergic amount of compound of claim 14 in admixture or
otherwise in association with an inert carrier.
19. A pharmaceutical composition comprising an effective
antiallergic amount of a compound of claim 15 in admixture or
otherwise in association with an inert carrier.
20. A pharmaceutical composition comprising an effective
antiallergic amount of a compound of claim 16 in admixture or
otherwise in association with an inert carrier.
21. A method of treating allergic reactions in a patient in need
thereof which comprises administering to said patient an
anti-allergically effective amount of a compound off claim 13.
22. A method of treating allergic reactions in a patient in need
thereof which comprises administering to said patient an
anti-allergically effective amount of a compound of claim 14.
23. A method of treating allergic reactions in a patient in need
therof which comprises administering to said patient an
anti-allergically effective amount of a compound of claim 15.
24. A method of treating allergic reactions,in a patient in need
thereof which comprises administering to said patient an
anti-allergically effective amount of a compound of claim 16.
25. A process for preparing the Form I anhydrous
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises subjecting Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to a
water-minimizing recrystallization.
26. A process according to claim 25 wherein suitable anhydrous
solvents or solvent mixtures which are sufficient to cause
dissolution are acetone and water and a suitable anhydrous
antisolvent is ethyl acetate.
27. A process for preparing the Form I anhydrous
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises subjecting Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to an azeotropic
distillation.
28. A process according to claim 27 wherein suitable solvents or
solvent mixtures which are sufficient to cause dissolution are
methanol, acteone/water and methyl ethyl ketone/water and a
suitable anhydrous antisolvent is methyl ethyl ketone.
29. A process for preparing the Form I anhydrous
4-[4-[4-(Hydroxydiphenylm-
ethy)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride which comprises subjecting Form III anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to a crystal
digestion.
30. A process for preparing the Form I anhydrous
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises subjecting Form IV hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to a
water-minimizing recrystallization.
31. A process according to claim 30 wherein suitable anhydrous
solvents or solvent mixtures which are sufficient to cause
dissolution are acetone and water and a suitable anhydrous
antisolvent is ethyl acetate.
32. A process for Preparing the Form I anhydrous
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises subjecting Form IV hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to an azeotropic
distillation.
33. A process according to claim 32 wherein suitable solvents or
solvent mixtures which are sufficient to cause dissolution are
methanol, acteone/water and methyl ethyl ketone/water and a
suitable anhydrous antisolvent is methyl ethyl ketone.
34. A process for preparing the Form II hydrated
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises: a) reacting ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetate hydrochloride with an appropriate reducing
agent in a suitable solvent; b) acidifying with hydrochloric acid;
and c) adding water over a period of tide ranging from 1 minute to
45 minutes at a temperature range of about -20.degree. C. to
50.degree. C.
35. A process according to claim 34 wherein the water is added over
a period of time ranging from 10 minutes to 30 minutes at a
temperature range of about 0.degree. C. to 40.degree. C.
36. A process according to claim 35 wherein the water is added over
a period of time ranging from 10 minutes to 30 minutes at a
temperature range of about 20.degree. C. to 40.degree. C.
37. A process for preparing the Form II hydrated
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises: a) reacting ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-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.degree. C. to
50.degree. C.
38. A process according to claim 37 wherein the water is added over
a period of time ranging from 10 minutes to 30 minutes at a
temperature range of about O.degree. C. to 40.degree. C.
39. A process according to claim 38 wherein the water is added over
a period of time ranging from 10 minutes to 30minutes a temperature
range of about 20.degree. C. to 40.degree. C.
40. A process for preparing the Form II hydrated
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c acid hydrochloride which comprises subjecting Form I anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to an aqueous
recrystallization.
41. A process for preparing the Form III anhydrous
4-[4-[4-(Hydroxydipheny-
lmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneace-
tic acid hydrochloride which comprises subjecting Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride to a
water-minimizing recrystallization.
42. A process for preparing the Form IV hydrated
4-[4-[4-(Hydroxydiphenylm-
ethyl)-1piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride which comprises: a) reacting ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetate hydrochloride with an appropriate reducing
agent in a suitable solvent; b) acidifying with hydrochloric acid;
and c) adding water over period of time ranging from 30 minutes to
24 hours at a temperature range of about 0.degree. C. to 50.degree.
C.
43. A process according to claim 42 wherein the water is added over
a period of time ranging from 1 hour to 12 hours at a temperature
range of about 10.degree. C. to 40.degree. C.
44. A process according to claim 43 wherein the water is added over
a period of time ranging from 2 hours to 8 hours at a temperature
range of about 20.degree. C. to 40.degree. C.
45. A process for preparing thee Form IV hydrated
4-[4-[4-(Hydroxydiphenyl-
methyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacet-
ic acid hydrochloride which comprises: a) reacting ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-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.degree. C. to 50.degree.
C.
46. A process according to claim 45 wherein the water is added over
a period of time ranging from 1 hour to 12 hours at a temperature
range of about 10.degree. C. to 40.degree. C.
47. A process according to claim 46 wherein the water is added over
a period of time ranging from 2 hours to 8 hours at a temperature
range of about 20.degree. C. to 40.degree. C.
Description
[0001] The present invention is related to novel processes for
preparing anhydrous and hydrated forms of piperidine derivatives,
polymorphs and pseudomorphs thereof which are useful as
antihistamines, antiallergic agents and bronchodilators [U.S. Pat.
No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981
and U.S. Pat. No. 4,285,958, Apr. 25, 1981].
SUMMARY OF THE INVENTION
[0002] The present invention provides a process for preparing
anhydrous, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formulas 2
[0003] wherein
[0004] R.sub.1 represents hydrogen or hydroxy;
[0005] R.sub.2 represents hydrogen; or
[0006] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0007] n is an integer of from 1 to 5;
[0008] R.sub.3 is --CH.sub.2OH, --COOH or --COOalkyl wherein the
alkyl moiety has from 1 to 6 carbon atoms and is straight or
branched;
[0009] each of A is hydrogen or hydroxy; and
[0010] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0011] comprising subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salt to an azeotropic
distillation.
[0012] In addition, the present invention also provides a process
for preparing anhydrous, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula 3
[0013] wherein
[0014] R.sub.1 represents hydrogen or hydroxy;
[0015] R.sub.2 represents hydrogen; or
[0016] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0017] n is an integer of from 1 to 5;
[0018] R.sub.3 is --CH.sub.2OH, --COOH or --COOalkyl wherein the
alkyl moiety has from 1 to 6 carbon atoms and is straight or
branched;
[0019] each of A is hydrogen or hydroxy; and
[0020] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0021] comprising subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salt to a
water-minimizing recrystallization.
[0022] In addition, the present invention provides a process for
preparing the hydrated, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula 4
[0023] wherein
[0024] R.sub.1 represents hydrogen or hydroxy;
[0025] R.sub.2 represents hydrogen; or
[0026] R.sub.1 and R.sub.2 taken together form a second bond
between the carbon atoms bearing R.sub.1 and R.sub.2;
[0027] n is an integer of from 1 to 5;
[0028] R.sub.3 is --CH.sub.2OH, --COOH or --COOalkyl wherein the
alkyl moiety has from 1 to 6 carbon atoms and is straight or
branched;
[0029] each of A is hydrogen or hydroxy; and
[0030] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0031] comprising subjecting the corresponding anhydrous,
pharmaceutically acceptable acid addition salts to an aqueous
recrystallization.
[0032] In addition, the present invention provides processes for
preparing polymorphs of anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1--
hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride designated herein as Form I and Form III and
processes for preparing psuedomorphs of hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-
-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride designated herein as Form II and Form IV.
[0033] The Form I polymorph may be identified by the following
characteristics: a visual melting point (capillary tube) in the
range of about 196-201.degree. C.; a melt endotherm with
extrapolated onset in the range of about 195-199.degree. C. as
determined by differential scanning calorimetry; and an X-ray
powder diffraction pattern essentially as shown in Table 1 wherein
the XRPD patterns were measured using a powder diffractometer
equipped with a Co X-ray tube source. The sample was illuminated
with Co K.alpha..sub.1 radiation and XRPD data were collected from
5 to 55.degree. 2.crclbar.. (intensities may vary radically due to
preferred orientation).
1 TABLE 1 D-Space, Angstroms Intensity, I/I.sub.o, % 11.8 30 7.3 30
6.3 65 5.9 35 5.0 45 4.8 100 4.4 45 3.9 60 3.8 75 3.7 30
[0034] The Form III polymorph may be identified by the following
characteristics: a visual melting point (capillary tube) in the
range of about 166-171.degree. C.; a broad endotherm below about
90.degree. C., a melt endotherm with an extrapolated onset of about
166.degree. C. as determined by differential scanning calorimetry;
and an X-ray powder diffraction pattern essentially as shown in
Table 2 wherein the XRPD patterns were measured using a powder
diffractometer equipped with a Co X-ray tube source. The sample was
illuminated with Co K.alpha..sub.1 radiation and XRPD data were
collected from 5 to 55.degree. 2.crclbar.. (intensities may vary
radically due to preferred orientation).
2 TABLE 2 D-Space, Angstroms Intensity, I/I.sub.o, % 9.0 95 4.9 100
4.8 35 4.6 25 4.5 25 3.7 25
[0035] The Form II pseudomorph may be identified by the following
characteristics: a visual melting point (capillary tube) in the
range of about 100-105.degree. C.; a large broad endotherm below
about 100.degree. C. and a small endothermic peak (about 2
joules/gram) with extrapolated onsets in the range of about
124-126.degree. C. as determined by differential scanning
calorimetry; and an X-ray powder diffraction pattern essentially as
shown in Table 3 wherein the XRPD patterns were measured using a
powder diffractometer equipped with a Co X-ray tube source. The
sample was illuminated with Co K.alpha..sub.1 radiation and XRPD
data were collected from 5 to 55.degree. 2.crclbar.. (intensities
may vary radically due to preferred orientation).
3 TABLE 3 D-Space, Angstroms Intensity, I/I.sub.o, % 7.8 45 6.4 44
5.2 85 4.9 60 4.7 80 4.4 55 4.2 50 4.1 60 3.7 75 3.6 60 3.5 50
[0036] The Form IV pseudomorph may be identified by the following
characteristics: a visual melting point (capillary tube) in the
range of about 113-118.degree. C.; two broad overlapping endotherms
below about 100.degree. C. and an additional endotherm with an
extrapolated onset at approximately 146.degree. C. as determined by
differential scanning calorimetry and an X-ray powder diffraction
pattern essentially as shown in Table 4 wherein the XRPD patterns
were measured using a powder diffractometer equipped with a Co
X-ray tube source. The sample was illuminated with Co
K.alpha..sub.1 radiation and XRPD data were collected from 5 to
55.degree. 2.crclbar.. (intensities may vary radically due to
preferred orientation).
4 TABLE 4 D-Space, Angstroms Intensity, I/I.sub.o, % 10.4 60 7.0 45
6.4 50 5.3 100 5.2 55 4.3 75 4.1 50 4.0 45 3.8 60 3.5 55
DETAILED DESCRIPTION OF THE INVENTION
[0037] Pharmaceutically acceptable acid addition salts of the
compounds of formula (I) and (II), both anhydrous and hydrated, are
those of any suitable inorganic or organic acid. Suitable inorganic
acids are, for example, hydrochloric, hydrobromic, sulfuric, and
phosphoric acids. Suitable organic acids include carboxylic acids,
such as, acetic, propionic, glycolic, lactic, pyruvic, malonic,
succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic,
maleic, hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic,
4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic,
4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic
acid, sulfonic acids, such as, methanesulfonic, ethanesulfonic and
.beta.-hydroxyethanesulfonic acid.
[0038] As used herein, the term "hydrate" refers to a combination
of water with a compound of formula (I) or (II) wherein the water
retains its molecular state as water and is either absorbed,
adsorbed or contained within a crystal lattice of the substrate
molecule of formula (I) or (II).
[0039] As used herein, the term "adsorped" refers to the physical
state wherein the water molecule in the hydrated, pharmaceutically
acceptable acid addition salts of piperidine derivatives of the
formula (I) and (II) is distributed over the surface of the solid
hydrated, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formula (I) and (II).
[0040] As used herein, the term "absorbed" refers to the physical
state wherein the water molecule in the hydrated, pharmaceutically
acceptable acid addition salts of piperidine derivatives of the
formula (I) and (II) is distributed throughout the body of the
solid hydrated, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formula (I) and (II).
[0041] Hydrated, pharmaceutically acceptable acid addition salts of
the compounds of formula (I) and (II) are those hydrates ranging
from essentially 0.10 to 5 molecules of water per molecule of
substrate salt of formula (I) or (II).
[0042] As used herein, the term "azeotropic mixture" refers to a
liquid mixture of two or more substances which behaves like a
single substance in that the vapor produced by partial evaporation
of liquid has the same composition as the liquid. The constant
boiling mixture exhibits either a maximum or minimum boiling point
as compared with that of other mixtures of the same substance.
[0043] As used herein, the term "azeotropic distillation" refers to
a type of distillation in which a substance is added to the mixture
to be separated in order to form an azeotropic mixture with one or
more of the constituents of the original mixture. The azeotrope or
azeotropes thus formed will have boiling points different from the
boiling points of the original mixture. As used herein, the term
"azeotropic distillation" also refers to co-distillation.
[0044] As used herein, the term "water-minimizing
recrystallization" refers to a recrystallization wherein the ratio
of anhydrous solvent to substrate hydrate is such that the
percentage of water present is minimized, thereby inducing
precipitation of the anhydrous form of the substrate.
[0045] As used herein, the term "aqueous recrystallization" refers
to those processes wherein either 1) a solid material is dissolved
in a volume of water or a water/organic solvent mixture sufficient
to cause dissolution and the solid material recovered by
evaporation of the solvent; 2) a solid material is treated with a
minimal amount of water or a water/organic solvent mixture which is
not sufficient to cause dissolution, heated to obtain dissolution
and cooled to induce crystallization or 3) a solid material is
dissolved in a volume of water or a water/organic solvent mixture
sufficient to cause dissolution and then the solvent is partially
evaporated to form a saturated solution which induces
crystallization.
[0046] As used herein, the term "crystal digestion" refers to that
process wherein a solid material is treated with a minimal amount
of water or water/organic solvent mixture which is not sufficient
to cause dissolution and either heating or stirring at ambient
temperature until the desired transformation has taken place.
[0047] As used herein, the term "antisolvent" refers to a poor
solvent for the substance in question which when added to a
solution of the substance, causes the substance to precipitate.
[0048] As used herein, the term "suitable temperature" refers to
that temperature which is sufficient to cause dissolution and to
permit the precipitation of the desired substance either upon
addition of an antisolvent or upon removal of the co-solvent by
azeotropic distillation.
[0049] The anhydrous, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula (I) and (II) may be
prepared from the corresponding hydrated, pharmaceutically
acceptable acid addition salts of piperidine derivatives of the
formula (I) and (II) by subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salts of piperidine
derivatives of the formula (I) and (II) to an azeotropic
distillation.
[0050] For example, the appropriate hydrated, pharmaceutically
acceptable acid addition salt of piperidine derivatives of the
formula (I) and (II) is first dissolved in a volume of a suitable
solvent or solvent mixture which is sufficient to cause
dissolution. Examples of such solvents are water, C.sub.1-C.sub.5
alkanols such as methanol, ethanol and the like; ketone solvents
such as acetone, methyl ethyl ketone and the like; aliphatic ester
solvents such as ethyl acetate, methyl acetate, methyl formate,
ethyl formate, isopropyl acetate and the like and aqueous mixtures
of these solvents, such as acetone/water, methyl ethyl
ketone/water, water/acetone and water/acetone/ethyl acetate. An
additional volume of the same solvent used to effect dissolution or
second suitable anhydrous antisolvent is then added to this
solution, which is then heated to a boiling point which is suitable
to azeotropically remove water and other low boiling components.
Suitable anhydrous antisolvents for use in the azeotropic
distillation are, for example, ketone solvents such as acetone,
methyl ethyl ketone and the like; aliphatic ester solvents such as
ethyl acetate, methyl acetate, methyl formate, ethyl formate,
isopropyl acetate and the like; C.sub.5-C.sub.8 aliphatic solvents
such as pentane, hexane and the like; aliphatic nitrites, such as
acetonitrile and mixtures of these solvents such as acetone/ethyl
acetate and the like. The azeotropic mixture of water and solvent
is removed by distillation until the temperature changes,
indicating that the azeotropic mixture is completely removed. The
reaction mixture is cooled and the corresponding anhydrous,
pharmaceutically acceptable acid addition salts of piperidine
derivatives of the formula (I) and (II) is recovered from the
reaction zone by, for example filtration.
[0051] In addition, the anhydrous, pharmaceutically acceptable acid
addition salts of piperidine derivatives of the formula (I) and
(II) may be prepared from the corresponding hydrated,
pharmaceutically acceptable acid addition salts of piperidine
derivatives of the formula (I) and (II) by subjecting the
corresponding hydrated, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula (I) and (II) to a
water-minimizing recrystallization.
[0052] For example, the appropriate hydrated, pharmaceutically
acceptable acid addition salt of piperidine derivatives of the
formula (I) and (II) is dissolved in a volume of a suitable
anhydrous solvent or solvent mixture which is sufficient to cause
dissolution and heated to reflux. Examples of such solvents are
water, C.sub.1-C.sub.5 alkanols such as methanol, ethanol and the
like; ketone solvents such as acetone, methyl ethyl ketone and the
like; aliphatic ester solvents such as ethyl acetate, methyl
acetate, methyl formate, ethyl formate, isopropyl acetate and the
like and aqueous mixtures of these solvents, such as acetone/water,
methyl ethyl ketone/water, water/acetone and water/acetone/ethyl
acetate. An additional volume of the same solvent used to effect
dissolution or second suitable anhydrous antisolvent is then added
in a quantity sufficient to initiate precipitation of the
anhydrous, pharmaceutically acceptable acid addition salt of
piperidine derivatives of the formula (I) and (II). Suitable
anhydrous antisolvents are, for example, ketone solvents such as
acetone, methyl ethyl ketone and the like; aliphatic ester solvents
such as ethyl acetate, methyl acetate, methyl formate, ethyl
formate, isopropyl acetate and the like; mixtures of ketone
solvents and aliphatic ester solvents such as acetone/ethyl acetate
and the like; C.sub.5-C.sub.8 aliphatic solvents such as pentane,
hexane and the like; aliphatic nitrites, such as acetonitrile and
mixtures of these solvents such as acetone/ethyl acetate and the
like as well as mixtures of water and ketone solvents such as
acetone/water and the like; and mixtures of water, ketone solvents
and aliphatic ester solvents such as acetone/water/ethyl acetate.
The reaction mixture is cooled and the corresponding anhydrous,
pharmaceutically acceptable acid addition salt of piperidine
derivatives of the formula (I) and (II) is recovered from the
reaction zone by, for example filtration.
[0053] Polymorphic forms of anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-pi-
peridinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride (Forms I and III) may be prepared by a variety
of methods as detailed below.
[0054] Form III to Form I
[0055] For example, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form I) may be prepared from anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form III), by
subjecting the anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybut-
yl]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
III) to a crystal digestion as described above.
[0056] Form II to Form III
[0057] In addition, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form III) may be prepared from hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form II), by
subjecting the nydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybuty-
l]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) to water-minimizing recrystallization as described above.
[0058] Form II to Form I
[0059] In addition, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form I) may be prepared from hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form II), by
subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybuty-
l]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) to water-minimizing recrystallization as described above or by
subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybuty-
l]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) to an azeotropic distillation.
[0060] Form IV to Form I
[0061] In addition, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form I) may be prepared from hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form IV), by
subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybuty-
l]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
IV) to water-minimizing recrystallization or to an azeotropic
distillation as described above.
[0062] The hydrated, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula (I) may be prepared
from the corresponding compound of the formula (II) wherein R.sub.3
is --COOalkyl by subjecting the corresponding compound of the
formula (II) wherein R.sub.3 is --COOalkyl to a reduction using an
appropriate reducing agent, such as sodium borohyride, potassium
borohydride, sodium cyanoborohydride, or tetramethylammonium
borohydride in a suitable solvent, such as, methanol, ethanol,
isopropyl alcohol or n-butanol, aqeuous mixtures thereof or basic
solutions thereof, at temperatures ranging from about 0.degree. C.
to the reflux temperature of the solvent, and the reaction time
varies from about 1/2 hour to 8 hours. After quenching and
acidifying with an suitable acid, such as hydrochloric acid, the
hydrated, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formula (I) are recovered from the
reaction zone by crystallization and filtration.
[0063] In addition, the hydrated, pharmaceutically acceptable acid
addition salts of piperidine derivatives of the formula (I) and
(II) may be prepared from the corresponding anhydrous,
pharmaceutically acceptable acid addition salts of the formula (I)
and (II) by subjecting the corresponding anhydrous,
pharmaceutically acceptable acid addition salts of formula (I) and
(II) to an aqueous recrystallization.
[0064] For example, the appropriate anhydrous, pharmaceutically
acceptable acid addition salt of piperidine derivatives of the
formula (I) and (II) is treated with a minimal volume of water or
suitable water/organic solvent mixture which is insufficient to
cause dissolution and heated to reflux. The reaction mixture is
cooled and the corresponding hydrated, pharmaceutically acceptable
acid addition salt of piperidine derivatives of the formula (I) and
(II) is recovered from the reaction zone by, for example
filtration. Alternatively, the appropriate anhydrous,
pharmaceutically acceptable acid addition salt of piperidine
derivatives of the formula (I) and (II) is treated with a volume of
water or a suitable water/organic solvent mixture which is
sufficient to cause dissolution and the water or water/organic
solvent is partially or completely evaporated to a volume which
induces crystallization of the hydrated, pharmaceutically
acceptable acid addition salts of piperidine derivatives of the
formula (I) and (II). Suitable solvents for use in the above
recrystallization are water, acetone/water, ethanol/water, methyl
ethyl ketone/aqueous methanol, methyl ethyl ketone/water and the
like.
[0065] The pseudomorphic forms of hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-
-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride (Forms II and IV) may be prepared by a variety
of methods as detailed below.
[0066] Ethyl Ester/Ketone to Form II
[0067] Hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu-
tyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
IV) may be prepared from ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-
-1-oxobutyl]-.alpha.,.alpha.-dimethylbenzeneacetate, hydrochloride
or free base as described above for the general preparation of the
hydrated, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formula (I) from the corresponding
compound of the formula (II) wherein R.sub.3 is --COOalkyl, but
rapdily adding water over a period of time ranging from 1 minute to
45 minutes at a temperature range of about -20.degree. C. to
50.degree. C. to precipitate the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form II).
[0068] Ethyl Ester/Ketone to Form IV
[0069] Hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu-
tyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
IV) may be prepared from ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-
-1-oxobutyl]-.alpha.,.alpha.-dimethylbenzeneacetate, hydrochloride
or free base as described above for the general preparation of the
hydrated, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formula (I) from the corresponding
compound of the formula (II) wherein R.sub.3 is --COOalkyl, but
slowly adding water over a period of time ranging from about 30
minutes to 24 hours and at a temperature range of about 0.degree.
C. to 50.degree. C., optionally with seeding, to precipitate the
hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-
-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form IV).
[0070] Form I to Form II
[0071] Hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu-
tyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) may be prepared from anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidi-
nyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form I) by subjecting hydrated
4-[4-[4-(Hydroxydiphenylmet-
hyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride (Form II) to an aqueous recrystallization as
defined above.
[0072] Starting materials for use in the present invention are
readily available to one of ordinary skill in the art. For example,
ethyl
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetate, hydrochloride is described in U.S. Pat.
No. 4,254,129, Mar. 3, 1981.
[0073] The following examples present typical processes for
preparing the anhydrous and hydrated, pharmaceutically acceptable
acid addition salts of piperidine derivatives of the formula (I)
and (II), polymorphs and pseudomorphs therof. These examples are
understood to be illustrative only and are not intended to limit
the scope of the present invention in any way. As used herein, the
following terms have the indicated meanings: "g" refers to grams;
"mol" refers to mole; "mmol" refers to millimoles; "mL" refers to
milliliters; "bp" refers to boiling point; "mp" refers to melting
point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to
millimeters of mercury; ".mu.L" refers to microliters; ".mu.g"
refers to micrograms; and ".mu.M" refers to micromolar.
[0074] Differential Scanning Calorimetry analysis were performed
using a TA 2910 DSC with open aluminum pans. The samples were
heated to 240.degree. C. at 5.degree. C./minute with a 5 mL/minute
nitrogen purge.
[0075] X-Ray Powder Diffraction analyses were performed as
follows:
[0076] The samples were loaded into a quartz (zero scatter) sample
holder for the XRPD pattern measurement. The XRPD patterns were
measured using a powder diffractometer equipped with a Co X-ray
tube source, primary beam monochromator, and position sensitive
detector (PSD). The incident beam was collimated using a 1.degree.
divergence slit. The active area on the PSD subtended approximately
5.degree.2.crclbar.. The source was operated at 35 kV and 30 mA and
the sample was illuminated with Co K.alpha..sub.1 radiation. XRPD
data were collected from 5 to 55.degree. 2.crclbar. at a rate of
0.25.degree.2.crclbar./minute and a step width of
0.02.degree.2.crclbar.. The XRPD patterns were measured without the
addition of an internal calibrant.
[0077] Peak positions and intensities for the most prominent
features were measured using a double-derivative peak picking
method. X-ray peaks with I/I.sub.o greater than 20% were reported.
The cutoff was chosen arbitrarily. The intensities are rounded to
the nearest 5%. Certain peaks appear sensitive to preferred
orientation that is caused by changes in crystallite morphology.
This results in large changes in the I/I.sub.o value.
EXAMPLE 1
Preparation of Form II
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hy-
droxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride
[0078] Method A
[0079] Mix ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetate, hydrochloride (101.92 g,
0.1807 mol) and methanol (510 mL) and stir. Rapidly add 50% sodium
hydroxide (72.27 g, 0.903 mol) and wash in with water (61 mL). Heat
to reflux for 2 hours, allow to cool to 35.degree. C. and treat
with sodium borohydride (3.42 g, 0.0903 mol). Add water (100 mL)
and maintain at 35.degree. C. for 10 hours. Add 37% hydrochloric
acid (53.0 g) to adjust pH to 11.5. Add acetone (26.5 mL) and water
(102 mL). Hold at 35.degree. C. for 2 hours and adjust to pH 2.5
with 37% hydrochloric acid (44.69 g). Dilute with water (408 mL),
cool to -15.degree. C., stir for 1.5 hours and collect the
precipitate by vacuum filtration. Wash the filtercake with
deionized water (3.times.100 mL) and vacuum dry to give
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride hydrate (97.10
g).
[0080] Method B
[0081] Place ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobut-
yl]-.alpha.,.alpha.-dimethylbenzeneacetate, hydrochloride (60.01 g,
0.106 mol) in a 1-L three necked round-bottom flask and fit the
flask with a mechanical stirrer, a Claisen head, a thermometer and
a reflux condenser with a nitrogen bubbler on top. Add methanol
(300 mL) and turn the stirrer on. Dilute the slurry with water (60
mL) and heat to 52-54.degree. C. over 15-20 minutes. Hold at
52.degree. C. for 2 hours and then add 50% sodium hydroxide (42.54
g, 0.532 mol). Heat at 73.degree. C. for approximately 1 hour, 45
minutes, cool to less than 35.degree. C. using a water bath and
then add sodium borohydride (2.02 g, 0.0534 mol). Stir overnight at
35.degree. C., treat with acetone (15.5 mL) and stir for 2 hours at
35.degree. C. Acidify the mixture to a pH of 1.85 with 28%
hydrochloric acid (75.72 g), dilute with water (282 mL), stir for
about 30 minutes and cool over about 2 hours to -15.degree. C.
Filter the solids off and wash with water (2.times.75 mL) and ethyl
acetate (2.times.75 mL). Vacuum dry the solid and allow to stand
for 2 days to give
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybuty-
l]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (57.97 g, 91.5%) as a fine powder.
[0082] Method C
[0083] Place ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobut-
yl]-.alpha.,.alpha.-dimethylbenzeneacetate (56.12 g, 0.1064 mol) in
a 1-L three necked round-bottom flask and fit the flask with a
mechanical stirrer, a Claisen head, a thermometer and a reflux
condenser with a nitrogen bubbler on top. Add methanol (300 mL) and
turn the stirrer on. Dilute the slurry with water (60 mL) and heat
to reflux using a heating mantle controlled by a Therm-O-Watch.
When the mixture reaches about 35.degree. C., treat with 50% sodium
hydroxide (34.05 g, 0.4256 mol) and rinse in with water (42 mL).
Stir at reflux for 2 hours, 15 minutes, cool over 1 hour to
35.degree. C. and then treat with sodium borohydride (2.02 g,
0.0534 mol). Stir for 7.5 hours and allow to stand at room
temperature without stirring for 1.75 days. Warm the mixture to
35.degree. C. and quench with acetone (15.5 mL, 0.21 mol) and stir
for 2 hours. Add water (60 mL) and adjust the pH to 2.5 with 32%
hydrochloric acid (65.22 g). Cool to 40.degree. C. and rinse the pH
probe with water (25 mL). Add water over about 30 minutes (192 mL),
hold the temperature at 33.degree. C. for 10 minutes and add a few
seed crystals. Cool the slurry to -12.degree. C. over about 45
minutes and isolate the solid by filtration (586.2 g). Wash with
water (2.times.100 mL) and then with ethyl acetate (100 mL,
prechilled to about -10.degree. C.). Vacuum dry overnight (1 mmHg,
50.degree. C.) to give
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride hydrate (Form II) (58.86 g, 98%) as a white
solid.
EXAMPLE 2
Preparation of Form IV
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hy-
droxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form IV)
[0084] Place ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobut-
yl]-.alpha.,.alpha.-dimethylbenzeneacetate (56.12 g, 0.1064 mol) in
a 1-L three necked round-bottom flask and fit the flask with a
mechanical stirrer, a Claisen head, a thermometer and a reflux
condenser with a nitrogen bubbler on top. Add methanol (300 mL) and
turn the stirrer on. Dilute the slurry with water (60 mL) and heat
to reflux using a heating mantle controlled by a Therm-O-Watch.
When the mixture reaches about 35.degree. C., treat with 50% sodium
hydroxide (34.05 g, 0.4256 mol) and rinse in with water (42 mL).
Stir at reflux for 2 hours, 15 minutes, cool over 1 hour to
35.degree. C. and then treat with sodium borohydride (2.02 g,
0.0534 mol). Stir for 7.5 hours and allow to stand at room
temperature without stirring for 1.75 days. Warm the mixture to
35.degree. C. and quench with acetone (15.5 mL, 0.21 mol) and stir
for 2 hours. Add water (60 mL) and adjust the pH to 2.5 with 32%
hydrochloric acid (65.22 g). Cool to 40.degree. C. and rinse the pH
probe with water (25 mL). Hold the temperature at 33.degree. C. for
10 minutes, add a few seed crystals and add water over about 4
hours (192 mL) at 35.degree. C. Cool the slurry to -12.degree. C.
over about 45 minutes and isolate the solid by filtration (586.2
g). Wash with water (2.times.100 mL) and then with ethyl acetate
(100 mL, prechilled to about -10.degree. C.). Vacuum dry overnight
(1 mmHg, 50.degree. C.) to give
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride hydrate (Form IV); mp 115-116.degree. C. (dec).
[0085] XRPD: Table 5
5 TABLE 5 D-Space, Angstroms Intensity, I/I.sub.o, % 10.38 60 6.97
45 6.41 50 5.55 30 5.32 100 5.23 55 5.11 35 4.98 25 4.64 30 4.32 35
4.28 75 4.12 50 4.02 45 3.83 60 3.65 20 3.51 55 3.46 25 2.83 20
EXAMPLE 3
Conversion of Form II to Form I
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidi-
nyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form I)
[0086] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (20.0 g, 0.0355 mol) with deionized water (2 g) and add
acetone (60 mL) in small portions over several minutes with
stirring. Filter through filter aid and wash the filter cake with
acetone (30 mL). Wash the filtercake with acetone (22 mL), reflux
filtrate and then slowly add ethyl acetate (32 mL over 15 minutes)
keeping the mixture at reflux. Reflux for 10 minutes, then slowly
add additional ethyl acetate (23 mL over 10 minutes) and reflux for
an additional 15 minutes. Add additional ethyl acetate (60 mL over
5-10 minutes) and continue refluxing for 15 minutes. Cool to
approximately 8.degree. C. in an ice bath, filter the solid and
wash with ethyl acetate (85 mL). Vacuum dry at 55.degree. C. for
1.5 hours to give the title compound (18.16 g, 95%).
EXAMPLE 4
Conversion of Form II to Form I
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidi-
nyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride
[0087] Method A
[0088] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (5.00 g, 0.0083 mol) with methylethyl ketone (130 mL).
Slowly add water (0.4 mL), filter through filter aid and wash the
filter cake with methylethyl ketone (20 mL). Heat to reflux and
distill off 75 mL of solvent, cool to -15.degree. C. and collect by
vacuum filtration. Wash with methylethyl ketone (2.times.10 mL) and
vacuum dry at 60.degree. C. to give the title compound (4.33 g,
97%); mp 196-198.degree. C.
[0089] Method B
[0090] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (1.4 g) with acetone (60 mL) and heat to reflux. Reduce
the volume to approximately 35 mL to remove all water which boils
off as an azeotrope (88/12:acetone/water). Cool the solution and
collect the title compound as a crystalline solid.
[0091] Method C:
[0092] Mix
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]--
.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (53.88 g, 0.100 mol) and add water (4.79 g) and methyl
ethyl ketone (240 mL). Stir until the solid is slurried up and add
additional methyl ethyl ketone (1L). Stir for 0.5 hours, filter
through a pad of filter aid, wash the filtercake with methyl ethyl
ketone (100 mL) and transfer the filtrate and wash to a 2L,
3-necked flask fitted with a thermometer, mechanical stirrer and
distillation head. Distill off a total of 721 mL of methyl ethyl
ketone, cool and stir over 1 hour to 40.degree. C. Cool to
-15.degree. C. and hold for 10 minutes. Collect the solid by vacuum
filtration and wash the filtercake with methyl ethyl ketone
(2.times.65 mL) and vacuum dry at 55.degree. C. overnight to give
the title compound (52.76 g, 97.9%); mp 197.5-200.degree. C.
[0093] Method D
[0094] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (40.0 g, 0.0696 mol, assayed at 93.6% purity, having 0.89
g water present and 35.1 g, 0.0575 mol, assayed at 88.0% purity,
having 2.47 g water present) with water (8.30 g; the amount
calculated to bring the weight of water present to 17% of the
anhydrous weight of
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride hydrate, taking into
account the water in the hydrated salt). Add methyl ethyl ketone
(approximately 500 mL) and stir until most of the solids dissolve.
Add additional methyl ethyl ketone (700 mL) in portions over
approximately 10 minutes and continue stirring for 1/2 hour. Filter
through a thin pad of filter aid, wash the filtercake and flask
with additional methyl ethyl ketone (100 mL) and transfer to a
boiling flask fitted with a thermometer, mechanical stirrer,
heating mantle, a 12-plate Oldershaw (vacuum-jacketed) distillation
column and a distillation head with the capability of regulating
the reflux ratio in a rough fashion, washing in with additional
methyl ethyl ketone (100 mL). Distill off 450 mL of solvent, cool
to -15.degree. C. and filter the solid. Wash with methyl ethyl
ketone (2.times.100 mL) and dry to give the title compound (68.3 g,
99.9%); mp 197-199.degree. C.
[0095] Method E
[0096] Bring methyl ethyl ketone (4 mL) to a boil and add
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (500 mg). Decant the
top layer and add methyl ethyl ketone (3 mL) to the aqeuous layer.
Boil the solution until the temperature reached 79.degree. C.,
reduce the volume by 25%, remove from heat and cover with aluminum
foil. Allow the solution to cool, filter the resulting crystals and
air dry to give the title compound.
EXAMPLE 5
Conversion of Form I to Form II
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidi-
nyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride hydrate
[0097] Method A
[0098] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form I)
(2.0 g) with ethanol (4 mL) and deionized water (20 mL). Heat at
80.degree. C. until a solution is formed and then stir at room
temperature for 23 hours. Filter the resulting slurry, wash with
water (2.times.10 mL) and dry under vacuum at 35.degree. C.
overnight to give the title compound (1.88 g); mp 100-105.degree.
C.
[0099] XRPD: Table 6
6 TABLE 6 D-Space, Angstroms Intensity, I/I.sub.o, % 11.41 20 7.98
20 7.83 45 6.58 45 6.42 60 5.66 20 5.52 45 5.39 30 5.23 65 5.14 45
4.86 65 4.72 100 4.45 65 4.40 45 4.32 45 4.18 45 4.06 65 4.02 55
3.85 25 3.79 75 3.74 95 3.61 80 3.56 25 3.47 65 3.41 20 2.74 20
[0100] Method B
[0101] Mix water (35.5 mL), methanol (26.3 mL) and sodium chloride
(2.59 g). Add
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.a-
lpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form I)
(4.77 g). Heat to reflux on a steam bath until dissolution and cool
to -10.degree. C. Filter the resulting solid, wash with water
(2.times.25 mL) and vacuum dry overnight to give the title compound
(4.80 g).
EXAMPLE 6
Conversion of Form II into Form III
4-[4-[4-(Hydroxydiphenylmethyl)-1-pipe-
ridinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride
[0102] (Form III)
[0103] Place
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (55.56 g, 0.0929 mol having 10% water) in a pressure
bottle along with water (2.96 g) and acetone (38.1 g). Seal the
bottle tightly and heat to approximately 80.degree. C. Cool to
about 50.degree. C., filter through filter aid in a coarse sintered
glass funnel and dilute with acetone (90 g). Transfer to a 1L flask
fitted with a mechanical stirrer, thermometer and a reflux
condenser. Heat the mixture to reflux and allow to cool and stir
over the weekend. Cool to -15.degree. C. and filter on a coarse
sintered glass funnel, wash with ethyl acetate (2.times.50 mL) and
vacuum dry at 50.degree. C.
[0104] Place a majority of the solid obtained (45.24 g) in a 500 mL
three necked flask fitted with a mechanical stirrer, thermometer
and a reflux condenser. Add acetone (240 mL) and water (4.82 g) and
reflux the mixture overnight. Allow the slurry to cool to
35.degree. C. and place in an ice water bath and cool to less then
5.degree. C. Filter the solid off on a coarse sintered glass
funnel, wash with ethyl acetate (50 mL) and vacuum dry at 50 C for
several hours to give the title compound as a white crystalline
powder (43.83 g, 97%); mp 166.5-170.5.degree. C.
7 TABLE 7 D-Space, Angstroms Intensity, I/I.sub.o, % 8.95 95 4.99
20 4.88 100 4.75 35 4.57 25 4.47 25 4.46 20 3.67 20 3.65 25
Example 7
Conversion of Form III into Form I
4-[4-[4-(Hydroxydiphenylmethyl)-1-piper-
idinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride
[0105] (Form I)
[0106] Place
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
III) (40.0 g as an ethyl acetate wetcake-27.9 g dry basis) in a 1L
three necked flask fitted with a mechanical stirrer, thermometer
and a reflux condenser. Add acetone (240 mL) and heat the mixture
to reflux for about 20 hours. Cool the slurry to -15.degree. C. and
isolate the solids by filtration on a coarse sintered glass frit
funnel. Wash with ethyl acetate (50 mL) and vacuum dry overnight to
give the title compound (26.1 g, 93.7%); mp 197.5-199.5.degree.
C.
[0107] XRPD: Table 8
8 TABLE 8 D-Space, Angstroms Intensity, I/I.sub.o, % 11.75 35 7.23
35 6.24 60 5.89 40 5.02 20 4.94 30 4.83 100 4.44 30 3.93 75 3.83 20
3.77 85 3.71 25 3.62 30 3.32 25 3.31 20
EXAMPLE 8
Conversion of Form IV into Form I
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperi-
dinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride
[0108] (Form I)
[0109] Place
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form IV) (54.35 g, 0.0970 mol, having 4% water present) in a
pressure bottle along with water (4.16 g) and acetone (38.1 g).
Seal the bottle tightly and heat to approximately 80.degree. C.
Cool to less then 60.degree. C., filter through filter aid in a
coarse sintered glass funnel and rinse the filter cake with acetone
(32.4 g). Place acetone (215 g) in a 1L three necked flask fitted
with a mechanical stirrer, thermometer, a reflux condenser and
containing a small amount of Form I crystals and heat to reflux.
Add a portion of the acetone/water solution of
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV)
(47.65 g) to the refluxing acetone over about 10 minutes. Slowly
add ethyl acetate (157.5 g) over 45 minutes then add the remaining
portion of the acetone/water solution of
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]--
1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride hydrate (Form IV), rinsed in with about 20 mL of
acetone. Add additional ethyl acetate (157.5 g) over 45 minutes to
1 hour, maintaining the slurry at reflux. Stir for 15 minutes, cool
to -15.degree. C. and vacuum filter the white solid on a 350 mL
coarse sintered glass funnel. Wash the solids with ethyl acetate
(2.times.50 mL) and vacuum dry overnight to give the title compound
(50.36 g, 97%); mp 198-199.5.degree. C.
[0110] XRPD: Table 9
9 TABLE 9 D-Space, Angstroms Intensity, I/I.sub.o, % 14.89 20 11.85
20 7.30 20 6.28 70 5.91 25 5.55 20 5.05 25 4.96 55 4.85 100 4.57 45
4.45 55 3.94 45 3.89 20 3.84 20 3.78 60 3.72 35 3.63 20 3.07 20
3.04 20 2.45 20
[0111] The polymorphic and pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-
-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride compounds of this invention are useful as
antihistamines, antiallergy agents and bronchodilators and may be
administered alone or with suitable pharmaceutical carriers, and
can be in solid or liquid form such as, tablets, capsules, powders,
solutions, suspensions or emulsions.
[0112] The polymorphic and pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-
-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride compounds of this invention can be administered
orally, parenterally, for example, subcutaneously, intravenously,
intramuscularly, intraperitoneally, by intranasal instillation or
by application to mucous membranes, such as, that of the nose,
throat and bronchial tubes, for example, in an aerosol spray
containing small particles of a compound of this invention in a
spray or dry powder form.
[0113] The quantity of polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride compound
administered will vary depending on the patient and the mode of
administration and can be any effective amount. The quantity of
polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride compound
administered may vary over a wide range to provide in a unit dosage
an effective amount of from about 0.01 to 20 mg/kg of body weight
of the patient per day to achieve the desired effect. For example,
the desired antihistamine, antiallergy and bronchodilator effects
can be obtained by consumption of a unit dosage form such as a
tablet containing 1 to 500 mg of a polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidiny-
l]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride compound of this invention taken 1 to 4 times
daily.
[0114] The solid unit dosage forms can be of the conventional type.
Thus, the solid form can be a capsule which can be the ordinary
gelatin type containing a polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-
-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride compound of this invention and a carrier, for
example, lubricants and inert fillers such as lactose, sucrose or
cornstarch. In another embodiment the polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride compound is tableted
with conventional tablet bases such as lactose, sucrose or
cornstarch or gelatin, disintegrating agents such as cornstarch,
potato starch or alginic acid, and a lubricant such as stearic acid
or magnesium stearate.
[0115] The polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1--
piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic
acid hydrochloride compounds of this invention may also be
administered in injectable dosages by solution or suspension of the
compounds in a physiologically acceptable diluent with a
pharmaceutical carrier which can be a sterile liquid such as water
and oils, with or without the addition of a surfactant and other
pharmaceutically acceptable adjuvants. Illustrative of oils there
can be mentioned those of petroleum, animal, vegatable or synthetic
origin, for example, peanut oil, soybean oil or mineral oil. In
general, water, saline, aqueous dextrose and related sugar
solutions and glycols such as propylene glycol or polyethylene
glycol are preferred liquid carriers, particularly for injectable
solutions.
[0116] For use as aerosols the compounds of this invention in
solution or suspension may be packaged in a pressurized aerosol
container together with suitable propellants, for example,
hydrocarbon propellants such as, propane, butane or isobutane with
the usual adjuvants as may be administered in a non-pressurized
form such as in a nebulizer or atomizer.
[0117] The term patient as used herein is taken to mean warm
blooded animals, birds, mammals, for example, humans, cats, dogs,
horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea
pigs.
* * * * *