U.S. patent application number 10/386812 was filed with the patent office on 2004-01-22 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 | 20040014976 10/386812 |
Document ID | / |
Family ID | 26937420 |
Filed Date | 2004-01-22 |
United States Patent
Application |
20040014976 |
Kind Code |
A1 |
Henton, Daniel R. ; et
al. |
January 22, 2004 |
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.; (Hilton Head, SC)
; Tripp, Susan I.; (Lee's Summit, MO) ; DeWitt,
Jill E.; (Kansas City, MO) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW,
GARRETT & DUNNER, L.L.P.
1300 I Street N.W.
Washington
DC
20005-3315
US
|
Family ID: |
26937420 |
Appl. No.: |
10/386812 |
Filed: |
March 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10386812 |
Mar 10, 2003 |
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10128926 |
Apr 24, 2002 |
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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: |
546/237 ;
546/241 |
Current CPC
Class: |
A61P 11/08 20180101;
A61P 43/00 20180101; A61P 11/00 20180101; C07D 211/22 20130101;
A61K 31/445 20130101; A61P 37/08 20180101 |
Class at
Publication: |
546/237 ;
546/241 |
International
Class: |
C07D 211/20; C07D
211/22 |
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 an 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 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]-,
-dimethylbenzeneacetic acid hydrochloride.
14. Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydr- oxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride.
15. Form III anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hy- droxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride.
16. Form IV hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydr- oxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form III anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form IV hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form IV hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl)-1-hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises: a)
reacting ethyl 4-[4-[4-(hydroxydiphenyl-
methyl)-1-piperidinyl]-1-oxobutyl]-, -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 50C.
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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises: a)
reacting ethyl 4-[4-[4-(hydroxydiphenyl-
methyl)-1-piperidinyl]-1-oxobutyl]-, -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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form I anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-dimethylbe-
nzeneacetic acid hydrochloride to an aqueous recrystallization.
41. A process for preparing the Form III anhydrous
4-[4-[4-(Hydroxydipheny- lmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride which comprises
subjecting Form II hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-dimethylbe-
nzeneacetic 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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises: a)
reacting ethyl 4-[4-[4-(hydroxydiphenyl-
methyl)-1-piperidinyl]-1-oxobutyl]-, -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]-,
-dimethylbenzeneacetic acid hydrochloride which comprises: a)
reacting ethyl 4-[4-[4-(hydroxydiphenyl-
methyl)-1-piperidinyl]-1-oxobutyl]-, -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 carbon atoms bearing R.sub.1 and R.sub.2;
[0008] n is an integer of from 1 to 5;
[0009] 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;
[0010] each of A is hydrogen or hydroxy; and
[0011] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0012] comprising subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salt to an azeotropic
distillation.
[0013] In addition, the present invention also provides a process
for preparing anhydrous, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula 3
[0014] wherein
[0015] R.sub.1 represents hydrogen or hydroxy;
[0016] R.sub.2 represents hydrogen; or
[0017] 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;
[0018] n is an integer of from 1 to 5;
[0019] 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;
[0020] each of A is hydrogen or hydroxy; and
[0021] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0022] comprising subjecting the corresponding hydrated,
pharmaceutically acceptable acid addition salt to a
water-minimizing recrystallization.
[0023] In addition, the present invention provides a process for
preparing the hydrated, pharmaceutically acceptable acid addition
salts of piperidine derivatives of the formula 4
[0024] wherein
[0025] R.sub.1 represents hydrogen or hydroxy;
[0026] R.sub.2 represents hydrogen; or
[0027] 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;
[0028] n is an integer of from 1 to 5;
[0029] 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;
[0030] each of A is hydrogen or hydroxy; and
[0031] pharmaceutically acceptable salts and individual optical
isomers thereof,
[0032] comprising subjecting the corresponding anhydrous,
pharmaceutically acceptable acid addition salts to an aqueous
recrystallization.
[0033] In addition, the present invention provides processes for
preparing polymorphs of anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-- hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride designated herein as Form
II and Form IV.
[0034] 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.sub.1 radiation and XRPD data were collected from 5 to
55.degree. 2. (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
[0035] 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.sub.1 radiation and XRPD data were collected
from 5 to 55.degree. 2. (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
[0036] 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.sub.1 radiation and XRPD data were
collected from 5 to 55.degree. 2. (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
[0037] 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.sub.1
radiation and XRPD data were collected from 5 to 55.degree. 2.
(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
[0038] 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
-hydroxyethanesulfonic acid.
[0039] 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).
[0040] 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).
[0041] 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).
[0042] 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).
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] Polymorphic forms of anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-pi- peridinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Forms I and III) may be
prepared by a variety of methods as detailed below.
[0055] Form III to Form I
[0056] For example, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny- l]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I) may be prepared
from anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidi-
nyl]-1-hydroxybutyl]-, -dimethylbenzeneacetic acid hydrochloride
(Form III), by subjecting the anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piper- idinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form III) to a crystal
digestion as described above.
[0057] Form II to Form III
[0058] In addition, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny- l]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form III) may be
prepared from hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidin-
yl]-1-hydroxybutyl]-, -dimethylbenzeneacetic acid hydrochloride
(Form II), by subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]- -1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form II). to
water-minimizing recrystallization as described above.
[0059] Form II to Form I
[0060] In addition, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny- l]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I) may be prepared
from hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidin-
yl]-1-hydroxybutyl]-, -dimethylbenzeneacetic acid hydrochloride
(Form II), by subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]- -1-hydroxybutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride (Form II) to an
azeotropic distillation.
[0061] Form IV to Form I
[0062] In addition, anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny- l]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I) may be prepared
from hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidin-
yl]-1-hydroxybutyl]-, -dimethylbenzeneacetic acid hydrochloride
(Form IV), by subjecting the hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]- -1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form IV) to
water-minimizing recrystallization or to an azeotropic distillation
as described above.
[0063] 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.
[0064] 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. 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]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride (Form IV) may be prepared
from ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,
-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-piperidi-
nyl]-1-hydroxybutyl]-, -dimethylbenzeneacetic acid hydrochloride
(Form II).
[0068] Ethyl Ester/Ketone to Form IV
[0069] Hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu- tyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form IV) may be prepared
from ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,
-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]-,
-dimethylbenzeneacetic acid hydrochloride (Form IV).
[0070] Form I to Form II
[0071] Hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu- tyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form II) may be prepared
from anhydrous
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybu- tyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I) by subjecting
hydrated
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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]-,
-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 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 1.degree.
divergence slit. The active area on the PSD subtended approximately
5.degree.2. The source was operated at 35 kV and 30 mA and the
sample was illuminated with Co.sub.1 radiation. XRPD data were
collected from 5 to 55.degree. 2 at a rate of 0.25.degree.2/minute
and a step width of 0.02.degree. 2. 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.
[0078] EXAMPLE 1
[0079] Preparation of Form II
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidiny- l]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride Method A
[0080] Mix ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl- ]-,
-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 (3'100
mL) and vacuum dry to give 4-[4-[4-(hydroxydiphenylmethyl)-1-
-piperidinyl]-1-hydroxybutyl]-, -dimethylbenzeneacetic acid
hydrochloride hydrate (97.10 g).
[0081] Method B
[0082] Place ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobut- yl]-,
-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-(hydroxydiphenylm- ethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (57.97
g, 91.5%) as a fine powder.
[0083] Method C
[0084] Place ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobut- yl]-,
-dimethylbenzeneacetate (56.129, 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-piperidinyl]-1-h- ydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride hydrate (Form II)
(58.869, 98%) as a white solid.
EXAMPLE 2
[0085] Preparation of Form IV
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidiny- l]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form IV)
[0086] Place ethyl
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobut- yl]-,
-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]-, -dimethylbenzeneacetic acid hydrochloride
hydrate (Form IV); mp 115-116.degree. C. (dec).
[0087] 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
[0088] Conversion of Form II to Form I
4-[4-[4-(hydroxydiphenylmethyl)-1-p- iperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I)
[0089] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl- ]-,
-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (20.09,
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
[0090] Conversion of Form II to Form I
4-[4-[4-(Hydroxydiphenylmethyl)-1-p- iperidinyl)-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride
[0091] Method A:
[0092] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl)-1-hydroxybutyl- ]-,
-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (5.00
g, 0.0083 mol) with methylethyl ketone (l30 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.
[0093] Method B:
[0094] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl)-1-hydroxybutyl- ]-,
-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.
[0095] Method C:
[0096] Mix
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-- ,
-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 (52.769,
97.9%); mp 197.5-200.degree. C.
[0097] Method D:
[0098] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl- ]-,
-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-piper- idinyl]-1-hydroxybutyl]-,
-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.
[0099] Method E
[0100] Bring methyl ethyl ketone (4 mL) to a boil and add
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (500mg). 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
[0101] Conversion of Form I to Form II
4-[4-[4-(Hydroxydiphenylmethyl)-1-p- iperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride hydrate
[0102] Method A
[0103] Treat
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl- ]-,
-dimethylbenzeneacetic acid hydrochloride (Form I) (2.0 g) with
ethanol (4mL) 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.
[0104] 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
[0105] Method B
[0106] Mix water (35.5 mL), methanol (26.3 mL) and sodium chloride
(2.59 g). Add
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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
[0107] Conversion of Form II into Form III
4-[4-[4-(Hydroxydiphenylmethyl)- -1-piperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form III)
[0108] Place
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl- ]-,
-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.
[0109] 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 50C for
several hours to give the title compound as a white crystalline
powder (43.83 g, 97%); mp 166.5-170.5.degree. C.
[0110] XRPD: Table 7
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
[0111] Conversion of Form III into Form I
4-[4-[4-(Hydroxydiphenylmethyl)-- 1-piperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I)
[0112] Place
4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl- ]-,
-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.
[0113] 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
[0114] Conversion of Form IV into Form I
4-[4-[4-(Hydroxydiphenylmethyl)-1- -piperidinyl]-1-hydroxybutyl]-,
-dimethylbenzeneacetic acid hydrochloride (Form I)
[0115] Place
4-(4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl- ]-,
-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]-, -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]-,
-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.
[0116] 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
[0117] The polymorphic and pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1- -piperidinyl]-1-hydroxybutyl]-,
-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.
[0118] The polymorphic and pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1- -piperidinyl]-1-hydroxybutyl]-,
-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.
[0119] The quantity of polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,
-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]-,
-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-piperidinyl]-1-hydroxybut- yl]-,
-dimethylbenzeneacetic acid hydrochloride compound of this
invention taken 1 to 4 times daily.
[0120] 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]-,
-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]-,
-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.
[0121] The polymorphic or pseudomorphic
4-[4-[4-(hydroxydiphenylmethyl)-1-- piperidinyl]-1-hydroxybutyl]-,
-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.
[0122] 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.
[0123] 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.
* * * * *