U.S. patent application number 09/803390 was filed with the patent office on 2001-08-16 for processes for preparing anhydrous 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 | 20010014741 09/803390 |
Document ID | / |
Family ID | 26937420 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014741 |
Kind Code |
A1 |
Henton, Daniel R. ; et
al. |
August 16, 2001 |
Processes for preparing anhydrous 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.; (Cincinnati, OH)
; Tripp, Susan I.; (Lee's Summit, MO) ; DeWitt,
Jill E.; (Kansas City, MO) |
Correspondence
Address: |
Aventis Pharmaceuticals Inc.
Patent Department
Route #202-206
P.O. Box 6800
Bridgewater
NJ
08807-0800
US
|
Family ID: |
26937420 |
Appl. No.: |
09/803390 |
Filed: |
March 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09803390 |
Mar 9, 2001 |
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09213162 |
Dec 17, 1998 |
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09213162 |
Dec 17, 1998 |
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08818087 |
Mar 14, 1997 |
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08818087 |
Mar 14, 1997 |
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08442460 |
May 16, 1995 |
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08442460 |
May 16, 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: |
546/232 ;
546/235 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 11/00 20180101; A61P 11/08 20180101; A61K 31/445 20130101;
C07D 211/22 20130101; A61P 37/08 20180101 |
Class at
Publication: |
546/232 ;
546/235 |
International
Class: |
C07D 211/32 |
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 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 a water-minimizing recrystallization.
3. 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; X is
a number ranging essentially from 0.1 to 5; 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, A, W and Y are as defined above, to
an aqueous recrystallization.
4. A process for preparing a compound of the formula 9and the
individual optical isomers thereof, wherein Y is a pharmaceutically
acceptable acid, comprising subjecting a compound of the formula
10wherein Y is as defined above and X is a number ranging
essentially from 0.10 to 5 to an azeotropic distillation.
5. 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 water-minimizing
recrystallization.
6. A process for preparing a compound of the formula 13and 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 14and 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 15wherein
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; 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 18wherein 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 20wherein 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 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 22and 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
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 a 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 of 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
thereof 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.-dimethylbenzeneacetic
acid hydrochloride which comprises subjecting Form II hydrated
4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.al-
pha.-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-
ethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneaceti-
c 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.-dimethylbenzenecacetic 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 time 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 0.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 30 minutes at 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)-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 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 the Form IV 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 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] This is a Continuation-In-Part application of patent
application Ser. No. 08/245,731, filed May 18, 1994.
[0002] 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
[0003] The present invention provides a process for preparing
anhydrous, pharmaceutically acceptable acid addition salts of
piperidine derivatives of the formulas 2
[0004] wherein
[0005] R.sub.1 represents hydrogen or hydroxy;
[0006] R.sub.2 represents hydrogen; or
[0007] R.sub.1 and R.sub.2 taken together form a second bond
between the
[0008] carbon atoms bearing R.sub.1 and R.sub.2;
[0009] n is an integer of from 1 to 5;
[0010] 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;
[0011] each of A is hydrogen or hydroxy; and
[0012] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0013] comprising subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salt to an azeotropic
distillation.
[0014] In addition, the present invention also provides a process
for preparing anhydrous, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula 3
[0015] wherein
[0016] R.sub.1 represents hydrogen or hydroxy;
[0017] R.sub.2 represents hydrogen; or
[0018] 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;
[0019] n is an integer of from 1 to 5;
[0020] 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;
[0021] each of A is hydrogen or hydroxy; and
[0022] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0023] comprising subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salt to a
water-minimizing recrystallization.
[0024] In addition, the present invention provides a process for
preparing the hydrated, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula 4
[0025] wherein
[0026] R.sub.1 represents hydrogen or hydroxy;
[0027] R.sub.2 represents hydrogen; or
[0028] 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;
[0029] n is an integer of from 1 to 5;
[0030] 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;
[0031] each of A is hydrogen or hydroxy; and
[0032] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0033] comprising subjecting the corresponding anhydrous,
pharmaceutically acceptable acid addition salts to an aqueous
recrystallization.
[0034] 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.
[0035] 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.l 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
[0036] 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.l 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
[0037] 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.l 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
[0038] 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.l 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
[0039] 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.
[0040] 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).
[0041] 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).
[0042] 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).
[0043] 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).
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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;
[0055] 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;
[0056] C.sub.5-C.sub.8 aliphatic solvents such as pentane, hexane
and the like; aliphatic nitriles, 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.
[0057] 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. Form III to Form I For example,
anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form I) may be
prepared from anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu-
tyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
III), by subjecting the anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl-
]-1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride (Form III) to a crystal digestion as described
above.
[0058] Form II to Form III
[0059] 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 hydrated
4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) to water-minimizing recrystallization as described above.
[0060] Form II 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 II), by
subjecting the hydrated
4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) to water-minimizing recrystallization as described above or by
subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1piperidinyl]-1-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
II) to an azeotropic distillation.
[0062] Form IV to Form I
[0063] 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-hydroxybutyl-
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride (Form
IV) to water-minimizing recrystallization or to an azeotropic
distillation as described above.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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. Ethyl Ester/Ketone to Form II
Hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.a-
lpha.-dimethylbenzeneacetic acid hydrochloride (Form IV) may be
prepared from ethyl
4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alp-
ha.,.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.,.al-
pha.-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(Hydroxydiphenylmeth-
yl)-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; "uL" refers to microliters; "Ugg" 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 50 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 10
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.l 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. 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/Io value.
EXAMPLE 1
Preparation of Form II
[0077]
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alp-
ha.,.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.,.al-
pha.-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
45minutes 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 mm g,
50.degree. C.) to give
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]--
1-hydroxybutyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid
hydrochloride hydrate (Form II) (58.86 g, 98%) as a white
solid.
EXAMPLE 2
Preparation of Form IV
[0084]
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alp-
ha.,.alpha.-dimethylbenzeneacetic acid hydrochloride
[0085] (Form IV)
[0086] 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).
[0087] XRPD: Table 5 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
[0088]
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alp-
ha.,.alpha.-dimethylbenzeneacetic acid hydrochloride
[0089] Method A:
[0090] 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.
[0091] Method B:
[0092] 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.
[0093] Method C:
[0094] Mix
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]--
.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride hydrate
(Form II) (53.88 g, 0.lOOmol) and add water (4.79 g) and methyl
ethyl ketone (240 mL). Stir until the solid is
[0095] Method B
[0096] 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
[0097]
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alp-
ha.,.alpha.-dimethylbenzeneacetic acid hydrochloride
[0098] (Form III)
[0099] 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 1 L
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.
[0100] 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.
[0101] XRPD: Table 7
5 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
[0102]
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alp-
ha.,.alpha.-dimethylbenzeneacetic acid hydrochloride
[0103] (Form I)
[0104] 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.
[0105] XRPD: Table 8
6 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
[0106]
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl
]-.alpha.,.alpha.-dimethylbenzeneacetic acid hydrochloride
[0107] (Form I)
[0108] 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.
[0109] XRPD: Table 9
7 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
[0110] 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.
[0111] 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.
[0112] The quantity of polymorphic or pseudomorphic
4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alpha.,.al-
pha.-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.,.al-
pha.-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.
[0113] 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)-
-1piperidinyl]-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.,.al-
pha.-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.
[0114] 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.
[0115] 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.
[0116] 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.
* * * * *