U.S. patent application number 14/551909 was filed with the patent office on 2015-06-04 for methods of manufacturing benzoquinoline compounds.
The applicant listed for this patent is Auspex Pharmaceuticals, Inc.. Invention is credited to Chengzhi Zhang.
Application Number | 20150152099 14/551909 |
Document ID | / |
Family ID | 53264424 |
Filed Date | 2015-06-04 |
United States Patent
Application |
20150152099 |
Kind Code |
A1 |
Zhang; Chengzhi |
June 4, 2015 |
METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS
Abstract
The present invention relates to new methods of manufacturing
benzoquinoline inhibitors of vesicular monoamine transporter 2
(VMAT2), and intermediates thereof. ##STR00001##
Inventors: |
Zhang; Chengzhi; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Auspex Pharmaceuticals, Inc. |
La Jolla |
CA |
US |
|
|
Family ID: |
53264424 |
Appl. No.: |
14/551909 |
Filed: |
November 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61911214 |
Dec 3, 2013 |
|
|
|
Current U.S.
Class: |
546/95 ; 546/139;
564/137; 564/468 |
Current CPC
Class: |
C07C 231/12 20130101;
C07D 217/04 20130101; C07B 59/001 20130101; C07C 221/00 20130101;
C07B 2200/05 20130101; C07D 455/06 20130101; C07C 231/02 20130101;
C07B 59/002 20130101; C07C 231/02 20130101; C07C 233/18 20130101;
C07C 221/00 20130101; C07C 223/02 20130101; C07C 231/12 20130101;
C07C 233/18 20130101 |
International
Class: |
C07D 455/06 20060101
C07D455/06; C07C 67/30 20060101 C07C067/30; C07C 231/12 20060101
C07C231/12; C07C 221/00 20060101 C07C221/00; C07C 231/02 20060101
C07C231/02; C07D 217/04 20060101 C07D217/04 |
Claims
1. A process of preparing a compound of Formula IV: ##STR00030## or
a salt thereof, comprising: a step of reacting a compound of
Formula II or a salt thereof with a compound of Formula III:
##STR00031## in the presence of a base; wherein: R.sub.7-R.sub.12
and R.sub.15 are independently selected from the group consisting
of hydrogen and deuterium; and Y.sub.1 is selected from the group
consisting of acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy,
heteroalkoxy, and aryloxy, any of which may be optionally
substituted.
2. (canceled)
3. The process of claim 1 wherein Y.sub.1 is ethoxy and said base
is sodium tert-butoxide.
4-9. (canceled)
10. A process of preparing a compound of Formula VI: ##STR00032##
comprising: a step of reacting a compound of Formula IV or a salt
thereof with a compound of Formula V: ##STR00033## in a solvent and
in the presence of a base; wherein: R.sub.1-R.sub.12 and R.sub.15
are independently selected from the group consisting of hydrogen
and deuterium; and Y.sub.2 is selected from the group consisting of
halogen, alkyl sulfate, alkyl sulfonate, halosulfonate,
perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate,
dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which
may be optionally substituted.
11. (canceled)
12. The process of claim 10 wherein Y.sub.2 is iodide and said base
is potassium carbonate.
13-16. (canceled)
17. The process of claim 10 wherein said solvent is acetone.
18. (canceled)
19. The process of claim 17 wherein the volume of said solvent is
between about 6 to about 10 times the mass of the compound of
Formula IV.
20. (canceled)
21. The process of claim 10 wherein said reaction step is carried
out in the presence of a phase transfer catalyst selected from the
group consisting of tetrabutylammonium bromide, tetrabutylammonium
iodide, and 18-crown-6.
22. (canceled)
23. The process of claim 21 wherein said phase transfer catalyst is
tetrabutylammonium bromide.
24. A process of preparing a solid salt of a compound of Formula
VII: ##STR00034## comprising: a first step of reacting a compound
of Formula VI: ##STR00035## with a dehydrating agent in a reaction
solvent; a second step of adding a quenching solvent and an
antisolvent to the reaction mixture; and a third step of isolating
the salt of the compound of Formula VII from the reaction mixture;
wherein: R.sub.1-R.sub.12 and R.sub.15 are independently selected
from the group consisting of hydrogen and deuterium.
25. The process of claim 24 wherein said salt of the compound of
Formula I is the hydrochloride salt.
26. The process of claim 25 wherein said dehydrating agent is
phosphorous oxychloride.
27. (canceled)
28. The process of claim 26 wherein the amount of said phosphorous
oxychloride is between about 1.6 to about 2.0 molar equivalents
relative to the compound of Formula VI.
29. (canceled)
30. (canceled)
31. The process of claim 24 wherein said reaction solvent is
acetonitrile.
32. (canceled)
33. The process of claim 31 wherein the volume of said acetonitrile
is between about 1.5 to about 2.5 times the mass of the compound of
Formula VI.
34-36. (canceled)
37. The process of claim 24 wherein said quenching solvent is
1-butanol.
38-39. (canceled)
40. The process of claim 37 wherein the amount of said 1-butanol is
between about 3.4 to about 4.2 molar equivalents relative to the
compound of Formula VI.
41-43. (canceled)
44. The process of claim 24 wherein said antisolvent is methyl
tert-butyl ether.
45. (canceled)
46. The process of claim 44 wherein the volume of said methyl
tert-butyl ether is between about 3 to about 5 times the mass of
the compound of Formula VI.
47-50. (canceled)
51. The process of claim 24 wherein said first reaction step is
held at a temperature of between about 80.degree. C. to about
85.degree. C.
52-55. (canceled)
56. The process of claim 24 wherein said second reaction step is
carried out at between about 25.degree. C. to about 35.degree.
C.
57-58. (canceled)
59. A process of purifying a hydrochloride salt of a compound of
Formula VII: ##STR00036## comprising: a first step of mixing the
compound of Formula VII with one or more solvents; and a second
step of filtering the salt of the compound of Formula VII from the
mixture; wherein: R.sub.1-R.sub.12 and R.sub.15 are independently
selected from the group consisting of hydrogen and deuterium.
60. (canceled)
61. The process of claim 59 wherein said solvent is a mixture of
ethanol and methyl tert-butyl ether.
62. The process of claim 61 wherein said solvent is a mixture of
10% ethanol and 90% methyl tert-butyl ether.
63-64. (canceled)
65. The process of claim 59 wherein said first mixing step is
carried out at between about 28.degree. C. to about 32.degree.
C.
66. A process of preparing a compound of Formula IX: ##STR00037##
comprising: a step of reacting a compound of Formula VII or a salt
thereof with a compound of Formula VIII in one or more solvents:
##STR00038## wherein: R.sub.1-R.sub.27 are independently selected
from the group consisting of hydrogen and deuterium; and X is
selected from the group consisting of halogen, alkyl sulfate, alkyl
sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate,
alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and
alkylcarbonate, any of which may be optionally substituted.
67. (canceled)
68. The process of claim 66 wherein said solvent is a mixture of
methanol and water.
69. (canceled)
70. The process of claim 68 wherein said methanol and water mixture
is between about four parts methanol to one part water and about
two parts methanol to one part water.
71. The process of claim 70 wherein said methanol and water mixture
is about three parts methanol to one part water.
72. (canceled)
73. The process of claim 71 wherein the volume of said mixture of
methanol and water is between about 4 and about 8 times the mass of
the compound of Formula VII.
74. (canceled)
75. The process of claim 66 wherein said solvent is a mixture of
ethanol and water.
76. (canceled)
77. The process of claim 75 wherein said ethanol and water mixture
is between about four parts ethanol to one part water and about two
parts ethanol to one part water.
78. The process of claim 77 wherein said ethanol and water mixture
is about three parts ethanol to one part water.
79. (canceled)
80. The process of claim 78 wherein the volume of said mixture of
ethanol and water is between about 4 and about 8 times the mass of
the compound of Formula VII.
81-83. (canceled)
84. The process of claim 66 wherein said reaction step is held at a
temperature of between about 40.degree. C. to about 60.degree.
C.
85-86. (canceled)
87. The process of claim 84 wherein said reaction step is carried
out for about 24 to about 72 hours.
88. (canceled)
89. The process of claim 66 wherein the compound of Formula VII is
the hydrochloride salt and a base is added during the reaction
step.
90-91. (canceled)
92. The process of claim 89 wherein said base is potassium
carbonate.
93. A process of preparing a compound of Formula XI: ##STR00039##
comprising: a first step of reacting a compound of Formula X or a
salt thereof with a base in one or more solvents: ##STR00040## a
second step of adjusting the pH of the reaction mixture by addition
of an acid; a third step of adding dimethylamine or a salt thereof
and a formaldehyde equivalent to the reaction mixture; a fourth
step of lowering the pH of the reaction mixture by addition of an
acid; a fifth step of raising the pH of the reaction mixture by
addition of an base; a sixth step of adding dimethylamine or a salt
thereof to the reaction mixture; wherein: R.sub.16-R.sub.27 are
independently selected from the group consisting of hydrogen and
deuterium.
94. The process of claim 93 wherein the base used in the first
hydrolysis step or the fifth pH adjustment step is potassium
hydroxide.
95-98. (canceled)
99. The process of claim 93 wherein said formaldehyde equivalent is
aqueous formaldehyde solution.
100. The process of claim 93 wherein the acid used in the second pH
adjustment step or the fourth pH adjustment step is hydrochloric
acid.
101. (canceled)
102. The process of claim 93 wherein a phase transfer catalyst
tetrabutylammonium bromide is added during the third reaction
step.
103-104. (canceled)
105. The process of claim 93 wherein said solvent is water.
106. The process of claim 93 wherein the first hydrolysis step is
carried out by the addition of about 1 to about 2 molar equivalents
of potassium hydroxide relative to said compound of Formula X.
107-109. (canceled)
110. The process of claim 93 wherein the first hydrolysis step is
carried out at a temperature of between about 20.degree. C. to
about 40.degree. C.
111. The process of claim 93 wherein the second pH adjustment step
results in a pH of about 6 to about 8.
112-114. (canceled)
115. The process of claim 93 wherein the third addition step is
carried out by the addition of about 1.25 to about 1.75 molar
equivalents of dimethylamine and about 1.25 to about 1.75 molar
equivalents of formaldehyde equivalents relative to said compound
of Formula X.
116-117. (canceled)
118. The process of claim 93 wherein the third addition step is
carried out at a temperature of between about 25.degree. C. to
about 35.degree. C.
119. (canceled)
120. The process of claim 118 wherein the reaction temperature is
maintained for about 9 to about 15 hours after third addition
step.
121-122. (canceled)
123. The process of claim 93 wherein the fourth pH adjustment step
results in a pH of less than 1.
124-126. (canceled)
127. The process of claim 93 wherein the fifth pH adjustment step
results in a pH of about 12 to about 13.
128-130. (canceled)
131. The process of claim 93 wherein the sixth addition step is
carried out by the addition of about 1.25 to about 1.75 molar
equivalents of dimethylamine relative to said compound of Formula
X.
132-137. (canceled)
Description
[0001] This application claims the benefit of priority of U.S.
provisional application No. 61/911,214, filed Dec. 3, 2013, the
disclosure of which is hereby incorporated by reference as if
written herein in its entirety.
[0002] Disclosed herein are methods of manufacturing benzoquinoline
compounds, and intermediates thereof.
[0003] Tetrabenazine (Nitoman, Xenazine, Ro 1-9569),
1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quin-
oline, is a vesicular monoamine transporter 2 (VMAT2) inhibitor.
Tetrabenazine is commonly prescribed for the treatment of
Huntington's disease (Savani et al., Neurology 2007, 68(10), 797;
and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1),
7-17).
##STR00002##
[0004] d.sub.6-Tetrabenazine is a deuterated analog of
tetrabenazine which has improved pharmacokinetic properties when
compared to the non-deuterated drug and is currently under clinical
development. U.S. Pat. No. 8,524,733.
##STR00003##
Deuterium Kinetic Isotope Effect
[0005] Tetrabenazine is a VMAT2 inhibitor. The carbon-hydrogen
bonds of tetrabenazine contain a naturally occurring distribution
of hydrogen isotopes, namely .sup.1H or protium (about 99.9844%),
.sup.2H or deuterium (about 0.0156%), and .sup.3H or tritium (in
the range between about 0.5 and 67 tritium atoms per 10.sup.18
protium atoms). Increased levels of deuterium incorporation may
produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that
could affect the pharmacokinetic, pharmacologic and/or toxicologic
profiles of tetrabenazine in comparison with tetrabenazine having
naturally occurring levels of deuterium.
[0006] Based on discoveries made in our laboratory, as well as
considering the literature, tetrabenazine is metabolized in humans
at the isobutyl and methoxy groups. The current approach reduces
metabolism at some or all of these sites. Limiting the production
of these metabolites has the potential to decrease the danger of
the administration of such drugs and may even allow increased
dosage and/or increased efficacy. All of these transformations can
occur through polymorphically-expressed enzymes, exacerbating
interpatient variability. Further, some disorders are best treated
when the subject is medicated around the clock or for an extended
period of time. For all of the foregoing reasons, a medicine with a
longer half-life may result in greater efficacy and cost savings.
Various deuteration patterns can be used to (a) reduce or eliminate
unwanted metabolites, (b) increase the half-life of the parent
drug, (c) decrease the number of doses needed to achieve a desired
effect, (d) decrease the amount of a dose needed to achieve a
desired effect, (e) increase the formation of active metabolites,
if any are formed, (f) decrease the production of deleterious
metabolites in specific tissues, and/or (g) create a more effective
drug and/or a safer drug for polypharmacy, whether the polypharmacy
be intentional or not. The deuteration approach has demonstrated
the ability to slow the metabolism of tetrabenazine and attenuate
interpatient variability.
[0007] Novel methods of manufacturing benzoquinoline compounds,
including tetrabenazine and deuterated tetrabenazine analogs such
as d.sub.6-tetrabenazine are disclosed herein.
[0008] In certain embodiments of the present invention, disclosed
herein is a process of preparing a compound of Formula IV:
##STR00004##
or a salt thereof, comprising:
[0009] a step of reacting a compound of Formula II or a salt
thereof with a compound of Formula III:
##STR00005##
[0010] in the presence of a base;
[0011] wherein:
[0012] R.sub.7-R.sub.12 and R.sub.15 are independently selected
from the group consisting of hydrogen and deuterium; and
[0013] Y.sub.1 is selected from the group consisting of acetoxy,
alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and
aryloxy, any of which may be optionally substituted.
[0014] In certain embodiments, Y.sub.1 is acetoxy.
[0015] In certain embodiments, Y.sub.1 is C.sub.1-C.sub.4
alkoxy.
[0016] In certain embodiments, Y.sub.1 is ethoxy.
[0017] In certain embodiments, Y.sub.1 is selected from the group
consisting of fluorine, chlorine, and bromine.
[0018] In certain embodiments, said base is selected from the group
consisting of alkali metal alkoxides, alkali metal hydroxides,
alkali metal hydrides, alkali metal carbonates, and
trialkylamines.
[0019] In certain embodiments, said base is an alkali metal
alkoxide.
[0020] In certain embodiments, said base is sodium
tert-butoxide.
[0021] In certain embodiments, Y.sub.1 is ethoxy.
[0022] In certain embodiments, disclosed herein is a process of
preparing a compound of Formula VI:
##STR00006##
comprising:
[0023] a step of reacting a compound of Formula IV or a salt
thereof with a compound of Formula V:
##STR00007##
[0024] in a solvent and in the presence of a base;
[0025] wherein:
[0026] R.sub.1-R.sub.12 and R.sub.15 are independently selected
from the group consisting of hydrogen and deuterium; and
[0027] Y.sub.2 is selected from the group consisting of halogen,
alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl
sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium,
alkylphosphate, and alkylcarbonate, any of which may be optionally
substituted.
[0028] In certain embodiments, Y.sub.2 is iodide or
methylsulfate.
[0029] In certain embodiments, Y.sub.2 is iodide.
[0030] In certain embodiments, said base is selected from the group
consisting of alkali metal carbonates, alkali metal bicarbonates,
alkali metal alkoxides, alkali metal hydroxides, alkali metal
hydrides, and trialkylamines.
[0031] In certain embodiments, said base is an alkali metal
carbonate.
[0032] In certain embodiments, said base is potassium
carbonate.
[0033] In certain embodiments, said solvent is selected from the
group consisting of acetone, acetonitrile, dimethyl formamide,
2-methyltetrahydrofuran, and tetrahydrofuran.
[0034] In certain embodiments, said solvent is acetone.
[0035] In certain embodiments, the volume of said solvent is
between about 5 to about 15 times the mass of the compound of
Formula IV.
[0036] In certain embodiments, the volume of said solvent is
between about 6 to about 10 times the mass of the compound of
Formula IV.
[0037] In certain embodiments, the volume of said solvent is about
8 times the mass of the compound of Formula IV.
[0038] In certain embodiments, said reaction step is carried out in
the presence of a phase transfer catalyst.
[0039] In certain embodiments, said phase transfer catalyst is
selected from the group consisting of tetrabutylammonium bromide,
tetrabutylammonium iodide, and 18-crown-6.
[0040] In certain embodiments, said phase transfer catalyst is
tetrabutylammonium bromide.
[0041] In certain embodiments, disclosed herein is a process of
preparing a solid salt of a compound of Formula VII:
##STR00008##
comprising:
[0042] a first step of reacting a compound of Formula VI:
##STR00009##
[0043] with a dehydrating agent in a reaction solvent;
[0044] a second step of adding a quenching solvent and an
antisolvent to the reaction mixture; and
[0045] a third step of isolating the salt of the compound of
Formula VII from the reaction mixture;
[0046] wherein:
[0047] R.sub.1-R.sub.12 and R.sub.15 are independently selected
from the group consisting of hydrogen and deuterium.
[0048] In certain embodiments, said salt of the compound of Formula
I is the hydrochloride salt.
[0049] In certain embodiments, said dehydrating agent is selected
from the group consisting of phosphorous oxychloride, phosphorus
pentachloride, and thionyl chloride.
[0050] In certain embodiments, the amount of said phosphorous
oxychloride is between about 0.5 to about 4 molar equivalents
relative to the compound of Formula VI.
[0051] In certain embodiments, the amount of said phosphorous
oxychloride is between about 1.6 to about 2.0 molar equivalents
relative to the compound of Formula VI.
[0052] In certain embodiments, the amount of said phosphorous
oxychloride is about 1.8 molar equivalents relative to the compound
of Formula VI.
[0053] In certain embodiments, said reaction solvent is selected
from the group consisting of methyl tert-butyl ether, toluene, and
acetonitrile.
[0054] In certain embodiments, said reaction solvent is
acetonitrile.
[0055] In certain embodiments, the volume of said acetonitrile is
between about 1 to about 4 times the mass of the compound of
Formula VI.
[0056] In certain embodiments, the volume of said acetonitrile is
between about 1.5 to about 2.5 times the mass of the compound of
Formula VI.
[0057] In certain embodiments, the volume of said acetonitrile is
about 2 times the mass of the compound of Formula VI.
[0058] In certain embodiments, said quenching solvent is anprotic
solvents selected from the group consisting of water, an alcohol,
and a protic acid.
[0059] In certain embodiments, said quenching solvent is selected
from the group consisting of ethanol, 1-propanol, isopropanol,
1-butanol, 2-methylpropanol, tert-butanol, and 1-pentanol.
[0060] In certain embodiments, said quenching solvent is
1-butanol.
[0061] In certain embodiments, the amount of said 1-butanol is
between about 2 to about 8 molar equivalents relative to the
compound of Formula VI.
[0062] In certain embodiments, the amount of said 1-butanol is
between about 2.4 to about 6 molar equivalents relative to the
compound of Formula VI.
[0063] In certain embodiments, the amount of said 1-butanol is
between about 3.4 to about 4.2 molar equivalents relative to the
compound of Formula VI.
[0064] In certain embodiments, the amount of said 1-butanol is
about 3.8 molar equivalents relative to the compound of Formula
VI.
[0065] In certain embodiments, said quenching solvent is selected
from the group consisting of hydrogen chloride, hydrogen bromide,
hydrogen iodide, phosphoric acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, and trifluoroacetic acid.
[0066] In certain embodiments, said antisolvent is selected from
the group consisting of methyl tert-butyl ether, ethyl acetate,
isopropyl acetate, 2-methyltetrahydrofuran, diethyl ether, toluene,
hexane, pentane, and cyclohexane.
[0067] In certain embodiments, said antisolvent is methyl
tert-butyl ether.
[0068] In certain embodiments, the volume of said methyl tert-butyl
ether is between about 1 to about 10 times the mass of the compound
of Formula VI.
[0069] In certain embodiments, the volume of said methyl tert-butyl
ether is between about 3 to about 5 times the mass of the compound
of Formula VI.
[0070] In certain embodiments, the volume of said methyl tert-butyl
ether is about 4 times the mass of the compound of Formula VI.
[0071] In certain embodiments, said first reaction step is carried
out at reflux.
[0072] In certain embodiments, said first reaction step is held at
a temperature of between about 0.degree. C. to about 100.degree.
C.
[0073] In certain embodiments, said first reaction step is held at
a temperature of between about 75.degree. C. to about 95.degree.
C.
[0074] In certain embodiments, said first reaction step is held at
a temperature of between about 80.degree. C. to about 85.degree.
C.
[0075] In certain embodiments, said first reaction step is held at
a temperature of between about 80.degree. C. to about 85.degree. C.
for about 2 hours.
[0076] In certain embodiments, after said first reaction step is
heated to between about 80.degree. C. to about 85.degree. C., the
reaction mixture is cooled to a temperature between about
25.degree. C. to about 35.degree. C.
[0077] In certain embodiments, said second reaction step is carried
out at between about 0.degree. C. to about 100.degree. C.
[0078] In certain embodiments, said second reaction step is carried
out at between about 10.degree. C. to about 50.degree. C.
[0079] In certain embodiments, said second reaction step is carried
out at between about 25.degree. C. to about 35.degree. C.
[0080] In certain embodiments, the reaction mixture is held at a
temperature between about 25.degree. C. to about 35.degree. C. for
about 12 hours after the addition of said quenching solvent and
said antisolvent.
[0081] In certain embodiments, said salt of the compound of Formula
VII is isolated by filtration.
[0082] In certain embodiments, disclosed herein is a process of
purifying a hydrochloride salt of a compound of Formula VII:
##STR00010##
comprising:
[0083] a first step of mixing the compound of Formula VII with one
or more solvents; and
[0084] a second step of filtering the salt of the compound of
Formula VII from the mixture;
[0085] wherein:
[0086] R.sub.1-R.sub.12 and R.sub.15 are independently selected
from the group consisting of hydrogen and deuterium.
[0087] In certain embodiments, said solvent is selected from the
group consisting of ethanol, 1-propanol, isopropanol,
2-methylpropanol, tert-butanol, 1-butanol, 1-pentanol, acetone,
acetonitrile, ethyl acetate, methyl tert-butyl ether, hydrogen
chloride, hydrogen bromide, hydrogen iodide, phosphoric acid,
sulfuric acid, methanesulfonic acid, formic acid, acetic acid, and
trifluoroacetic acid.
[0088] In certain embodiments, said solvent is a mixture of ethanol
and methyl tert-butyl ether.
[0089] In certain embodiments, said solvent is a mixture of 10%
ethanol and 90% methyl tert-butyl ether.
[0090] In certain embodiments, said first mixing step is carried
out at between about 0.degree. C. to about 60.degree. C.
[0091] In certain embodiments, said first mixing step is carried
out at between about 20.degree. C. to about 40.degree. C.
[0092] In certain embodiments, said first mixing step is carried
out at between about 28.degree. C. to about 32.degree. C.
[0093] In certain embodiments, disclosed herein is a process of
preparing a compound of Formula IX:
##STR00011##
comprising:
[0094] a step of reacting a compound of Formula VII or a salt
thereof with a compound of Formula VIII in one or more
solvents:
##STR00012##
[0095] wherein:
[0096] R.sub.1-R.sub.27 are independently selected from the group
consisting of hydrogen and deuterium; and
X is selected from the group consisting of halogen, alkyl sulfate,
alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl
sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and
alkylcarbonate, any of which may be optionally substituted.
[0097] In certain embodiments, said solvent is selected from the
group consisting of water, methanol, and ethanol.
[0098] In certain embodiments, said solvent is a mixture of
methanol and water.
[0099] In certain embodiments, said methanol and water mixture is
between about five parts methanol to one part water and about one
part methanol to one part water.
[0100] In certain embodiments, said methanol and water mixture is
between about four parts methanol to one part water and about two
parts methanol to one part water.
[0101] In certain embodiments, said methanol and water mixture is
about three parts methanol to one part water.
[0102] In certain embodiments, the volume of said mixture of
methanol and water is between about 2 and about 10 times the mass
of the compound of Formula VII.
[0103] In certain embodiments, the volume of said mixture of
methanol and water is between about 4 and about 8 times the mass of
the compound of Formula VII.
[0104] In certain embodiments, the volume of said mixture of
methanol and water is about 6 times the mass of the compound of
Formula VII.
[0105] In certain embodiments, said solvent is a mixture of ethanol
and water.
[0106] In certain embodiments, said ethanol and water mixture is
between about five parts ethanol to one part water and about one
part ethanol to one part water.
[0107] In certain embodiments, said ethanol and water mixture is
between about four parts ethanol to one part water and about two
parts ethanol to one part water.
[0108] In certain embodiments, said ethanol and water mixture is
about three parts ethanol to one part water.
[0109] In certain embodiments, the volume of said mixture of
ethanol and water is between about 2 and about 10 times the mass of
the compound of Formula VII.
[0110] In certain embodiments, the volume of said mixture of
ethanol and water is between about 4 and about 8 times the mass of
the compound of Formula VII.
[0111] In certain embodiments, the volume of said mixture of
ethanol and water is about 6 times the mass of the compound of
Formula VII.
[0112] In certain embodiments, said reaction step is held at a
temperature of between about 0.degree. C. to about 100.degree.
C.
[0113] In certain embodiments, said reaction step is held at a
temperature of between about 25.degree. C. to about 70.degree.
C.
[0114] In certain embodiments, said reaction step is held at a
temperature of between about 40.degree. C. to about 60.degree.
C.
[0115] In certain embodiments, said reaction step is held at a
temperature of between about 45.degree. C. to about 50.degree.
C.
[0116] In certain embodiments, said reaction step is carried out
for about 1 to about 96 hours.
[0117] In certain embodiments, said reaction step is carried out
for about 24 to about 72 hours.
[0118] In certain embodiments, said reaction step is carried out
for about 48 hours.
[0119] In certain embodiments, wherein the compound of Formula VII
is the hydrochloride salt and a base is added during the reaction
step.
[0120] In certain embodiments, said base is selected from the group
consisting of alkali metal carbonates, alkali metal bicarbonates,
alkali metal alkoxides, alkali metal hydroxides, alkali metal
hydrides, and trialkylamines.
[0121] In certain embodiments, said base is an alkali metal
carbonate.
[0122] In certain embodiments, said base is potassium
carbonate.
[0123] In certain embodiments, disclosed herein is a process of
preparing a compound of Formula XI:
##STR00013##
comprising:
[0124] a first step of reacting a compound of Formula X or a salt
thereof with a base in one or more solvents:
##STR00014##
[0125] a second step of adjusting the pH of the reaction mixture by
addition of an acid;
[0126] a third step of adding dimethylamine or a salt thereof and a
formaldehyde equivalent to the reaction mixture;
[0127] a fourth step of lowering the pH of the reaction mixture by
addition of an acid;
[0128] a fifth step of raising the pH of the reaction mixture by
addition of an base;
[0129] a sixth step of adding dimethylamine or a salt thereof to
the reaction mixture; wherein:
[0130] R.sub.16-R.sub.27 are independently selected from the group
consisting of hydrogen and deuterium.
[0131] In certain embodiments, the base used in the first
hydrolysis step or the fifth pH adjustment step is selected from
the group consisting of alkali metal carbonates and alkali metal
hydroxides.
[0132] In certain embodiments, said base is an alkali metal
hydroxide.
[0133] In certain embodiments, said base is potassium
hydroxide.
[0134] In certain embodiments, said dimethylamine is dimethylamine
hydrochloride.
[0135] In certain embodiments, said formaldehyde equivalent is
selected from the group consisting of formaldehyde, aqueous
formaldehyde solution, paraformaldehyde, and trioxane.
[0136] In certain embodiments, said formaldehyde equivalent is
aqueous formaldehyde solution.
[0137] In certain embodiments, the acid used in the second pH
adjustment step or the fourth pH adjustment step is selected from
the group consisting of hydrochloric acid, sulfuric acid,
phosphoric acid, and methanesulfonic acid.
[0138] In certain embodiments, said acid is hydrochloric acid.
[0139] In certain embodiments, a phase transfer catalyst is added
during the third reaction step.
[0140] In certain embodiments, said phase transfer catalyst is
tetrabutylammonium bromide.
[0141] In certain embodiments, the amount of said
tetrabutylammonium bromide is about 0.1 molar equivalents relative
to said compound of Formula X.
[0142] In certain embodiments, said solvent is water.
[0143] In certain embodiments, the first hydrolysis step is carried
out by the addition of about 1 to about 2 molar equivalents of
potassium hydroxide relative to said compound of Formula X.
[0144] In certain embodiments, the first hydrolysis step is carried
out by the addition of about 1 to about 1.2 molar equivalents of
potassium hydroxide relative to said compound of Formula X.
[0145] In certain embodiments, the first hydrolysis step is carried
out by the addition of about 1.1 molar equivalents of potassium
hydroxide relative to said compound of Formula X.
[0146] In certain embodiments, the first hydrolysis step is carried
out at a temperature of between about 0.degree. C. to about
100.degree. C.
[0147] In certain embodiments, the first hydrolysis step is carried
out at a temperature of between about 20.degree. C. to about
40.degree. C.
[0148] In certain embodiments, the second pH adjustment step
results in a pH of about 6 to about 8.
[0149] In certain embodiments, the second pH adjustment step
results in a pH of about 6.8 to about 7.2.
[0150] In certain embodiments, the second pH adjustment step is
carried out at a temperature of between about 10.degree. C. to
about 60.degree. C.
[0151] In certain embodiments, the third addition step is carried
out by the addition of about 1 to about 2 molar equivalents of
dimethylamine and formaldehyde equivalents relative to said
compound of Formula X.
[0152] In certain embodiments, the third addition step is carried
out by the addition of about 1.25 to about 1.75 molar equivalents
of dimethylamine and about 1.25 to about 1.75 molar equivalents of
formaldehyde equivalents relative to said compound of Formula
X.
[0153] In certain embodiments, the third addition step is carried
out by the addition of about 1.5 molar equivalents of dimethylamine
and about 1.68 molar equivalents of formaldehyde equivalents
relative to said compound of Formula X.
[0154] In certain embodiments, the third addition step is carried
out at a temperature of between about 10.degree. C. to about
60.degree. C.
[0155] In certain embodiments, the third addition step is carried
out at a temperature of between about 25.degree. C. to about
35.degree. C.
[0156] In certain embodiments, the reaction temperature is
maintained for about 1 to about 24 hours after third addition
step.
[0157] In certain embodiments, the reaction temperature is
maintained for about 9 to about 15 hours after third addition
step.
[0158] In certain embodiments, the reaction temperature is
maintained for about 12 hours after third addition step.
[0159] In certain embodiments, the fourth pH adjustment step
results in a pH of less than 3.
[0160] In certain embodiments, the fourth pH adjustment step
results in a pH of less than 1.
[0161] In certain embodiments, the fourth pH adjustment step is
carried out at a temperature of between about 10.degree. C. to
about 60.degree. C.
[0162] In certain embodiments, the fourth pH adjustment step is
carried out at a temperature of between about 25.degree. C. to
about 35.degree. C.
[0163] In certain embodiments, the fifth pH adjustment step results
in a pH of greater than 10.
[0164] In certain embodiments, the fifth pH adjustment step results
in a pH of about 12 to about 13.
[0165] In certain embodiments, the fifth pH adjustment step is
carried out at a temperature of between about 10.degree. C. to
about 60.degree. C.
[0166] In certain embodiments, the fifth pH adjustment step is
carried out at a temperature of between about 25.degree. C. to
about 35.degree. C.
[0167] In certain embodiments, the sixth addition step is carried
out by the addition of about 1 to about 2 molar equivalents of
dimethylamine relative to said compound of Formula X.
[0168] In certain embodiments, the sixth addition step is carried
out by the addition of about 1.25 to about 1.75 molar equivalents
of dimethylamine relative to said compound of Formula X.
[0169] In certain embodiments, the sixth addition step is carried
out by the addition of about 1.5 molar equivalents of dimethylamine
relative to said compound of Formula X.
[0170] In certain embodiments, the sixth addition step is carried
out at a temperature of between about 10.degree. C. to about
60.degree. C.
[0171] In certain embodiments, the sixth addition step is carried
out at a temperature of between about 25.degree. C. to about
35.degree. C.
[0172] In certain embodiments, the reaction temperature is
maintained for about 1 to about 96 hours after third addition
step.
[0173] In certain embodiments, the reaction temperature is
maintained for about 24 to about 48 hours after third addition
step.
[0174] In certain embodiments, the reaction temperature is
maintained for about 36 hours after third addition step.
[0175] The compounds as disclosed herein may also contain less
prevalent isotopes for other elements, including, but not limited
to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen.
[0176] All publications and references cited herein are expressly
incorporated herein by reference in their entirety. However, with
respect to any similar or identical terms found in both the
incorporated publications or references and those explicitly put
forth or defined in this document, then those terms definitions or
meanings explicitly put forth in this document shall control in all
respects.
[0177] As used herein, the terms below have the meanings
indicated.
[0178] The singular forms "a," "an," and "the" may refer to plural
articles unless specifically stated otherwise.
[0179] The term "about," as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as
variable within a margin of error. When no particular margin of
error, such as a standard deviation to a mean value given in a
chart or table of data, is recited, the term "about" should be
understood to mean that range which would encompass the recited
value and the range which would be included by rounding up or down
to that figure as well, taking into account significant
figures.
[0180] When ranges of values are disclosed, and the notation "from
n.sub.1 . . . to n.sub.2" or "n.sub.1-n.sub.2" is used, where
n.sub.1 and n.sub.2 are the numbers, then unless otherwise
specified, this notation is intended to include the numbers
themselves and the range between them. This range may be integral
or continuous between and including the end values.
[0181] The term "deuterium enrichment" refers to the percentage of
incorporation of deuterium at a given position in a molecule in the
place of hydrogen. For example, deuterium enrichment of 1% at a
given position means that 1% of molecules in a given sample contain
deuterium at the specified position. Because the naturally
occurring distribution of deuterium is about 0.0156%, deuterium
enrichment at any position in a compound synthesized using
non-enriched starting materials is about 0.0156%. The deuterium
enrichment can be determined using conventional analytical methods
known to one of ordinary skill in the art, including mass
spectrometry and nuclear magnetic resonance spectroscopy.
[0182] The term "is/are deuterium," when used to describe a given
position in a molecule such as R.sub.1-R.sub.27 or the symbol "D",
when used to represent a given position in a drawing of a molecular
structure, means that the specified position is enriched with
deuterium above the naturally occurring distribution of deuterium.
In one embodiment deuterium enrichment is no less than about 1%, in
another no less than about 5%, in another no less than about 10%,
in another no less than about 20%, in another no less than about
50%, in another no less than about 70%, in another no less than
about 80%, in another no less than about 90%, or in another no less
than about 98% of deuterium at the specified position.
[0183] The term "isotopic enrichment" refers to the percentage of
incorporation of a less prevalent isotope of an element at a given
position in a molecule in the place of the more prevalent isotope
of the element.
[0184] The term "non-isotopically enriched" refers to a molecule in
which the percentages of the various isotopes are substantially the
same as the naturally occurring percentages.
[0185] Asymmetric centers exist in the compounds disclosed herein.
These centers are designated by the symbols "R" or "S," depending
on the configuration of substituents around the chiral carbon atom.
It should be understood that the invention encompasses all
stereochemical isomeric forms, including diastereomeric,
enantiomeric, and epimeric forms, as well as D-isomers and
L-isomers, and mixtures thereof. Individual stereoisomers of
compounds can be prepared synthetically from commercially available
starting materials which contain chiral centers or by preparation
of mixtures of enantiomeric products followed by separation such as
conversion to a mixture of diastereomers followed by separation or
recrystallization, chromatographic techniques, direct separation of
enantiomers on chiral chromatographic columns, or any other
appropriate method known in the art. Starting compounds of
particular stereochemistry are either commercially available or can
be made and resolved by techniques known in the art. Additionally,
the compounds disclosed herein may exist as geometric isomers. The
present invention includes all cis, trans, syn, anti, entgegen (E),
and zusammen (Z) isomers as well as the appropriate mixtures
thereof. Additionally, compounds may exist as tautomers; all
tautomeric isomers are provided by this invention. Additionally,
the compounds disclosed herein can exist in unsolvated as well as
solvated forms with pharmaceutically acceptable solvents such as
water, ethanol, and the like. In general, the solvated forms are
considered equivalent to the unsolvated forms.
[0186] The terms "3S,11bS enantiomer" or the term "3R,11bR
enantiomer" refers to either of the d.sub.6-tetrabenazine
stereoisomers having the structural formulas shown below:
##STR00015##
In certain embodiments, a chemical structure may be drawn as either
the 3S,11bS enantiomer or the 3R,11bR enantiomer, but the text of
the specification may indicate that the 3S,11bS enantiomer, the
3R,11bR enantiomer, a racemic mixture thereof (which may be
described as (RR, SS)-d6-tetrabenazine), or all of the foregoing
may be intended to be described.
[0187] The terms "(3S,11bS)-enantiomer" or "(3R,11bR)-enantiomer"
or the as applied to a compound of Formula I refers to either of
the stereoisomers of compounds of Formula I shown below:
##STR00016##
[0188] The term "bond" refers to a covalent linkage between two
atoms, or two moieties when the atoms joined by the bond are
considered to be part of larger substructure. A bond may be single,
double, or triple unless otherwise specified. A dashed line between
two atoms in a drawing of a molecule indicates that an additional
bond may be present or absent at that position.
[0189] The term "alkoxy," as used herein, alone or in combination,
refers to an alkyl ether radical, wherein the term alkyl is as
defined below. Examples of suitable alkyl ether radicals include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,
sec-butoxy, tert-butoxy, and the like.
[0190] The term "alkyl," as used herein, alone or in combination,
refers to a straight-chain or branched-chain alkyl radical
containing from 1 to 20 carbon atoms. In certain embodiments, said
alkyl will comprise from 1 to 10 carbon atoms. In further
embodiments, said alkyl will comprise from 1 to 6 carbon atoms.
Alkyl groups may be optionally substituted as defined herein.
Examples of alkyl radicals include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as
used herein, alone or in combination, refers to a saturated
aliphatic group derived from a straight or branched chain saturated
hydrocarbon attached at two or more positions, such as methylene
(--CH.sub.2--). Unless otherwise specified, the term "alkyl" may
include "alkylene" groups.
[0191] The term "alkylamino," as used herein, alone or in
combination, refers to an alkyl group attached to the parent
molecular moiety through an amino group. Suitable alkylamino groups
may be mono- or dialkylated, forming groups such as, for example,
N-methylamino, N-ethylamino, N,N-dimethylamino,
N,N-ethylmethylamino and the like.
[0192] The term "amino," as used herein, alone or in combination,
refers to NRR', wherein R and R' are independently selected from
the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl,
cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may
themselves be optionally substituted. Additionally, R and R' may
combine to form heterocycloalkyl, either of which may be optionally
substituted.
[0193] The term "aryl," as used herein, alone or in combination,
means a carbocyclic aromatic system containing one, two or three
rings wherein such polycyclic ring systems are fused together. The
term "aryl" embraces aromatic groups such as phenyl, naphthyl,
anthracenyl, and phenanthryl.
[0194] The term "halo," or "halogen," as used herein, alone or in
combination, refers to fluorine, chlorine, bromine, or iodine.
[0195] The term "haloalkoxy," as used herein, alone or in
combination, refers to a haloalkyl group attached to the parent
molecular moiety through an oxygen atom.
[0196] The term "haloalkyl," as used herein, alone or in
combination, refers to an alkyl radical having the meaning as
defined above wherein one or more hydrogens are replaced with a
halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals. A monohaloalkyl radical, for one example,
may have an iodo, bromo, chloro or fluoro atom within the radical.
Dihalo and polyhaloalkyl radicals may have two or more of the same
halo atoms or a combination of different halo radicals. Examples of
haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl. "Haloalkylene" refers to a haloalkyl group
attached at two or more positions. Examples include fluoromethylene
(--CFH--), difluoromethylene (--CF.sub.2--), chloromethylene
(--CHCl--) and the like.
[0197] The term "perhaloalkoxy" refers to an alkoxy group where all
of the hydrogen atoms are replaced by halogen atoms.
[0198] The term "perhaloalkyl" as used herein, alone or in
combination, refers to an alkyl group where all of the hydrogen
atoms are replaced by halogen atoms.
[0199] The terms "sulfonate," "sulfonic acid," and "sulfonic," as
used herein, alone or in combination, refer the --SO.sub.3H group
and its anion or the --SO.sub.3-- group.
[0200] The terms "sulfate," "sulfuric acid," and "sulfuric," as
used herein, alone or in combination, refer the HOS(.dbd.O).sub.2OH
group and its mono- or dianion or the --SO.sub.4-- group.
[0201] The terms "phosphate," "phosphoric acid," and "phosphoric,"
as used herein, alone or in combination, refer the
P(.dbd.O)(OH).sub.3 group and its mono-, di, or trianion or the
--PO.sub.4-- group.
[0202] The terms "carbonate," as used herein, alone or in
combination, refer the --OC(.dbd.O)O-- group.
[0203] The term "VMAT2" refers to vesicular monoamine transporter
2, an integral membrane protein that acts to transport
monoamines--particularly neurotransmitters such as dopamine,
norepinephrine, serotonin, and histamine--from cellular cytosol
into synaptic vesicles.
[0204] The term "VMAT2-mediated disorder," refers to a disorder
that is characterized by abnormal VMAT2 activity. A VMAT2-mediated
disorder may be completely or partially mediated by modulating
VMAT2. In particular, a VMAT2-mediated disorder is one in which
inhibition of VMAT2 results in some effect on the underlying
disorder e.g., administration of a VMAT2 inhibitor results in some
improvement in at least some of the patients being treated.
[0205] The term "VMAT2 inhibitor", "inhibit VMAT2", or "inhibition
of VMAT2" refers to the ability of a compound disclosed herein to
alter the function of VMAT2. A VMAT2 inhibitor may block or reduce
the activity of VMAT2 by forming a reversible or irreversible
covalent bond between the inhibitor and VMAT2 or through formation
of a noncovalently bound complex. Such inhibition may be manifest
only in particular cell types or may be contingent on a particular
biological event. The term "VMAT2 inhibitor", "inhibit VMAT2", or
"inhibition of VMAT2" also refers to altering the function of VMAT2
by decreasing the probability that a complex forms between a VMAT2
and a natural substrate
[0206] VMAT2-mediated disorders include, but are not limited to
chronic hyperkinetic movement disorders, which can be psychogenic
(e.g., tics), idiopathic (as in, e.g., Tourette's syndrome and
Parkinson's Disease, genetic (as in, e.g., the chorea
characteristic of Huntington's Disease), infectious (as in, e.g.,
Sydenham's Chorea), or, drug induced, as in tardive dyskinesia.
Unless otherwise stated, "chronic hyperkinetic movement disorders"
refers to and includes all psychogenic, idiopathic, genetic, and
drug-induced movement disorders. VMAT2 disorders also include
disorders such as oppositional defiant disorder.
[0207] The compounds disclosed herein can exist as therapeutically
acceptable salts. The term "therapeutically acceptable salt," as
used herein, represents salts or zwitterionic forms of the
compounds disclosed herein which are therapeutically acceptable as
defined herein. The salts can be prepared during the final
isolation and purification of the compounds or separately by
reacting the appropriate compound with a suitable acid or base.
Therapeutically acceptable salts include acid and basic addition
salts. For a more complete discussion of the preparation and
selection of salts, refer to "Handbook of Pharmaceutical Salts,
Properties, and Use," Stah and Wermuth, Ed., (Wiley-VCH and VHCA,
Zurich, 2002) and Berge et al., J. Pharm. Sci. 1977, 66, 1-19.
[0208] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0209] Suitable bases for use in the preparation of
pharmaceutically acceptable salts, including, but not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, secondary amines, triethanolamine, trimethylamine,
triethylamine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
[0210] While it may be possible for the compounds of the subject
invention to be administered as the raw chemical, it is also
possible to present them as a pharmaceutical composition.
Accordingly, provided herein are pharmaceutical compositions which
comprise one or more of certain compounds disclosed herein, or one
or more pharmaceutically acceptable salts, prodrugs, or solvates
thereof, together with one or more pharmaceutically acceptable
carriers thereof and optionally one or more other therapeutic
ingredients. Proper formulation is dependent upon the route of
administration chosen. Any of the well-known techniques, carriers,
and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences. The
pharmaceutical compositions disclosed herein may be manufactured in
any manner known in the art, e.g., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes. The
pharmaceutical compositions may also be formulated as a modified
release dosage form, including delayed-, extended-, prolonged-,
sustained-, pulsatile-, controlled-, accelerated- and fast-,
targeted-, programmed-release, and gastric retention dosage forms.
These dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art (see,
Remington: The Science and Practice of Pharmacy, supra;
Modified-Release Drug Deliver Technology, Rathbone et al., Eds.,
Drugs and the Pharmaceutical Science, Marcel Dekker, Inc., New
York, N.Y., 2002; Vol. 126).
General Synthetic Methods for Preparing Compounds
[0211] Isotopic hydrogen can be introduced into a compound as
disclosed herein by synthetic techniques that employ deuterated
reagents, whereby incorporation rates are pre-determined; and/or by
exchange techniques, wherein incorporation rates are determined by
equilibrium conditions, and may be highly variable depending on the
reaction conditions. Synthetic techniques, where tritium or
deuterium is directly and specifically inserted by tritiated or
deuterated reagents of known isotopic content, may yield high
tritium or deuterium abundance, but can be limited by the chemistry
required. Exchange techniques, on the other hand, may yield lower
tritium or deuterium incorporation, often with the isotope being
distributed over many sites on the molecule.
[0212] The compounds as disclosed herein can be prepared by methods
known to one of skill in the art and routine modifications thereof,
and/or following procedures similar to those described in the
Example section herein and routine modifications thereof, and/or
procedures found in WO 2005077946; WO 2008/058261; EP 1716145; Lee
et al., J. Med. Chem., 1996, (39), 191-196; Kilbourn et al.,
Chirality, 1997, (9), 59-62; Boldt et al., Synth. Commun., 2009,
(39), 3574-3585; Rishel et al., J. Org. Chem., 2009, (74),
4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993, 44(4),
673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873; Ivanov
et al., Heterocycles 2001, 55(8), 1569-1572; U.S. Pat. No.
2,830,993; U.S. Pat. No. 3,045,021; WO 2007130365; WO 2008058261,
which are hereby incorporated in their entirety, and references
cited therein and routine modifications thereof. Compounds as
disclosed herein can also be prepared as shown in any of the
following schemes and routine modifications thereof.
[0213] The following schemes can be used to practice the present
invention. Any position shown as hydrogen may optionally be
replaced with deuterium.
##STR00017##
[0214] Compound 1 is reacted with compound 2, wherein Y.sub.1 is as
defined in paragraph [0008], in the presence of an appropriate
basic catalyst, such as sodium tert-butoxide, at an elevated
temperature to give compound 3. Compound 3 is reacted with compound
4 in the presence of an appropriate base, such as potassium
carbonate, in an appropriate solvent, such as acetone, to afford
compound 5. Compound 5 is reacted with an appropriate dehydrating
agent, such as phosphorous oxychloride, in an appropriate solvent,
such as acetonitrile, at an elevated temperature to give compound
6. Compound 7 is reacted with an appropriate methylating agent,
such as methyl iodide, in an appropriate solvent, such as methyl
tert-butyl ether, at an elevated temperature to give compound 8.
Compound 6 is reacted with compound 8, in the presence of an
appropriate base, such as potassium carbonate, in an appropriate
solvent, such as a mixture of methanol and water, at an elevated
temperature to afford compound 9 of Formula I. Compound 9 may be
optionally purified by recrystallization from an appropriate
solvent, such as ethanol.
[0215] Deuterium can be incorporated to different positions
synthetically, according to the synthetic procedures as shown in
Scheme I, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.7-R.sub.12, compound 1 with the corresponding deuterium
substitutions can be used. To introduce deuterium at R.sub.15,
compound 2 with the corresponding deuterium substitution can be
used. To introduce deuterium at one or more positions of
R.sub.1-R.sub.6, compound 4 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R.sub.16-R.sub.29, compound 7 with the corresponding
deuterium substitutions can be used.
[0216] Deuterium can also be incorporated to various positions
having an exchangeable proton, via proton-deuterium equilibrium
exchange.
##STR00018##
[0217] Compound 10 is reacted with compound 11, in the presence of
an appropriate base, such as potassium carbonate, an optional
alkylation catalyst, such as potassium iodide, and an optional
phase transfer catalyst, such as tetrabutylammonium bromide, in an
appropriate solvent, such as dimethylformamide, at an elevated
temperature to give compound 12. Compound 12 is reacted with an
appropriate base, such as potassium hydroxide, in an appropriate
solvent, such as water, to afford an intermediate carboxylic acid
which is further reacted with an appropriate secondary amine or
salt thereof, such as dimethylamine hydrochloride, and an
appropriate formaldehyde equivalent, such as aqueous formaldehyde
solution, in the presence of an appropriate acid, such as
hydrochloric acid, and an optional phase transfer catalyst, such as
tetrabutylammonium bromide, to give a mixture of compound 7 and
compound 13. The mixture of compound 7 and compound 13 is further
reacted with an appropriate secondary amine or salt thereof, such
as dimethylamine hydrochloride, in the presence of an appropriate
base, such as potassium hydroxide, in an appropriate solvent, such
as water, to give compound 7.
[0218] Deuterium can be incorporated to different positions
synthetically, according to the synthetic procedures as shown in
Scheme I, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.16-R.sub.18, compound 10 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R.sub.19-R.sub.27, compound 11 with the corresponding
deuterium substitutions can be used.
[0219] Deuterium can also be incorporated to various positions
having an exchangeable proton, via proton-deuterium equilibrium
exchange.
[0220] The invention is further illustrated by the following
examples. All IUPAC names were generated using CambridgeSoft's
ChemDraw 13.0.
EXAMPLE 1
N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide
##STR00019##
[0221] Step 1
##STR00020##
[0222] Optimization of Reaction Conditions
[0223] General Procedure:
[0224] Dopamine hydrochloride is suspended in ethyl formate at
25-30.degree. C. The suspension is cooled to 10-15.degree. C. and
sodium tert-butoxide is added portionwise maintaining the same
temperature. The reaction mixture is warmed to 50-55.degree. C. for
12 hours. After completion of the reaction, ethanol is added to the
reaction mass and the temperature is maintained for 2 hours. The
reaction mass is filtered and washed with 2 volumes of ethanol. The
filtrate is concentrated under vacuum and water (0.5 volumes) is
added to the residue and stirred for 1 hour at 25-30.degree. C. The
solid is filtered and washed with water (0.25 volumes) and dried in
an hot air oven at 55-60.degree. C. for 8 hours.
TABLE-US-00001 TABLE 1 Optimization of reaction conditions by
varying equivalents of sodium tert- butoxide Exp. Batch Product
Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1
250 g Ethyl formate (10 eq) 151 g 63% 98.2% Sodium tert-butoxide (2
eq) Ethanol (5 vol) 50-55.degree. C., 12 hours 2 250 g Ethyl
formate (10 eq) 175 g 73% 92.7% Sodium tert-butoxide (1.6 eq)
Ethanol (5 vol) 50-55.degree. C., 12 hours 3 50 g Ethyl formate (10
eq) 18.5 g 38% 96.8% Sodium tert-butoxide (1.3 eq) Ethanol (5 vol)
50-55.degree. C., 12 hours 4 50 g Ethyl formate (10 eq) 32.6 g 68%
94.4% Sodium tert-butoxide (1.8 eq) Ethanol (5 vol) 50-55.degree.
C., 12 hours
Representative Example
Step 1
N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide
[0225] Dopamine hydrochloride (250.0 g, 1.323 mol, 1.0 eq) was
suspended in ethyl formate (2.5 L, 10.0 vol) at 25-30.degree. C.
The suspension was cooled to 10-15.degree. C. and sodium
tert-butoxide (202 g, 2.12 mol, 1.60 eq) was added portionwise
maintaining the same temperature. The reaction mixture was warmed
to 55-60.degree. C. for 12 hours and then concentrated under
reduced pressure. To the remaining residue, water (125 mL, 0.5 vol)
was added and stirred for 15 minutes. The volatile organic solvents
were distilled under vacuum whereupon the product precipitated. The
suspension was cooled to 25-30.degree. C. and purified water (500
mL, 2.0 vol) was added. The solid was filtered and washed with
water (125 mL, 0.5 vol) and dried in an oven at 55-60.degree. C.
for 8 hours to afford the title compound as a brown powder (203 g,
yield=84.5%). .sup.1H NMR (300 MHz, CDCl.sub.3), .delta. 8.72 (s,
broad, 2H), 7.96 (s, 1H), 6.548-6.630 (dd, 2H, J=8.1), 6.407-6.441
(d, 1H, J=2.1), 3.169-3.237 (q, 2H, J=6.9), 2.485-2.535 (t, 2H,
J=7.8); LC-MS: m/z=181.92 (MH).sup.+.
EXAMPLE 2
d.sub.6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride
##STR00021##
[0226] Step 1
##STR00022##
[0227] Optimization of Reaction Conditions
[0228] General Procedure:
[0229] N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide is charged with
solvent, base, phase transfer catalyst if any, and d.sub.3-methyl
iodide (CD.sub.3I) at 25-30.degree. C. The reaction temperature is
set and maintained for the specified time. The reaction is
filtered, the filtrate distilled under reduced pressure, and the
crude product partitioned between dichloromethane (6.0 vol) and
water (4.0 vol). The layers are separated and the organic layer is
washed twice with 3% aqueous NaOH solution (2.times.4.0 vol)
followed by water (4.0 vol). The organic layer is distilled under
reduced pressure to give crude
d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.
TABLE-US-00002 TABLE 2 Optimization of reaction conditions by
varying solvent Exp. Batch Product Product HPLC No. Size Reaction
Conditions Quantity Yield Purity 1 50 g K.sub.2CO.sub.3 (3 eq) 50 g
86.6% 93.9% CH.sub.3I (2.2 eq) Acetone (8 vol) Tetrabutylammonium
bromide (0.05 eq) 38-42.degree. C., 36 hours 2 25 g K.sub.2CO.sub.3
(3 eq) 21 g 75% -- CH.sub.3I (2.2 eq) Acetonitrile (8 vol)
Tetrabutylammonium bromide (0.05 eq) 38-42.degree. C., 36 hours 3
50 g K.sub.2CO.sub.3 (3 eq) Not -- -- CH.sub.3I (2.2 eq) isolated
2-Methyl-tetrandrofuran (8 vol) Tetrabutylammonium bromide (0.05
eq) 38-42.degree. C., 36 hours
TABLE-US-00003 TABLE 3 Optimization of reaction conditions by
varying solvent volume Exp. Batch Product Product HPLC No. Size
Reaction Conditions Quantity Yield Purity 1 20 g K.sub.2CO.sub.3 (3
eq) 22 g 95.3% -- CH.sub.3I (3 eq) Acetone (6 vol) 18-crown-6 (0.05
eq) 38-42.degree. C., 12 hours 2 100 g K.sub.2CO.sub.3 (3 eq) 116 g
~100% 92.4% CH.sub.3I (3 eq) Acetone (8 vol) 18-crown-6 (0.05 eq)
38-42.degree. C., 12 hours
TABLE-US-00004 TABLE 4 Optimization of reaction conditions by
varying molar equivalents of methyl iodide Exp. Batch Product
Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1
50 g K.sub.2CO.sub.3 (3 eq) 44.3 g 76.7% 94.2% CH.sub.3I (2.2 eq)
Acetone (8 vol) 28-35.degree. C., 36 hours 2 50 g K.sub.2CO.sub.3
(3 eq) 47.6 g 82.4% 90.9% CH.sub.3I (2.4 eq) Acetone (8 vol)
28-35.degree. C., 36 hours 3 50 g K.sub.2CO.sub.3 (3 eq) 48 g 83.0%
93.5% CH.sub.3I (2.6 eq) Acetone (8 vol) 28-35.degree. C., 36
hours
TABLE-US-00005 TABLE 5 Optimization of reaction conditions by
varying reaction temperature Exp. Batch Product Product HPLC No.
Size Reaction Conditions Quantity Yield Purity 1 200 g
K.sub.2CO.sub.3 (3 eq) 198.9 g 83.7% 93.1% CH.sub.3I (2.2 eq)
Acetone (8 vol) 28-35.degree. C., 36 hours 2 25 g K.sub.2CO.sub.3
(3 eq) 21 g 72.9% 95.8% CH.sub.3I (2.2 eq) Acetone (8 vol)
28-40.degree. C., 36 hours
TABLE-US-00006 TABLE 6 Optimization of reaction conditions by
varying phase transfer catalyst and methyl iodide equivalents Phase
Exp. Batch Transfer CH.sub.3I Base Solvent/ No. Size Catalyst (eq)
(eq) (eq) Conditions Result 1 10 g Tetrabutyl 3 K.sub.2CO.sub.3
Acetone Worked well ammonium (3.0) 35-45.degree. C., bromide 45
hours (0.05) 2 10 g Tetrabutyl 3 K.sub.2CO.sub.3 Acetone Worked
well ammonium (3.0) 35-45.degree. C., bromide 45 hours (0.08) 3 10
g None 2.2 Cs.sub.2CO.sub.3 Acetone 1.5% Formanide (2.0)
35-45.degree. C., methylation, 5% 20 hours monomethylated phenol
remain- ing 4 10 g None 2.5 Cs.sub.2CO.sub.3 Acetone 2% Formanide
(2.0) 35-45.degree. C., methylation, 3% 20 hours monomethylated
phenol remain- ing 5 10 g Tetrabutyl 2.2 K.sub.2CO.sub.3 Acetone
Worked well ammonium (3.0) 35-45.degree. C., bromide 20 hours
(0.05) 6 10 g Tetrabutyl 2.5 K.sub.2CO.sub.3 Acetone Worked well
ammonium (3.0) 35-45.degree. C., bromide 20 hours (0.05)
TABLE-US-00007 TABLE 7 Optimization of reaction conditions by
varying phase transfer catalyst Exp. Batch Product Product HPLC No.
Size Reaction Conditions Quantity Yield Purity 1 30 g
K.sub.2CO.sub.3 (3 eq) 28 g 82.3% -- CH.sub.3I (2.2 eq) Acetone (8
vol) 28-42.degree. C., 36 hours 2 25 g K.sub.2CO.sub.3 (3 eq) 24 g
81% -- CH.sub.3I (2.2 eq) Acetone (8 vol) 28-42.degree. C., 36
hours 3 25 g K.sub.2CO.sub.3 (3 eq) 23 g 79.8% 83.4% CH.sub.3I (2.2
eq) Acetone (8 vol) Tetrabutylammonium iodid (0.05) 28-42.degree.
C., 36 hours
TABLE-US-00008 TABLE 8 Optimization of reaction conditions by
varying phase transfer catalyst quantity Exp. Batch Product Product
HPLC No. Size Reaction Conditions Quantity Yield Purity 1 50 g
K.sub.2CO.sub.3 (3 eq) 50 g 86.6% 93.9% CH.sub.3I (2.2 eq) Acetone
(8 vol) Tetrabutylammonium bromide (0.05) 28-42.degree. C., 36
hours 2 25 g K.sub.2CO.sub.3 (3 eq) 22 g 76.3% 90.78% CH.sub.3I
(2.2 eq) Acetone (8 vol) Tetrabutylammonium bromide (0.01)
28-40.degree. C., 36 hours 3 25 g K.sub.2CO.sub.3 (3 eq) 21 g 72.9%
95.85% CH.sub.3I (2.2 eq) Acetone (8 vol) Without
tetrabutylammonium bromide 28-42.degree. C., 36 hours
Representative Example
Step 1
d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide
[0230] N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide (190 g, 1.049
mol, 1.00 eq) was charged with acetone (1.52 L, 8.0 vol), followed
by K.sub.2CO.sub.3 (434 g, 3.149 mol, 3.00 eq) at 25-30.degree. C.
CD.sub.3I (334 g, 2.309 mol, 2.20 eq) was added to the reaction
mixture over 1 hour at 25-30.degree. C. The reaction temperature
was maintained for 36 hours at 25-35.degree. C. The reaction was
filtered, the filtrate was distilled under reduced pressure, and
the crude product was partitioned between dichloromethane (1.14 L,
6.0 vol) and water (760 mL, 4.0 vol). The layers were separated and
the organic layer was washed twice with 3% aqueous NaOH solution
(2.times.760 mL, 2.times.4.0 vol) followed by water (760 mL, 4.0
vol). The organic layer was distilled under reduced pressure to
give 158 g crude
d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.
Step 2
##STR00023##
[0231] Optimization of Reaction Conditions
[0232] General Procedure:
[0233] N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide is charged with
solvent and POCl.sub.3 at 10-15.degree. C. The mixture is heated to
an elevated temperature for 1 or 2 hours and then is cooled to
ambient temperature, after which a quenching solvent (for example,
a protic solvent such as an alcohol) is added and the mixture is
stirred for 1 hour followed by addition of an anti-solvent if
applicable. In some cases,
d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride
precipitates in the form of a salt directly from the reaction
mixture. In others, d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline
is isolated after acid-base workup.
TABLE-US-00009 TABLE 9 Optimization of reaction conditions by
varying the solvent Exp. Batch Reaction Quenching/ Product Product
HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 93 g
POCl.sub.3 (1 eq) None 49 g 57.6% 90.0% Acetonitrile (10 vol)
80-85.degree. C., 2 hours 2 200 g POCl.sub.3 (1 eq) None 112 g
61.5% 84.6% Toluene (2 vol) 90-95.degree. C., 1 hours 3 20 g
POCl.sub.3 (1 eq) None sticky -- -- MTBE* (4 vol) mass 0-30.degree.
C. 4 20 g POCl.sub.3 (1 eq) None sticky -- -- DCM* (2 vol) mass
0-30.degree. C. *DCM = Dichloromethane; MTBE = Methyl tert-butyl
ether.
TABLE-US-00010 TABLE 10 Optimization of reaction conditions by
varying quenching solvent and anti- solvent (reaction solvent
toluene) Exp. Batch Reaction Quenching/ Product HPLC No. Size
Conditions Anti-Solvent Quantity Yield Purity 1 48 g POCl.sub.3
(1.8 eq) Ethanol (3.8 eq) Product not -- -- Toluene (2 vol) MTBE*
(4 vol) obtained as 90-95.degree. C., 1 hour a free solid 2 48 g
POCl.sub.3 (distilled, Ethanol (3.8 eq) 20.2 g 46% 91.9% 1.8 eq)
MTBE* (4 vol) Toluene (2 vol) 90-95.degree. C., 1 hour 3 50 g
POCl.sub.3 (1 eq) Ethyl Acetate (2 35 g 76% -- Toluene (2 vol) vol)
90-95.degree. C., 1 hour Ethyl Acetate/ HCl (2 vol) 4 20 g
POCl.sub.3 (distilled, Ethanol (2.4 eq) Product not -- -- 1.8 eq)
MTBE* (4 vol) obtained as Toluene (2 vol) a free solid
40-45.degree. C., 1 hour 5 50 g POCl.sub.3 (distilled, Ethanol (3.8
eq) Product not -- -- 1.8 eq) MTBE* (4 vol) obtained as Toluene (2
vol) 80-85.degree. C., 1 hour, a free solid seeded with product 6
28 g POCl.sub.3 (1.8 eq) Ethanol (3.8 eq) 24 g >100% Isolated
Toluene (2 vol) MTBE* (4 vol) by acid- 90-95.degree. C., 2 hours
base workup 7 25 g POCl.sub.3 (1.8 eq) IPA* (3.8 eq) 14.5 g 53.2%
80.2% Toluene (2 vol) MTBE* (4 vol) (black 90-95.degree. C., 2
hours 12 hours solid) 8 25 g POCl.sub.3 (1.8 eq) 1-Butanol (3.8
20.1 g 73.5% 80.1% Toluene (2 vol) eq) (black 90-95.degree. C., 2
hours MTBE* (4 vol) solid) 12 hours 9 25 g POCl.sub.3 (1.8 eq)
1-Propanol (3.8 Product not -- -- Toluene (2 vol) eq) obtained as
90-95.degree. C., 2 hours Cyclohexane (4 a free solid vol) 12 hours
*IPA = Isopropyl alcohol; MTBE = Methyl tert-butyl ether.
TABLE-US-00011 TABLE 11 Optimization of reaction conditions by
varying quenching solvent and anti- solvent (reaction solvent
acetonitrile) Exp. Batch Reaction Quenching/ Product HPLC No. Size
Conditions Anti-Solvent Quantity Yield Purity 1 100 g POCl.sub.3
(1.8 eq) Ethanol (3.8 eq) 110 g -- 93.3% Acetonitrile (2 vol) MTBE*
(4 vol) (hygroscopic) 80-85.degree. C., 1 hour 12 hours, seeded
with product 2 25 g POCl.sub.3 (1.8 eq) IPA* (3.8 eq) 17 g 62.4%
87.1% Acetonitrile (2 vol) MTBE* (4 vol) (black 80-85.degree. C., 2
hours 12 hours, solid) 3 25 g POCl.sub.3 (1.8 eq) 1-Butanol (3.8
17.3 g 63.8% 95.6% Acetonitrile (2 vol) eq) (grey 80-85.degree. C.,
2 hours MTBE* (4 vol) solid) 12 hours 5 25 g POCl.sub.3 (1.8 eq)
t-Butanol (3.8 Solid not -- -- Acetonitrile (2 vol) eq) isolated
80-85.degree. C., 2 hours MTBE* (4 vol) 12 hours 6 25 g POCl.sub.3
(1.8 eq) 1-Propanol (3.8 17 g 62.4% 88.8% Acetonitrile (2 vol) eq)
(gray 80-85.degree. C., 2 hours MTBE* (4 vol) solid) 12 hours 7 25
g POCl.sub.3 (1.8 eq) 1-Pentanol (3.8 13.4 g 49.2% Brown
Acetonitrile (2 vol) eq) solid 80-85.degree. C., 2 hours MTBE* (4
vol) 12 hours 8 25 g POCl.sub.3 (1.8 eq) 2-methyl 12.77 g 46.9%
87.6% Acetonitrile (2 vol) propanol (3.8 eq) (gray 80-85.degree.
C., 2 hours MTBE* (4 vol) solid) 12 hours *IPA = Isopropyl alcohol;
MTBE = Methyl tert-butyl ether.
TABLE-US-00012 TABLE 12 Optimization of reaction conditions by
varying anti-solvent (reaction solvent acetonitrile, 1-butanol as a
quenching solvent) Exp. Batch Reaction Quenching/ Product Product
HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g
POCl.sub.3 (1.8 eq) 1-butanol 13.3 g 48.8% 91.9% Acetonitrile (3.8
eq) (2 vol) Ethyl acetate 80-85.degree. C., (4 vol) 2 hours 12
hours 2 25 g POCl.sub.3 (1.8 eq) 1-butanol) 14.83 g 54.5% 94.4%
Acetonitrile (3.8 eq (2 vol) Isopropyl 80-85.degree. C., acetate 2
hours (4 vol) 12 hours 3 25 g POCl.sub.3 (1.8 eq) 1-butanol 14.2 g
52.2% 93.3% Acetonitrile (3.8 eq) (2 vol) 2-methyl-THF*
80-85.degree. C., (4 vol) 2 hours 12 hours 4 25 g POCl.sub.3 (1.8
eq) 1-butanol 13.0 g 47.7% 94.2% Acetonitrile (3.8 eq) (2 vol)
Ethyl acetate/ 80-85.degree. C., HCl (4 vol) 2 hours 12 hours 5 25
g POCl.sub.3 (1.8 eq) 1-butanol 18.3 g 67.2% 93.5% Acetonitrile
(3.8 eq) (2 vol) MTBE* (4 vol) 80-85.degree. C., 12 hours 2 hours 6
25 g POCl.sub.3 (1.8 eq) 1-butanol 17.5 g 64.3% 91.3% Acetonitrile
(3.8 eq) (2 vol) MTBE* (8 vol) 80-85.degree. C., 12 hours 2 hours *
MTBE = Methyl tert-butyl ether; 2-methyl-THF =
2-methyltetrahydrofuran (4 vol).
TABLE-US-00013 TABLE 13 Optimization of reaction conditions by
varying equivalents of 1-butanol (reaction solvent acetonitrile,
1-butanol as a quenching solvent) Exp. Batch Reaction Quenching/
Product Product HPLC No. Size Conditions Anti-Solvent Quantity
Yield Purity 1 25 g POCl.sub.3 (1.8 eq) 1-butanol 14.7 g 54% 84.1%
Acetonitrile (6.0 eq) (2 vol) MTBE* 80-85.degree. C., (4 vol) 2
hours 12 hours 2 28 g POCl.sub.3 (1.8 eq) 1-butanol 21.3 g 70%
94.6% Acetonitrile (3.8 eq) (2 vol) MTBE* 80-85.degree. C., (4 vol)
2 hours 12 hours * MTBE = Methyl tert-butyl ether;
TABLE-US-00014 TABLE 14 Optimization of reaction conditions by
using methyl tert-butyl ether as reaction solvent and varying the
quenching solvent Exp. Batch Reaction Quenching/ Product Product
HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g
POCl.sub.3 Ethanol Solid not -- -- (1.8 eq) (3.8 eq) isolated MTBE*
12 hours (4 vol) 55-60.degree. C., 2 hours 2 25 g POCl.sub.3
1-butanol 10.5 g 38.5% 74.4% (1.8 eq) (3.8 eq) (brown MTBE* 12
hours solid) (4 vol) 45-50.degree. C., 2 hours *MTBE = Methyl
tert-butyl ether;
TABLE-US-00015 TABLE 15 Optimization of reaction conditions by
varying the equivalents of POCl.sub.3 used Exp. Batch Reaction
Quenching/ Product Product HPLC No. Size Conditions Anti-Solvent
Quantity Yield Purity 1 50 g POCl.sub.3 (0.5 eq) 1-butanol -- --
Product Acetonitrile (3.8 eq) obtained (2 vol) MTBE* as a
80-85.degree. C., (4 vol) gummy 2 hours 12 hours solid 2 50 g
POCl.sub.3 (1.0 eq) 1-butanol -- -- Product Acetonitrile (3.8 eq)
obtained (2 vol) MTBE* as a 80-85.degree. C., (4 vol) gummy 2 hours
12 hours solid 3 25 g POCl.sub.3 (1.8 eq) 1-butanol 17.3 g 63.8%
98.6% Acetonitrile (3.8 eq) (2 vol) MTBE* 80-85.degree. C., (4 vol)
2 hours 12 hours
Representative Example
Step 2
d.sub.6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride
[0234] To the crude
d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide from step 1,
(158 g, 0.734 mol, 1.00 eq), acetonitrile (316 mL, 2.0 vol) was
added followed by POCl.sub.3 (202 g, 1.322 mol, 1.80 eq) at
10-15.degree. C. The reaction mixture was heated to reflux for 2
hours and then cooled to 25-35.degree. C. The temperature was
maintained for 12 hours after which it was quenched with n-butanol
(255 mL, 2.79 mol, 3.8 eq) and methyl tert-butyl ether (1.26 L, 8.0
vol). The precipitated product was filtered, washed with ethyl
acetate (632 mL, 4.0 vol), and dried under vacuum. The crude
product was further purified by slurrying in 10% Ethanol in MTBE
(944 mL, 8.0 vol) whereupon an orange brown product (108 g,
yield=44.0%) was obtained after drying. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta. 14.456 (br s, 1H), 9.105-9.133 (d, 1H, J=8.4),
7.497 (s, 1H), 6.806 (s, 1H), 3.951-4.000 (t, 2H, J=7.5),
3.089-3.144 (t, 2H, J=8.4); LC-MS: m/z=198.06 (MH).sup.+.
Step 3
Optional purification of
d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride
[0235] To increase the purity of
d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride various
purification procedures were attempted.
TABLE-US-00016 TABLE 16 Recrystallization of
d.sub.6-6,7-dimethoxy-3,4- dihydroisoquinoline hydrochloride Exp.
Batch Product Product HPLC No. Size Reaction Conditions Quantity
Yield Purity 1 5 g 6,7-Dimethoxy-3,4- 2.1 g 42% 94.5%
dihydroisoquinoline hydrochloride (1 eq) Ethanol (3 vol)
60-65.degree. C., 1 hour Cooled and filtered at 25-30.degree. C. 2
5 g 6,7-Dimethoxy-3,4- 1.4 g 28.0% 89.0% dihydroisoquinoline
hydrochloride (1 eq) Ethanol (8 vol) 75-80.degree. C., 16 hour
Cooled and filtered at 25-30.degree. C. 3 5 g 6,7-Dimethoxy-3,4-
1.02 g 20.4% 84.8% dihydroisoquinoline 1-Propanol (8 vol)
95-100.degree. C., 16 hour Cooled and filtered at 25-30.degree. C.
4 5 g 6,7-Dimethoxy-3,4- 0.85 g 17.0% 76.0% dihydroisoquinoline
hydrochloride (1 eq) 1-Butanol (8 vol) 115-120.degree. C., 16 hour
Cooled and filtered at 25-30.degree. C. 5 5 g 6,7-Dimethoxy-3,4-
1.19 g 23.8% 85.7% dihydroisoquinoline hydrochloride (1 eq)
1-Pentanol (8 vol) 135-140.degree. C., 16 hour Cooled and filtered
at 25-30.degree. C.
TABLE-US-00017 TABLE 17 Reslurry and washing of
d.sub.6-6,7-dimethoxy-3,4- dihydroisoquinoline hydrochloride Exp.
Batch Product Product HPLC No. Size Reaction Conditions Quantity
Yield Purity 1 2 g 6,7-Dimethoxy-3,4- 1.75 g 83.3% 93.3%
dihydroisoquinoline hydrochloride (1 eq) Acetone (3 vol) Stirred at
25-30.degree. C. for 2 hour, then filtered and dried 2 2 g
6,7-Dimethoxy-3,4- 1.21 g 60% 94.5% dihydroisoquinoline
hydrochloride (1 eq) Acetonitrile (2 vol) Stirred at 25-30.degree.
C. for 2 hour, then filtered and dried 3 2 g 6,7-Dimethoxy-3,4-
1.35 g 67.5% -- dihydroisoquinoline hydrochloride (1 eq)
Ethanol/acetonitrile/acetone (1:1:8) (3 vol) Stirred at
25-30.degree. C. for 2 hour, then filtered and dried 4 2 g
6,7-Dimethoxy-3,4- 1.78 g 89% -- dihydroisoquinoline hydrochloride
(1 eq) Methanol/ethyl acetate (5:95) (3 vol) Stirred at
25-30.degree. C. for 2 hour, then filtered and dried 5 2 g
6,7-Dimethoxy-3,4- 1.34 g 67% -- dihydroisoquinoline hydrochloride
(1 eq) Methanol/ethyl acetate (5:95) (3 vol) Stirred at
25-30.degree. C. for 1 hour, then filtered and dried 6 2 g
6,7-Dimethoxy-3,4- 1.46 g 73% -- dihydroisoquinoline hydrochloride
(1 eq) Ethanol/acetone/ethyl acetate (1:1:8) (3 vol) Stirred at
25-30.degree. C. for 1 hour, then filtered and dried 7 1 g
6,7-Dimethoxy-3,4- 0.55 g 55% -- dihydroisoquinoline hydrochloride
(1 eq) Ethanol/ethyl acetate (1:9) (3 vol) Stirred at 25-30.degree.
C. for 1 hour, then filtered and dried 8 5 g 6,7-Dimethoxy-3,4- 4.8
g 96.0% 93.5% dihydroisoquinoline hydrochloride (1 eq) Ethyl
acetate (5 vol) Stirred at 28-32.degree. C. for 16 hour, then
filtered and dried 9 5 g 6,7-Dimethoxy-3,4- 4.87 g 97.4% 79.1%
dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether (5
vol) Stirred at 28-32.degree. C. for 16 hour, then filtered and
dried 10 5 g 6,7-Dimethoxy-3,4- 4.31 g 86.2% 94.1%
dihydroisoquinoline hydrochloride (1 eq) Acetone (3 vol) Stirred at
28-32.degree. C. for 16 hour, then filtered and dried 11 5 g
6,7-Dimethoxy-3,4- 1.63 g 32.6% 90.9% dihydroisoquinoline
hydrochloride (1 eq) Acetonitrile (3 vol) Stirred at 28-32.degree.
C. for 16 hour, then filtered and dried 12 5 g 6,7-Dimethoxy-3,4-
3.4 g 68% 91.7% dihydroisoquinoline hydrochloride (1 eq) Methyl
tert-butyl ether (6 vol) 50-55.degree. C. 1-butanol (12 vol)
Stirred at 28-32.degree. C. for 16 hour, then filtered and dried 13
5 g 6,7-Dimethoxy-3,4- dihydroisoquinoline hydrochloride (1 eq)
Methyl tert-butyl ether/ethanol (9:1) (6 vol) Stirred at
28-32.degree. C. for 16 hour, then filtered and dried 14 150 g
6,7-Dimethoxy-3,4- 138 g 92% 99.0% dihydroisoquinoline
hydrochloride (1 eq) Methyl tert-butyl ether/ethanol (9:1) (6 vol)
Stirred at 28-32.degree. C. for 16 hour, then filtered and
dried
EXAMPLE 3
(RR,
SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpropy-
l)-2H-benzo[a]quinolizin-2-one ((+/-)-d.sub.6-Tetrabenazine)
##STR00024##
[0236] Step 1
##STR00025##
[0237] Representative Example
Step 1
2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide
[0238] 3-[(dimethylamino)methyl]-5-methyl-hexan-2-one (90 g, 0.526
mol, 1.00 eq) was charged with methyl tert-butyl ether (1.35 L,
15.0 vol) and cooled 0-10.degree. C. Methyl iodide (171 g, 1.209
mol, 2.3 eq) was added slowly to the reaction mixture and stirred
for 15 hours at 25-35.degree. C. The reaction was warmed to
35-40.degree. C. for 2 hours. The precipitated solid was filtered
under nitrogen and was washed with methyl tert-butyl ether (900 mL,
10.0 vol). The crude product was further purified by slurrying in
ethyl acetate (1.46 L, 10 vol) and filtered to give
2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (146 g) as a
white solid.
Step 2
##STR00026##
[0239] Optimization of Reaction Conditions
[0240] General Procedure:
[0241] 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide is
charged to a suspension containing
d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline (hydrochloride or
freebase, 1.00 eq) and solvent. If
d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride is
used, a base is added to the reaction mixture at room temperature.
The reaction mixture is stirred at the appropriate temperature,
cooled, and water is added. The reaction mass is filtered and the
solids are washed with water and dried to afford the title compound
[The (RR, SS)-diastereomer of d.sub.6-tetrabenazine is the desired
product].
TABLE-US-00018 TABLE 18 Optimization of the reaction by varying the
solvent Exp. Batch Product Product No. Size Reaction Conditions
Quantity Yield HPLC Purity 1 30 g 6,7-Dimethoxy-3,4- 20.3 g 40.7%
98.8% dihydro isoquinoline 0.56% free base (1 eq) Diastereomer
2-acetyl-N,N,N,4- impurity* tetramethyl-1- pentanaminium iodide
(0.75 eq) Water (6 vol) 100.degree. C., 48 hour 2 10 g
6,7-Dimethoxy-3,4- 1.4 g 8.3% 97.8% dihydro isoquinoline 1.45% free
base (1 eq) Diastereomer 2-acetyl-N,N,N,4- impurity* tetramethyl-1-
pentanaminium iodide (0.75 eq) Water (6 vol) 65-70.degree. C., 48
hour 3 10 g 6,7-Dimethoxy-3,4- 1.4 g 8.3% 98.1% dihydro
isoquinoline 0.75% free base (1 eq) Diastereomer 2-acetyl-N,N,N,4-
impurity* tetramethyl-1- pentanaminium iodide (0.75 eq) Ethanol (6
vol) 75-80.degree. C., 48 hour 4 10 g 6,7-Dimethoxy-3,4- 6.8 g
40.8% 99.1% dihydro isoquinoline 0.04% free base (1 eq)
Diastereomer 2-acetyl-N,N,N,4- impurity* tetramethyl-1-
pentanaminium iodide (0.75 eq) Mathanol/water (1:1) (6 vol)
45-50.degree. C., 90 hour *The diastereomer impurity is the (RS,
SR) diastereomer of d.sub.6-tetrabenazine.
[0242] Tables 19 and 20--In-Process HPLC Results
TABLE-US-00019 Ex. 2 - Methanol Ex. 3 - Ethanol Diaste- Diaste-
Time SM* Product reomer* SM* Product reomer* 6 h 17.2% 12.5% 2.6%
3.3% 12.4% 3.0% 18 h 4.3% 17.1% 3.8% 0.2% 14.6% 3.9% 24 h 1.2%
16.8% 4.5% 0.1% 17.2% 5.2% 30 h 0.5% 14.0% 3.2% 0.3% 12.4% 3.3% 42
h 0.3% 12.3% 3.1% 0.2% 9.6% 2.6% 48 h 0.3% 12.1% 2.9% 0.2% 12.0%
2.9% -- 97.8% 1.4% -- 98.1% 0.75% Prod- Wt (g) 1.38 Wt (g) 1.38 uct
Y (%) 8.3 Y (%) 8.3 *SM = Starting material -
[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer impurity
is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.
TABLE-US-00020 Ex. 4-Methanol:Water (1:1) Time SM* Product
Diastereomer* 6 h -- -- -- 18 h 3.1% 21.% 0.7% 24 h -- -- -- 30 h
-- -- -- 42 h 1.8% 23.9% 0.5% 48 h -- -- -- 90 h -- 28.1% 1.0%
Product 99.1% 0.04% Wt (g) 6.78 g Y (%) 40.8 *SM = Starting
material-[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer
impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.
TABLE-US-00021 TABLE 21 Optimization of the reaction by varying the
reaction temperature Exp. Batch Product Product No. Size Reaction
Conditions Quantity Yield HPLC Purity 1 8 g 6,7-Dimethoxy-3,4- 8.3
g 74.5% 99.1% dihydroiso-quinoline 0.04% hydrochloride (1 eq)
Diastereomer 2-acetyl-N,N,N,4- impurity* tetramethyl-1-
pentanaminium iodide (1.08 eq) Methanol/water (1:1) (6 vol)
K.sub.2CO.sub.3 (1 eq) 45-50.degree. C., 63 hour 2 8 g
6,7-Dimethoxy-3,4- 8.5 g 76.7% 99.1% dihydroiso-quinoline 0.04%
hydrochloride (1 eq) Diastereomer 2-acetyl-N,N,N,4- impurity*
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (1:1)
(6 vol) K.sub.2CO.sub.3 (1 eq) 25-30.degree. C., 63 hour 3 8 g
6,7-Dimethoxy-3,4- 8.3 g 75% 99.1% dihydroiso-quinoline 0.1%
hydrochloride (1 eq) Diastereomer 2-acetyl-N,N,N,4- impurity*
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (1:1)
(6 vol) K.sub.2CO.sub.3 (1 eq) 65-70.degree. C., 63 hour
[0243] Tables 22 and 23--In-Process HPLC Results
TABLE-US-00022 Ex. 3 - Methanol:Water (1:1) Ex. 2 - Methanol:Water
(1:1) 65-70.degree. C. 45-50.degree. C. Diaste- Diaste- Hours SM*
Product reomer* SM* Product reomer* 15 h 0.8% 8.1% 0.5% -- 23.5%
0.1% 23 h -- 33.1% 0.5% -- 17.1% 0.2% 39 h -- 14.3% 0.4% -- 22.0%
0.1% 47 h -- 17.9% 0.5% -- 35.9% 0.3% 63 h -- 44.4% 0.8% -- 58.2%
0.4% Crude -- 88.6% 1.8% -- 92.3% 0.6% After -- 91.6% 1.3% -- 95.2%
0.6% EA Final -- 99.19% 0.1% -- 99.15% 0.04% Product Wt (g) 8.38 Wt
(g) 8.32 Y (%) 75 Y (%) 74.5 *SM = Starting material -
[6,7-Dimethoxy-3,4-dihydro isoquinoline];The diastereomer impurity
is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.
TABLE-US-00023 Ex. 1-Methanol:Water (1:1) 25-30.degree. C. Hours
SM* Product Diastereomer* 15 h -- 31.6% 0.2% 23 h -- 29.5% 0.2% 39
h -- 35.2% 0.2% 47 h -- 20.9% 0.1% 63 h -- 63.4% 0.3% Crude --
95.7% 0.5% After EA* -- 95.5% 0.4% treatment Final -- 99.16% 0.04%
Product Wt (g) 8.56 Y (%) 76.7 *SM = Starting
material-[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl
Acetate; The diastereomer impurity is the (RS, SR) diastereomer of
d.sub.6-tetrabenazine.
TABLE-US-00024 TABLE 24 Optimization of the reaction by varying the
solvent mixture ratio Exp. Batch Product Product HPLC No. Size
Reaction Conditions Quantity Yield Purity 1 8 g 6,7-Dimethoxy-3,4-
8.3 g 76.9% 98.9% dihydroiso-quinoline 0.09% hydrochloride (1 eq)
undesired 2-acetyl-N,N,N,4- isomer tetramethyl-1- pentanaminium
iodide (1.08 eq) Methanol/water (1:3) (6 vol) K.sub.2CO.sub.3 (1
eq) 45-50.degree. C., 63 hour 2 8 g 6,7-Dimethoxy-3,4- 8.6 g 77.1%
99.6% dihydroiso-quinoline 0.03% hydrochloride (1 eq) undesired
2-acetyl-N,N,N,4- isomer tetramethyl-1- pentanaminium iodide (1.08
eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq)
45-50.degree. C., 63 hour 3 10 g 6,7-Dimethoxy-3,4- 9.6 g 68.9%
99.3% dihydroiso-quinoline off-white hydrochloride (1 eq) product
2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq)
Methanol/water (4:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree.
C., 63 hour 4 10 g 6,7-Dimethoxy-3,4- 7.6 g 54.4% 99.2%
dihydroiso-quinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol (6 vol)
K.sub.2CO.sub.3 (1 eq) 45-50.degree. C., 63 hour
[0244] Tables 25 and 26--In-Process HPLC Results
TABLE-US-00025 Ex. 1 - Methanol: Water (1:3) Ex. 2 - Methanol:
Water (3:1) 45-50.degree. C. 45-50.degree. C. Diaste- Diaste- Hours
SM* Product reomer* SM* Product reomer* 24 h -- 44.7% 0.4% -- 18.6%
0.5% 48 h -- 54.8% 0.6% -- 18.9% 0.5% 63 h -- 70.0% 0.8% -- 16.0%
0.8% Crude -- 91.1% 1.3% -- 98.5% 0.4% After -- 92.6% 1.0% -- 98.7%
0.4% EA* treatment Final -- 98.98% 0.09% -- 99.64% 0.03% Product Wt
(g) 8.59 8.61 Y (%) 76.9 77.1 *SM = Starting material -
[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; The
diastereomer impurity is the (RS, SR) diastereomer of
d.sub.6-tetrabenazine.
TABLE-US-00026 Ex. 3 - Methanol: Water (4:1) Ex. 4 - Methanol,
45-50.degree. C. 45-50.degree. C. Diaste- Diaste- Hours SM* Product
reomer* SM* Product reomer* 24 h -- -- -- -- -- -- 48 h -- -- -- --
-- -- 63 h -- 17.75% 2.57% -- 17.75% 2.57% Crude -- 97.97% 0.59% --
97.97% 0.59% After EA* -- 98.15% 0.35% -- 98.15% 0.35% treatment
Final -- 99.28% 0.03% -- 99.28% 0.03% Product 7.58 7.58 54.4 54.4
*SM = Starting material - [6,7-Dimethoxy-3,4-dihydro isoquinoline];
EA = Ethyl Acetate; The diastereomer impurity is the (RS, SR)
diastereomer of d.sub.6-tetrabenazine.
TABLE-US-00027 TABLE 27 Optimization of the reaction by varying the
reaction time Exp. Batch Product Product HPLC No. Size Reaction
Conditions Quantity Yield Purity 1 10 g 6,7-Dimethoxy-3,4- 8.5 g
61% 92.2% dihydroiso-quinoline hydrochloride (1 eq)
2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq)
Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree.
C., 24 hour 2 10 g 6,7-Dimethoxy-3,4- 9.4 g 67.4% 99.5%
dihydroiso-quinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1)
(6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree. C., 48 hour 3 10 g
6,7-Dimethoxy-3,4- 9.2 g 66% 99.2% dihydroiso-quinoline
hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium
iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1
eq) 45-50.degree. C., 63 hour
[0245] Tables 28 and 29--In-Process HPLC Results
TABLE-US-00028 Ex. 1 - Methanol:Water Ex. 2 - Methanol:Water (3:1)
45-50.degree. C., 24 h (3:1) 45.degree. C., 48 h Diaste- Diaste-
Hours SM* Product reomer* SM* Product reomer* 24 h 1.52% 15.65%
1.38% -- -- -- 48 h -- -- -- -- 23.73% 0.66% 63 h -- -- -- -- -- --
Crude -- 92.1% 1.96% -- 91.83% 1.53% After -- 91.96% 1.17% --
91.64% 1.57% EA* treat- ment Final -- 99.25% 0.08% -- 99.58% 0.03%
Product Wt (g) 8.5 Wt (g) 9.4 Y (%) 61 Y (%) 67.4 *SM = Starting
material - [6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl
Acetate; The diastereomer impurity is the (RS, SR) diastereomer of
d.sub.6-tetrabenazine.
TABLE-US-00029 Ex. 3-Methanol:Water (3:1) 45.degree. C., 63 h Hours
SM* Product Diastereomer* 24 h -- -- -- 48 h -- -- -- 63 h --
13.63% 0.71% Crude -- 98.43% 0.34% After EA* -- 98.24% 0.45%
treatment Final -- 99.29% 0.04% Product Wt (g) 9.2 Y (%) 66.0 *SM =
Starting material-[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA =
Ethyl Acetate; The diastereomer impurity is the (RS, SR)
diastereomer of d.sub.6-tetrabenazine.
TABLE-US-00030 TABLE 30 Comparison of
d.sub.0-6,7-dimethoxy-3,4-dihydroiso- quinoline hydrochloride and
d.sub.6-6,7-dimethoxy- 3,4-dihydroiso-quinoline hydrochloride Exp.
Batch Product Product HPLC No. Size Reaction Conditions Quantity
Yield Purity 1 10 g d.sub.0-6,7-Dimethoxy-3,4- 9.4 g 67.4% 99.5%
dihydro isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1)
(6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree. C., 48 hour 2 10 g
d.sub.0-6,7-Dimethoxy-3,4- 9.96 g 72.0% 99.9% dihydro isoquinoline
hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium
iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1
eq) 45-50.degree. C., 48 hour 3 10 g d.sub.0-6,7-Dimethoxy-3,4- 9.4
g 68.3% 99.8% dihydro isoquinoline hydrochloride (1 eq)
2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq)
Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree.
C., 48 hour 4 125 g d.sub.0-6,7-Dimethoxy-3,4- 125.7 g 72.77%
99.64% dihydro isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1)
(6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree. C., 48 hour
TABLE-US-00031 Comparison of d.sub.0-6,7-dimethoxy-3,4-dihydroiso-
quinoline hydrochloride and d.sub.6-6,7-dimethoxy-
3,4-dihydroiso-quinoline hydrochloride Exp. Batch Product Product
HPLC No. Size Reaction Conditions Quantity Yield Purity 1 10 g
6,7-Dimethoxy-3,4- 9.2 g 66% 99.5% (87.1%) dihydro isoquinoline
hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium
iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1
eq) 45-50.degree. C., 63 hour 2 8 g 6,7-Dimethoxy-3,4- 8.61 g 77.1%
99.9% (90.3%) dihydro isoquinoline hydrochloride (1 eq)
2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq)
Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree.
C., 63 hour 3 4 g 6,7-Dimethoxy-3,4- 4.72 g 84.7% 99.8% (99.0%)
dihydro isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-
tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1)
(6 vol) K.sub.2CO.sub.3 (1 eq) 45-50.degree. C., 63 hour 4 50 g
6,7-Dimethoxy-3,4- 59.7 g 85.6% 99.64% (99.0%) dihydro isoquinoline
hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium
iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1
eq) 45-50.degree. C., 63 hour
Representative Example
Step 2
(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpropyl-
)-2H-benzo[a]quinolizin-2-one
[0246] The 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide from
step 1 (146 g) was charged to a suspension containing
d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (90 g,
0.385 mol, 1.00 eq), methanol (405 mL, 4.5 vol) and water (135 mL,
1.5 vol) at 25-30.degree. C. To the reaction mixture
K.sub.2CO.sub.3 (54 g, 0.385 mol, 1.00 eq) was added at
25-30.degree. C. and stirred at 40-45.degree. C. for 30 hours. The
reaction mixture was cooled and water (270 mL, 3.0 vol) was added.
The reaction mass was filtered and the solids were washed with
water (270 mL, 3.0 vol) and dried in an oven for 12 hours at
50-55.degree. C. to afford the crude title compound as a light
brown powder (100 g, yield=80.6%). .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta. 6.62 (s, 1H), 6.55 (s, 1H), 3.54 (d, 1H,
J=11.7), 3.31 (dd, 1H, J=11.4 and 6.3), 3.11 (m, 2H), 2.92 (dd, 1H,
J=13.5 and 3.3), 2.73 (m, 2H), 2.59 (m, 2H), 2.39 (t, 1H, J=11.7),
1.82 (m, 1H), 1.65 (m, 1H), 1.03 (m, 1H), 0.90 (m, 6H); LC-MS:
m/z=324.18 (MH).sup.+.
Step 3
Purification of
(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpropy-
l)-2H-benzo[a]quinolizin-2-one
Representative Example
[0247] Crude
(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpropy-
l)-2H-benzo[a]quinolizin-2-one from step 2 (90 g) was charged into
absolute ethanol (540 mL, 6.0 vol) and heated to 75-85.degree. C.
for 1 hour. The reaction mass was filtered through a Buchner funnel
at 75-85.degree. C. and the filter cake was washed with hot ethanol
(45 mL, 0.5 vol). The filtrate was cooled to 25-30.degree. C. over
4 hours and further cooled to 0-5.degree. C. over 3-4 hours. The
resulting solid was filtered, washed with cold ethanol (180 mL, 2.0
vol), and dried under vacuum to afford the title compound as a pale
yellow crystalline powder (75 g, yield=83.3%). .sup.1H NMR (300
MHz, CDCl.sub.3), .delta. 6.62 (s, 1H), 6.55 (s, 1H), 3.54 (d, 1H,
J=11.7), 3.31 (dd, 1H, J=11.4 and 6.3), 3.11 (m, 2H), 2.92 (dd, 1H,
J=13.5 and 3.3), 2.73 (m, 2H), 2.59 (m, 2H), 2.39 (t, 1H, J=11.7),
1.82 (m, 1H), 1.65 (m, 1H), 1.03 (m, 1H), 0.90 (m, 6H); LC-MS:
m/z=324.18 (MH).sup.+.
EXAMPLE 4
3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one
##STR00027##
[0248] Step 1
##STR00028##
[0249] 2-Acetyl-4-methylpentanoic acid ethyl ester
[0250] To a solution of ethyl acetoacetate (500 g, 3.842 mol, 1.00
eq) in DMF (1.5 L, 3.0 vol), KI (63.7 g, 0.384 mol, 0.10 eq),
tetrabutylammonium bromide (136 g, 0.422 mol, 0.11 eq) and
K.sub.2CO.sub.3 (632 g, 4.572 mol, 1.19 eq) were charged at
25-35.degree. C. The reaction mixture was heated to 40-50.degree.
C. and 1-bromo 2-methyl propane (579 g, 4.226 mol, 1.10 eq) was
added over 1 hour. The reaction mixture was heated to 65-75.degree.
C. for 6 hours, cooled and quenched with water (5.0 L, 10.0 vol).
The reaction mixture was extracted with toluene (2.times.2.0 L,
2.times.4.0 vol) and the combined organic layers were washed with
water (2.times.1.5 L, 2.times.3.0 vol). The organic layer was
evaporated under reduced pressure to obtain crude
2-acetyl-4-methylpentanoic acid ethyl ester.
Step 2
##STR00029##
[0251] 3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one
[0252] The ester was hydrolyzed using potassium hydroxide (212 g,
3.78 mol, 1.1 eq) in water (3.84 L, 6.0 vol). After the hydrolysis,
the reaction mixture was washed with methyl tert-butyl ether
(2.times.2.56 L, 2.times.4.0 vol) and the pH of the reaction
mixture was adjusted to 6.8-7.2 using concentrated HCl (96 mL, 0.15
vol). Dimethylamine hydrochloride solution (420 g, 5.16 mol, 1.50
eq dissolved in 0.224 L, 0.35 vol of purified water), and
formaldehyde solution (0.428 L, 5.763 mol, 1.675 eq) and
tetrabutylammonium bromide (110 g, 0.344 mol, 0.10 eq) were added
to the reaction mixture, and the pH was adjusted to below 1 using
concentrated HCl (0.352 L, 0.55 vol) over 1 hour at 25-35.degree.
C. The reaction mixture was stirred for 15 hours at 25-35.degree.
C. and the pH was adjusted to 12.0-13.0 using 20% aqueous KOH (3.20
L, 5.0 vol) solution at 25-35.degree. C. and dimethylamine
hydrochloride (420 g, 5.16 mol, 1.5 eq) was added. The reaction
mixture was stirred for 36 hours at 25-35.degree. C. and the pH of
the reaction mixture was adjust to below 1 using concentrated HCl
(0.84 L, 0.13 vol) at 25-35.degree. C. over 1 h. The reaction
mixture was washed with methyl tert-butyl ether (2.times.2.56 L,
2.times.4.0 vol) and the pH of the reaction mixture was adjusted to
9-10 by using 20% aqueous KOH solution (1.72 L, 2.68 vol) at
25-35.degree. C. The product was extracted with ethyl acetate
(2.times.2.56 L, 2.times.4.0 vol and 1.times.1.28 L, 1.times.2.0
vol) and the combined organic layers were washed sequentially with
purified water (2.times.1.92 L, 2.times.3.0 vol) and 10% ammonium
chloride solution (2.times.3.2 L, 2.times.5.0 vol). Activated
carbon (32 g, 0.05% w/w) was added to the organic layer and the
mixture was stirred for 30-45 minutes at 25-35.degree. C. The
organic layer was filtered through celite (106 g) and was washed
with ethyl acetate (0.32 L, 0.5 vol). The filtrate was distilled
under reduced pressure to afford the title compound as a pale
yellow liquid (151 g, yield=22.3%). .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta. 2.7-2.85 (m, 1H), 2.56-2.6 (m, 1H), 2.16 (s,
7H), 2.13 (s, 3H), 1.12-1.55 (m, 3H), 0.92 (d, 3H), 0.89 (d, 3H);
LC-MS: m/z=172.11 (MH).sup.+.
[0253] From the foregoing description, one skilled in the art can
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
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