U.S. patent application number 17/074049 was filed with the patent office on 2021-06-10 for purified cenicriviroc and purified intermediates for making cenicriviroc.
The applicant listed for this patent is Tobira Therapeutics, Inc.. Invention is credited to Nicholas Morra, Pasit Phiasivongsa.
Application Number | 20210171504 17/074049 |
Document ID | / |
Family ID | 1000005417278 |
Filed Date | 2021-06-10 |
United States Patent
Application |
20210171504 |
Kind Code |
A1 |
Morra; Nicholas ; et
al. |
June 10, 2021 |
Purified cenicriviroc and purified intermediates for making
cenicriviroc
Abstract
The disclosure includes high purity compounds having CCR5 and/or
CCR2 antagonism, or salts thereof, high purity intermediates
thereto and processes for synthesizing the same.
Inventors: |
Morra; Nicholas;
(Parsippany, NJ) ; Phiasivongsa; Pasit;
(Parsippany, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tobira Therapeutics, Inc. |
Parsippany |
NJ |
US |
|
|
Family ID: |
1000005417278 |
Appl. No.: |
17/074049 |
Filed: |
October 19, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16561969 |
Sep 5, 2019 |
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17074049 |
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15628968 |
Jun 21, 2017 |
10407411 |
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16561969 |
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62352885 |
Jun 21, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 31/24 20130101;
B01J 2231/4211 20130101; C07D 403/12 20130101; B01J 2531/824
20130101; B01J 31/2239 20130101; B01J 31/2404 20130101; B01J
31/2208 20130101 |
International
Class: |
C07D 403/12 20060101
C07D403/12; B01J 31/22 20060101 B01J031/22; B01J 31/24 20060101
B01J031/24 |
Claims
1-30. (canceled)
31. A composition of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(2-(1-propyl-1H-imidazol-5-y-
l)acetyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH), or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher, wherein said compound
comprises one or more of the following: (a) about .ltoreq.0.50% to
about .gtoreq.0.30% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); (b) about
.ltoreq.0.50% to about .gtoreq.0.30% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX); (c) about 0.50% to about
.gtoreq.0.30% of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A); (d) about .ltoreq.0.50% to
about .gtoreq.0.30% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B); (e) about .ltoreq.0.50% to
about .gtoreq.0.45% of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C); (f) about .ltoreq.0.50% to
about .gtoreq.0.45% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E); (g) about .ltoreq.0.50% to
about .gtoreq.0.45% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F); and (h) about .ltoreq.0.50%
to about .gtoreq.0.45% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G).
32. The composition of claim 31, further comprising .ltoreq.1.0% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH).
33. The composition of claim 32, wherein .ltoreq.0.50% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH) is present.
34. The composition of claim 31, further comprising 2000 ppm or
less of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline
(Compound III).
35. The composition of claim 34, wherein
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) is present in 1500 ppm or less.
36. The composition of claim 31, further comprising .ltoreq.2.0% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D).
37. The composition of claim 36, wherein .ltoreq.1.0% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D) is present.
38. The composition of claim 31, wherein .ltoreq.0.10% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) is present,
provided there is present one or more of compounds (b)-(h).
39. The composition of claim 31, wherein .ltoreq.0.10% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) is present, provided there is present
one or more of compounds (a) and (c)-(h).
40-45. (canceled)
46. The composition of claim 31, said compound comprises one or
more of the following: (i) .ltoreq.0.30% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH); (ii) .ltoreq.0.05% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); and (iii)
.ltoreq.0.05% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound IX), provided there is present one or
more of compounds (c)-(h)
47. The composition of claim 31, said compound comprises one or
more of the following: (i) 1300 ppm or less wherein
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III); (ii) .ltoreq.0.10% of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A); (iii) .ltoreq.0.10% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B); (iv) .ltoreq.0.20% of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C); (v) .ltoreq.0.80% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D); (vi) .ltoreq.0.20% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E); (vii) .ltoreq.0.15% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F); and (viii) .ltoreq.0.10% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G), provided
there is present one or more of compounds (a)-(b).
48. The composition of claim 31, wherein mesylate ester resulting
from MsOH is present in 0.001% or less, or 10 ppm or less.
49. The composition of claim 31, wherein said compound is
(S)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((S)-Compound I-MsOH).
50. The composition of claim 49, wherein .ltoreq.0.5% of
(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((R)-Compound I-MsOH) is present.
51. The composition of claim 50, wherein .ltoreq.0.2% of
(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((R)-Compound I-MsOH) is present.
52. The composition of claim 51, comprising 5.0% w/w or less or
2.0% w/w or less water content.
53-59. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/561,969 filed Sep. 5, 2019, which is a
continuation of U.S. patent application Ser. No. 15/628,968 filed
Jun. 21, 2017, issued as U.S. Pat. No. 10,407,411, which claims the
benefit of priority to U.S. Provisional Patent Application No.
62/352,885 filed Jun. 21, 2016, the disclosures of which are hereby
incorporated by reference in its entirety for all purposes.
FIELD
[0002] The present disclosure relates to purified compounds having
CCR5 and/or CCR2 antagonism, or a salt thereof, and purified
intermediates for making the compounds.
BACKGROUND
[0003] It is known that cenicriviroc (CVC) inhibits CCR5 and CCR2
receptors and prevents virus from entering into a human cell, such
as the HIV virus (U.S. Pat. No. 8,183,273). The synthesis of CVC is
also previously disclosed in U.S. patent application Ser. No.
10/506,955 and Int. Pat. Pub. No. WO 2001017947.
##STR00001##
[0004] The present disclosure provides for purified CVC, CVC salts,
including CVC methane sulfonic acid salt, or related analogs, and
purified intermediates for preparing the aforesaid.
[0005] Conventional methods of synthesizing CVC, CVC salts, and
related analogs, resulted in the presence of undesirable
impurities. Thus, there is a need for highly pure CVC, purified
intermediates thereto and process of making the same.
SUMMARY OF THE DISCLOSURE
[0006] This disclosure is directed to highly purified Compound I, a
racemic or optically pure form of CVC, and the formation of its
methane sulfonic acid salt (Compound I-MsOH) and highly purified
intermediate compound II useful for preparing Compound I, and the
process for making them. In some embodiments, Compound I and
Compound I-MsOH are racemic. In other embodiments, Compound I and
Compound I-MsOH comprises an optically active sulfoxide, such as
the (S)-isomer denoted as (S)-Compound I-MsOH.
##STR00002##
[0007] Compound I is synthesized by a reaction between Compound II
and Compound III:
##STR00003##
[0008] wherein R.sub.1 is selected from the group consisting of H,
OH, Cl, Br, OR.sub.2, OCOR.sub.2, and NHR.sub.2; and
[0009] wherein R.sub.2 is selected from the group consisting of H,
alkyl, substituted alkyl, aryl, and substituted aryl.
[0010] Compound I is synthesized by a reaction between Compound II
where R.sub.1.dbd.OH (Compound II-OH) and Compound III.
##STR00004##
[0011] Compound II-OH is synthesized by a reaction between Compound
IV and Compound V and/or Compound V-3:
##STR00005##
[0012] wherein R.sub.3 is Ar.sub.1 or OR.sub.5; R.sub.4 is Ar.sub.2
or OR.sub.6; and R.sub.5, and R.sub.6 are independently selected
from the group consisting of H, alkyl, and substituted alkyl; or
R.sub.5 and R.sub.6 together forms an optionally substituted alkyl
or an optionally substituted aryl; Ar.sub.1 and Ar.sub.2 are
independently aryl or substituted aryl.
[0013] In some embodiments, R.sub.3 and R.sub.4 are both OMe or
both OH for Compound V, which are denoted as Compound V-OMe or
Compound V-OH, respectively.
[0014] In some embodiments, Compound V is synthesized from Compound
VI.
##STR00006##
[0015] This disclosure is directed to a process route to minimize
impurities represented by Compounds I-MsOH-A, I-MsOH-B, I-MsOH-C,
I-MsOH-D, I-MsOH-E, (R)-I-MsOH, VII, VIII, IX, and mesylate esters
resulting from MsOH.
##STR00007## ##STR00008##
[0016] The present disclosure includes a process for preparing
highly purified
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imid-
azol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carb-
oxamide methanesulfonate (Compound I-MsOH). For example, the
synthesis of Compound I-MsOH includes formation of dimethyl
(4-(2-butoxyethoxy)phenyl)boronate (Compound V-OMe) which is
subsequently used in formation of highly pure
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH).
[0017] Compound I-MsOH is prepared from
(4-(2-butoxyethoxy)phenyl)boronate (Compound V-OMe) and/or
(4-(2-butoxyethoxy)phenyl)boronic acid (Compound V-OH) and/or
2,4,6-tris(4-(2-butoxyethoxy)phenyl)-1,3,5,2,4,6-trioxatriborinane
(Compound V-3). Compound I-MsOH is prepared from Compound V-OH
and/or Compound V-3. Compound I-MsOH is prepared from Compound V-OH
and/or Compound V-3 which is essentially free of Compounds V-A,
V-B, and/or V-C:
##STR00009## [0018] wherein R.sub.3 and R.sub.4 are both OMe or
OH.
[0019] In some embodiments, Compound V is prepared by a) activating
magnesium in tetrahydrofuran (THF) with heating, b) initiating
Grignard formation by the addition of a portion of
1-bromo-4-(2-butoxyethoxy)benzene (Compound VI) to a mixture of
step a) with heating, c) continuing to add the remaining Compound
VI slowly with heating, d) cooling the mixture of step c) to about
-25.degree. C. and slowly adding trimethoxyborane, and e) stirring
the mixture of step d at about -25.degree. C. for about 1 hour and
then warming up the reaction to about 20.degree. C. for about 1
hour.
[0020] In some embodiments, the molar ratio of Compound VI and
trimethoxyborane used is about 1:1.
[0021] In some embodiments, neat Compound VI is used in steps b)
and/or c). In other embodiments, step c) requires reaction to stir
at about 55.degree. C. for about 3 hours to about 5 hours.
[0022] Compound V synthesized as described herein, in one
embodiment, is then utilized in the synthesis of Compound II-OH. In
some embodiments, Compound II-OH is prepared by a) forming a
biphasic mixture by adding a basic aqueous solution to a solution
of Compound V, b) adding a catalyst and a ligand to mixture of step
a), c) adding
8-bromo-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic
acid (Compound IV) to the mixture of step b) and heating the
reaction mixture, and d) acidifying the mixture of step c). The
base used in step a), in some embodiments, is selected from the
group consisting of potassium phosphate, potassium carbonate,
potassium acetate, potassium fluoride, potassium hydroxide,
potassium tert-butoxide, sodium carbonate, sodium phosphate, sodium
hydroxide, sodium tert-butoxide, sodium bicarbonate, cesium
carbonate, cesium fluoride, and a combination thereof. In some
embodiments, the catalyst used in step b) is selected from the
group consisting of palladium acetate, tetrakis(triphenylphosphine)
palladium, tri(dibenzylideneacetone)dipalladium, palladium
chloride, palladium acetylacetonate and a combination thereof. In
some embodiments, the ligand used in step b) is selected from the
group consisting of tri(o-tolyl)phosphine, triphenylphosphine,
tri(t-butyl)phosphine, tricyclohexylphosphine, pyridine,
bipyridine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and a
combination thereof. In another embodiment, the catalyst system of
step b) comprises palladium acetate and tri(o-tolyl)phosphine.
[0023] In some embodiments, the ratio of catalyst to ligand is
about 1:2. In other embodiments, the catalyst used in step b) is in
an amount from about 0.001 equivalents (equiv) to about 2.500 equiv
with respect to Compound IV. In a further embodiment, the catalyst
is used in an amount of about 0.001 equiv to about 0.005 equiv with
respect to Compound IV. In some embodiments, nitrogen is bubbled
into the reaction after step a) up to step d) or during any steps
a) through d).
[0024] In some embodiments, Compound V is used in an amount of
about 1.5 equiv to about 2.2 equiv with respect to Compound IV in
the formation of Compound II-OH. In another embodiment, the heating
of step c) is maintained at .ltoreq.65.degree. C. for about 2 hours
to about 6 hours and ensured high conversion to Compound II-OH.
[0025] In other embodiments, during purification step after step
d), charcoal is added, with or without Celite.RTM. to the reaction
mixture containing Compound II-OH. In another embodiment, the
mixture containing charcoal and/or Celite.RTM. and Compound II-OH
is stirred, and then filtered. In one embodiment, the ratio of
charcoal to Celite.RTM. is about 1:2.
[0026] In another embodiment, during purification step after step
d), Celite.RTM. is added to the reaction mixture containing
Compound II-OH, stirred, and then filtered. In one embodiment,
during the purification step after step d), the reaction mixture is
filtered to remove any solid particulates.
[0027] In some embodiments, purification of Compound II-OH involves
an antisolvent recrystallization and/or a hot recrystallization. In
some embodiments, the antisolvent used in the antisolvent
recrystallization is heptane, to obtain a crude material. In other
embodiments, hot recrystallization involves the steps of i)
dissolving crude material obtained from antisolvent
recrystallization with a non-protic polar solvent and a short-chain
alcohol at about 70.degree. C., ii) reducing the temperature of the
mixture of step i) to about 20.degree. C. over a period of about 3
hours to about 7 hours, and iii) stirring the mixture of step ii)
at about 20.degree. C. for about 2 hours to about 6 hours. In one
embodiment, the non-protic solvent is ethyl acetate. In another
embodiment, the short-chain alcohol is isopropanol.
[0028] The present disclosure further describes the process for the
preparation of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH). The disclosed process for
synthesizing Compound I-MsOH involves a) reacting Compound II with
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) in the presence of a base to form
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
(Compound I), b) quenching step a) with an aqueous solution, c)
adding methanesulfonic acid, and d) crystallizing Compound I-MsOH.
In some embodiments, R.sub.1 of Compound II is selected from the
group consisting of H, OH, Cl, Br, OR.sub.2, OCOR.sub.2, and
NHR.sub.2, and R.sub.2 of Compound II is selected from the group
consisting of H, alkyl, substituted alkyl, aryl, and substituted
aryl.
[0029] In some embodiments, R.sub.1 of Compound II is Cl. In one
embodiment, synthesis of Compound II involves the steps of i)
dissolving Compound II-OH in a solvent and ii) adding a
chlorinating reagent to the mixture of step i). In some
embodiments, the chlorinating reagent is selected from the group
consisting of thionyl chloride, phosphorous trichloride, phosphorus
pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene,
and a combination thereof. In one embodiment, the chlorinating
reagent is thionyl chloride. In some embodiments, the chlorinating
reagent is used in about 1.0 equiv to about 1.2 equiv with respect
to Compound II-OH.
[0030] In some embodiments, step a) of the synthesis of Compound
I-MsOH uses dichloromethane as the solvent. In other embodiments,
step a) synthesis of Compound I-MsOH uses pyridine as the base. In
another embodiments, step a) synthesis of Compound I-MsOH uses
optically pure (S)-Compound III as Compound III.
[0031] In some embodiments, the amount of Compound III used is
about 1.0 equiv to about 1.2 equiv with respect to Compound II-OH.
In some embodiments, the amount of methane sulfonic acid used is
about 0.97 equiv to about 1.02 equiv with respect to Compound
II-OH. In other embodiments, the ratio of methane sulfonic acid and
Compound II-OH is about 1:1.
[0032] In some embodiments, step b) of the synthesis of Compound
I-MsOH uses citric acid as the aqueous solution. In other
embodiments, step b) of the synthesis of Compound I-MsOH further
comprises extracting Compound I and drying the extracted solution
with 3 .ANG. molecular sieves.
[0033] In some embodiments, pure sample of Compound I-MsOH is used
to seed in the crystallization step d) of the synthesis of Compound
I-MsOH. The seeded crystallization solution of step d), in some
embodiments, comprise further steps of stirring at about 0.degree.
C. to allow crystallization, collecting formed crystals, and
washing collected crystals with chilled ethyl acetate. In one
embodiment, the formed crystals are collected by filtration.
[0034] In other embodiments, further purification is required by
employing hot recrystallization after step d). The hot
recrystallization of Compound I-MsOH involves i) dissolving crude
crystals of Compound I-MsOH obtained in step d) in acetonitrile at
about 70.degree. C., ii) reducing the temperature of the mixture of
step i) to about 50.degree. C. to about 55.degree. C. over about 1
hour, iii) seeding step ii) with Compound I-MsOH, iv) stirring at
about 50.degree. C. to about 55.degree. C. for about 6 hours, v)
reducing the temperature of the mixture of step iii to about
20.degree. C., vi) stirring at about 20.degree. C. for about 8
hours, vii) collecting crystals of Compound I-MsOH by filtration,
and viii) washing crystals with cold acetonitrile.
[0035] The present disclosure describes
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH), which can be characterized by
its purity and by the amount of impurities. In one embodiment,
Compound II-OH comprises one or more of the following: (a) about
.ltoreq.0.50% to about .gtoreq.0.30% or about .ltoreq.0.01% of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A); (b) about .ltoreq.0.50% to
about .gtoreq.0.30% or about .ltoreq.0.01% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B); (c) about .ltoreq.0.50% to
about .gtoreq.0.30% of 4,4'-bis(2-butoxyethoxy)biphenyl (Compound
VII); and (d) about .ltoreq.0.50% to about .gtoreq.0.30% or about
.ltoreq.0.01% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); and optionally
further comprises one or both of about .ltoreq.0.50% of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C); and about .ltoreq.0.50% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX).
[0036] In one embodiment, Compound II-OH comprises one or both of
(a) about .ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-A;
and (b) about .ltoreq.0.50% to about 0.30% of Compound II-OH-B; and
optionally further comprises about .ltoreq.0.50% of Compound
II-OH-C. In other embodiments, Compound II-OH comprises: (a) about
.ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-A; (b) about
.ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-B; and (c)
about .ltoreq.0.50% of Compound II-OH-C.
[0037] In one embodiment, Compound II-OH comprises one or both of
(a) about .ltoreq.0.01% of Compound II-OH-A; and (b) about
.ltoreq.0.01% of Compound II-OH-B; and optionally further comprises
about .ltoreq.0.10% of Compound II-OH-C. In some embodiments,
Compound II-OH comprises (a) about .ltoreq.0.01% of Compound
II-OH-A; (b) about .ltoreq.0.01% of Compound II-OH-B; and (c) about
.ltoreq.0.10% of Compound II-OH-C.
[0038] In one embodiment, Compound II-OH comprises one or both of:
(a) about .ltoreq.0.50% to about 0.30% of Compound VII; and (b)
about .ltoreq.0.50% to about 0.30% of Compound VIII; and optionally
further comprises about .ltoreq.0.50% of Compound IX. In other
embodiments, Compound II-OH comprises (a) about .ltoreq.0.50% to
about 0.30% of Compound VII; (b) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound VIII; and (c) about .ltoreq.0.50% of
Compound IX. In some embodiments, Compound II-OH comprises about
.ltoreq.0.01% of Compound VIII, and optionally further comprises
one or both of (i) about .ltoreq.0.05% of Compound VII, and (ii)
about .ltoreq.0.15% of Compound IX. In further embodiment, Compound
II-OH comprises: (a) about .ltoreq.0.05% of Compound VII; (b) about
.ltoreq.0.01% of Compound VIII; and (c) about .ltoreq.0.15% of
Compound IX.
[0039] In one embodiment, Compound II-OH comprises about
.ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-A. In some
embodiments, Compound II-OH comprises .ltoreq.0.01% of Compound
II-OH-A.
[0040] In one embodiment, Compound II-OH comprises about
.ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-B. In some
embodiments, Compound II-OH comprises .ltoreq.0.01% of Compound
II-OH-B.
[0041] In one embodiment, Compound II-OH comprises about
.ltoreq.0.50% to about .gtoreq.0.30% of Compound VII. In one
embodiment, Compound II-OH comprises about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound VIII. In some embodiments, Compound II-OH
comprises .ltoreq.0.01% of Compound VIII.
[0042] In some embodiments, Compound II-OH has about 95.0% to about
.ltoreq.96.0% purity. In another embodiment, Compound II-OH has
about .gtoreq.97.0% purity.
[0043] In some embodiments, Compound II-OH has about .gtoreq.95.0%
to about .ltoreq.96.0% purity and comprises
4,4'-bis(2-butoxyethoxy)biphenyl (Compound VII) in 0.20% or less.
In some embodiments, Compound II-OH has about .gtoreq.95.0% to
about .ltoreq.96.0% purity and comprises
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in 0.50% or less.
In one embodiment, Compound II-OH has about .gtoreq.95.0% to about
.ltoreq.96.0% purity and comprises
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in 0.50% or less.
[0044] In some embodiments, Compound II-OH has about .gtoreq.95.0%
to about .ltoreq.96.0% purity and comprises
4,4'-bis(2-butoxyethoxy)biphenyl (Compound VII) t in 0.10% or less;
or
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in 0.10% or less;
or
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in 0.15% or less. In other
embodiments, Compound II-OH has about .gtoreq.95.0% to about
.ltoreq.96.0% purity and comprises one or more of the following:
(a) 0.50% or less of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A); (b) 0.50% or less of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B); (c) 0.50% or less of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C); (d) 0.50% or less of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); and/or (e) 0.50%
or less of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]az-
ocine-5-carboxylic acid (Compound IX).
[0045] In one embodiment, Compound II-OH has about .gtoreq.95.0% to
about .ltoreq.96.0% purity and comprises Compound II-OH-A in 0.10%
or less. In other embodiments, Compound II-OH has about
.gtoreq.95.0% to about .ltoreq.96.0% purity and comprises Compound
II-OH-C in 0.10% or less. In some embodiments, Compound II-OH has
about .gtoreq.95.0% to about .ltoreq.96.0% purity and comprises
Compound VIII in 0.10% or less. In a further embodiment, Compound
II-OH has about .gtoreq.95.0% to about .ltoreq.96.0% purity and
comprises Compound IX in 0.20% or less.
[0046] In other embodiments, Compound II-OH has about .gtoreq.95.0%
to about .ltoreq.96.0% purity and comprises one or more of the
following: (a) 0.05% or less of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A); (b) 0.05% or less of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B); (c) 0.05% or less of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C); (d) 0.05% or less of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); and/or (e) 0.15%
or less of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]az-
ocine-5-carboxylic acid (Compound IX).
[0047] The present disclosure describes
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(2-(1-propyl-1H-imidazol-5-y-
l)acetyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH), which can be characterized by
its purity and by the amount of impurities. In one embodiment,
Compound I-MsOH, or an enantiomer, a stereoisomer, or a combination
thereof, with a purity of .gtoreq.96.0% or .gtoreq.98.5% or higher,
wherein said compound comprises one or more of the following: (a)
about .ltoreq.0.50% to about .gtoreq.0.30% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); (b) about
.ltoreq.0.50% to about 0.30% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX); (c) about .ltoreq.0.50% to about
0.30% of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A); (d) about .ltoreq.0.50% to
about .gtoreq.0.30% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B); (e) about .ltoreq.0.50% to
about .gtoreq.0.45% of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C); (f) about .ltoreq.0.50% to
about .gtoreq.0.45% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E); (g) about .ltoreq.0.50% to
about .gtoreq.0.45% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F); and (h) about .ltoreq.0.50%
to about .gtoreq.0.45% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G).
[0048] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.1.0% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH). In another embodiment,
Compound I-MsOH, or an enantiomer, a stereoisomer, or a combination
thereof, with a purity of .gtoreq.96.0% or .gtoreq.98.5% or higher
comprises 2000 ppm or less of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III). In some embodiments, Compound III is present in 1500 ppm or
less.
[0049] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.2.0% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D). In some embodiment, Compound
I-MsOH-D is present in .ltoreq.1.0%.
[0050] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.0.10% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII), provided that
there is present one or more of (b) about .ltoreq.0.50% to about
0.30% of Compound IX; (c) about .ltoreq.0.50% to about 0.30% of
Compound I-MsOH-A; (d) about .ltoreq.0.50% to about .gtoreq.0.30%
of Compound I-MsOH-B; (e) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-C; (f) about .ltoreq.0.50% to about .gtoreq.0.45%
of Compound I-MsOH-E; (g) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-F; and (h) about .ltoreq.0.50% to about
.gtoreq.0.45% of Compound I-MsOH-G.
[0051] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or 98.5% or higher comprises .ltoreq.0.10% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX), provided that there is present one
or more of (a) about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound VIII; (c) about .ltoreq.0.50% to about 0.30% of Compound
I-MsOH-A; (d) about .ltoreq.0.50% to about 0.30% of Compound
I-MsOH-B; (e) about .ltoreq.0.50% to about 0.45% of Compound
I-MsOH-C; (f) about .ltoreq.0.50% to about .gtoreq.0.45% of
Compound I-MsOH-E; (g) about .ltoreq.0.50% to about .gtoreq.0.45%
of Compound I-MsOH-F; and (h) about .ltoreq.0.50% to about
.gtoreq.0.45% of Compound I-MsOH-G.
[0052] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.0.10% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX), provided that there is present one
or more of (a) about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound VIII; (b) about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound IX; (d) about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound I-MsOH-B; (e) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-C; (f) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-E; (g) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-F; and (h) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-G.
[0053] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.0.15% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B), provided that there is
present one or more of (a) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound VIII; (b) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound IX; (d) about .ltoreq.0.50% to about
0.30% of Compound I-MsOH-B; (c) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound I-MsOH-A; (e) about .ltoreq.0.50% to
about .gtoreq.0.45% of Compound I-MsOH-C; (f) about .ltoreq.0.50%
to about .gtoreq.0.45% of Compound I-MsOH-E; (g) about
.ltoreq.0.50% to about .gtoreq.0.45% of Compound I-MsOH-F; and (h)
about .ltoreq.0.50% to about 0.45% of Compound I-MsOH-G.
[0054] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or 98.5% or higher comprises .ltoreq.0.30% of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C), provided that there is
present one or more of (a) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound VIII; (b) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound IX; (d) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound I-MsOH-B; (c) about .ltoreq.0.50% to
about .gtoreq.0.30% of Compound I-MsOH-A; (d) about .ltoreq.0.50%
to about .gtoreq.0.30% of Compound I-MsOH-B; (f) about
.ltoreq.0.50% to about .gtoreq.0.45% of Compound I-MsOH-E; (g)
about .ltoreq.0.50% to about .gtoreq.0.45% of Compound I-MsOH-F;
and (h) about .ltoreq.0.50% to about .gtoreq.0.45% of Compound
I-MsOH-G.
[0055] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.0.30% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E), provided that there is
present one or more of (a) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound VIII; (b) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound IX; (d) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound I-MsOH-B; (c) about .ltoreq.0.50% to
about 0.30% of Compound I-MsOH-A; (d) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound I-MsOH-B; (e) about .ltoreq.0.50% to
about .gtoreq.0.45% of Compound I-MsOH-C; (g) about .ltoreq.0.50%
to about .gtoreq.0.45% of Compound I-MsOH-F; and (h) about
.ltoreq.0.50% to about .gtoreq.0.45% of Compound I-MsOH-G.
[0056] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises .ltoreq.0.20% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F), provided that there is
present one or more of (a) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound VIII; (b) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound IX; (d) about .ltoreq.0.50% to about
0.30% of Compound I-MsOH-B; (c) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound I-MsOH-A; (d) about .ltoreq.0.50% to
about .gtoreq.0.30% of Compound I-MsOH-B; (e) about .ltoreq.0.50%
to about .gtoreq.0.45% of Compound I-MsOH-C; (f) about
.ltoreq.0.50% to about .gtoreq.0.45% of Compound I-MsOH-E; and (h)
about .ltoreq.0.50% to about .gtoreq.0.45% of Compound
I-MsOH-G.
[0057] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or 98.5% or higher comprises .ltoreq.0.15% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G), provided that
there is present one or more of (a) about .ltoreq.0.50% to about
0.30% of Compound VIII; (b) about .ltoreq.0.50% to about 0.30% of
Compound IX; (d) about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound I-MsOH-B; (c) about .ltoreq.0.50% to about 0.30% of
Compound I-MsOH-A; (d) about .ltoreq.0.50% to about 0.30% of
Compound I-MsOH-B; (e) about .ltoreq.0.50% to about 0.45% of
Compound I-MsOH-C; (f) about .ltoreq.0.50% to about .gtoreq.0.45%
of Compound I-MsOH-E; and (g) about .ltoreq.0.50% to about
.gtoreq.0.45% of Compound I-MsOH-F.
[0058] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises one or more of
the following: (i) .ltoreq.0.30% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH); (ii) .ltoreq.0.05% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); and (iii)
.ltoreq.0.05% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound IX), provided there is present one or
more of compounds: (c) about .ltoreq.0.50% to about .gtoreq.0.30%
of Compound I-MsOH-A; (d) about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound I-MsOH-B; (e) about .ltoreq.0.50% to
about .gtoreq.0.45% of Compound I-MsOH-C; (f) about .ltoreq.0.50%
to about .gtoreq.0.45% of Compound I-MsOH-E; (g) about
.ltoreq.0.50% to about .gtoreq.0.45% of Compound I-MsOH-F; and (h)
about .ltoreq.0.50% to about .gtoreq.0.45% of Compound
I-MsOH-G.
[0059] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprises one or more of
the following: (i) 1300 ppm or less wherein
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III); (ii) .ltoreq.0.10% of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A); (iii) .ltoreq.0.10% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B); (iv) .ltoreq.0.20% of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C); (v) .ltoreq.0.80% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D); (vi) .ltoreq.0.20% of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E); (vii) .ltoreq.0.15% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F); and (viii) .ltoreq.0.10% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G), provided
there is present one or more of compounds (a) about .ltoreq.0.50%
to about .gtoreq.0.30% of Compound VIII and (b) about .ltoreq.0.50%
to about .gtoreq.0.30% of Compound IX.
[0060] In one embodiment, Compound I-MsOH, or an enantiomer, a
stereoisomer, or a combination thereof, with a purity of
.gtoreq.96.0% or .gtoreq.98.5% or higher comprising mesylate ester
resulting from MsOH in 0.001% or less, or 10 ppm or less.
[0061] In one embodiment, Compound I-MsOH as disclosed herein is
(S)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((S)-Compound I-MsOH). In some embodiments,
(S)-Compound I-MsOH comprises .ltoreq.0.5% of
(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((R)-Compound I-MsOH). In some embodiments,
(S)-Compound I-MsOH comprises .ltoreq.0.2% of (R)-Compound
I-MsOH.
[0062] In some embodiments, (S)-Compound I-MsOH comprises 5.0% w/w
or less or 2.0% w/w or less water content.
BRIEF DESCRIPTION OF THE FIGURES
[0063] FIG. 1. shows a proton NMR (nuclear magnetic resonance
spectroscopy) spectrum of (S)-Compound II-OH.
[0064] FIG. 2. shows a proton NMR spectra of Compound V-3 (top),
Compound V-3 with D.sub.2O (middle), and Compound II-OH
(bottom).
[0065] FIG. 3. shows an expansion of the aromatic region of the NMR
spectra of FIG. 2.
DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions
[0066] While the following terms are believed to be well understood
by one of ordinary skill in the art, the following definitions are
set forth to facilitate explanation of the presently disclosed
subject matter.
[0067] The term "a" or "an" refers to one or more of that entity;
for example, "a halogen" refers to one or more halogens or at least
one halogen. As such, the terms "a" (or "an"), "one or more" and
"at least one" are used interchangeably herein. In addition,
reference to "an alkyl group" by the indefinite article "a" or "an"
does not exclude the possibility that more than one of the alkyl
group is present, unless the context clearly requires that there is
one and only one of the alkyl groups.
[0068] As used herein, the verb "comprise" as is used in this
description and in the claims and its conjugations are used in its
non-limiting sense to mean that items following the word are
included, but items not specifically mentioned are not
excluded.
[0069] As used herein, the phrase "alkyl group" refers to a
straight chain, a branched chain or a cyclic hydrocarbons having
from 1 up to about 10 carbon atoms. Non-limiting examples of an
alkyl group includes C1-C10 alkyl group such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the
like.
[0070] As used herein the phrase "aryl group" refers to an aromatic
group having from 6 up to 14 carbon atoms. Non-limiting examples of
an aryl group includes phenyl, naphthyl, anthryl, fluorenyl, and
the like.
[0071] As used herein, the phrase "substituent(s)" in the
optionally substituted alkyl group and the optionally substituted
aryl group includes a halogen atom (e.g., fluorine, chlorine,
bromine, iodine, etc.), a nitro group, a cyano group, an optionally
substituted hydroxyl group (e.g., a hydroxyl group, C1-C4 alkoxy,
etc.), an optionally substituted thiol group (e.g., thiol, C1-C4
alkylthio, etc.), an optionally substituted amino group (e.g.,
amino, mono-C1-C4 alkylamino, di-C1-C4 alkylamino, a 5- or
6-membered cyclic amino group such as, pyrrolidine, piperazine,
piperidine, morpholine, thiomorpholine, pyrrole and imidazole,
etc.), an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-C4 alkoxycarbonyl, carbamoyl, mono-C1-C4
alkylcarbamoyl, di-C1-C4 alkylcarbamoyl, etc.), an optionally
halogenated C1-C4 alkoxy group (e.g., methoxy, ethoxy, propoxy,
butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally
halogenated C1-C4 alkoxy-C1-C4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-C4 alkanoyl
group (e.g., acetyl, propionyl, etc.) and a C1-C4 alkylsulfonyl
group (e.g., methanesulfonyl, ethanesulfonyl, etc.).
[0072] As used herein, the phrase "short-chain alcohol" refers to
alcohol containing 1-8 carbon atoms. Non-limiting examples of
short-chain alcohol includes methanol, ethanol, propanol,
isopropanol, butanol, pentanol, hexanol, heptanol, octanol, and the
like.
[0073] As used herein, the phrase "nonprotic solvent" or
"non-protic solvent" refers to an organic solvent or mixtures of
organic solvents that is not readily deprotonated in the presence
of a strongly basic reactant. Non-limiting examples of non-protic
solvents include ethers, dimethylformamide (DMF), dimethylacetamide
(DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),
formamide, N-methylacetamide, N-methylformamide, acetonitrile,
dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate,
hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,
sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,
nitrobenzene, or hexamethylphosphoramide, diethoxymethane,
tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,
tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycol
dimethyl ether, ethylene glycol diethyl ether, diethylene glycol
dimethyl ether, diethylene glycol diethyl ether, triethylene glycol
dimethyl ether, anisole, t-butyl methyl ether, and the like.
[0074] As used herein, the phrase "protic solvent" refers to a
solvent or solvent mixtures that is capable of functioning as an
acid for purposes of protonating any unreacted, strongly basic
reaction intermediates. Non-limiting examples of protic solvents
include water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,
2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,
2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl
alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,
neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl
ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl
alcohol, phenol, glycerol, and the like.
[0075] As used herein, the phrase "part(s)" when used to describe
volume of a liquid refers to an approximate estimate of the volume
multiplier to a compound, substance, or liquid in which it refers
to or which is stated previously. For example, 50 parts water with
respect to Compound A means water with approximately 50 times the
volume of Compound A is used.
[0076] As used herein, the symbol ".ltoreq." means "not more than"
or "equal to or less than"; "<" means "less than"; ".gtoreq."
means "not less than" or "equal to or more than"; and ">" means
"more than". Furthermore, the numerical numbers, when used herein
in connection with purity or impurity content, include not only the
exact number but also the approximate range around the number. For
example, the phrase "purity of 99.0%" denotes a purity of about
99.0%.
Compounds and Purities/Impurities
[0077] The compounds of the disclosure, or their pharmaceutically
acceptable salts can contain one or more asymmetric centers and can
thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that can be defined, in terms of absolute
stereochemistry, as (R)- or (S)-. The present disclosure is meant
to include all such possible isomers, as well as their racemic and
optically pure forms whether or not they are specifically depicted
herein. Optically active (+) and (-), or (R)- and (S)-isomers can
be prepared using chiral synthons or chiral reagents, or resolved
using conventional techniques, for example, chromatography and
fractional crystallization.
[0078] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposable mirror images
of one another. In one embodiment, compounds disclosed herein
include racemic mixtures, enantiomers, diastereomers, or
enantiomerically or diasteriomerically enriched mixtures.
[0079] The disclosed process, in some embodiments, for the
synthesis of Compound II-OH provides Compound II-OH in about
.gtoreq.95.0% to about .ltoreq.96.0% purity. In another embodiment,
the disclosed process for the synthesis of Compound II-OH provides
Compound II-OH in about .gtoreq.97.0% purity. In one embodiment,
the disclosed process for the synthesis of Compound II-OH provides
Compound II-OH in about .gtoreq.97.5% purity. In another
embodiment, the disclosed process for the synthesis of Compound
II-OH provides Compound II-OH in about .gtoreq.98.0% purity. In
some embodiments, the disclosed process for the synthesis of
Compound II-OH provides Compound II-OH in about .gtoreq.99.0%
purity.
[0080] In other embodiments, the disclosed synthesis of Compound
II-OH results in the presence of 4,4'-bis(2-butoxyethoxy)biphenyl
(Compound VII) in about .ltoreq.0.50% to about .gtoreq.0.30%. In
one embodiment, the disclosed synthesis of Compound II-OH results
in the presence of Compound VII in about .ltoreq.0.20%. In one
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of Compound VII in about .ltoreq.0.10%. In some
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of Compound VII in about .ltoreq.0.05%.
[0081] In other embodiments, the disclosed synthesis of Compound
II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.50% to about .gtoreq.0.20%. In other embodiments, the
disclosed synthesis of Compound II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.50% to about .gtoreq.0.25%. In other embodiments, the
disclosed synthesis of Compound II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.50% to about .gtoreq.0.30%. In one embodiment, the
disclosed synthesis of Compound II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.20%. In other embodiments, the disclosed synthesis of
Compound II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.10%. In one embodiment, the disclosed synthesis of
Compound II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.05%. In some embodiments, the disclosed synthesis of
Compound II-OH results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.01%.
[0082] In other embodiments, the disclosed synthesis of Compound
II-OH results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.50%. In another
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.25%. In one
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.15%. In one
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of Compound IX in about .ltoreq.0.10%. In one
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of Compound IX in about .ltoreq.0.05%.
[0083] In some embodiments, the disclosed synthesis of Compound
II-OH result in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.50% to
about .gtoreq.0.20%. In some embodiments, the disclosed synthesis
of Compound II-OH result in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.50% to
about .gtoreq.0.25%. In some embodiments, the disclosed synthesis
of Compound II-OH result in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.50% to
about .gtoreq.0.30%. In one embodiment, the disclosed synthesis of
Compound II-OH results in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.20%. In
other embodiments, the disclosed synthesis of Compound II-OH
results in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.10%. In
one embodiment, the disclosed synthesis of Compound II-OH results
in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.05%. In
another embodiment, the disclosed synthesis of Compound II-OH
results in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A) in about .ltoreq.0.01%.
[0084] In some embodiments, the disclosed synthesis of Compound
II-OH results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B) in about .ltoreq.0.50% to
about .gtoreq.0.20%. In some embodiments, the disclosed synthesis
of Compound II-OH results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II--OH-B) in about .ltoreq.0.50% to
about .gtoreq.0.25%. In some embodiments, the disclosed synthesis
of Compound II-OH results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B) in about .ltoreq.0.50% to
about .gtoreq.0.30%. In one embodiment, the disclosed synthesis of
Compound II-OH results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B) in about .ltoreq.0.20%. In
one embodiment, the disclosed synthesis of Compound II-OH results
in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II--OH-B) in about .ltoreq.0.10%. In
one embodiment, the disclosed synthesis of Compound II-OH results
in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B) in about .ltoreq.0.05%. In
another embodiment, the disclosed synthesis of Compound II-OH
results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II-OH-B) in about .ltoreq.0.01%.
[0085] In one embodiment, the disclosed synthesis of Compound II-OH
results in the presence of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C) in about .ltoreq.0.50%. In some
embodiments, the disclosed synthesis of Compound II-OH results in
the presence of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C) in about .ltoreq.0.25%. In one
embodiment, the disclosed synthesis of Compound II-OH results in
the presence of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C) in about .ltoreq.0.15%. In other
embodiments, the disclosed synthesis of Compound II-OH results in
the presence of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C) in about .ltoreq.0.10%. In other
embodiments, the disclosed synthesis of Compound II-OH results in
the presence of Compound II-OH-C in about .ltoreq.0.05%. In other
embodiments, the disclosed synthesis of Compound II-OH results in
the presence of Compound II-OH-C in about .ltoreq.0.01%.
[0086] In one embodiment, the disclosed synthesis of Compound II-OH
results in the presence of one or more of the following:
[0087] (a) about .ltoreq.0.50% to about .gtoreq.0.30% or about
.ltoreq.0.01% of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH-A);
[0088] (b) about .ltoreq.0.50% to about .gtoreq.0.30% or about
.ltoreq.0.01% of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocin-
e-5-carboxylic acid (Compound II--OH-B);
[0089] (c) about .ltoreq.0.50% to about .gtoreq.0.30% of
4,4'-bis(2-butoxyethoxy)biphenyl (Compound VII); and
[0090] (d) about .ltoreq.0.50% to about .gtoreq.0.30% or about
.ltoreq.0.01% of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII); and optionally
further comprises one or both of [0091] (i) about .ltoreq.0.50% of
8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxy-
lic acid (Compound II-OH-C); and [0092] (ii) about .ltoreq.0.50% of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX).
##STR00010##
[0093] The disclosed process, in some embodiments, the synthesis of
Compound I-MsOH provides Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, in about .gtoreq.95.0% to
about .ltoreq.95.5% purity. In one embodiment, the disclosed
process for the synthesis of Compound I-MsOH provides Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
in about .gtoreq.96.0% purity. In another embodiment, the disclosed
process for the synthesis of Compound I-MsOH provides Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
in about .gtoreq.97.0% purity. In one embodiment, the disclosed
process for the synthesis of Compound I-MsOH provides Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
in about .gtoreq.98.0% purity. In some embodiments, the disclosed
process for the synthesis of Compound I-MsOH provides Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
in about .gtoreq.98.5% purity.
[0094] In other embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH) in about .ltoreq.1.0%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH) in about .ltoreq.0.80% or about
.ltoreq.0.50%. In some embodiments, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-
-5-carboxylic acid (Compound II-OH) in about .ltoreq.0.25%.
[0095] In other embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.50% to about .gtoreq.0.20%. In other embodiments, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.50% to about .gtoreq.0.25%. In other embodiments, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.50% to about .gtoreq.0.30%. In some embodiments, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.20%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.10%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.05%. In another embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrob-
enzo[b]azocine-5-carboxylic acid) (Compound VIII) in about
.ltoreq.0.01%.
[0096] In other embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.50% to about
.gtoreq.0.20%. In other embodiments, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.50% to about
.gtoreq.0.25%. In other embodiments, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.50% to about
.gtoreq.0.30%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.25%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.20%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.15%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.10%. In some
embodiments, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5--
carboxylic acid (Compound IX) in about .ltoreq.0.05%.
[0097] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
4-(((1-propyl-H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.0.50% to about .gtoreq.0.35%. In one embodiment, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.0.25%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.0.15%. In another embodiment, the disclosed synthesis
of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.0.10%.
[0098] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
4-(((1-propyl-H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.2000 ppm. In some embodiments, the disclosed
synthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.1750 ppm. In some embodiments, the disclosed
synthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.1500 ppm. In some embodiments, the disclosed
synthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound
III) or an enantiomer, a stereoisomer, or a combination thereof, in
about .ltoreq.1250 ppm.
[0099] In one embodiment, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
(S)-4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline
((S)-Compound III) in about .ltoreq.1500 ppm.
[0100] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A) in about .ltoreq.0.50% to
about .gtoreq.0.25%. In some embodiments, the disclosed synthesis
of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A) in about .ltoreq.0.50% to
about .gtoreq.0.30%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A) in about .ltoreq.0.25%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A) in about .ltoreq.0.15%. In
another embodiment, the disclosed synthesis of Compound I-MsOH or
an enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-A) in about .ltoreq.0.10%.
[0101] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B) in about .ltoreq.0.50% to
about .gtoreq.0.25%. In some embodiments, the disclosed synthesis
of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B) in about .ltoreq.0.50% to
about .gtoreq.0.30%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B) in about .ltoreq.0.25%. In
other embodiments, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B) in about .ltoreq.0.15%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-y-
l)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-B) in about .ltoreq.0.10%.
[0102] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C) in about .ltoreq.0.50% to
about .gtoreq.0.40%. In some embodiments, the disclosed synthesis
of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C) in about .ltoreq.0.50% to
about .gtoreq.0.45%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C) in about .ltoreq.0.40%. In
other embodiments, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C) in about .ltoreq.0.30%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C) in about .ltoreq.0.20%. In
another embodiment, the disclosed synthesis of Compound I-MsOH or
an enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)su-
lfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-C) in about .ltoreq.0.10%.
[0103] In one embodiment, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D) in about .ltoreq.2.0%. In
other embodiments, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D) in about .ltoreq.1.0%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D) in about .ltoreq.0.50%. In
another embodiment, the disclosed synthesis of Compound I-MsOH or
an enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-D) in about .ltoreq.0.10%.
[0104] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E) in about .ltoreq.0.50% to
about .gtoreq.0.40%. In some embodiments, the disclosed synthesis
of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E) in about .ltoreq.0.50% to
about .gtoreq.0.45%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E) in about .ltoreq.0.40%. In
other embodiments, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E) in about .ltoreq.0.30%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E) in about .ltoreq.0.20%. In
another embodiment, the disclosed synthesis of Compound I-MsOH or
an enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl-
)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-E) in about .ltoreq.0.10%.
[0105] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.50% to
about .gtoreq.0.40%. In some embodiments, the disclosed synthesis
of Compound I-MsOH or an enantiomer, a stereoisomer, or a
combination thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.50% to
about .gtoreq.0.45%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.40%. In
other embodiments, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.30%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.20%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.15%. In one
embodiment, the disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)me-
thyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide
methanesulfonate (Compound I-MsOH-F) in about .ltoreq.0.10%.
[0106] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.50% to about .gtoreq.0.40%. In some embodiments, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.50% to about .gtoreq.0.45%. In some embodiments, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.50% to about .gtoreq.0.30%. In one embodiment, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or a combination thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.40%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.30%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.20%. In one embodiment, the disclosed synthesis of
Compound I-MsOH or an enantiomer, a stereoisomer, or a combination
thereof, results in the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.15%. The disclosed synthesis of Compound I-MsOH or an
enantiomer, a stereoisomer, or a combination thereof, results in
the presence of
8,8'-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-
-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-
-carboxamide) dimethanesulfonate (Compound I-MsOH-G) in about
.ltoreq.0.10%.
[0107] In another embodiment, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or combinations thereof,
results in the presence of mesylate esters, resulting from MsOH, in
about .ltoreq.1.0%. In other embodiments, the disclosed synthesis
of Compound I-MsOH results in the presence of mesylate esters,
resulting from MsOH, in about .ltoreq.0.50%. In one embodiment, the
disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or combinations thereof, results in the presence of
mesylate esters, resulting from MsOH, in about .ltoreq.0.25%.
[0108] In one embodiment, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or combinations thereof,
results in the presence of mesylate esters, resulting from MsOH, in
about .ltoreq.20 ppm. In other embodiments, the disclosed synthesis
of Compound I-MsOH results in the presence of mesylate esters,
resulting from MsOH, in about .ltoreq.10 ppm. In one embodiment,
the disclosed synthesis of Compound I-MsOH or an enantiomer, a
stereoisomer, or combinations thereof, results in the presence of
mesylate esters, resulting from MsOH, in about .ltoreq.5 ppm. In
some embodiments, Compound I-MsOH or an enantiomer, a stereoisomer,
or a combination thereof contains 10 ppm mesylate ester for a 150
mg dose.
##STR00011##
[0109] In one embodiment, the disclosed synthesis of Compound
I-MsOH results in (S)-Compound I-MsOH. In some embodiments, the
disclosed synthesis provides (S)-Compound I-MsOH in greater than
96% purity or greater than 98.5% purity.
[0110] In some embodiments, the disclosed synthesis of (S)-Compound
I-MsOH results in the presence of
(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((R)-Compound I-MsOH) in about .ltoreq.1.00%.
In another embodiment, the disclosed synthesis of (S)-Compound
I-MsOH results in the presence of
(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((R)-Compound I-MsOH) in about .ltoreq.0.50%.
In one embodiment, the disclosed synthesis of (S)-Compound I-MsOH
results in the presence of
(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol--
5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxami-
de methanesulfonate ((R)-Compound I-MsOH) in about
.ltoreq.0.25%.
[0111] In some embodiments, the disclosed synthesis of Compound
I-MsOH or an enantiomer, a stereoisomer, or a combination thereof,
results in the presence of 5.0% w/w or less or 2.0% w/w or less
water content.
[0112] In some embodiments, the disclosed synthesis of (S)-Compound
I-MsOH results in the presence of .ltoreq.3.0% impurity including
(R)-Compound I-MsOH but excluding (S)-Compound III. In one
embodiment, the disclosed synthesis of (S)-Compound I-MsOH results
in the presence of .ltoreq.2.5% impurity including (R)-Compound
I-MsOH but excluding (S)-Compound III. In another embodiment, the
disclosed synthesis of (S)-Compound I-MsOH results in the presence
of .ltoreq.2.3% impurity including (R)-Compound I-MsOH but
excluding (S)-Compound III. In some embodiments, the disclosed
synthesis of (S)-Compound I-MsOH results in the presence of
.ltoreq.2.0% impurity including (R)-Compound I-MsOH but excluding
(S)-Compound III.
Process for the Synthesis of Compound V
[0113] Compound V, in some embodiments, represents boronic acids,
boronic esters, pinacolboranes, boronic acid dimers, boronic acid
trimers, mixtures thereof, or the like. It is commonly understood
in the art that Compound V can be presented as various derivatives
of boronic acids.
[0114] In some embodiments, dimethyl
(4-(2-butoxyethoxy)phenyl)boronate (Compound V-OMe) is prepared by
a Grignard formation of 1-bromo-4-(2-butoxyethoxy)benzene (Compound
VI) and a subsequent reaction with trimethoxyborane.
[0115] It was discovered in a large scale batch that Grignard
initiation was difficult. The previous process employed a dilute
solution of Compound VI, approximately 50-70 parts tetrahydrofuran
(THF) with respect to Compound VI. The initiation was very slow in
the dilute solution of Compound VI with isopropylmagnesium chloride
(iPrMgCl), which only occurred after prolonged reflux and addition
of increased amounts of Compound VI, bringing the concentration to
approximately 25 parts THE with respect to Compound VI. In addition
to the difficulties in initiating the Grignard, it was found that
the use of iPrMgCl had an adverse effect in the subsequent step
(lower conversion of the Suzuki coupling step; see section Process
for the synthesis of Compound II-OH).
[0116] To overcome the Grignard initiation issues, the activation
step of the magnesium turnings, by heating and agitation, prior to
the Grignard formation is necessary. In some embodiments, magnesium
turnings were stirred for about 1 hour in about 9 parts of an
ethereal solvent, such as THF. Subsequently, the solvent can be
reduced to about 3 parts by distillation.
[0117] The Grignard initiation challenges, in some embodiments, are
solved by using neat Compound VI to provide a more concentrated
solution than the previous methods. In some embodiments,
approximately 20% of the total amount of Compound VI is added neat
to the solution of activated magnesium turnings over a period of at
least 15 minutes, while the exotherm is controlled, such that the
temperature of the reaction is maintained below the boiling point
of the solvent. The resulting solution is heated at or around the
boiling point of the solvent for about 1 hours to about 4 hours.
The reaction mixture is then cooled by about 10.degree. C. and
diluted with the same solvent as used previously (5 parts). This
disclosed Grignard initiation step, in some embodiments, results in
the complete omission of iPrMgCl.
[0118] To the hot initiated Grignard solution, which is further
diluted, the remaining Compound VI is slowly added neat over a
period of about 30 minutes to about 1 hour. The addition of
Compound VI is exothermic and the reaction mixture is carefully
maintained to be well below the boiling point during the addition.
The resulting mixture is stirred and heated to temperature below
the boiling point of the solvent, for example about 55.degree. C.
for THF, for about 3 hours to about 4 hours. The heating time can
be extended until high-performance liquid chromatography (HPLC)
analysis indicates less than about 1% of Compound VI is remaining.
It was noted that prolong heating time had no beneficial effect on
the yield of the subsequent step or in the prevention of key
impurity formations.
[0119] Previous process route for the synthesis of Compound V-OMe
involved cooling the Grignard mixture to about -15.degree. C. and
adding a solution of trimethoxyborane in THF. The inventors
discovered that this temperature range was not optimal and lead to
lower yields and higher impurities. Also, it was found that the
reaction was sensitive to the rate of addition of
trimethoxyborane.
[0120] Considering the above findings, in some embodiments,
Grignard mixture (once formation is complete) is cooled to about
-25.degree. C. and neat trimethoxyborane is added portion-wise over
about 2 hours. The reaction mixture was stirred at about
-25.degree. C. for about 1 hour to about 2 hours upon completion of
the trimethoxyborane addition, then warmed up to about 20.degree.
C. and stirred for about 1 hour to about 2 hours to provide
Compound V-OMe. In some embodiments, the neat trimethoxyborane was
chilled prior to the addition to the Grignard mixture.
[0121] In some embodiments, the ratio of magnesium turning,
Compound VI, and trimethoxyborane is about 1.08:1:1.
[0122] In some embodiments, anhydrous solvents are used in the
synthesis of Compound V. In other embodiments, the reaction for the
synthesis of Compound V is maintained under atmospheric pressure of
nitrogen or argon and the reaction vessels and equipment are rid of
moisture prior to use.
[0123] In some embodiments, Compound VI and trimethoxyborane is
both used as a neat solution to minimize reactor usage.
[0124] It was noted that filtration of the crude Compound V-OMe to
remove excess magnesium and magnesium salts is not necessary as it
had no effect on the subsequent step in terms of preventing key
impurity formation.
Preparation of Compound V-OH
[0125] In some embodiments, Compound V is Compound V-OH. In one
embodiment, Compound V-OH is synthesized by process known to one
skilled in the art. In one embodiment, commercially available
Compound V-OH (CAS No. 279262-28-1) is purified to obtain a
crystalline Compound V-OH which is essentially free of Compounds
V-A, V-B, and V-C.
[0126] In one embodiment, Compound V is Compound V-OH with
.ltoreq.0.10% of Compound V-OH-A, Compound V-OH-B and/or Compound
V-OH-C.
##STR00012##
[0127] In some embodiments, Compound V-OH is dried such that the
loss on drying (LOD) is below about 20%, about 19%, about 18%,
about 17%, about 16%, about 15%, about 14%, about 13%, about 12%,
about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or
about 5%. In one embodiment, Compound V-OH is dried such that the
loss on drying (LOD) is about 15%, about 14%, about 13%, about 12%,
about 11%, or about 10%. In some embodiment, prolonged drying of
Compound V-OH results in the formation of Compound V-3.
[0128] In one embodiment, Compound V-OH is about .gtoreq.85%, about
.gtoreq.90%, about .gtoreq.95%, about .gtoreq.96%, about
.gtoreq.97%, about .gtoreq.98%, or about .gtoreq.99% pure.
[0129] In other embodiments, dried sample of Compound V-OH can
contain Compound V-3 in about 30%, about 29%, about 28%, about 27%,
about 26%, about 25%, about 24%, about 23%, about 22%, about 21%,
about 20%, about 19%, about 18%, about 17%, about 16%, about 15%,
about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,
about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about
2%, or about 1%. In one embodiment, isolated crystalline Compound
V-OH comprises Compound V-3 in less than about 5%, about 4%, about
3%, about 2%, about 1%, or about 0.5%.
[0130] In one embodiment, Compound V-3 is about .gtoreq.85%, about
.gtoreq.90%, about .gtoreq.95%, about .gtoreq.96%, about
.gtoreq.97%, about .gtoreq.98%, or about .gtoreq.99% pure.
[0131] In one embodiment, a mixture of dried Compound V-OH and
Compound V-3 can be used in the reaction with Compound IV. In some
embodiments, mixture of Compound V-OH and Compound V-3 can be in
the ratio of about 1:99 to about 99:1. In other embodiments, the
ratio of Compound V-OH and Compound V-3 can be about 5:95 to about
95:5. In one embodiment, the mixture of dried Compound V-OH and
Compound V-3 is essentially free of Compounds V-A, V-B, and V-C. In
other embodiments, the mixture of dried Compound V-OH and Compound
V-3 comprises .ltoreq.0.10% of Compound V-OH-A, Compound V-OH-B
and/or Compound V-OH-C.
[0132] In one embodiment, the mixture of Compound V-OH and Compound
V-3 is about .gtoreq.85%, about .gtoreq.90%, about .gtoreq.95%,
about .gtoreq.96%, about .gtoreq.97%, about .gtoreq.98%, or about
.gtoreq.99% pure.
Process for the Synthesis of Compound II-OH
[0133] In some embodiments, Compound II-OH is prepared by the
reaction between Compound IV and Compound V. In other embodiments,
Compound II-OH is prepared by a transition metal-catalyzed process,
such as a Suzuki coupling reaction, between Compound IV and
Compound V. In one embodiment, the amount of Compound V used is
about 1 equivalent (equiv) to about 3 equiv with respect to
Compound IV. In other embodiments, the amount of Compound V used is
about 2 equiv with respect to Compound IV.
[0134] A previous process for the synthesis of Compound II-OH also
involved a Suzuki coupling reaction where the reaction mixture
containing Compound V was charged with palladium acetate
(Pd(OAc).sub.2) catalyst and triphenylphosphine ligand (PPh.sub.3),
prior to the addition of aqueous base solution (water and solid
base). This synthetic route yielded Compound II-OH in a moderate
yield of about 55% to about 64% yield with purity ranging from
about 92% to about 99%.
[0135] It was discovered that, in some embodiments, the addition of
the aqueous base solution to form a biphasic mixture prior to the
addition of the palladium (Pd) catalyst and the ligand is
beneficial in reducing Compound VII impurity, resulting from
homo-coupling of Compound V. In some embodiments, a solution of a
base in about 6.5 parts water is added to the reaction mixture
containing Compound V, prepared as described previously. In other
embodiments, base may be selected from the group consisting of
alkali carbonates (potassium carbonate, sodium carbonate, cesium
carbonate, etc), alkali metal hydrogen carbonates (potassium
bicarbonate, sodium bicarbonate, etc), alkaline metal acetates
(potassium acetate, sodium acetate, etc), alkaline metal phosphates
(potassium phosphate, sodium phosphate, etc), alkali metal
fluorides (potassium fluoride, cesium fluoride, etc), alkaline
metal alkoxides (potassium tert-butoxide, sodium tert-butoxide,
etc), alkali metal hydroxides (potassium hydroxide, sodium
hydroxide, etc), and organic bases such as alkyl amines
(triethylamine, diisopropylamine, diisopropylethyl amine, etc)
pyridines (pyridine, dimethylaminopyridine, etc), cyclic amines
(morpholine, 4-methylmorpholine, etc), and the combination thereof.
In one embodiment, the base is potassium carbonate
(K.sub.2CO.sub.3). In some embodiments, the equivalent of base is
about 1 equiv to about 8 equiv with respect to Compound IV.
[0136] The addition of the aqueous base solution, in some
embodiments, is carried out over a period of at least 30 minutes to
at least 1 hour. The slow addition of the base solution was found
critical in the yield of the Suzuki coupling reaction. Without
being bound to any theory, this is presumably due to the prevention
of salt formation during the biphasic mixture formation.
[0137] Previous synthetic routes of the Suzuki coupling reaction
raised issues regarding reaction conversion when carried out in a
large scale. It was discovered that purging the biphasic reaction
mixture with nitrogen (N.sub.2), by bubbling N.sub.2 directly into
the reaction mixture, for about 1 hour to rid air content, such as
oxygen, provided the desired reaction conversion. This process is
known as the degassing. Degassing the reaction mixture was also
found beneficial in reducing Compound VII impurities from the
Suzuki coupling step.
[0138] In some embodiments, to a degassed biphasic reaction mixture
containing Compound V, a Pd-catalyst and a ligand is added.
Previous synthetic route utilized tetrakis(triphenylphosphine)
palladium (Pd(PPh.sub.3).sub.4) catalyst system achieved by adding
Pd(OAc).sub.2 and PPh.sub.3. The yield of the Suzuki reaction using
Pd(PPh.sub.3).sub.4 catalyst system was not optimal as represented
by the moderate yield of Compound II-OH (about 55% to about 64%
yield).
[0139] Further optimization of the catalyst system was undertaken
to improve yields and to lower Compound VIII impurity. As described
in Example 1 and Table 1, optimization of the Pd(PPh.sub.3).sub.4
catalyst system demonstrated that good conversion was achieved only
when catalyst loading was significantly increased (from about 2 mol
% to about 10 mol %, Table 1 entry 6) or when the reaction was
refluxed substantially longer time (about 27 hours, entry 5). It
was also noted that when high catalyst loading was employed, the
amount of Compound VIII impurity was significantly lower (0.04%,
entry 6); however, high catalyst loading interfered with the
crystallization of the product. Also, lowering the temperature for
the Suzuki coupling reaction showed unsuccessful in preventing
Compound VIII impurity.
[0140] Next, different catalyst systems were considered as shown in
Example 2 and Table 2. Removal of the phosphine ligands (Table 2,
entry 1) was shown detrimental to the reaction conversion. The
inventors discovered that catalyst system of
Pd(OAc).sub.2/P(o-tol).sub.3 increased reaction yield (about
80-85%) and product purity (>99%) compared to the previous
Pd(PPh.sub.3).sub.4 catalyst system. Furthermore, with the newly
discovered Pd(OAc).sub.2/P(o-tol).sub.3 catalyst system, the
catalyst loading could be minimized significantly from about 2 mol
% to about 0.25 mol %. It was also noted that with the disclosed
catalyst system, degassing the reaction did not affect conversion
rate, purity of the product, or the amount of Compound VIII. The
catalyst optimization study from Examples 1-2 both indicate the
amount of Compound VIII impurity has very little to no correlation
with the Suzuki coupling reaction conditions.
[0141] In some embodiments, Pd-catalyst and ligands are added to
the reaction biphasic reaction mixture containing Compound V. In
some embodiments, Pd-catalyst can be a Pd(0) species or a Pd(II)
species. Non-limiting examples of Pd-catalyst include
tetrakis(triphenylphosphine) palladium (Pd(PPh.sub.3).sub.4),
tri(dibenzylideneacetone) dipalladium, bis(tri-t-butylphosphine)
palladium, bis[1,2-bis(diphenylphophino)ethane] palladium,
bis(tricyclohexylphosphine) palladium, palladium acetate
(Pd(OAc).sub.2), palladium chloride (PdCl.sub.2),
dichlorobis(triphenylphosphine) palladium, palladium
acetylacetonate, palladium bromide, palladium iodide, palladium
cyanide, palladium hydroxide, palladium nitrate, tetraammine
palladium(II) chloride hydrate, dinitrodiammine palladium,
di-.mu.-chlorobis(.eta.-allyl) palladium, dichlorobis(benzonitrile)
palladium, dichlorobis(acetonitrile) palladium, palladium
propionate, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
chloride, tetrakis(tri-o-tolylphosphine) palladium,
tetrakis(tri-t-butylphosphine) palladium,
bis(1,2-bis(diphenylphosphino)ethane) palladium,
bis(1,1'-bis(diphenylphosphino)ferrocene) palladium,
tetrakis(triethylphosphite) palladium, and combinations
thereof.
[0142] In some embodiments, the ligand is selected from the group
consisting of phosphine ligands (tritolylphosphine,
triphenylphosphine, trimethylphosphine, triethylphosphine,
trimethylphosphite, triethylphosphite, tri-n-butylphosphite,
tri-tert-butylphosphine, di-tert-butylmethylphosphine, etc),
nitrogen based ligands (pyridine, bipyridine, etc), NHC ligands
(N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene etc), and
combinations thereof.
[0143] In some embodiments, the Pd-catalyst/ligand system is
Pd(OAc).sub.2/P(o-tol).sub.3. In other embodiments, the Pd-catalyst
and the ligand are added with continuous degassing of the reaction
mixture.
[0144] In some embodiments, the amount of Pd-catalyst used is about
0.001 mol % to about 10.0 mol % with respect to Compound IV. In one
embodiment, the amount of Pd-catalyst used is about 0.05 mol % to
about 0.25 mol % with respect to Compound IV.
[0145] In some embodiments, the ratio of the ligand to the
Pd-catalyst is about 1:1 to about 3:1. In some embodiments, the
ratio of the ligand to the Pd-catalyst is about 2:1.
[0146] In some embodiments, Compound IV is added to the biphasic
mixture containing Compound V and Pd-catalyst/ligand system. In one
embodiment, Compound IV is added with continuous degassing of the
reaction mixture.
[0147] In some embodiments, the reaction mixture upon the addition
of Compound IV is heated for about 2 hours to about 5 hours and
then cooled to ambient temperature. In some embodiments, the
reaction mixture is heated to no greater than 65.degree. C. It was
noted that Pd-catalyst becomes inactive when temperature is raised
above 65.degree. C. For example, a Suzuki reaction set at a
temperature of 90.degree. C. did not go to completion. In one
embodiment, the reaction was heated until HPLC analysis indicates
2% Compound IV remaining and indicates formation of Compound
II-OH.
[0148] Once the reaction was deemed complete by HPLC, in some
embodiments, the reaction is cooled to ambient temperature and the
pH of the reaction mixture was adjusted to about 2.0 to about 3.0
using aqueous acid solutions. In some embodiment, hydrochloric acid
(HCl) is used.
[0149] In some embodiments, Compound V is Compound V-OMe.
[0150] In some embodiments, Compound V is Compound V-OH. In one
embodiment, commercially available Compound V-OH (CAS No.
279262-28-1) is purified to obtain a crystalline Compound V-OH
which is essentially free of Compounds V-A, V-B, and V-C.
[0151] In one embodiment, Compound V is Compound V-OH with
.ltoreq.0.10% of Compound V-OH-A, Compound V-OH-B and/or Compound
V-OH-C. In one embodiment, Compound V-OH comprises one or both of
(a) about .ltoreq.0.01% of Compound II-OH-A; and (b) about
.ltoreq.0.01% of Compound II-OH-B; and optionally further comprises
about .ltoreq.0.10% of Compound II-OH-C. In another embodiment,
Compound V-OH comprises (a) about .ltoreq.0.01% of Compound
II-OH-A; (b) about .ltoreq.0.01% of Compound II-OH-B; and (c) about
.ltoreq.0.10% of Compound II-OH-C.
[0152] In one embodiment, isolated Compound V-OH is
crystalline.
[0153] In one embodiment, Compound V-OH comprises less than about
15%, less than about 10%, or less than about 5% Compound V-3.
[0154] In one embodiment, Compound V-3 is used instead of Compound
V-OMe or Compound V-OH. In another embodiment, Compound V-3 is used
as a mixture of Compound V-OH. In one embodiment, Compound V-3 is
essentially free of Compounds V-A, V-B, and V-C. In other
embodiment, Compound V-3 comprises .ltoreq.0.10% of Compound
V-OH-A, Compound V-OH-B and/or Compound V-OH-C. In one embodiment,
Compound V-3 comprises one or both of (a) about .ltoreq.0.01% of
Compound II-OH-A; and (b) about .ltoreq.0.01% of Compound II-OH-B;
and optionally further comprises about .ltoreq.0.10% of Compound
II-OH-C. In another embodiment, Compound V-3 comprises (a) about
.ltoreq.0.01% of Compound II-OH-A; (b) about .ltoreq.0.01% of
Compound II-OH-B; and (c) about .ltoreq.0.10% of Compound
II-OH-C.
[0155] In one embodiment, dried Compound V-3 comprises less than
about 25%, less than about 20%, less than about 15%, less than
about 10%, or less than about 5% Compound V-OH.
[0156] In one embodiment, isolated Compound V-3 is crystalline.
Purification of Compound II-OH
[0157] Previous purification process for Compound II-OH required
two hot recrystallizations and two charcoal treatments. The
disclosed purification process, in some embodiments, requires one
charcoal treatment, one anti-solvent recrystallization, and/or one
hot recrystallization.
[0158] In one embodiment the improvement in purity of Compound
II-OH from previous synthesis methods which led to reduction number
of steps for purification of Compound II-OH is attributed to the
use of isolated Compound V-OH and/or Compound V-3 in the reaction
with Compound IV. In one embodiment, the improvement in purity of
Compound II-OH from previous synthesis methods which led to
reduction of number of steps for purification of Compound II-OH is
attributed to the use of crystalline, isolated Compound V-OH and/or
Compound V-3 in the reaction with Compound IV. In a further
embodiment, the isolated Compound V-OH and/or Compound V-3 or the
crystalline, isolated Compound V-OH and/or Compound V-3 is
essentially free of Compounds V-A, V-B, and V-C.
[0159] In one embodiment, the improvement in purity of compound
II-OH from previous synthesis methods which led to reduction number
of steps for purification of Compound II-OH is attributed to the
use of isolated Compound V-OH in the reaction with Compound IV.
[0160] The acidified biphasic reaction mixture containing crude
Compound II-OH is, in some embodiments, separated into an aqueous
layer and an organic layer. In some embodiments, the resulting
aqueous layer is extracted with an organic solvent. In one
embodiment, the aqueous layer is extracted with toluene (about 10
parts).
[0161] The volume of the combined organic layers is, in some
embodiments, reduced to about 6.5 parts. In some embodiments, the
volume of the combined organic layer is reduced by distillation.
The resulting reduced organic layer is, in some embodiments,
treated with charcoal. In other embodiments, the resulting reduced
organic layer is treated with charcoal and Celite.RTM.. In one
embodiment, the ratio of charcoal to Celite.RTM. is about 1:2 by
weight. The reaction mixture containing charcoal is, in some
embodiment, stirred for about 1 hour to about 5 hours at an ambient
temperature. The charcoal is then, in other embodiments, filtered
and the volume of the reaction is reduced to about 3 parts. In one
embodiment, the volume is reduced by distillation.
[0162] In some embodiments, antisolvent recrystallization is used
for purification of Compound II-OH. To the reduced crude mixture,
polar solvents, such as isopropanol and ethyl acetate, is added and
concentrated to an oil. In one embodiment, a non-polar antisolvent
is added over a period of about 1 hour, portion wise, to the crude
oil mixture. The resulting suspension was stirred at ambient
temperature for about 1 hour to about 8 hours. In some embodiments,
the precipitated crystals are then collected by filtration. In some
embodiments, the mother liquor is not recirculated to remove any
remaining crystals from the reaction vessels; instead multiple
solvent wash may be added using fresh solvents.
[0163] In some embodiments, the antisolvent is heptanes. In other
embodiments, the polar solvent is isopropanol or a mixture of
isopropanol and ethyl acetate. In some embodiments, the product
precipitates without the addition of the antisolvent.
[0164] In some embodiments, a hot recrystallization is used for
purification of Compound II-OH. The crude material containing
Compound II-OH or crude crystals of Compound II-OH are dissolved in
polar solvents such as isopropanol and ethyl acetate at an elevated
temperature. The temperature of the solution is slowly reduced to
ambient temperature and stirred until recrystallization is complete
and then the crystals are collected by filtration.
[0165] In some embodiments, the polar solvent used is isopropanol
or isopropanol and ethyl acetate mixture. In some embodiments, the
crude Compound II-OH is dissolved in mixture of isopropanol and
ethyl acetate in about 9:1 ratio at about 70.degree. C. In other
embodiments, the temperature of the hot solution is decreased by
about 10.degree. C. every about 1 hour until it reaches ambient
temperature. In some embodiments, once the solvent is cooled to an
ambient temperature, the solution is stirred for about 2 hours to
about 6 hours. The resulting crystals are, in some embodiments,
collected by filtration. In some embodiments, the mother liquor is
not recirculated to remove any remaining crystals from the reaction
vessels; instead multiple solvent wash may be added using fresh
solvents.
[0166] Recrystallization solvent study revealed that when hot
recrystallization is carried out in isopropanol alone, the recovery
of Compound II-OH was high (90-93%) and decreased impurity Compound
VIII by about 50-60%. When hot recrystallization is carried out in
ethyl acetate alone, the recovery of Compound II-OH was lower
(70-75%) than isopropanol system but the reduction in impurity
Compound VIII was greater (by 80-83%). When hot recrystallization
is carried out in a mixture of isopropanol and ethyl acetate, both
high recovery of Compound II-OH (90-92%) and effective reduction in
impurity Compound VIII (by 75-80%) was obtained.
[0167] In some embodiments, both antisolvent recrystallization and
hot recrystallization is utilized. In some embodiments, the
combination of antisolvent recrystallization and hot
recrystallization reduces impurity Compounds VIII and IX
significantly. In some embodiments, recrystallization steps can be
repeated to reach the desired purity. In one embodiment, following
the disclosed process for the synthesis of Compound II-OH as
described herein, the purity of Compound II-OH is about
.gtoreq.95.0% to about .ltoreq.96.0% or .gtoreq.97.0%, with one or
both of about .ltoreq.0.50% to about .gtoreq.0.30% of Compound VII,
and about .ltoreq.0.50% to about .gtoreq.0.30% of Compound VIII,
and optionally further comprises about .ltoreq.0.50% of Compound
IX. In one embodiment, following the disclosed process for the
synthesis of Compound II-OH as described herein, the purity of
Compound II-OH is about .gtoreq.95.0% to about .ltoreq.96.0% or
.gtoreq.97.0%, with about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound VII, with about .ltoreq.0.50% to about .gtoreq.0.30% of
Compound VIII, and with about .ltoreq.0.50% of Compound IX. In
other embodiments, following the disclosed process for the
synthesis of Compound II-OH as described herein, the purity of
Compound II-OH is about .gtoreq.95.0% to about .ltoreq.96.0%, with
about .ltoreq.0.20% of Compound VII, with about .ltoreq.0.20% of
Compound VIII, and with about .ltoreq.0.50% of Compound IX. In some
embodiments, following the disclosed process for the synthesis of
Compound II-OH as described herein, the purity of Compound II-OH is
about .gtoreq.95.0% to about .ltoreq.96.0%, with about
.ltoreq.0.10% of Compound VII, with about .ltoreq.0.10% of Compound
VIII, and with about .ltoreq.0.25% of Compound IX. In one
embodiment, following the disclosed process for the synthesis of
Compound II-OH as described herein, the purity of Compound II-OH is
about .gtoreq.95.0% to about .ltoreq.96.0%, with about
.ltoreq.0.05% of Compound VII, with about .ltoreq.0.05% of Compound
VIII, and with about .ltoreq.0.15% of Compound IX. In one
embodiment, following the disclosed process for the synthesis of
Compound II-OH as described herein, the purity of Compound II-OH is
about .gtoreq.95.0% to about .ltoreq.96.0% or .gtoreq.97.0%, with
about .ltoreq.0.01% of Compound VIII, and optionally further
comprises one or both of about .ltoreq.0.05% of Compound VII, and
about .ltoreq.0.15% of Compound IX. In one embodiment, following
the disclosed process for the synthesis of Compound II-OH as
described herein, the purity of Compound II-OH is about
.gtoreq.95.0% to about .ltoreq.96.0% or .gtoreq.97.0%, with about
.ltoreq.0.05% of Compound VII, with about .ltoreq.0.01% of Compound
VIII, and with about .ltoreq.0.15% of Compound IX.
[0168] In one embodiment, following the disclosed process for the
synthesis of Compound II-OH as described herein, the purity of
Compound II-OH is about .gtoreq.95.0% to about .ltoreq.96.0% or
.gtoreq.97.0%, with one or both of about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound II-OH-A, and about .ltoreq.0.50% to about
.gtoreq.0.30% of Compound II-OH-B, and optionally further comprises
about .ltoreq.0.50% of Compound II-OH-C. In one embodiment,
following the disclosed process for the synthesis of Compound II-OH
as described herein, the purity of Compound II-OH is about
.gtoreq.95.0% to about .ltoreq.96.0% or .gtoreq.97.0%, with about
.ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-A, with
about .ltoreq.0.50% to about .gtoreq.0.30% of Compound II-OH-B, and
with about .ltoreq.0.50% of Compound II-OH-C. In one embodiment,
following the disclosed process for the synthesis of Compound II-OH
as described herein, the purity of Compound II-OH is about
.gtoreq.95.0% to about .ltoreq.96.0%, with about .ltoreq.0.20% of
Compound II-OH-A, with about .ltoreq.0.20% of Compound II-OH-B, and
with about .ltoreq.0.50% of Compound II-OH-C. In another
embodiment, following the disclosed process for the synthesis of
Compound II-OH as described herein, the purity of Compound II-OH is
about .gtoreq.95.0% to about .ltoreq.96.0%, with about
.ltoreq.0.10% of Compound II-OH-A, with about .ltoreq.0.10% of
Compound II-OH-B, and with about .ltoreq.0.25% of Compound II-OH-C.
In some embodiments, following the disclosed process for the
synthesis of Compound II-OH as described herein, the purity of
Compound II-OH is about .gtoreq.95.0% to about .ltoreq.96.0%, with
about .ltoreq.0.05% of Compound II-OH-A, with about .ltoreq.0.05%
of Compound II-OH-B, and with about .ltoreq.0.15% of Compound
II-OH-C. In some embodiments, following the disclosed process for
the synthesis of Compound II-OH as described herein, the purity of
Compound II-OH is about .gtoreq.95.0% to about .ltoreq.96.0% or
.gtoreq.97.0%, with one or both of about .ltoreq.0.01% of Compound
II-OH-A, and about .ltoreq.0.01% of Compound II-OH-B, and
optionally further comprises about .ltoreq.0.10% of Compound
II-OH-C. In some embodiments, following the disclosed process for
the synthesis of Compound II-OH as described herein, the purity of
Compound II-OH is about .gtoreq.95.0% to about .ltoreq.96.0% or
.gtoreq.97.0%, with about .ltoreq.0.01% of Compound II-OH-A, with
about .ltoreq.0.01% of Compound II-OH-B, and with about
.ltoreq.0.10% of Compound II-OH-C.
Preparation of Compound I
[0169] The previous process for preparing Compound I and
subsequently Compound I-MsOH presented challenges with the presence
of Compound II-OH (starting material) in the final product. It was
discovered that the formation of Compound II-OH is dependent on
several steps or features of the reaction. First, the formation of
acid chloride Compound II-Cl (Compound II where R.sub.1.dbd.Cl).
Second, the solvent choice of the reaction affected the amount of
Compound II-OH produced. Third, is regarding the salt formation
step. The disclosed process, described herein, addresses these
challenges and describes protocols that reduce the formation of
Compound II-OH significantly.
[0170] In some embodiments, Compound I is synthesized by a reaction
between Compound II and Compound III. In some embodiments, Compound
II-OH is reacted with a chlorinating reagent to form Compound
II-Cl. In some embodiments, Compound II-Cl reacts with Compound III
to produce Compound I.
[0171] In some embodiments, Compound II-OH is dissolved in a
solvent and a chlorinating reagent is added to yield Compound
II-Cl. In some embodiments, the solvent used include, but are not
limited to, tetrahydrofuran (THF), dimethylformamide (DMF),
diethylether, and methylene chloride (DCM). In one embodiment, the
solvent is methylene chloride.
[0172] Previous process utilized THE as the solvent for the acid
chloride formation with the addition of DMF. It was discovered that
the formation of Compound II-OH could be minimized when DCM is used
as the solvent for the acid chloride formation.
[0173] Prior to the addition of the chlorinating reagent, the
solution containing Compound II-OH is cooled below ambient
temperature. In some embodiments, the solution containing Compound
II-OH is cooled to about 10.degree. C. to about 15.degree. C. In
some embodiments, the chlorinating reagent is added over about 10
minutes to about 30 minutes while the temperature of the solution
was maintained below ambient temperature. In some embodiments, the
mixture is maintained at about 10.degree. C. to about 15.degree. C.
and stirred for about 2 hours to about 4 hours then cooled to about
0.degree. C. or below. In one embodiment, the reaction was stirred
until HPLC analysis indicated .ltoreq.3.0% of Compound II-OH is
present.
[0174] Non-limiting examples of chlorinating reagents include
thionyl chloride, phosphorous trichloride, phosphorus
pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene,
and the like or the combinations thereof. In one embodiment, the
chlorinating reagent is thionyl chloride. In another embodiment,
the chlorinating reagent is used in about 1.0 equiv to about 2.0
equiv with respect to Compound II-OH. In one embodiment, the
chlorinating reagent is used in about 1.0 equivalent to about 1.1
equiv with respect to Compound II-OH. In another embodiment, the
ratio of the chlorinating reagent and the Compound II-OH is about
1:1.
[0175] Ina separate reaction vessel, Compound III is dissolved in a
solvent with abase. To the solution of Compound III and a base, a
solution of Compound II-Cl is slowly added. In some embodiment, the
solvent used for dissolving Compound III can be tetrahydrofuran,
dimethylformamide, diethylether, methylene chloride, and mixtures
thereof. In one embodiment, the solvent is methylene chloride. In
some embodiments, the reaction is cooled to about 0.degree. C.
before the addition of Compound III. In one embodiment, the
reaction is maintained at about 0.degree. C. for about 3 hours to
about 7 hours after the addition of Compound III until HPLC
analysis indicates .ltoreq.0.5% of Compound II-Cl is present. In
another embodiment, Compound III is used in about 1.0 equiv to
about 1.2 equiv with respect to Compound II-OH.
[0176] In some embodiments, the base is used in about 1 equiv to
about 4 equiv. Non-limiting example of base includes alkali
carbonates (potassium carbonate, sodium carbonate, cesium
carbonate, etc), alkali metal hydrogen carbonates (potassium
bicarbonate, sodium bicarbonate, etc), alkaline metal acetates
(potassium acetate, sodium acetate, etc), alkaline metal phosphates
(potassium phosphate, sodium phosphate, etc), alkali metal
fluorides (potassium fluoride, cesium fluoride, etc), alkaline
metal alkoxides (potassium tert-butoxide, sodium tert-butoxide,
etc), alkali metal hydroxides (potassium hydroxide, sodium
hydroxide, etc), and organic bases such as alkyl amines
(triethylamine, diisopropylamine, diisopropylethyl amine, etc)
pyridines (pyridine, dimethylaminopyridine, etc), cyclic amines
(morpholine, 4-methylmorpholine, etc), and the combinations
thereof. In one embodiment, the base is pyridine. In some
embodiments, pyridine reacts with Compound II-Cl to form
pyridine-HCl salt and vigorous agitation may be necessary to
prevent aggregation of the salt.
[0177] Upon the indication of the conversion of Compound II-Cl to
Compound I, the reaction mixture is, in one embodiment, acidified.
In some embodiments, citric acid solution is used to acidify the
reaction mixture containing crude Compound I. In one embodiment,
citric acid is used in about 1.5 equiv to about 2.0 equiv in about
10 parts water with respect to Compound II-OH and added over about
30 minutes to about 1 hour. In one embodiment, a chilled citric
acid aqueous solution is added to a cooled reaction mixture while
maintaining an internal temperature of about 0.degree. C.
[0178] In some embodiments, the volatile solvent is removed to
provide a total volume of about 13 parts. In other embodiments, a
different solvent is added (about 5 parts) to the reduced reaction
mixture, and reduced once again to provide a total volume of about
13 parts. In some embodiments, a polar solvent such as ethyl
acetate is used. In other embodiment, the solvent is removed under
reduced pressure.
[0179] The reduced reaction mixture which consists of a majority of
an acidic aqueous layer, in some embodiments, is extracted with a
polar solvent such as ethyl acetate in about 10 parts. In some
embodiments, the organic layer containing the desired product,
Compound I, is washed with aqueous solutions several times, for
example with a solution of sodium bicarbonate and brine.
[0180] The stability of Compound I during workup procedure was
studied. It was demonstrated that Compound I is not particularly
sensitive to light during workup and the use of clear reaction
vessel or an amber reaction vessel did not display increased
hydrolysis of Compound I to Compound II-OH. Additionally, Compound
I was studied in various pH and temperature during workup
procedures; however, no correlation was discovered for increased
hydrolysis of Compound I to Compound II-OH. Although it is still a
possibility that Compound I can hydrolyze to Compound II-OH during
workup, the amide bond is fairly stable under the workup
conditions.
[0181] Water content in the organic layer resulting from the
extraction workup is found to have an impact on the overall yield
of the salt formation of Compound I (Compound I-MsOH). In some
embodiments, the presence of water during the salt formation
increased the hydrolysis of Compound I back to Compound II-OH, thus
a rigorous drying process is ideal. In some embodiments, the
organic layer, containing Compound I, is dried with 3 .ANG.
powdered molecular sieves. In some embodiments, the resulting
slurry is stirred for about 15 hours to about 30 hours at an
ambient temperature before the molecular sieves are removed by
filtration. The filtered molecular sieves are washed with a polar
solvent such as ethyl acetate. In some embodiments, the residual
water content is determined by titration. In some embodiments, the
drying step using molecular sieves can be repeated until the
residual water is .ltoreq.2.5%.
[0182] Once the organic layer containing Compound I is dried and
determined to be substantially free of water, in some embodiments,
the solvent is removed to give a total volume of about 3 parts. In
some embodiments, the solvent is removed by distillation. In other
embodiment, the solution is assayed by HPLC before or after the
solvent reduction to calculate the amount of Compound I
present.
[0183] Alternatively, in one embodiment, Compound I is synthesized
from Compound II and Compound III using coupling reaction
conditions commonly known in the art, using reagents including but
are not limited to carbodiimides, 1-hydroxybenzotriazole,
hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,
N-hydroxysuccinimide, 1-hydroxy-7-aza-1H-benzotriazole,
2-(1H-Benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium
tetrafluoroborate/hexafluorophosphate,
2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium
hexafluorophosphate, and/or
2-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium
hexafluorophosphate, 2-propanephosphonic acid anhydride, and
1,1'-carbonyldiimidazole.
Preparation of Compound I-MsOH
[0184] To the concentrated crude solution of Compound I, in some
embodiments, a solvent is added in about 4 parts. In one
embodiment, the solvent used is acetonitrile. To the solution
containing Compound I, methane sulfonic acid (MsOH) is added. In
some embodiments, MsOH is added in a single portion. In other
embodiments, MsOH is used in about 0.9 equiv to about 1.5 equiv
with respect to Compound I as determined by the HPLC assay. In one
embodiment, MsOH is used in about 0.97 equiv to about 1.02
equiv.
[0185] In some embodiments, MsOH is washed into solution containing
Compound I and MsOH with additional solvent such as acetonitrile or
ethyl acetate. The reaction mixture is stirred at an ambient
temperature for about 30 minutes to about 1 hour. It was discovered
that excess MsOH had an adverse effect on the formation of Compound
II-OH by hydrolysis of the amide bond of Compound I, therefore an
accurate assay of Compound I is critical to determine the exact
amount of Compound I present and the exact amount of MsOH required
to achieve a 1:1 stoichiometric ratio during salt formation. In one
embodiment, Compound I and MsOH are used in 1:1 ratio to minimize
amide bond hydrolysis.
[0186] In one embodiment, the solvent used in the step of
converting Compound I into Compound I-MsOH, is free of alcohol
solvents. It was discovered that residual levels of alcohol
solvents (e.g., methanol, ethanol, etc.) in the reaction lead to
contamination of Compound I-MsOH with mesylate esters. These
resulting mesylate esters are known mutagens.
[0187] In some embodiments, prior to crystallization, the reaction
mixture was washed with brine and dried using 3 .ANG. molecular
sieves. In some cases, it was determined that slight amount of
water present in the reaction mixture could prevent crystallization
to occur and/or result in lower yield of Compound I-MsOH. Not
wishing to be bound by any theory, the lower yield resulted in
systems with higher water content is due to higher hydrolysis rate
to give Compound II-OH which was found in the mother liquor at a
higher concentration in a study with higher water content.
[0188] To crystalize Compound I-MsOH from the reaction mixture, in
some embodiments, a pure sample of Compound I-MsOH is used as a
seed. The solution, with or without seeding, is in some
embodiments, stirred at an ambient temperature for about 6 hours to
about 10 hours. Additionally, in some embodiments, the solution is
stirred at about 0.degree. C. for about 6 hours to about 10 hours.
The precipitated crystals are, in some embodiments, collected by
filtration. In some embodiments, the crystals are washed with cold
solvent such as ethyl acetate to obtain crude Compound I-MsOH.
[0189] The crude crystals of Compound I-MsOH are, in some
embodiments, further purified using hot recrystallization
technique. In some embodiments, crystals of Compound I-MsOH are
dissolved in solvents (about 10 parts) at an elevated temperature.
In other embodiments, crystals of Compound I-MsOH are dissolved in
acetonitrile at about 70.degree. C. The hot solution of Compound
I-MsOH was slowly cooled to about 50.degree. C. to about 55.degree.
C. over a period of about 1 hour. In some embodiments, the solution
of Compound I-MsOH was seeded with pure sample of Compound I-MsOH
at about 50.degree. C. to about 55.degree. C. The solution, with or
without seeding, is stirred at about 50.degree. C. to about
55.degree. C. for about 4 hours to about 8 hours, in some
embodiments. The hot solution is, in some embodiments, cooled to an
ambient temperature over about 1 hour and stirred at an ambient
temperature for about 6 hours to about 10 hours. In one embodiment,
hot recrystallization of Compound I-MsOH from acetonitrile reduces
contamination, including mesylate esters.
[0190] The precipitated crystals of Compound I-MsOH, in some
embodiments, are collected by filtration. In other embodiments, the
filtered crystals of Compound I-MsOH are washed with acetonitrile.
In one embodiment, the filtered crystals of Compound I-MsOH are
washed with cold acetonitrile. The purity of the crystals is
assayed by titration and HPLC. If necessary, hot recrystallization
can be repeated until the desired purity is obtained. In some
embodiments, the filtered crystals of Compound I-MsOH are dried
under reduced pressure. In other embodiments, the dried crystals
are further pulverized by a powder mill and a jet mill or the
like.
[0191] The study of the Compound I-MsOH crystals under a microscope
revealed that the surface of the crystals became oily with time,
which is identified as a result of hydrolysis on the surface of the
crystals. Acetonitrile was found to be a solvent that Compound
II-OH is more soluble in than Compound I-MsOH. Therefore, upon
recrystallization, it is beneficial to wash the filtered crystals
with acetonitrile. Due to Compound I-MsOH also being soluble in
acetonitrile to some degree, in some embodiments, cold acetonitrile
should be used to wash the crystals, and the volume and the
frequency of the wash should be limited to about twice with about 2
parts volume to about 3 parts volume.
[0192] The hydrolysis of Compound I or Compound I-MsOH is
susceptible in the presence of water or acid. In some embodiments,
the reaction mixture should be substantially free of water prior
and during purification steps of Compound I-MsOH. In other
embodiments, the reaction mixture should be substantially free of
aqueous acid prior and during purification steps of Compound
I-MsOH. In some embodiments, gentle agitation should be maintained
through the salt formation and purification steps of Compound
I-MsOH.
[0193] In some embodiments, Compound III used in the reaction to
obtain Compound I or Compound I-MsOH is optically pure. In which
case, it will result in an optically pure Compound I or optically
pure Compound I-MsOH. In one embodiment, Compound III is
(S)-Compound III. In another embodiment, Compound I-MsOH is
(S)-Compound I-MsOH.
[0194] The disclosed process of the synthesis of Compound II-OH and
its subsequent use in the disclosed process of the synthesis of
Compound I-MsOH, in some embodiments, results in highly pure
Compound I-MsOH that is substantially free of Compounds I-MsOH-A,
I-MsOH-B, I-MsOH-C, I-MsOH-D, I-MsOH-E, I-MsOH-F, I-MsOH-G, II-OH,
III, VI, VII, VIII, IX, and mesylate esters resulting from MsOH. In
some embodiments, Compound I-MsOH, e.g., synthesized by the
disclosed process, disclosed herein will result in >96% purity.
In other embodiments, Compound I-MsOH, e.g., synthesized by the
disclosed process, disclosed herein will result in >97% purity.
In one embodiment, Compound I-MsOH, e.g., synthesized by the
disclosed process, disclosed herein will result in >98% purity.
In another embodiment, Compound I-MsOH, e.g., synthesized by the
disclosed process, disclosed herein will result in >99%
purity.
[0195] The disclosed process of the synthesis of Compound II-OH and
its subsequent use in the disclosed process of the synthesis of
Compound I-MsOH, in some embodiments, results in highly pure
(S)-Compound I-MsOH that is substantially free of (R)-Compound
I-MsOH, R or S versions of (I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-D,
I-MsOH-E, I-MsOH-F, I-MsOH-G), II-OH, III, VI, VII, VIII, IX, and
mesylate esters resulting from MsOH. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
disclosed herein will result in >96% purity. In other
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, disclosed herein will result in >97% purity.
In one embodiment, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, disclosed herein will result in >98% purity.
In another embodiment, (S)-Compound I-MsOH, e.g., synthesized by
the disclosed process, disclosed herein will result in >99%
purity.
[0196] In other embodiments, Compound I-MsOH, e.g., synthesized by
the disclosed process, will contain .ltoreq.0.2% of each impurities
including Compounds I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-F,
I-MsOH-G, VII, VIII, and IX. In other embodiments, Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.1.0%, .ltoreq.0.8%, .ltoreq.0.6%, or .ltoreq.0.4% of each
impurities including I-MsOH-D and Compound II-OH. In other
embodiments, Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.1,500 ppm of Compound III. In another
embodiment, Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.0.3% of each impurities including
Compounds I-MsOH-C, I-MsOH-E, and I-MsOH-F. In some embodiments,
Compound I-MsOH, e.g., synthesized by the disclosed process, will
contain .ltoreq.0.002% (20 ppm) mesylate ester resulting from MsOH.
In some embodiments, Compound I-MsOH contains .ltoreq.0.002% (20
ppm) mesylate ester for a 150 mg dose. In some embodiments,
Compound I-MsOH contains .ltoreq.15 ppm mesylate ester for a 150 mg
dose. In one embodiment, Compound I-MsOH contains .ltoreq.0.001%
(10 ppm) mesylate ester for a 150 mg dose.
[0197] In other embodiments, Compound I-MsOH, e.g., synthesized by
the disclosed process, will contain .ltoreq.0.3% of each impurities
including Compounds I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-F,
I-MsOH-G, VII, VIII, and IX. In other embodiments, Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.0.5% of each impurities including I-MsOH-D and Compound
II-OH. In other embodiments, Compound I-MsOH, e.g., synthesized by
the disclosed process, will contain .ltoreq.1,000 ppm of Compound
III. In another embodiment, Compound I-MsOH, e.g., synthesized by
the disclosed process, will contain .ltoreq.0.15% of each
impurities including Compounds I-MsOH-C, I-MsOH-E, and I-MsOH-F,
VII, VIII, and IX. In some embodiments, Compound I-MsOH, e.g.,
synthesized by the disclosed process, will contain .ltoreq.0.001%
(10 ppm) mesylate ester resulting from MsOH.
[0198] In other embodiments, Compound I-MsOH, e.g., synthesized by
the disclosed process, will contain .ltoreq.0.05% of each
impurities including Compounds I-MsOH-A, I-MsOH-B, I-MsOH-C,
I-MsOH-F, I-MsOH-G, VII, VIII, and IX. In other embodiments,
Compound I-MsOH, e.g., synthesized by the disclosed process, will
contain .ltoreq.0.30% of each impurities including Compound
I-MsOH-D and Compound II-OH. In some embodiments, Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.0.1% of each impurities including I-MsOH-A, I-MsOH-B,
I-MsOH-C, I-MsOH-F, I-MsOH-G, VII, VIII, and IX. In other
embodiments, Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.0.15% of each impurities including
Compound I-MsOH-D and Compound II-OH. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.1.0% of (R)-Compound I-MsOH. In another
embodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.0.5% of (R)-Compound I-MsOH. In one
embodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.0.25% of (R)-Compound I-MsOH. In one
embodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.0.20% of (R)-Compound I-MsOH.
[0199] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.5.0% w/w water
content as measured by U.S. Pharmacopeia (USP) <921>, method
1C. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by
the disclosed process, will contain .ltoreq.2.5% w/w water content
as measured by USP <921>, method 1C. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.2.0% w/w water content as measured by USP
<921>, method 1C. In some embodiments, (S)-Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.1.0% w/w water content as measured by USP <921>,
method 1C.
[0200] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.20% w/w
methanesulfonic acid. In some embodiments, (S)-Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.15% w/w methanesulfonic acid. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.13% w/w methanesulfonic acid. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain between about 5% to about 15% w/w
methanesulfonic acid. In some embodiments, (S)-Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain between
about 11% to about 13% w/w methanesulfonic acid.
[0201] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.500 ppm acetonitrile
as residual solvent. In some embodiments, (S)-Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.425 ppm acetonitrile as residual solvent. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.410 ppm acetonitrile as
residual solvent. In some embodiments, (S)-Compound I-MsOH, e.g.,
synthesized by the disclosed process, will contain .ltoreq.350 ppm
acetonitrile as residual solvent.
[0202] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.7500 ppm ethyl
acetate as residual solvent. In some embodiments, (S)-Compound
I-MsOH, e.g., synthesized by the disclosed process, will contain
.ltoreq.5000 ppm ethyl acetate as residual solvent. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.4000 ppm ethyl acetate as
residual solvent.
[0203] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.300 ppm pyridine as
residual solvent. In some embodiments, (S)-Compound I-MsOH, e.g.,
synthesized by the disclosed process, will contain .ltoreq.200 ppm
pyridine as residual solvent. In some embodiments, (S)-Compound
I-MsOH, e.g., synthesized by the disclosed process, will contain
.ltoreq.100 ppm pyridine as residual solvent.
[0204] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.750 ppm
dichloromethane as residual solvent. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.600 ppm dichloromethane as residual solvent.
In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.500 ppm dichloromethane as
residual solvent.
[0205] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.1.0 ppm elemental
impurities of cadmium as measured by USP <232> and/or
.ltoreq.1.0 ppm lead. In some embodiments, (S)-Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.0.5 ppm elemental impurities of cadmium as measured by USP
<232> and/or .ltoreq.0.5 ppm lead. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.0.25 ppm elemental impurities of cadmium as
measured by USP <232> and/or .ltoreq.0.25 ppm lead.
[0206] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.2.0 ppm elemental
impurities of arsenic as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.1.5 ppm elemental
impurities of arsenic as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.1.0 ppm elemental
impurities of arsenic as measured by USP <232>.
[0207] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.10.0 ppm elemental
impurities of mercury as measured by USP <232> and/or
.ltoreq.10.0 ppm cobalt. In some embodiments, (S)-Compound I-MsOH,
e.g., synthesized by the disclosed process, will contain
.ltoreq.5.0 ppm elemental impurities of mercury as measured by USP
<232> and/or .ltoreq.5.0 ppm cobalt. In some embodiments,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.3.0 ppm elemental impurities of mercury as
measured by USP <232> and/or .ltoreq.2.5 ppm cobalt. In one
embodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.2.0 ppm elemental impurities of
mercury as measured by USP <232>. In one embodiment,
(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,
will contain .ltoreq.2.0 ppm elemental impurities of cobalt as
measured by USP <232>.
[0208] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.20.0 ppm elemental
impurities of vanadium as measured by USP <232> and/or
.ltoreq.20.0 ppm palladium. In some embodiments, (S)-Compound
I-MsOH, e.g., synthesized by the disclosed process, will contain
.ltoreq.10.0 ppm elemental impurities of vanadium as measured by
USP <232> and/or .ltoreq.10.0 ppm palladium. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.5.0 ppm elemental
impurities of vanadium as measured by USP <232> and/or
.ltoreq.5.0 ppm palladium.
[0209] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.30.0 ppm elemental
impurities of nickel as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.20.0 ppm elemental
impurities of nickel as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.10.0 ppm elemental
impurities of nickel as measured by USP <232>.
[0210] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.1500 ppm elemental
impurities of chromium as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.1250 ppm elemental
impurities of chromium as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.1100 ppm elemental
impurities of chromium as measured by USP <232>. In one
embodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.1000 ppm elemental impurities of
chromium as measured by USP <232>.
[0211] In some embodiments, (S)-Compound I-MsOH, e.g., synthesized
by the disclosed process, will contain .ltoreq.500 ppm elemental
impurities of molybdenum as measured by USP <232>. In some
embodiments, (S)-Compound I-MsOH, e.g., synthesized by the
disclosed process, will contain .ltoreq.300 ppm elemental
impurities of molybdenum as measured by USP <232>. In one
embodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosed
process, will contain .ltoreq.250 ppm elemental impurities of
molybdenum as measured by USP <232>.
EXAMPLES
[0212] Unless otherwise noted, the purity of the compounds was
assessed using standard HPLC analysis. For example, a CAPCELL
PAK.RTM. C18 column (Shisedo) with the dimensions of 4.6
cm.times.150 cm, 5 micron was used with a PDA 290 nm detector. The
column temperature was set to 40.degree. C., and the two mobile
phases were A: 100% 0.05M NH.sub.4OAc in water and B: 100%
acetonitrile. The flow rate was set at 1.0 mL/min with the run time
of about 45-60 minutes per sample. The injection volume was 10
.mu.L. In a different system, Clark instrument was used with PDA
293 nm detector. The injection volume was 20 .mu.L and the run time
was 120 minutes per sample.
Example 1: Optimization of Suzuki Coupling with Pd(PPh.sub.3).sub.4
System
[0213] Table 1 describes the optimization efforts for the Suzuki
coupling reaction using Pd(PPh.sub.3).sub.4 catalyst system between
Compound IV and Compound V-OMe. The reaction represented in Table 1
used Compound IV (5 g, 1 equiv), Compound V-OMe (2 equiv), and base
(6.3 equiv) in solvent (ratio v/w with respect to Compound IV) and
heated at reflux. This series of experiments show varying the
reaction conditions did result in some reduction of impurity
Compound VIII using the Pd(PPh.sub.3).sub.4 system, although
stalling or failure to recrystallize product was observed under
most conditions.
TABLE-US-00001 TABLE 1 Base Solvents Exp. # Catalyst (ratio)
Comments 1 Pd(OAc).sub.2/PPh.sub.3 K.sub.3PO.sub.4 3 h: 50%
conversion 2.0/8.0 mol % THF:water 6 h: 75% conversion (25:8)
Compound VIII: 0.25% 2 Pd(PPh.sub.3).sub.4 K.sub.3PO.sub.4 4 h: 65%
conversion 2.0 mol % THF:water Compound VIII: 0.135% (25:8) 3
Pd(OAc).sub.2/PPh.sub.3 K.sub.3PO.sub.4 Grignard refluxed 27 h
2.0/8.0 mol % THF:water 4 h: 64% conversion (25:8) Compound VIII:
0.22% 4 Pd(OAc).sub.2/PPh.sub.3 K.sub.3PO.sub.4 Using 1 equiv.
boronic ester 2.0/8.0 mol % THF:water 8 h: 50% conversion (25:8)
Compound VIII: 0.11% 5 Pd(OAc).sub.2/PPh.sub.3 K.sub.3PO.sub.4 At
45.degree. C. instead of 2.0/8.0 mol % THF:water refluxing 27 h:
(25:8) 100% conversion Compound VIII: 0.15% 6
Pd(OAc).sub.2/PPh.sub.3 K.sub.3PO.sub.4 4 h: 100% conversion
10.0/40.0 mol % THF:water Compound VIII: 0.04% (25:8) Trituration
failed to produce crystals
Example 2: Optimization of Suzuki Coupling with Pd Catalyst
System
[0214] Table 2 outlines the optimization efforts for the Suzuki
coupling reaction using Pd(PPh.sub.3).sub.4 catalyst system between
Compound IV and Compound V-OMe. The reaction represented in Table 2
used Compound IV (5 g, 1 equiv), Compound V-OMe (2 equiv), and base
(6.3 equiv) in solvent (ratio v/w with respect to Compound IV) and
heated at reflux. According to the results from Table 2, the
Pd(OAc).sub.2/P(o-tol).sub.3 system uses significantly less
catalyst, significantly less phosphine ligand and generally always
proceeded to completion within 2 hours with no stalling observed,
even without degassing. The Pd(OAc).sub.2/P(o-tol).sub.3 catalyst
system produced Compound II-OH in increased yield and increased
purity (>99%) when compared to the original Pd(PPh.sub.3).sub.4
catalyst system. Additionally, this series of experiments also show
varying the reaction conditions did not result in significant
reduction of impurity Compound VIII compared with the
Pd(PPh.sub.3).sub.4 systems.
TABLE-US-00002 TABLE 2 Base Solvents Exp. # Catalyst (ratio)
Comments 1 Pd(OAc).sub.2 K.sub.2CO.sub.3 27 h: 17% conversion 10.0
mol % THF:water Compound VIII: 0.15% (25:8) 2
Pd(dba).sub.2/PtBu.sub.3 K.sub.3PO.sub.4 4 h: 100% conversion
2.0/8.0 mol % THF:water Compound VIII: 0.15% (25:8) Trituration
failed to produce crystals 3 Pd(OAc).sub.2/P(o-tol).sub.3
K.sub.2CO.sub.3 2 h: 100% conversion 2.0/8.0 mol % THF:water
Compound VIII: 0.08% (25:8) Compound II-OH.sup.2 > 99% purity 4
Pd(OAc).sub.2/P(o-tol).sub.3 K.sub.2CO.sub.3 1 h: 100% conversion
2.0/8.0 mol % THF:water Compound VIII: 0.06% (25:8) Compound
II-OH.sup.2 > 99% purity 5 Pd(OAc).sub.2/P(o-tol).sub.3
K.sub.2CO.sub.3 100% conversion 1.0/2.0 mol % THF:water Compound
VIII: 0.15% (25:8) Compound II-OH.sup.2 > 99% purity. 6
Pd(OAc).sub.2/P(o-tol).sub.3 K.sub.2CO.sub.3 1.5 h. 100% conversion
0.5/1.0 mol % THF:water Compound VIII: 0.13% (25:8) Compound
II-OH.sup.2 > 99% purity 7 Pd(OAc).sub.2/P(o-tol).sub.3
K.sub.2CO.sub.3 2 h: 100% conversion 0.25/0.5 mol % THF:water
Compound VIII: 0.17%, (25:8) 0.38%.sup.1 Compound II-OH.sup.2 >
99% purity 8 Pd(OAc).sub.2/P(o-tol).sub.3 K.sub.2CO.sub.3 Reaction
was degassed for 0.25/0.5 mol % THF:water 4 h 2 h: 100% conversion
(25:8) Compound VIII: 0.28% Compound II-OH.sup.2 > 99% purity 9
Pd(OAc).sub.2/P(o-tol).sub.3 K.sub.2CO.sub.3 Reaction was not
degassed 0.25/0.5 mol % THF:water 2 h: 100% conversion (25:8)
Compound VIII: 0.29% Compound II-OH.sup.2 > 99% purity
.sup.1Showing results of two different trials. .sup.2Compound II-OH
was triturated.
Example 3: Synthesis of Compound II-OH, with Recrystallization
[0215] Anhydrous tetrahydrofuran (THF, 9 parts) was added to
magnesium (0.185 kg, 2.15 equiv) and the solution was stirred for 1
hour. THF was removed by distillation until the total volume of the
solution was about 3 parts. To that, neat Compound VI (0.775 kg,
0.4 equiv) was added and the solution was heated to about
66.degree. C. for 2 hours. The reaction was cooled to about
55.degree. C. and additional anhydrous THE (5 parts) was added. To
the hot solution, neat Compound VI (1.163 kg, 1.6 equiv) was added
over 1 hour and the mixture was stirred at about 55.degree. C. for
about 4 hours to form the Grignard reagent. After HPLC analysis
indicated less than about 1% of Compound VI was remaining, the
reaction mixture was cooled to about -25.degree. C. To the cooled
reaction mixture, neat trimethoxyborane (0.739 kg, 2.0 equiv) was
added portion-wise over 2 hours. The resulting mixture was stirred
at -25.degree. C. for 1 hour then warmed up to about 20.degree. C.
and stirred for 1 hour to yield Compound V-OMe.
[0216] To the reaction mixture containing Compound V-OMe, a
solution of potassium carbonate (3.06 kg, 6.25 equiv) in water (5.5
parts) was portion-wise added over 1 hour. The biphasic solution
was degassed with nitrogen for 1 hour then palladium acetate (0.002
kg, 0.0025 equiv) and tri-o-tolylphosphine (0.0054 kg, 0.0050
equiv) was added, while degassing continued. Subsequently, Compound
IV (1.200 kg, 1.0 equiv) was added while degassing continued. The
resulting reaction mixture was stirred at or below 65.degree. C.
for 4 hours or until HPLC analysis indicated .ltoreq.2% Compound IV
was remaining. Once the reaction was deemed complete, it was cooled
to an ambient temperature.
[0217] The reaction mixture was acidified using aqueous
hydrochloric acid until the pH was adjusted to about 2.0-3.0. Once
acidified, the layers were separated and the aqueous layer was
extracted with toluene (10 parts). The combined organic layers were
distilled to an approximate volume of 6.5 parts then Celite.RTM.
(0.6 w/w, 0.720 kg) and Draco KBG (0.3 w/w, 0.360 kg, charcoal)
were added and stirred for 3 hours at about 20.degree. C. The
charcoal and Celite.RTM. were removed by filtration and the
filtrate was concentrated under reduced pressure to afford a volume
of about 3 parts.
[0218] To the reduced solution, isopropanol (5 parts) was added and
the mixture was again concentrated to a volume of 3 parts. To the
resulting oil, heptanes (12 parts) were added portion-wise over 1
hour. The resulting suspension was stirred at about 20.degree. C.
for 6 hours and the crystals were collected by filtration.
[0219] The crude crystals collected by the filtration were then
dissolved in ethyl acetate (0.4 parts) and isopropanol (3.6 parts)
at 70.degree. C. The temperature of the solution was reduced by
10.degree. C. every 1 hour until the temperature reached 20.degree.
C. The solution was stirred at 20.degree. C. for 4 hours and the
crystals were collected by filtration and washed with heptanes.
Compound II-OH was dried to yield 0.938 kg of yellow solid (58.5%
yield, 99.42% purity).
[0220] HPLC purity method:
TABLE-US-00003 Column: CAPCELL PAK .RTM. C18, Shisedo, 4.6 .times.
150 cm, 5 micron Detector wavelength: PDA 290 nm Column
temperature: 40.degree. C. Mobile phase: A: 100% 0.05M NH.sub.4OAc
in water B: 100% ACN Flow rate: 1.0 mL/min Run time: 45 minutes.
Injection volume: 10 .mu.L Gradient Table: Time (min) % A % B 0 90
10 5 90 10 8 10 90 10 10 90 11.01 90 10 20 90 10 Compound VI = 8.3
minute Compound V = 2.3-2.6 minutes (three species in the mixture:
Compound V-(OMe)2, Compound V-(OMe)(Ar.sub.1), and Compound
V-(Ar.sub.1)(Ar.sub.2)) Compound IV = 3.0 minute Compound II-OH =
8.3 minute; purity = 99.42%.
Example 4: Synthesis of Compound II-OH, with In Situ Generated
Compound V Versus Crystalline, Isolated Compound V-OH
[0221] To the reaction mixture containing either a) 2.0 equiv of in
situ solution of Compound V-OMe or b) 2.0 equiv solution of
Compound V-OH in water/THF prepared by dissolving isolated and
crystalline Compound V-OH in water/THF, a solution of potassium
carbonate (3.03 g, 6.25 equiv) in water (5.5 parts) was
portion-wise added over 1 hour. The biphasic solution was degassed
with nitrogen for 1 hour then palladium acetate (0.002 g, 0.0025
equiv) and tri-o-tolylphosphine (0.0045 g, 0.0050 equiv) was added,
while degassing continued. Subsequently, Compound IV (1.00 g, 1.0
equiv) was added while degassing continued. The resulting reaction
mixture was stirred at or below 65.degree. C. for 4 hours or until
HPLC analysis indicated .ltoreq.2% Compound IV was remaining. Once
the reaction was deemed complete, it was cooled to an ambient
temperature.
[0222] The reaction mixture was acidified using aqueous
hydrochloric acid until the pH was adjusted to about 2.0-3.0. Once
acidified, the layers were separated and the aqueous layer was
extracted with toluene (10 parts). The combined organic layers were
distilled to an approximate volume of 6.5 parts then Celite.RTM.
(0.6 w/w, 0.600 kg) and Draco KBG (0.3 w/w, 0.300 g, charcoal) were
added and stirred for 3 hours at about 20.degree. C. The charcoal
and Celite.RTM. were removed by filtration and the filtrate was
concentrated under reduced pressure to afford a volume of about 3
parts.
[0223] To the reduced solution, isopropanol (5 parts) was added and
the mixture was again concentrated to a volume of 3 parts. To the
resulting oil, heptanes (12 parts) were added portion-wise over 1
hour. The resulting suspension was stirred at about 20.degree. C.
for 6 hours and the crystals were collected by filtration. Compound
II-OH was dried to yield a yellow solid (Table 3 shows yield,
purity and related substances). The HPLC condition from Example 3
was used to assess the purity represented in Table 3.
TABLE-US-00004 TABLE 3 Crystalline, In situ Generated Isolated
Condition Compound V-OMe Compound V-OH Yield (%) of Compound II-OH
70 67 Product Analysis by HPLC Compound IV-OH (% area) 0.01 0.00
Compound II-OH-A (% area) 0.07 0.00 Compound II-OH-B (% area) 0.05
0.00 Compound II-OH (% area) 99.21 99.71 Compound II-OH-C (% area)
0.16 0.06 Compound VIII (% area) 0.10 0.00
[0224] Table 3 indicates that using crystalline, isolated compound
V-OH in reaction with Compound IV reduced the impurities, namely
Compound IV-OH, Compound II-OH-A, Compound II-OH-B, Compound
II-OH-C, and Compound VIII. In particular, the presence of Compound
IV-OH, Compound II-OH, Compound OH-B, and Compound VIII were
reduced below detection. Further, the presence of Compound II-OH-C
was also significantly reduced from 0.16% to 0.06%.
[0225] Previous synthesis utilized in situ solution of Compound
V-OMe in reaction with Compound IV to prepare Compound II-OH. This
reaction produced impurities of Compound IV-OH, Compound II-OH-A,
Compound II-OH-B, Compound II-OH-C, and/or Compound VIII, which
were very difficult to eliminate and necessitating multiple
recrystallization purifications in order to provide Compound II-OH
that met the impurity specifications. See, e.g., WO 2016/105527,
the contents of this publication are herein incorporated by
reference in their entirety for all intended purposes.
[0226] Thus, by substituting in situ solution of Compound V-OMe
with a solution prepared from a crystalline and isolated Compound
V-OH significantly reduced the purification process for Compound
V-OH. In some embodiment, only one purification step is required
when using crystalline and isolated Compound V-OH in reaction with
Compound IV. In one embodiment, the purity of Compound II-OH is
higher when prepared from crystalline and isolated Compound V-OH in
reaction with Compound IV when compared from the purity of Compound
II-OH prepared from in situ solution of Compound V-OMe in reaction
with Compound IV.
[0227] In one embodiment, Compound II-OH prepared from crystalline,
isolated Compound V-OH has about .ltoreq.0.01% of Compound II-OH-A,
about .ltoreq.0.01% of Compound II-OH-B, and/or about .ltoreq.0.10%
of Compound II-OH-C. In another embodiment, Compound II-OH prepared
from crystalline, isolated Compound V-OH has about .ltoreq.0.01% of
Compound II-OH-A, about .ltoreq.0.01% of Compound II-OH-B, and
about .ltoreq.0.10% of Compound II-OH-C.
Example 5: Compound V-OH and Compound V-3
##STR00013##
[0229] Compound V-3 was formed during prolonged drying of Compound
V-OH at higher temperatures, resulting in loss of water. Compound
V-3 formation was observed when Compound V-OH was subject to drying
to achieve loss on drying (LOD) below about 0.5%. As shown in FIG.
2, Compound V-3 (top spectrum) is characterized by a .sup.1H NMR
doublet in the 8.1-8.2 ppm region whereas Compound V-OH (bottom
spectrum) is characterized by .sup.1H NMR doublet in the 7.8-7.6
ppm region. FIG. 3 shows the aromatic region of the .sup.1H NMR
spectra of FIG. 2. The conversion of Compound V-3 to Compound V-OH
in the presence of water was observed when D.sub.2O is added to the
.sup.1H NMR sample of Compound V-3 (FIG. 2, middle spectrum).
[0230] As demonstrated above, Compound V-3 readily converts to
Compound V-OH under aqueous conditions, thus, in one embodiment,
Compound V-3 and Compound V-OH can be used interchangeably or as a
mixture in the reaction with Compound IV to prepare Compound II-OH.
In one embodiment, when Compound V-3 is used in the reaction with
Compound IV, about one third molar equivalence (compared to
Compound V-OH) is necessary.
Example 6: Synthesis of Compound I-MsOH
[0231] Compound II-OH (34.7 kg, 1.0 equiv) was dissolved in
dichloromethane (5 parts) and cooled to about 10-15.degree. C. Neat
thionyl chloride (10.1 kg, 1.10 equiv) was added portion-wise over
10 minutes and the mixture was stirred at about 10-15.degree. C.
for 3 hours. After HPLC analysis indicated .ltoreq.3% Compound
II-OH was remaining, the reaction mixture was cooled to 0.degree.
C. A solution of (S)-Compound III (21.2 kg, 1.05 equiv) and
pyridine (21.3 kg, 3.5 equiv) in dichloromethane (6 parts) was
separately prepared and cooled to 0.degree. C. To the solution of
(S)-Compound III, the acid chloride solution was slowly added at
0.degree. C. and stirred for 5 hours.
[0232] Upon completion of the reaction as indicated by HPLC
analysis showing Compound II-Cl is 0.5%, a chilled solution of
citric acid (27.7 kg, 1.7 equiv) in water (10 parts) was added over
30 minutes while maintaining an internal temperature of 0.degree.
C. Dichloromethane was removed under reduced pressure to a total
volume of about 13 parts then ethyl acetate (5 parts) was added and
the volume was again reduced under pressure to about 13 parts. The
resulting residue was extracted with ethyl acetate (10 parts) and
the organic layer was washed with aqueous solution of sodium
bicarbonate (41.7 kg, 6.45 equiv) in water (10 parts) and the wash
was repeated. The organic layer is further washed with brine (10
parts).
[0233] To the resulting organic layer was added 3 .ANG. powdered
molecular sieves (100% w/w, 34.8 kg) and the slurry was stirred for
20 hours then filtered. The filter cake was washed with ethyl
acetate (2 parts). The dried organic layer containing Compound I
was assayed by HPLC to determine the amount present. To the
solution, acetonitrile (4 parts) was added then methanesulfonic
acid (6.9 kg, 1.01 equiv) was added in one portion. Ethyl acetate
(1 part) was used to transfer all of the methane sulfonic acid. The
mixture was stirred at 20.degree. C. for about 30 minutes.
[0234] The reaction mixture was then seeded with (S)-Compound
I-MsOH and the mixture was stirred at 20.degree. C. for 8 hours.
The precipitated crystals were collected by filtration and washed
with chilled ethyl acetate (1 part). The crude crystals were
dissolved in acetonitrile (10 parts) at 70.degree. C. and the
solution was cooled to 50-55.degree. C. over 1 hour and seeded with
(S)-Compound I-MsOH. The solution was stirred at 50-55.degree. C.
for 6 hours then cooled to 20.degree. C. over 1 hour then stirred
for 8 hours. The precipitated crystals were collected by filtration
and washed twice with chilled acetonitrile (2.5 parts each). The
crystals were dried to provide 47.72 kg of (S)-Compound I-MsOH as a
bright yellow solid (78% yield, 99.10% purity). The dried crystals
were then pulverized by a powder mill and jet mill to give the
final product composition.
[0235] HPLC Purity Method:
TABLE-US-00005 Column: CAPCELL PAK .RTM. C18, Shisedo, 4.6 .times.
150 cm, 5 micron Detector wavelength: PDA290 nm Column temperature:
40.degree. C. Mobile phase: A: 100% 0.05M NH.sub.4OAc in water B:
100% ACN Flow rate: 1.0 mL/min Run time: 60 minutes Injection
volume: 10 .mu.L Gradient Table: Time (min) % A % B 0 55 45 20 55
45 25 95 5 48 95 5 50 55 45 60 55 45 61 55 45 62 55 45 Compound
II-OH = 18.54 min Compound I/Compound I-MsOH = 26.05
[0236] It should be understood that the above description is only
representative of illustrative embodiments and examples. For the
convenience of the reader, the above description has focused on a
limited number of representative examples of all possible
embodiments, examples that teach the principles of the disclosure.
The description has not attempted to exhaustively enumerate all
possible variations or even combinations of those variations
described. That alternate embodiments may not have been presented
for a specific portion of the disclosure, or that further
undescribed alternate embodiments may be available for a portion,
is not to be considered a disclaimer of those alternate
embodiments. One of ordinary skill will appreciate that many of
those undescribed embodiments, involve differences in technology
and materials rather than differences in the application of the
principles of the disclosure. Accordingly, the disclosure is not
intended to be limited to less than the scope set forth in the
following claims.
INCORPORATION BY REFERENCE
[0237] All references, articles, publications, patents, patent
publications, and patent applications cited herein are incorporated
by reference in their entireties for all purposes. However, mention
of any reference, article, publication, patent, patent publication,
and patent application cited herein is not, and should not be taken
as acknowledgment or any form of suggestion that they constitute
valid prior art or form part of the common general knowledge in any
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