U.S. patent application number 16/407375 was filed with the patent office on 2019-08-29 for processes for preparing tph1 inhibitors.
This patent application is currently assigned to ALTAVANT SCIENCES GmbH. The applicant listed for this patent is ALTAVANT SCIENCES GmbH. Invention is credited to STEPHANE DE LOMBAERT, DANIEL R. GOLDBERG.
Application Number | 20190263815 16/407375 |
Document ID | / |
Family ID | 61163735 |
Filed Date | 2019-08-29 |
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United States Patent
Application |
20190263815 |
Kind Code |
A1 |
DE LOMBAERT; STEPHANE ; et
al. |
August 29, 2019 |
PROCESSES FOR PREPARING TPH1 INHIBITORS
Abstract
The present disclosure is directed to intermediates and salts
thereof useful for the preparation of spirocyclic compounds which
are inhibitors of tryptophan hydroxylase (TPH), particularly
isoform 1 (TPH 1). Processes of preparing the intermediates, salts,
and TPH inhibitors are also provided.
Inventors: |
DE LOMBAERT; STEPHANE;
(Brisbane, CA) ; GOLDBERG; DANIEL R.; (Seattle,
WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALTAVANT SCIENCES GmbH |
Basel |
|
CH |
|
|
Assignee: |
ALTAVANT SCIENCES GmbH
Basel
CH
|
Family ID: |
61163735 |
Appl. No.: |
16/407375 |
Filed: |
May 9, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/IB2017/001594 |
Nov 9, 2017 |
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16407375 |
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62419557 |
Nov 9, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/10
20130101 |
International
Class: |
C07D 471/10 20060101
C07D471/10 |
Claims
1. A process of increasing the amount of an isomeric compound of
Formula I-(S): ##STR00029## wherein R.sup.1 is C.sub.1-6 alkyl and
Pg.sup.1 is an amino protecting group, relative to an amount of an
isomeric compound of Formula I-(R): ##STR00030## in a starting
mixture comprising both isomeric compounds of Formula I-(S) and
Formula I-(R), the process comprising: reacting the starting
mixture with 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, or
a hydrate thereof, in the presence of an aldehyde to form a salt
mixture comprising 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic
acid salts of the isomeric compounds, wherein the salt mixture has
an increased amount of the gulonic acid salt of the isomeric
compound of Formula I-(S) relative to the amount of gulonic acid
salt of the isomeric compound of Formula I-(R) when compared with
the relative amounts of the isomeric compounds of Formulas I-(S)
and I-(R) present in the starting mixture.
2. The process of claim 1, wherein the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, or a hydrate
thereof, is 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid
monohydrate.
3. The process of claim 1, wherein the reacting is carried out with
about 1 molar equivalent of the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, or a hydrate
thereof, with respect to the combined amount of both isomeric
compounds of Formula I-(S) and Formula I-(R) in the starting
mixture.
4. The process of claim 1, wherein the aldehyde is
benzaldehyde.
5. The process of claim 1, wherein the reacting is carried out with
less than 1 molar equivalent of the aldehyde with respect to the
combined amount of both isomeric compounds of Formula I-(S) and
Formula I-(R) in the starting mixture.
6. The process of claim 1, wherein the reacting is carried out with
about 0.01 to about 0.1 molar equivalents of the aldehyde with
respect to the combined amount of both isomeric compounds of
Formula I-(S) and Formula I-(R) in the starting mixture.
7. The process of claim 1, wherein the reacting is carried out at a
temperature of about 30.degree. C. to about 40.degree. C.
8. The process of claim 1, wherein the reacting is carried out in
the presence of an organic solvent.
9. The process of claim 1, wherein the reacting is carried out in
the presence of an ether solvent.
10. The process of claim 1, wherein the reacting is carried out in
the presence of an organic solvent comprising
2-methyltetrahydrofuran.
11. The process of claim 1, wherein the enantiomeric excess of the
gulonic acid salt of the isomeric compound of Formula I-(S) in the
salt mixture is about 75% or greater.
12. The process of claim 1, wherein the enantiomeric excess of the
gulonic acid salt of the isomeric compound of Formula I-(S) in the
salt mixture is about 90% or greater.
13. The process of claim 1, further comprising recrystallizing the
salt mixture to form a purified salt mixture having an increased
amount of the gulonic acid salt of the isomeric compound of Formula
I-(S) relative to the gulonic acid salt of the isomeric compound of
Formula I-(R) when compared with the relative amounts of the
gulonic acid salts of the isomeric compounds prior to the
purification.
14. The process of claim 13, wherein the enantiomeric excess of the
gulonic acid salt of the isomeric compound of Formula I-(S) is
about 90% or greater.
15. The process of claim 13, wherein the enantiomeric excess of the
gulonic acid salt of the isomeric compound of Formula I-(S) is
about 95% or greater.
16. The process of claim 13, further comprising reacting the
purified salt mixture with a base to form a freebased mixture
comprising isomeric compounds having Formula I-(S) and Formula
I-(R): ##STR00031##
17. The process of claim 16, wherein the base is in the form of an
aqueous solution.
18. The process of claim 16, wherein the base is an aqueous
solution of sodium carbonate.
19. The process of claim 16, wherein the reacting of the purified
salt mixture is carried out with a molar excess amount of base with
respect to the combined amount of both gulonic acid salts of the
isomeric compounds of Formula I-(S) and Formula I-(R) in the salt
mixture.
20. The process of claim 16, wherein the reacting of the purified
salt mixture is carried out in the presence of an organic
solvent.
21. The process of claim 16, wherein the reacting of the purified
salt mixture is carried out in the presence of an organic solvent
comprising an ether solvent and a hydrocarbon solvent.
22. The process of claim 16, wherein the reacting of the purified
salt mixture is carried out in the presence of an organic solvent
comprising 2-methyltetrahydrofuran and n-heptane.
23. The process of claim 16, wherein the enantiomeric excess of the
isomeric compound of Formula I-(S) in the freebased mixture is
about 90% or greater.
24. The process of claim 16, wherein the enantiomeric excess of the
isomeric compound of Formula I-(S) in the freebased mixture is
about 95% or greater.
25. The process of claim 1, wherein R.sup.1 is ethyl.
26. The process of claim 1, wherein Pg.sup.1 is
tert-butoxycarbonyl.
27. A mixture of isomeric compounds having Formulas I-(S) and
I-(R): ##STR00032## wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1
is an amino protecting group, and wherein the enantiomeric excess
of the isomeric compound of Formula I-(S) is about 90% or
greater.
28. The mixture of claim 27, wherein the enantiomeric excess of the
isomeric compound of Formula I-(S) is about 95% or greater.
29. The mixture of claim 27, wherein R.sup.1 is ethyl.
30. The mixture of claim 27, wherein Pg.sup.1 is
tert-butoxycarbonyl.
31. A 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S) or Formula I-(R): ##STR00033##
wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group.
32. The salt of claim 31, wherein R.sup.1 is ethyl.
33. The salt of claim 31, wherein Pg.sup.1 is
tert-butoxycarbonyl.
34. The salt of claim 31, which is the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S).
35. A mixture of isomeric compounds having Formulas I-(S) and
I-(R): ##STR00034## wherein the mixture is prepared according to
the process of claim 16, wherein R.sup.1 is C.sub.1-6 alkyl and
Pg.sup.1 is an amino protecting group, and wherein the enantiomeric
excess of the isomeric compound of Formula I-(S) is about 90% or
greater.
36. The mixture of claim 35, wherein the enantiomeric excess of the
isomeric compound of Formula I-(S) is about 95% or greater.
37. The mixture of claim 35, wherein R.sup.1 is ethyl.
38. The mixture of claim 35, wherein Pg.sup.1 is
tert-butoxycarbonyl.
39. A 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S) or Formula I-(R): ##STR00035##
wherein the salt is prepared according to the process of claim 1,
and wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group.
40. The salt of claim 39, wherein R.sup.1 is ethyl.
41. The salt of claim 39, wherein Pg.sup.1 is
tert-butoxycarbonyl.
42. The salt of claim 39, which is the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S).
43. A process of increasing the amount of an isomeric compound of
Formula Ia-(S): ##STR00036## relative to an amount of an isomeric
compound of Formula Ia-(R): ##STR00037## in a starting mixture
comprising both isomeric compounds of Formula Ia-(S) and Formula
Ia-(R), the process comprising: reacting the starting mixture with
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate in
the presence of benzaldehyde to form a salt mixture comprising
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salts of the
isomeric compounds, wherein the salt mixture has an increased
amount of the gulonic acid salt of the isomeric compound of Formula
Ia-(S) relative to the amount of gulonic acid salt of the isomeric
compound of Formula Ia-(R) when compared with the relative amounts
of the isomeric compounds of Formulas Ia-(S) and Ia-(R) present in
the starting mixture; recrystallizing the salt mixture to form a
purified salt mixture having an increased amount of the gulonic
acid salt of the isomeric compound of Formula Ia-(S) relative to
the gulonic acid salt of the isomeric compound of Formula Ia-(R)
when compared with the relative amounts of the gulonic acid salts
of the isomeric compounds prior to the purification; and reacting
the purified salt mixture in the presence of sodium carbonate to
form a freebased mixture comprising isomeric compounds having
Formula Ia-(S) and Formula Ia-(R), wherein the enantiomeric excess
of the isomeric compound of Formula Ia-(S) in the freebased mixture
is about 90% or greater.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
PCT/IB2017/001594, filed Nov. 9, 2017, which claims priority from
U.S. Provisional Application No. 62/419,557, filed Nov. 9, 2016,
both of which are incorporated herein by reference in their
entireties.
BACKGROUND OF THE DISCLOSURE
1. Field of the Invention
[0002] The present disclosure is directed to a process of preparing
intermediates useful for the preparation of spirocyclic compounds
which are inhibitors of tryptophan hydroxylase (TPH), particularly
isoform 1 (TPH1), that are useful in the treatment of diseases or
disorders associated with peripheral serotonin including, for
example, gastrointestinal, cardiovascular, pulmonary, inflammatory,
metabolic, and low bone mass diseases, as well as serotonin
syndrome, and cancer.
2. Description of the Prior Art
[0003] Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter
that modulates central and peripheral functions by acting on
neurons, smooth muscle, and other cell types. 5-HT is involved in
the control and modulation of multiple physiological and
psychological processes. In the central nervous system (CNS), 5-HT
regulates mood, appetite, and other behavioral functions. In the GI
system, 5-HT plays a general prokinetic role and is an important
mediator of sensation (e.g., nausea and satiety) between the GI
tract and the brain. Dysregulation of the peripheral 5-HT signaling
system has been reported to be involved in the etiology of several
conditions such as osteoporosis, cancer, cardiovascular diseases,
diabetes, atherosclerosis, as well as gastrointestinal, pulmonary,
inflammatory, and liver diseases or disorders.
[0004] Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have
been identified. TPH1 is primarily expressed in the pineal gland
and non-neuronal tissues, such as enterochromaffin (EC) cells
located in the gastrointestinal (GI) tract. TPH2 (the dominant form
in the brain) is expressed exclusively in neuronal cells, such as
dorsal raphe or myenteric plexus cells. The peripheral and central
systems involved in 5-HT biosynthesis are isolated, with 5-HT being
unable to cross the blood-brain barrier. Therefore, the
pharmacological effects of 5-HT can be modulated by agents
affecting TPH in the periphery, mainly TPH1 in the gut.
[0005] Recent reports have described the development of new
spirocyclic TPH1 inhibitors useful for selectively reducing
intestinal 5-HT levels as a means for treating and preventing
5-HT-associated diseases (see e.g., U.S. Pat. No. 9,199,994, the
disclosure of which is incorporated herein by reference in its
entirety). The processes of the present disclosure are useful for
preparing TPH1 inhibitors described in U.S. Pat. No. 9,199,994,
such as (S)-ethyl
8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy-
)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
SUMMARY OF THE DISCLOSURE
[0006] The present disclosure provides, inter alia, a process of
increasing the amount of an isomeric compound of Formula I-(S):
##STR00001##
relative to an amount of an isomeric compound of Formula I-(R):
##STR00002##
in a starting mixture comprising both isomeric compounds of Formula
I-(S) and Formula I-(R), the process comprising:
[0007] reacting the starting mixture with
2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, or a hydrate
thereof, in the presence of an aldehyde to form a salt mixture
comprising 2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salts
of the isomeric compounds,
[0008] wherein the salt mixture has an increased amount of the
gulonic acid salt of the isomeric compound of Formula I-(S)
relative to the amount of gulonic acid salt of the isomeric
compound of Formula I-(R) when compared with the relative amounts
of the isomeric compounds of Formulas I-(S) and I-(R) present in
the starting mixture, and wherein constituent variables are defined
herein.
[0009] The present disclosure further provides a mixture of
isomeric compounds having Formulas I-(S) and I-(R), wherein the
enantiomeric excess of the isomeric compound of Formula I-(S) is
about 90% or greater.
[0010] The present disclosure further provides a
2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compounds of Formula I-(S) or Formula I-(R).
[0011] The details of one or more embodiments of the disclosure are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the disclosure will be
apparent from the description and drawings, and from the
claims.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0012] The present application provides, inter alia, a process of
increasing the amount of an isomeric compound of Formula I-(S):
##STR00003##
wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group, relative to an amount of an isomeric compound of
Formula I-(R):
##STR00004##
in a starting mixture comprising both isomeric compounds of Formula
I-(S) and Formula I-(R), the process comprising:
[0013] reacting the starting mixture with
2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, or a hydrate
thereof, in the presence of an aldehyde to form a salt mixture
comprising 2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salts
of the isomeric compounds,
[0014] wherein the salt mixture has an increased amount of the
gulonic acid salt of the isomeric compound of Formula I-(S)
relative to the amount of gulonic acid salt of the isomeric
compound of Formula I-(R) when compared with the relative amounts
of the isomeric compounds of Formulas I-(S) and I-(R) present in
the starting mixture.
[0015] In some embodiments, the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, or a hydrate
thereof, used in the reaction is
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate. In
some embodiments, the reacting is carried out with about 1 molar
equivalent of the 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic
acid, or a hydrate thereof, with respect to the combined amount of
both isomeric compounds of Formula I-(S) and Formula I-(R) in the
starting mixture.
[0016] In some embodiments, the aldehyde used in the reaction is an
aromatic aldehyde such as benzaldehyde. The amount of aldehyde can
be used in a catalytic amount with respect to the combined amount
of both isomeric compounds of Formula I-(S) and Formula I-(R) in
the starting mixture. In some embodiments, the reacting is carried
out with less than 1 molar equivalent of the aldehyde with respect
to the combined amount of both isomeric compounds of Formula I-(S)
and Formula I-(R) in the starting mixture, for example, less than 1
molar equivalent, less than 0.8 molar equivalents, less than 0.6
molar equivalents, less than 0.4 molar equivalents, less than 0.2
molar equivalents, or less than 0.1 molar equivalents. In some
embodiments, the reacting is carried out with about 0.01 to about
0.5 molar equivalents of the aldehyde with respect to the combined
amount of both isomeric compounds of Formula I-(S) and Formula
I-(R) in the starting mixture, for example, about 0.01 to about
0.5, about 0.01 to about 0.4, about 0.01 to about 0.3, about 0.01
to about 0.2, or about 0.01 to about 0.1 molar equivalents. In
further embodiments, the reaction can be carried out, at least at
some point during the reaction, at an elevated temperature. In some
embodiments, the temperature can range from about 35.degree. C. to
about 45.degree. C., about 30.degree. C. to about 40.degree. C.,
about 25.degree. C. to about 35.degree. C., about 20.degree. C. to
about 30.degree. C., or about 15.degree. C. to about 25.degree. C.
A solvent may also be used to carry out the reaction, such as an
organic solvent (e.g. an ether solvent such as
2-methyltetrahydrofuran).
[0017] In some embodiments, the enantiomeric excess of the gulonic
acid salt of the isomeric compound of Formula I-(S) is about 75% or
greater, about 80% or greater, about 85% or greater, about 90% or
greater, about 95% or greater, about 97% or greater, about 98% or
greater, or about 99% or greater.
[0018] In some embodiments, the enantiomeric excess of the gulonic
acid salt of the isomeric compound of Formula I-(S) can range from
about 75% to about 99.9%, about 80% to about 99.9%, about 85% to
about 99.9%, about 90% to about 99.9%, about 95% to about 99.9%,
about 96% to about 99.9%, about 97% to about 99.9%, about 98% to
about 99.9%, about 99% to about 99.9%, or about 99.5% to about
99.9%.
[0019] In some embodiments, the process further comprises purifying
the salt mixture (e.g., via recrystallization) to form a purified
salt mixture having an increased amount of the gulonic acid salt of
the isomeric compound of Formula I-(S) relative to the gulonic acid
salt of the isomeric compound of Formula I-(R) when compared with
the relative amounts of the gulonic acid salts of the isomeric
compounds prior to the purification. The purification can be
carried out in a solvent such as an organic solvent (e.g., an ether
solvent such as 2-methyltetrahydrofuran).
[0020] In some embodiments, the enantiomeric excess of the gulonic
acid salt of the isomeric compound of Formula I-(S) after the
purifying step is about 90% or greater, about 95% or greater, about
96% or greater, about 97% or greater, about 98% or greater, or
about 99% or greater.
[0021] In some embodiments, the enantiomeric excess of the gulonic
acid salt of the isomeric compound of Formula I-(S) after the
purifying step can range from about 90% to about 99.9%, about 95%
to about 99.9%, about 96% to about 99.9%, about 97% to about 99.9%,
about 98% to about 99.9%, about 99% to about 99.9%, or about 99.5%
to about 99.9%.
[0022] In some embodiments, the process further comprises reacting
the purified salt mixture with a base to form a freebased mixture
comprising isomeric compounds having Formula I-(S) and Formula
I-(R):
##STR00005##
[0023] In some embodiments, the base used in the freebasing
reaction is an alkali metal base such as sodium carbonate. The
amount of base used can be in a molar excess with respect to the
combined amount of gulonic acid salts in the salt mixture (e.g.,
greater than 1 molar equivalent with respect to the amount of
gulonic acid salts in the salt mixture), or in any amount to that
is sufficient to convert the gluonic acid salts to freebase
compounds. In some embodiments, the amount of base used in the
freebasing reaction is from about 1.1 to about 100 molar
equivalents, about 1.1 to about 50 molar equivalents, about 1.1 to
about 25 molar equivalents, about 1.1 to about 10 molar
equivalents, or about 1.1 to about 5 molar equivalents with respect
to the amount of gulonic acid salts in the salt mixture. In further
embodiments, the base is provided as an aqueous solution, such as a
10% aqueous solution, a 20% aqueous solution, a 30% aqueous
solution, a 40% aqueous solution, and the like. The freebasing
reaction can further be carried out, at least at some point during
the reaction, at an elevated temperature. In some embodiments, the
temperature can range from about 10.degree. C. to about 30.degree.
C., about 15.degree. C. to about 25.degree. C., or about 15.degree.
C. to about 20.degree. C. A solvent may also be used to carry out
the freebasing reaction, such as an organic solvent comprising an
ether solvent (e.g., a furan such as 2-methyltetrahydrofuran) or
hydrocarbon solvent (e.g., such as n-heptane), or a combination
thereof.
[0024] In some embodiments, the enantiomeric excess of the isomeric
compound of Formula I-(S) in the freebased mixture is about 90% or
greater, about 95% or greater, about 97% or greater, about 98% or
greater, about 99% or greater, or about 99.9% or greater.
[0025] In some embodiments, the enantiomeric excess of the isomeric
compound of Formula I-(S) in the freebased mixture can range from
about 90% to about 99.9%, about 95% to about 99.9%, about 96% to
about 99.9%, about 97% to about 99.9%, about 98% to about 99.9%,
about 99% to about 99.9%, or about 99.5% to about 99.9%.
[0026] As used herein, the term "C.sub.i-j alkyl," employed alone
or in combination with other terms, refers to a saturated
hydrocarbon group that may be straight-chain or branched, having i
to j carbon atoms. In some embodiments, the alkyl group contains
from 1 to 6, 1 to 4, or from 1 to 3 carbon atoms. Examples of alkyl
moieties include, but are not limited to, chemical groups such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl,
n-pentyl, and n-hexyl. In some embodiments, R.sup.1 is ethyl.
[0027] Processes for preparing of the compounds and salts described
herein can involve the protection and deprotection of various
chemical groups (e.g., protection and deprotection of amine groups
with an amino protecting group). The need for protection and
deprotection, and the selection of appropriate protecting groups,
can be readily determined by one skilled in the art. The chemistry
of protecting groups can be found, for example, in Wuts and Greene,
Protective Groups in Organic Synthesis, 4th ed., John Wiley &
Sons: New Jersey. (2007), which is incorporated herein by reference
in its entirety. Adjustments to the protecting groups and formation
and cleavage methods described herein may be adjusted as necessary
in light of the various substituents.
[0028] For example, appropriate Pg.sup.1 protecting groups include,
but are not limited to the protecting groups for amines described
in Wuts and Greene, Protective Groups in Organic Synthesis, 4th
ed., John Wiley & Sons: New Jersey, pages 696-887 (and, in
particular, pages 872-887) (2007), the disclosure of which is
incorporated herein by reference in its entirety. Example amino
protecting groups include, but are not limited to,
benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc),
2-(trimethylsilyl)ethoxycarbonyl (Teoc),
2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc),
tert-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc),
2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl
(Doc), cyclohexyloxycarbonyl (Hoc),
1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl,
2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl,
4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazinyl,
methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or
2-tetrahydropyranyl (THP), tri(C.sub.1-4 alkyl)silyl (e.g.,
tri(isopropyl)silyl), 1,1-diethoxymethyl, or N-pivaloyloxymethyl
(POM). In some embodiments, Pg.sup.1 is tert-butoxycarbonyl.
[0029] In some embodiments, the starting mixture comprising both
isomeric compounds of Formula I-(S) and Formula I-(R) is prepared
according to a process comprising reacting a compound of Formula
II:
##STR00006##
with hydrogen gas in the presence of a hydrogenation catalyst,
wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group. In some embodiments. R.sup.1 is ethyl. In some
embodiments, Pg.sup.1 is tert-butoxycarbonyl.
[0030] As used herein, the term "hydrogenation catalyst" refers to
a metal (e.g., palladium, nickel, or rhodium) catalyst suitable to
catalyze a hydrogenation reaction (i.e., reaction of a compound
with hydrogen gas). Example hydrogenation catalysts include, but
are not limited to, palladium on carbon, Lindlar's catalyst
(palladium deposited on calcium carbonate or barium sulfate), Raney
Ni (e.g., Raney Ni A5000), Wilkinson's catalyst.
HRuCl(PPh.sub.3).sub.3, RhCl(PPh.sub.3).sub.3, [Rh(COD)Cl].sub.2,
[Ir(COD)PMePh.sub.2).sub.2].sup.+,
[Rh(1,5-cyclooctadiene)(PPh.sub.3).sub.2].sup.+, PtO.sub.2 (Adam's
catalyst), palladium on carbon, palladium black, and the like.
Additional examples of hydrogenation catalysts may be found in
Nishimura. Heterogeneous Catalytic Hydrogenation for Organic
Synthesis, Edition 1, Wiley (Apr. 17, 2001) and Chaloner,
Homogeneous Hydrogenation, Edition 1, Springer Netherlands (Dec. 6,
2010), the disclosure of each of which is incorporated by reference
herein in its entirety.
[0031] In some embodiments, the hydrogenation catalyst used in the
reaction is Raney Ni A5000. The hydrogenation catalyst can be used
in a catalytic amount with respect to the amount of the compound of
Formula II used in the reaction. A solvent may also be used to
carry out the hydrogenation reaction, such as an organic solvent
comprising a protic solvent (e.g., ethanol), or an ether solvent
(e.g., a furan solvent such as tetrahydrofuran), or a combination
thereof. In further embodiments, the reaction can be carried out,
at least at some point during the reaction, at an elevated
temperature. In some embodiments, the temperature can range from
about 30.degree. C. to about 45.degree. C., about 30.degree. C. to
about 40.degree. C., or about 35.degree. C. to about 40.degree.
C.
[0032] In some embodiments, the compound of Formula II is prepared
according to a process comprising reacting a compound of Formula
III:
##STR00007##
with a compound of Formula IV:
##STR00008##
in the presence of a base, wherein R.sup.1 is C.sub.1-6 alkyl and
Pg.sup.1 is an amino protecting group. In some embodiments, R.sup.1
is ethyl. In some embodiments, Pg.sup.1 is tert-butoxycarbonyl.
[0033] In some embodiments, the base used in the reaction of the
compounds of Formula III and IV is an amine base such as pyridine,
triethylamine, or N,N-diisopropylethylamine. The amount of base
used can be a molar excess with respect to the amount of the
compound of Formula IV. In some embodiments, the amount of base
used can range from about 1.1 to about 3 molar equivalents, about
1.1 to about 2 molar equivalents, about 1.4 to about 2 molar
equivalents, or about 1.4 to about 1.8 molar equivalents with
respect to 1 molar equivalent of the compound of Formula III. In
some embodiments, the reacting is carried out using about 1 molar
equivalent of the compound of Formula III with respect to 1 molar
equivalent of the compound of Formula IV. In further embodiments,
the reaction can be carried out, at least at some point during the
reaction, at a temperature that is about room temperature or lower.
In some embodiments, the temperature can range from about
-10.degree. C. to about 25.degree. C., about -10.degree. C. to
about 20.degree. C., about 0.degree. C. to about 20.degree. C.,
about 0.degree. C. to about 15.degree. C., or about 10.degree. C.
to about 15.degree. C. A solvent may also be used to carry out the
reaction, such as an organic solvent comprising a hydrocarbon
solvent (e.g., toluene), or an ether solvent (e.g., a furan solvent
such as 2-methyltetrahydrofuran), or a combination thereof.
[0034] In some embodiments, the compound of Formula III is prepared
according to a process comprising reacting a compound of Formula
V:
##STR00009## [0035] with hydroxylamine, or a salt thereof, wherein
R.sup.1 is C.sub.1-6 alkyl. In some embodiments, R.sup.1 is
ethyl.
[0036] In some embodiments, the hydroxylamine is a hydroxylamine
salt, such as hydroxylamine hydrochloride. The amount of the
hydroxylamine, or salt thereof, used can range from about 1.1 to
about 2 molar equivalents, about 1.1 to about 1.8 molar
equivalents, about 1.1 to about 1.6 molar equivalents, or about 1.1
to about 1.4 molar equivalents based on 1 molar equivalent of the
compound of Formula V. In further embodiments, the reaction can be
carried out, at least at some point during the reaction, at a
temperature that is about room temperature or lower. In some
embodiments, the temperature can range from about 10.degree. C. to
about 30.degree. C., about 10.degree. C. to about 25.degree. C., or
about 15.degree. C. to about 25.degree. C. A solvent may also be
used to carry out the reaction, such as a hydrocarbon solvent
(e.g., toluene), or a protic solvent (e.g., water), or a
combination thereof.
[0037] In some embodiments, the compound of Formula IV is prepared
according to a process comprising reacting a compound of Formula
VI:
##STR00010##
with pyrrolidine, wherein Pg.sup.1 is an amino protecting group. In
some embodiments, Pg.sup.1 is tert-butoxycarbonyl.
[0038] The amount of pyrrolidine used can be a molar excess with
respect to the amount of the compound of Formula VI used. In some
embodiments, the amount of pyrrolidine used can range from about
1.1 to about 3 molar equivalents, about 1.1 to about 2 molar
equivalents, or about 1.1 to about 1.8 molar equivalents with
respect to 1 molar equivalent of the compound of Formula VI. A
solvent may also be used to carry out the reaction, such as an
organic solvent (e.g., a hydrocarbon solvent such as toluene). In
further embodiments, the reaction can be carried out, at least at
some point during the reaction, at an elevated temperature. In some
embodiments, the reaction can be carried out at the solvents
boiling temperature.
[0039] In some embodiments, the present application provides a
process of increasing the amount of an isomeric compound of Formula
Ia-(S):
##STR00011##
relative to an amount of an isomeric compound of Formula
Ia-(R):
##STR00012##
in a starting mixture comprising both isomeric compounds of Formula
Ia-(S) and Formula Ia-(R), the process comprising:
[0040] reacting the starting mixture with
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate in
the presence of benzaldehyde to form a salt mixture comprising
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salts of the
isomeric compounds, wherein the salt mixture has an increased
amount of the gulonic acid salt of the isomeric compound of Formula
Ia-(S) relative to the amount of gulonic acid salt of the isomeric
compound of Formula Ia-(R) when compared with the relative amounts
of the isomeric compounds of Formulas Ia-(S) and Ia-(R) present in
the starting mixture;
[0041] recrystallizing the salt mixture to form a purified salt
mixture having an increased amount of the gulonic acid salt of the
isomeric compound of Formula Ia-(S) relative to the gulonic acid
salt of the isomeric compound of Formula Ia-(R) when compared with
the relative amounts of the gulonic acid salts of the isomeric
compounds prior to the purification; and
[0042] reacting the purified salt mixture in the presence of sodium
carbonate to form a freebased mixture comprising isomeric compounds
having Formula Ia-(S) and Formula Ia-(R), wherein the enantiomeric
excess of the isomeric compound of Formula Ia-(S) in the freebased
mixture is greater than about 90%.
[0043] The starting mixture comprising both isomeric compounds of
Formula I-(S) and Formula I-(R) may be prepared according to the
embodiments described above and also, for example, as further
illustrated by Scheme 1.
##STR00013##
[0044] The salt mixture described herein having an increased amount
of the gulonic acid salt of the isomeric compound of Formula I-(S)
relative to the gulonic acid salt of the isomeric compound of
Formula I-(R) (i.e., a salt mixture enriched in the isomeric
compound of Formula I-(S)) may be prepared according to the
embodiments described above and also, for example, as shown below
in Scheme 2.
##STR00014##
wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group.
[0045] As used herein, the term "reacting" is used as known in the
art and generally refers to the bringing together of chemical
reagents in such a manner so as to allow their interaction at the
molecular level to achieve a chemical or physical transformation.
In some embodiments, the reacting involves two reagents, wherein
one or more molar equivalents of second reagent are used with
respect to the first reagent. The reacting steps of the processes
described herein can be conducted for a time and under conditions
suitable for preparing the identified product.
[0046] In some embodiments, preparation of compounds or salts can
involve the addition of acids or bases to affect, for example,
catalysis of a desired reaction or formation of salt forms such as
acid addition salts (e.g. formation of a
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt).
[0047] Example acids can be inorganic or organic acids and include,
but are not limited to, strong and weak acids. Some example acids
include, but are not limited to, hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid,
4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid,
trifluoroacetic acid, nitric acid,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, acetic acid,
propionic acid, butanoic acid, benzoic acid, tartaric acid,
pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid,
nonanoic acid, and decanoic acid.
[0048] Some example bases include, but are not limited to,
carbonates (e.g., sodium carbonate), bicarbonates (e.g., sodium
bicarbonate), hydroxides (e.g., sodium hydroxide, potassium
hydroxide), alkoxides, metal amides, metal hydrides, metal
dialkylamides, and arylamines, wherein; alkoxides include lithium,
sodium and potassium salts of methyl, ethyl and tert-butyl oxides;
metal amides include sodium amide, potassium amide and lithium
amide; metal hydrides include sodium hydride, potassium hydride and
lithium hydride; and metal dialkylamides include lithium, sodium,
and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl,
t-butyl, trimethylsilyl and cyclohexyl substituted amides.
[0049] All compounds, and salts thereof, can be found together with
other substances such as water and solvents (e.g., hydrates and
solvates) or can be isolated.
[0050] As used herein, the term "enriched," refers to an increased
amount of a particular compound or salt (e.g. an (S)-isomeric
compound or salt) in a mixture when compared with the amount of the
compound in the mixture prior to being enriched. In some
embodiments, a mixture may be enriched in the amount of a first
isomeric compound or salt (e.g., an (S)-isomeric compound or salt)
relative to a second isomeric compound or salt (e.g., an
(R)-isomeric compound) when compared with the relative amount of
the isomeric compounds in a starting mixture (e.g., prior to
forming the enriched mixture). For example, a mixture enriched in
an isomeric compound or salt of Formula I-(S) has an increased
amount of the isomeric compound of Formula I-(S) relative isomeric
compound of Formula I-(R) when compared with the relative amounts
of the isomeric compounds of Formulas I-(S) and I-(R) in a starting
mixture (e.g. a racemic mixture of the isomeric compounds of
Formulas I-(S) and I-(R)).
[0051] The reactions of the processes described herein can be
carried out in suitable solvents which can be readily selected by
one of skill in the art of organic synthesis. Suitable solvents can
be substantially nonreactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected. In some embodiments, reactions can
be carried out in the absence of solvent, such as when at least one
of the reagents is a liquid or gas.
[0052] Suitable halogenated solvents include, but are not limited
to, carbon tetrachloride, bromodichloromethane,
dibromochloromethane, bromoform, chloroform, bromochloromethane,
dibromomethane, butyl chloride, dichloromethane,
tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane,
1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane,
1,1,1-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane,
hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene,
chlorobenzene, and fluorobenzene.
[0053] Suitable ether solvents include, but are not limited to,
dimethoxymethane, tetrahydrofuran, 2-methyltetrahydrofuran,
1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol
dimethyl ether, ethylene glycol diethyl ether, diethylene glycol
dimethyl ether (diglyme), diethylene glycol diethyl ether,
triethylene glycol dimethyl ether, anisole, and t-butyl methyl
ether.
[0054] Suitable protic solvents include but are not limited to,
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, and glycerol.
[0055] Suitable aprotic solvents include but are not limited to,
tetrahydrofuran (THF), N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA),
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, and hexamethylphosphoramide.
[0056] Suitable hydrocarbon solvents include, but are not limited
to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane,
methylcyclohexane, n-heptane, ethylbenzene, m-, o-, or p-xylene,
octane, indane, nonane, and naphthalene.
[0057] The reactions of the processes described herein can be
carried out in air or under an inert atmosphere (e.g., nitrogen or
argon atmosphere). Typically, reactions containing reagents or
products that are substantially reactive with air can be carried
out using air-sensitive synthetic techniques that are well known to
the skilled artisan.
[0058] Upon carrying out preparation of compounds and salts
according to the processes described herein, the usual isolation
and purification operations such as concentration, filtration,
extraction, solid-phase extraction, recrystallization,
chromatography, and the like may be used, to isolate the desired
products.
[0059] The reactions of the processes described herein can be
carried out at appropriate temperatures which can be readily
determined by the skilled artisan. Reaction temperatures will
depend on, for example, the melting and boiling points of the
reagents and solvent, if present; the thermodynamics of the
reaction (e.g., vigorously exothermic reactions may need to be
carried out at reduced temperatures); and the kinetics of the
reaction (e.g., a high activation energy barrier may need elevated
temperatures). For example, the expression, "room temperature," as
used herein, is understood in the art and refer generally to a
temperature (e.g. a reaction temperature) that is about the
temperature of the room in which the reaction is carried out, for
example, a temperature from about 20.degree. C. to about 30.degree.
C.
[0060] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatographic methods such as high performance liquid
chromatography (HPLC) or thin layer chromatography (TLC).
Compounds and Salts of the Invention
[0061] The present application further provides a mixture of
isomeric compounds having Formulas I-(S) and I-(R):
##STR00015##
wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group, and wherein the enantiomeric excess of the
isomeric compound of Formula I-(S) is about 90% or greater, about
95% or greater, about 97% or greater, about 98% or greater, about
99% or greater, or about 99.9% or greater. In some embodiments,
R.sup.1 is ethyl. In some embodiments, Pg.sup.1 is
tert-butoxycarbonyl.
[0062] In some embodiments, the enantiomeric excess of the isomeric
compound of Formula I-(S) can range from about 90% to about 99.9%,
about 95% to about 99.9%, about 96% to about 99.9%, about 97% to
about 99.9%, about 98% to about 99.9%, about 99% to about 99.9%, or
about 99.5% to about 99.9%.
[0063] In some embodiments, the mixture of isomeric compounds
having Formulas I-(S) and I-(R) is prepared according to a process
provided herein, wherein the mixture is enriched in the isomeric
compound of Formula I-(S).
[0064] The present application further provides a
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S) or Formula I-(R):
##STR00016##
wherein R.sup.1 is C.sub.1-6 alkyl and Pg.sup.1 is an amino
protecting group. In some embodiments, R.sup.1 is ethyl. In some
embodiments, Pg.sup.1 is tert-butoxycarbonyl.
[0065] In some embodiments, the salt is the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S).
[0066] In some embodiments, the salt is the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(R).
[0067] In some embodiments, the
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt of the
isomeric compound of Formula I-(S) or Formula I-(R) is prepared
according to a process provided herein.
[0068] Compounds and salts of the disclosure can also include
tautomeric forms. Tautomeric forms result from the swapping of a
single bond with an adjacent double bond together with the
concomitant migration of a proton. Tautomeric forms include
prototropic tautomers which are isomeric protonation states having
the same empirical formula and total charge. Example prototropic
tautomers include ketone--enol pairs, amide--imidic acid pairs,
lactam--lactim pairs, amide--imidic acid pairs, enamine--imine
pairs, and annular forms where a proton can occupy two or more
positions of a heterocyclic system, for example, 1H- and
3H-imidazole, 1H-, 2H- and 4H-1, 2, 4-triazole, 1H- and
2H-isoindole, and 1H- and 2H-pyrazole.
[0069] The term "compound," as used herein, is meant to include all
stereoisomers, geometric isomers, tautomers, and isotopes of the
structures depicted. Compounds and salts herein identified by name
or structure as one particular tautomeric form are intended to
include other tautomeric forms unless otherwise specified.
Compounds and salts herein identified by name or structure without
specifying the particular configuration of a stereocenter are meant
to encompass all the possible configurations at the stereocenter.
For example, if a particular stereocenter in a compound of the
disclosure could be R or S, but the name or structure of the
compound does not designate which it is, than the stereocenter can
be either R or S.
[0070] The compounds and salts described herein can be asymmetric
(e.g., having one or more stereocenters). All stereoisomers, such
as enantiomers and diastereoisomers, are intended unless otherwise
indicated. Compounds and salts of the present disclosure that
contain asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Many geometric isomers of
olefins, C.dbd.N double bonds, and the like can also be present in
the compounds or salts described herein, and all such stable
isomers are contemplated in the present disclosure. Cis and trans
geometric isomers of the compounds of the present disclosure may be
isolated as a mixture of isomers or as separated isomeric
forms.
[0071] In some embodiments, the compounds or salts of the
disclosure are substantially isolated. By "substantially isolated"
is meant that the compound is at least partially or substantially
separated from the environment in which it was formed or detected.
Partial separation can include, for example, a composition enriched
in the compounds of the disclosure. Substantial separation can
include compositions containing at least about 50%, at least about
60%, at least about 70%, at least about 80%, at least about 90%, at
least about 95%, at least about 97%, or at least about 99% by
weight of the compounds or salts of the disclosure, or salt
thereof. Methods for isolating compounds and their salts are
routine in the art.
[0072] Compounds and salts of the disclosure can also include all
isotopes of atoms occurring in the intermediates or final
compounds. Isotopes include those atoms having the same atomic
number but different mass numbers. For example, isotopes of
hydrogen include tritium and deuterium.
Synthesis of TPH1 Inhibitors
[0073] The salt mixture enriched in the isomeric compound of
Formula I-(S) described herein may be further reacted, for example,
to prepare intermediates useful for the preparation of compounds
which are TPH1 inhibitors, as shown below in Scheme 3. For example,
the salt mixture enriched in the isomeric compound of Formula I-(S)
is prepared according to one or more embodiments described herein
(Step 1), and the free-base form of the isomeric compound of
Formula I-(S) is subsequently formed (e.g., via reaction with
sodium carbonate) and isolated (Step 2). The free amine of the
isomeric compound of Formula I-(S) can then protected using
standard amine protection conditions as shown in Step 3, for
example, reaction with Pg.sup.2-X in the presence of a base (e.g.,
trimethylamine), wherein Pg.sup.2 is an amino protecting group
(e.g., tert-butoxycarbonyl, carbobenzyloxy, and the like) and X is
halo (e.g., Cl). Selective deprotection of the amino protecting
group Pg.sup.1 (Step 4) forms the desired Intermediate 1, an
intermediate useful in the preparation of compounds which are TPH1
inhibitors.
##STR00017##
[0074] Intermediate 1 may be used in the preparation of
TPH1-inhibiting compounds, for example, as shown below in Scheme 4,
wherein R.sup.1 is C.sub.1-6 alkyl, Pg.sup.2 is an amino protecting
group, and variables W, X, Y, R.sup.2, R.sup.3, R.sup.A, R.sup.E,
R.sup.C, R.sup.D, and Ring A are as defined in U.S. Pat. No.
9,199,994, the disclosure of which is incorporated herein by
reference in its entirety. For example, Intermediate 1 (e.g.,
2-benzyl 3-ethyl (S)-2,8-diazaspiro[4,5]decane-2,3-dicarboxylate)
is added to a solution of compound A in a solvent (e.g., dioxane)
in the presense of a base (e.g., NaHCO.sub.3), and heated to reflux
to provide a compound of formula C. In step 2, the Pg.sup.2 group
(e.g., a carbobenzyloxy (CBZ)) group of formula C is removed (e.g.
via reaction with trimethylsilyl iodide (TMSI), a strong acid, or
transition metal-catalyzed hydrogenation) to form the desired TPH
i-inhibiting compound.
##STR00018##
[0075] Intermediate 1 of Scheme 3 may also be used in the
preparation of TPH1-inhibiting compounds, for example, as shown
below in Scheme 5. For example, Intermediate 1 (e.g., 2-benzyl
3-ethyl (S)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) is added
to a solution of compound A in a solvent (e.g., dioxane) in the
presence of a base (e.g., NaHCO.sub.3), and heated to reflux to
provide a compound of formula B. Subsequent reaction with phenyl
boronic acid under standard aryl-aryl coupling conditions (e.g.,
reaction in the presence of a palladium catalyst such as
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 in the presence of a base such as
KHCO.sub.3) affords compound C. The amino protecting group Pg.sup.2
group (e.g., a carbobenzyloxy (CBZ)) group of formula C is then
removed (e.g., reaction with TMSI) to form the desired
TPH1-inhibiting compound of formula D.
##STR00019##
[0076] As used herein, the term "amino" refers to a group of
formula --NH.sub.2.
[0077] As used herein, the term "halo" refers to a halogen atom
selected from F, Cl, I, and Br. In some embodiments, the halo group
is Cl.
[0078] As used herein, the term "deprotection" refers to conditions
suitable to cleave an amine protecting group. In some embodiments,
deprotection may include cleavage of a protecting group in the
presence of a strong acid, in the presence of a strong base, in the
presence of a reducing agent, or in the presence of an oxidizing
agent. For example, deprotection of an amine protecting group can
be accomplished by methods known in the art for the removal of
particular protecting groups for amines, such as those in Wuts and
Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley
& Sons: New Jersey, pages 696-887 (and, in particular, pages
872-887) (2007), which is incorporated herein by reference in its
entirety. In some embodiments, the deprotecting comprises reacting
the protected compound under acidic conditions (e.g., hydrochloric
acid or trifluoroacetic acid).
[0079] It will be appreciated by one skilled in the art that the
processes described are not the exclusive means by which compounds
and salts provided herein may be synthesized and that a broad
repertoire of synthetic organic reactions is available to be
potentially employed in synthesizing compounds provided herein. The
person skilled in the art knows how to select and implement
appropriate synthetic routes. Suitable synthetic methods of
starting materials, intermediates and products may be identified by
reference to the literature, including reference sources such as:
Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier,
1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal
of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)
Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates
KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et
al. (Ed.) Comprehensive Organic Functional Group Transformations,
(Pergamon Press, 1996) Katritzky et al. (Ed.); Comprehensive
Organic Functional Group Transformations II (Elsevier, 2.sup.nd
Edition, 2004); Katritzkv et al. (Ed.), Comprehensive Heterocyclic
Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive
Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al.,
March's Advanced Organic Chemistry: Reactions, Mechanisms. and
Structure, 6.sup.th Ed. (Wiley, 2007); Trost et al. (Ed.),
Comprehensive Organic Synthesis (Pergamon Press, 1991), the
disclosures of each of which are incorporated by reference herein
in their entireties.
EXAMPLES
[0080] The disclosure will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the disclosure
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters which can be changed or modified
to yield essentially the same results.
[0081] HPLC analysis was performed on an Agilent 1100 machine the
following conditions: Column: Altima C18, 150 mm length, 3.1 mm
diameter 3 .mu.m particle size. Mobile Phase A: 0.1% formic acid in
milli-q water. Mobile Phase B: 0.1% formic acid in
acetonitrile.
[0082] Enantiomeric purity was determined using one of the
following conditions:
[0083] Enantiomeric Purity Method A:
[0084] YMC Chiral Amylose-SA column (250 mm length, 4.6 mm
diameter, 5 .mu.m particle size) on an Agilent 1100 HPLC machine
with n-heptane:isopropanol:ethanol:diethyl amine (80:10:10:0.1,
v:v:v:v %) as the eluent.
[0085] Enantiomeric Purity Method B:
[0086] YMC Chiral NEA [NR30S05-2546WT] (250 mm length, 4.6 mm
diameter, 5 .mu.m particle size) on an Agilent 11 1100 HPLC machine
with 150 mmol/L sodium perchlorate (pH 2.5) in milli-q water and
ethanol as the eluent.
Example 1. 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (Isomeric Mixture)
##STR00020##
[0087] Step 1. ethyl (Z)-3-bromo-2-(hydroxyimino)propanoate
##STR00021##
[0089] A reactor was charged with hydroxylamine.HCl (13.4 kg, 192.8
mol, 1.25 eq), potable water (2.5 vol) and toluene (5 vol). The
mixture was stirred and cooled to about 15.degree. C. ethyl
bromopyruvate (29.9 kg, 153.3 mol, 1.0 eq) and toluene (1.5 vol)
were added and the mixture was stirred for 16-20 hours between
15-25.degree. C. The phases were then separated after settling for
at least 15 minutes. The aqueous layer was removed and the organic
layer was maintained in the reactor. The reactor with subsequently
charged with potable water (0.5 vol) and the resulting mixture was
stirred for at least 15 minutes. The aqueous layer was removed, the
organic layer was maintained in the reactor, and the aqueous
extraction was performed two additional times. The organic layer
was concentrated using vacuum distillation at 35-40.degree. C.
(.about.3.5 vol. removed; 3.6 relative volumes remaining). The
reactor was subsequently charged with n-heptane (3 vol) and the
resulting solution was concentrated using vacuum distillation at
35-40.degree. C. until about 3.6 relative volumes remained.
Additional n-heptane was added (3 vol) and the resulting solution
was concentrated using vacuum distillation at 35-40.degree. C.
until about 3.6 relative volumes remained. The resulting mixture
was then cooled about 10.degree. C. and stirred for about 20-25
minutes. The mixture was filtered and the resulting mother liquor
was removed. The reactor was charged with n-heptane (0.73 vol) and
stirred for at least 5 minutes. The resulting filter cake was
rinsed with n-heptane and dried for at least 5 minutes at ambient
temperature. The rinsing and drying steps were repeated, at which
time the filter cake was dried for between 0.5-2.5 days under
vacuum and nitrogen flow at ambient temperature. HPLC purity: Batch
1: 93.21 area-%. Batch 2: 93.76 area-%. .sup.1H-NMR purity (two
batches): Batch 1: 51.9 wt-%; Batch 2: 93.7 wt-%.
Step 2. tert-butyl
4-(pyrrolidin-1-ylmethylene)piperidine-1-carboxylate
##STR00022##
[0091] The reaction was charged with
N-Boc-piperidine-4-carbaldehyde (18.2 kg, 85.3 mol, 1.0 eq) and
toluene (16 vol), and the mixture was stirred until dissolution of
the N-Boc-piperidine-4-carbaldehyde. Pyrrolidine (10.2 kg, 143.3
mol, 1.6 eq) and additional toluene (0.5 vol) were added, and the
resulting mixture was heated to reflux (-111.degree. C.) to remove
water via azeotropic distillation. The resulting solution was then
concentrated using vacuum distillation between 35-40.degree. C.
until 12.2 relative volumes remained. Additional toluene (6 vol)
was added, and the resulting solution was concentrated between
35-40.degree. C. until 12.2 relative volumes remained. The
resulting mixture was cooled to approximately 20.degree. C. and
used in the next step without further purification. Batch 1: 84.1
area-% tert-butyl
4-(pyrrolidin-1-ylmethylene)piperidine-1-carboxylate; 8.8 area-%
N-Boc-piperidine-4-carbaldehyde; 7.0 area-% pyrrolidine. KF:
<0.1 wt-%. Batch 2: 86.6 area-% tert-butyl
4-(pyrrolidin-1-ylmethylene)piperidine-1-carboxylate; 6.3 area-%
N-Boc-piperidine-4-carbaldehyde; 6.2 area-% pyrrolidine. KF:
<0.1 wt-%.
Step 3. 9-(tert-butyl) 4-ethyl
1-hydroxy-2-oxa-3,9-diazaspiro[5.5]undec-3-ene-4,9-dicarboxylate
##STR00023##
[0093] A first reactor was charged with ethyl
(Z)-3-bromo-2-(hydroxyimino)propanoate (from Example 1, Step 1;
Batch 1: 18.81 kg, 89.6 mol, 1.06 eq; Batch 2: 18.9 kg, 90.0 mol,
1.06 eq) and 2-methyltetrahydrofuran (1.7-1.92 vol) and the
resulting mixture was stirred and cooled to -5.degree. C. In a
second reactor, a solution of tert-butyl
4-(pyrrolidin-1-ylmethylene)piperidine-1-carboxylate in toluene
(from Example 1, Step 2; Batch 1: 22.7 kg, 85.3 mol, 1.00 eq. Batch
2: 22.7 kg, 85.3 mol, 1.00 eq.) was cooled to -5.degree. C. and
N,N'-diisopropylethylamine (Batch 1: 17.4 kg, 134.2 mol, 1.6 eq.
Batch 2:17.5 kg, 135.4 mol, 1.6 eq.) and toluene (0.5 vol) were
added. The solution of (Z)-3-bromo-2-(hydroxyimino)propanoate and
2-methyltetrahydrofuran was then added to the second reactor over
about 1-2 hours while maintaining a temperature below 10.degree. C.
The first reactor was then rinsed with additional
2-methyltetrahydrofuran (0.22 vol) which was added to the second
reactor. Upon complete addition of the
(Z)-3-bromo-2-(hydroxyimino)propanoate solution to the second
reactor, the resulting mixture was heated to about 15.degree. C.
and stirred for about 45 minutes. Aqueous hydrochloric acid
solution (30% HCl prepared from 2.2 eq. HCl and 3.5 vol of potable
water) was added to the reaction mixture (Batch 1: 24.2 kg, 199.1
mol, 2.3 eq; Batch 2: 23.9 kg, 196.7 mol, 2.3 eq.) and the
resulting mixture was heated to 30.degree. C. and stirred for about
45 minutes. The organic and aqueous phases were separated after
allowing settling for at least 15 minutes and the aqueous layer was
removed. The organic phase was washed with potable water (1.0 vol)
and the mixture was stirred for at least 5 minutes. The phases were
separated after allowing settling for at least 10 minutes and the
aqueous phase was removed and further extracted with additional
2-methyltetrahydrofuran (5 vol). The organic layers were combined,
washed with an additional portion of potable water (1 vol), and the
aqueous phase was removed. The resulting combined organic phases
were concentrated using vacuum distillation between 35-40.degree.
C. until about 5.4 relative volumes remained, at which time
n-heptane (3 vol) was added and the resulting mixture was
concentrated at 35-40.degree. C. until about 5.4 relative volumes
remained. Addition of n-heptane and vacuum distillation was
repeated, at which time additional n-heptane (3 vol) was added and
the resulting mixture was cooled to about 20.degree. C. The mixture
was filtered, and the resulting filter cake was washed with
n-heptane (2.57 vol) and toluene (0.14 vol) (2x). The filter cake
was dried, washed with an additional portion of n-heptane (2.57
vol), and stirred. The n-heptane was then removed and the resulting
filter cake was dried under nitrogen for between 18-72 hours at
ambient temperature and used in the next step without further
purification. Batch 1: HPLC purity: 98.37 area-%. .sup.1H-NMR: 91.8
wt %. Batch 2: HPLC purity: 99.52 area-%. .sup.1H-NMR: 90.7 wt
%.
Step 4. 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4,5]decane-3,8-dicarboxylate (Isomeric Mixture)
[0094] A reactor was charged with 9-(tert-butyl) 4-ethyl
1-hydroxy-2-oxa-3,9-diazaspiro[5,5]undec-3-ene-4,9-dicarboxylate
(from Example 1. Step 3, 38.2 kg, 111.8 mol, 1.0 eq), ethanol
(abs., 4 vol) and tetrahydrofuran (4 vol) and the mixture was
stirred. Sponge catalyst A5000 (28.9 kg) was then added and the
reactor was purged several times with vacuum and nitrogen and then
purged with vacuum and hydrogen. The resulting mixture was then
heated to about 30.degree. C. and the reactor was pressurized with
hydrogen to 4.+-.0.5 bar and the mixture was stirred for about
16-22 hours at 30.+-.5.degree. C. under hydrogen. The reactor was
then depressurized and charged with nitrogen. The reactor was then
purged with vacuum and hydrogen, pressurized with hydrogen to
4.+-.0.5 bar, and stirring was continued for about 46 hours at
30.+-.5.degree. C. under hydrogen. The reactor was depressurized
and the reaction mixture was filtered over a dicalite filter and
rinsed with 2-methyltetrahydrofuran. The filtrate was collected,
washed with additional 2-methyltetrahydrofuran, and concentrated
under reduced pressure between 35-40.degree. C. until about 3.75
relative volumes remained. The distillation process was repeated
two additional times at which time the resulting mixture was cooled
to about 20.degree. C. and the resulting product was used without
further purification. HPLC purity: 78.8 area-%.
Example 2A. 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4,5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt (Isomeric
mixture enriched in the (S)-isomer)
##STR00024##
[0096] A reactor was charged with
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate
(32.65 kg, 111.5 mol, 1.0 eq), 2-methyltetrahydrofuran (2 vol), and
benzaldehyde (0.04 vol). Next, a solution of the 8-(tert-butyl)
3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (isomeric
mixture of Example 1) was added with additional
2-methyltetrahydrofuran (1 vol). The resulting mixture was stirred
and heated at 28.degree. C. until a solution was formed. The
solution was then stirred for at least 30 minutes at
40.+-.3.degree. C. The resulting mixture was then cooled to
30.+-.3.degree. C. and stirred for an additional 2 hours. The
mixture was then seeded with 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt (2 g), and
the resulting mixture was stirred for about 14-15 hours at
30.+-.3.degree. C. The reaction mixture was then cooled to about
20.+-.3.degree. C. over 4 hours and then stirred for an additional
15 hours. The mixture was filtered and the filtrate was separated
for further reaction. The resulting filter cake was washed with
2-methyltetrahydrofuran (1 vol, 3x) and dried for 5 minutes between
each addition of 2-methyltetrahydrofuran to afford a mixture of
8-(tert-butyl) 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers enriched
in the 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt. HPLC
purity: 95.67 area-%. Enantiomeric purity of the (S-) isomer; 78.55
area-%. The separated filtrate was separately concentrated between
35-40.degree. C. until 3.5 relative volumes remained and the
mixture was cooled to 27.5.degree. C. The mixture was then seeded
with 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt and stirred
for at least 16 hours at 20.+-.3.degree. C. The resulting mixture
was filtered, the filtrate was removed, and the resulting filter
cake was washed with 2-methyltetrahydrofuran (0.57 vol) and dried
(3x) to afford a second crop of a mixture of 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4.5]decane-3,8-dicarboxylate
2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers enriched
in the 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt. HPLC
purity: 98.29 area-%; Enantiomeric purity of the (S-) isomer
(Method A): 93.60 area-%. Volumes and molar ratios provided are
relative to the isomeric mixture of 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4,5]decane-3,8-dicarboxylate prepared in Example
1.
[0097] The obtained mixture of 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4.5]decane-3,8-dicarboxylate
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers (23.2 kg,
39.5 mol, 1.0 eq) was then added to a reactor with
2-methyltetrahydrofuran (16 vol) and the mixture was heated to
reflux (about 80 (C) until the solids dissolved. The mixture was
then cooled to 40.+-.3.degree. C. over about 2 hours and
crystallization was observed. The mixture was then concentrated
between 35-40.degree. C. until about 9 relative volumes remained.
The mixture was then cooled to 20.+-.3.degree. C. and stirring was
continued for about 2-3 hours. The resulting mixture was filtered
and rinsed with 2-methyltetrahydrofuran (1.4 vol, 2.times. with
drying under nitrogen for 5 minutes between each washing). The
filter cake was then dried under nitrogen for about 14-16 hours to
afford the desired mixture of 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4.5]decane-3,8-dicarboxylate
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers enriched
in the 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt. Batch 1:
HPLC purity: 99.49 area-%; Enantiomeric purity of the (S-) isomer
(Method A): 93.98 area-%. Batch 2: HPLC purity: >99.9 area-%;
Enantiomeric purity of the (S-) isomer (Method A): 95.22 area-%. A
second recrystallization of the 8-(tert-butyl) 3-ethyl
2,8-diazaspiro[4.5]decane-3,8-dicarboxylate
2.3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers was
performed which further enriched the isomeric mixture in the (S-)
isomer. Batch 1: HPLC purity: 99.49 area-%; Enantiomeric purity of
the (S-) isomer (Method A): 99.02 area-%. Batch 2: HPLC purity:
99.95 area-%; Enantiomeric purity of the (S-) isomer (Method A):
99.48 area-%.
Example 2B
[0098] Alternate Preparation of 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt
8-(tert-Butyl) 3-ethyl 2,8-diazaspiro[4,5]decane-3,8-dicarboxylate
(1 g, 3.20 mmol) was dissolved in THF (5 vol, 5 ml) at r.t. The
solution was treated with 1 molar equivalent of
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate and
then the temperature was slowly raised to 40.degree. C. After 20
min, a precipitate started to form at 40.degree. C. at which time,
TBME (5 vol, 5 ml) was added to the mixture after which time, the
reaction was slowly cooled to 5.degree. C. at a rate of 1.degree.
C./min. After this time, the solid formed was filtered and then
washed with cold TBME. The solid was dried in vacuo to provide
8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4,5]decane-3,8-dicarboxylate,
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt (45%,
>99% ee) as a crystalline solid suitable for seeding.
Example 3. 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4,5]decane-3,8-dicarboxylate
##STR00025##
[0100] A reactor was charged with the enriched mixture of
8-(tert-butyl) 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers (Example
2, 23.80 kg, 40.5 mol, 1.0 eq), 2-methyltetrahydrofuran (2 vol),
and n-heptane (8 vol), and the mixture was stirred at
15.+-.3.degree. C. Sodium carbonate (10% solution in water; 125.8
kg) was added over 15 minutes while maintaining the temperature of
the reaction mixture between 15-20.degree. C. and the resulting
mixture was stirred for at least 35 minutes. The phases were
separated and the aqueous phase was removed. To the remaining
organic phase was added additional sodium carbonate (10% solution
in water; 27.4 kg) while maintaining the temperature of the
reaction mixture between 15-20.degree. C. and the resulting mixture
was stirred for at least 35 minutes. The phases were separated, the
aqueous phase was removed, and the organic phase was concentrated
to dryness to afford the title compound. HPLC purity: 97.65 area-%.
Enantiomeric purity of the (S-) isomer (Method A): 98.89 area-%.
Volumes and molar ratios provided are relative to the
8-(tert-butyl) 3-ethyl 2,8-diazaspiro[4,5]decane-3,8-dicarboxylate
2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid isomers prepared
in Example 2A.
Example 4. 2-benzyl 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4,5]decane-2,3,8-tricarboxylate
##STR00026##
[0102] A reactor was charged with 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (Example 3, 12.6
kg, 32.2 mol, 1.0 eq.), sodium carbonate (10% in water, 86.4 kg),
and 2-methyltetrahydrofuran (0.55 rel. vol), and the mixture was
cooled to 0.+-.3.degree. C. A solution of benzyl chloroformate (6.7
kg, 38.76 mol, 1.0 eq) in 2-methyltetrahydrofuran (0.25 vol) was
then added over 40 minutes while maintaining the temperature of the
reaction mixture between -2-2.degree. C. Additional
2-methyltetrahydrofuran (0.25 vol) was used to rinse residual
benzyl chloroformate solution into the reaction mixture, and the
resulting mixture was stirred for 5-10 minutes at 0.+-.3.degree. C.
The mixture was then heated to 30.+-.3.degree. C. and stirred for
an additional 20-30 minutes. The phases were then separated and the
aqueous phase was removed. The organic phase was washed with a
portion of potable water (1 vol) and the mixture was heated to
30.+-.3.degree. C. and stirred for at least 5 minutes. The aqueous
phase was then removed and the remaining organic phase was
concentrated using vacuum distillation between 35-40.degree. until
about 3 relative volumes remained. Absolute ethanol (3 vol) was
then added and the resulting mixture was concentrated using vacuum
distillation between 35-40.degree. until about 3 relative volumes
remained. The addition of ethanol and distillation was performed a
second time to afford the title product. HPLC purity: 65.58 area-%.
The deprotected compound, 2-benzyl 3-ethyl
(S)-2,8-diazaspiro[4,5]decane-2,3-dicarboxylate was also observed.
The combined HPLC purity of the title product and the
BOC-deprotected product was 80.45 area-%.
Example 5. 2-benzyl 3-ethyl
(S)-2,8-diazaspiro[4,5]decane-2,3-dicarboxylate hydrochloride
##STR00027##
[0104] A reactor was charged with absolute ethanol (67 kg, 3.75
vol) and cooled to about 12.5.degree. C. Acetyl chloride (10.0 kg,
6.00 eq) was added over 55 minutes, while maintaining the
temperature of the mixture below 15.degree. C. Ethyl acetate (10.2
kg, 0.5 vol) was added, and the mixture was stirred for 15-25
minutes while increasing the temperature to 17.degree. C. Next, a
solution of 2-benzyl 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate in ethanol
(Example 4, 17.3 kg of 2-benzyl 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate; total solution
of 2-benzyl 8-(tert-butyl) 3-ethyl
(S)-2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate and ethanol: 87
kg) was added over 25 minutes while maintaining the temperature of
the reaction mixture at about 16.degree. C. Additional absolute
ethanol (0.5 vol) was added and the reaction mixture was heated to
30.+-.3.degree. C. and stirred for about 16 hours. The mixture was
then concentrated using vacuum distillation between 35-40.degree.
C. until about 4 relative volumes remained. 2-methyltetrahydrofuran
(3 vol) was added, and the resulting mixture was concentrated using
vacuum distillation between 35-40.degree. C. until about 4 relative
volumes remained. The addition of 2-methyltetrahydrofuran and
distillation was performed three times using 3 vol of
2-methyltetrahydrofuran and a final time using 2 vol of
2-methyltetrahydrofuran. The reaction mixture was then heated to
about 30-35.degree. C. and stirred for about 40 minutes. Additional
2-methyltetrahydrofuran (1.5 vol) was then added while maintaining
the temperature at about 29.degree. C. The mixture was cooled to
25.+-.3.degree. C. over a period of 1 h, then stirred for about 18
hours. The mixture was filtered and the filter cake was washed with
2-methyltetrahydrofuran (1.0 vol) and stirred for at least 5
minutes. The washing was repeated with the filter cake drying for
at least 5 minutes between washes. The filter cake was then dried
under nitrogen flow for about 19 hours at ambient temperature to
afford the title product. HPLC purity: 99.09%/o. Chiral purity
(Method B): 99.85%. Enantiomeric excess of (S-) isomer (Method B);
.gtoreq.98%.
[0105] A second crop of the title compound was prepared by
combining the filtrates and wash solvents and concentrated to about
35 L followed by addition of 35 L of methyl tert-butyl ether (MTBE)
over 45 minutes. The mixture was then stirred for 1 hour at
25.degree. C. and filtered. The resulting filter cake was washed
with additional MTBE and dried for 17 hours to afford a second crop
of the title product. HPLC purity: 98.56%. Chiral purity (Method
B): 99.27%. Enantiomeric excess of the (S-) isomer (Method B):
.gtoreq.98%.
Example 6. (S)-ethyl
8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy-
)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate
##STR00028##
[0107] The title compound was prepared from 2-benzyl 3-ethyl
(S)-2,8-diazaspiro[4,5]decane-2,3-dicarboxylate hydrochloride
(Example 5) according to the procedures shown in Scheme 5 and in
U.S. Pat. No. 9,199,994, the disclosure of which is incorporated
herein by reference in its entirety. The title compound has been
found to be an inhibitor of TPH1 according to one or more assays
described in U.S. Pat. No. 9,199,994.
[0108] Various modifications of the disclosure, in addition to
those described herein, will be apparent to those skilled in the
art from the foregoing description. Such modifications are also
intended to fall within the scope of the appended claims. Each
reference, including all patent, patent applications, and
publications, cited in the present application is incorporated
herein by reference in its entirety.
* * * * *