U.S. patent application number 16/567471 was filed with the patent office on 2020-01-02 for methods of synthesizing a prostacyclin analog.
This patent application is currently assigned to CAYMAN CHEMICAL COMPANY INCORPORATED. The applicant listed for this patent is CAYMAN CHEMICAL COMPANY INCORPORATED. Invention is credited to Gilles CHAMBOURNIER, Gregory William ENDRES, Victor FEDIJ, Kirk William Hering, Thomas James KRELL, II, Hussien Mahmoud MAHMOUD.
Application Number | 20200002261 16/567471 |
Document ID | / |
Family ID | 49881039 |
Filed Date | 2020-01-02 |
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United States Patent
Application |
20200002261 |
Kind Code |
A1 |
Hering; Kirk William ; et
al. |
January 2, 2020 |
METHODS OF SYNTHESIZING A PROSTACYCLIN ANALOG
Abstract
The present invention provides processes for preparing a
prostacyclin analogue of Formula I ##STR00001## or a
pharmaceutically acceptable salt thereof, wherein R.sup.10 is a
linear or branched C.sub.1-6 alkyl. The processes of the present
invention comprise steps that generate improved yields and fewer
byproducts than traditional methods. The processes of the present
invention employ reagents (e.g., the oxidizing reagent) that are
less toxic that those used in the traditional methods (e.g., oxalyl
chloride). Many of the processes of the present invention generate
intermediates with improved e.e. and chemical purity; thereby
eliminating the need of additional chromatography steps. And, the
processes of the present invention are scalable to generate
commercial quantities of the final compound.
Inventors: |
Hering; Kirk William;
(Canton, MI) ; CHAMBOURNIER; Gilles; (Ann Arbor,
MI) ; ENDRES; Gregory William; (Saline, MI) ;
FEDIJ; Victor; (Ypsilanti, MI) ; KRELL, II; Thomas
James; (Ypsilanti, MI) ; MAHMOUD; Hussien
Mahmoud; (Ann Arbor, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CAYMAN CHEMICAL COMPANY INCORPORATED |
Ann Arbor |
MI |
US |
|
|
Assignee: |
CAYMAN CHEMICAL COMPANY
INCORPORATED
Ann Arbor
MI
|
Family ID: |
49881039 |
Appl. No.: |
16/567471 |
Filed: |
September 11, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15874093 |
Jan 18, 2018 |
10450257 |
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16567471 |
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15583457 |
May 1, 2017 |
9908834 |
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15874093 |
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14650234 |
Jun 5, 2015 |
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PCT/US2013/073474 |
Dec 6, 2013 |
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15583457 |
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61777882 |
Mar 12, 2013 |
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61734672 |
Dec 7, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/12 20180101; C07C
205/57 20130101; C07F 7/1804 20130101; C07C 2603/14 20170501; C07C
51/412 20130101; C07C 41/44 20130101; C07D 301/32 20130101; C07C
51/09 20130101; C07C 41/26 20130101; C07C 51/347 20130101; C07D
303/16 20130101; C07D 303/14 20130101; C07D 301/00 20130101; C07D
317/22 20130101; C07C 45/29 20130101; C07C 51/09 20130101; C07C
59/72 20130101; C07C 51/412 20130101; C07C 59/72 20130101; C07C
41/26 20130101; C07C 43/23 20130101 |
International
Class: |
C07C 51/347 20060101
C07C051/347; C07D 301/32 20060101 C07D301/32; C07C 41/44 20060101
C07C041/44; C07C 45/29 20060101 C07C045/29; C07D 301/00 20060101
C07D301/00; C07F 7/18 20060101 C07F007/18; C07D 317/22 20060101
C07D317/22; C07D 303/14 20060101 C07D303/14; C07D 303/16 20060101
C07D303/16; C07C 205/57 20060101 C07C205/57; C07C 41/26 20060101
C07C041/26; C07C 51/09 20060101 C07C051/09; C07C 51/41 20060101
C07C051/41 |
Claims
1. A compound of Formula 13 ##STR00316## wherein R.sup.1 is
C.sub.1-6 alkyl and each R.sup.2 is independently selected from
C.sub.1-6 alkyl or phenyl.
2. A method of generating a compound of Formula 13 ##STR00317##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.2 is
independently selected from C.sub.1-6 alkyl or phenyl, comprising
x) reacting a compound of Formula 12 with
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole
in the presence of an organic solvent comprising THF and toluene to
generate a compound of Formula 13 ##STR00318## wherein the compound
of Formula 13 has a chemical purity of about 97% or greater and a
d.e. of about 97% or greater.
3. A method of generating a compound of Formula I ##STR00319## or a
pharmaceutically acceptable salt thereof, comprising the steps of:
xv) reacting a compound of Formula 21a with n-butyllithium in the
presence of an organic solvent and a transition metal catalyst to
generate a compound of Formula 22a ##STR00320## wherein R.sup.1 is
C.sub.1-6 alkyl; and xvi) converting the compound of Formula 22a to
the compound of Formula I.
4. The method of claim 3, wherein the transition metal catalyst
comprises a compound or complex either of which comprises copper
having a +1 oxidation state.
5. The method of claim 4, wherein the transition metal catalyst
comprises CuI.
6. The method of claim 3, further comprising the steps of: xvii)
reacting a compound of Formula 19a with triisopropylbenzenesulfonyl
chloride under basic conditions to generate a compound of Formula
20a; and ##STR00321## xviii) reacting the compound of Formula 20a
with methanol under basic conditions to generate the compound of
Formula 21a.
7. The method of claim 6, further comprising the steps of xix)
reacting a compound of Formula 16a with a reducing agent to
generate a compound of Formula 17a; ##STR00322## xx) reacting the
compound of Formula 17a with TBDPSCl under basic conditions to
generate a compound of Formula 18a; and ##STR00323## xxi)
selectively deprotecting the compound of Formula 18a to generate
the compound of Formula 19a.
8. The method of claim 7, further comprising the steps of: xii)
hydrogenating a compound of Formula 15a ##STR00324## in the
presence of an alcohol, optionally substituted THF, or any
combination thereof to generate the compound of Formula 16a.
9. The method of claim 8, further comprising the steps of: x)
reacting a compound of Formula 12a with a reducing agent to
generate a compound of Formula 13a; and ##STR00325## xiv)
converting the compound of Formula 13a to the compound of Formula
15a.
10. The method of claim 9, further comprising the step of: v)
reacting a compound of Formula 11a ##STR00326## with an oxidizing
agent to generate the compound of Formula 12a, wherein the
oxidizing agent comprises MnO.sub.2.
11. The method of claim 9, further comprising the steps of: i)
reacting a compound of Formula 9 with an oxidizing agent to
generate a compound of Formula 10; and ##STR00327## ii) reacting
the compound of Formula 10 with a compound of Formula 5a in the
presence of a base and an organic solvent to generate a compound of
Formula 11a ##STR00328##
12. The method of claim 11, further comprising the steps of: iv)
refluxing the compound of Formula 1a in the presence of methanol to
generate a compound of Formula 1 having an e.e. of greater than
about 98%; ##STR00329## v) reacting the compound of Formula 1 with
TBSCl under basic conditions to generate the compound of Formula
2a; ##STR00330## vi) reacting the compound of Formula 2a with
1-TMS-1-propyne to generate the compound of Formula 3a; and
##STR00331## vii) converting the compound of Formula 3a to the
compound of Formula 5a.
13. The method of claim 12, further comprising the steps of: xxii)
reacting a compound of Formula 7a with a 3-haloprop-1-ene in the
presence of a base and an organic solvent to generate a compound of
Formula 8a; and ##STR00332## xxiii) deprotecting the compound of
Formula 8a to generate the compound of Formula 9.
14. A method of generating a compound of Formula I ##STR00333## or
a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent to
generate a compound of Formula 10; ##STR00334## ii) reacting the
compound of Formula 10 with a compound of Formula 5a in the
presence of a base and an organic solvent to generate a compound of
Formula 11a; ##STR00335## iv) refluxing the compound of Formula 1a
in the presence of methanol to generate a compound of Formula 1
having an e.e. of greater than about 98%; ##STR00336## v) reacting
the compound of Formula 1 with TBSCl under basic conditions to
generate the compound of Formula 2a; ##STR00337## vi) reacting the
compound of Formula 2a with 1-TMS-1-propyne to generate the
compound of Formula 3a; ##STR00338## vii) converting the compound
of Formula 3a to the compound of Formula 5a; viii) reacting a
compound of Formula 11a with an oxidizing agent to generate the
compound of Formula 12a, wherein the oxidizing agent comprises
MnO.sub.2; ##STR00339## x) reacting a compound of Formula 12a with
a reducing agent to generate a compound of Formula 13a;
##STR00340## xiv) converting the compound of Formula 13a to the
compound of Formula 15a; ##STR00341## xii) hydrogenating a compound
of Formula 15a in the presence of methanol, ethanol, THF,
2-methyl-THF, or any combination thereof to generate the compound
of Formula 16a; ##STR00342## xix) reacting a compound of Formula
16a with a reducing agent to generate a compound of Formula 17a;
xx) reacting the compound of Formula 17a with TDPSCl under basic
conditions to generate a compound of Formula 18a; ##STR00343## xxi)
selectively deprotecting the compound of Formula 18a to generate
the compound of Formula 19a; ##STR00344## xvii) reacting a compound
of Formula 19a with triisopropylbenzenesulfonyl chloride under
basic conditions to generate a compound of Formula 20a;
##STR00345## xviii) reacting the compound of Formula 20a with
methanol under basic conditions to generate the compound of Formula
21a; ##STR00346## xv) reacting a compound of Formula 21a with
n-butyllithium in the presence of an organic solvent and a
transition metal catalyst to generate a compound of Formula 22a;
and ##STR00347## xvi) converting the compound of Formula 22a to the
compound of Formula I.
15. The method of claim 14, further comprising the step of: xxiv)
reacting the compound of Formula I with diethanolamine in the
presence of an organic solvent to generate the diethanolamine salt
of the compound of Formula I.
16. A compound of Formula 1a ##STR00348##
17. A method of purifying a compound of Formula 1 comprising:
##STR00349## xxx) reacting a compound of Formula 1 with a
derivatizing reagent to generate a precipitate that is
substantially insoluble in dichloromethane or mixtures thereof;
xxxi) collecting the precipitate and refluxing the precipitate in a
solvent comprising an alcohol to generate the compound of Formula 1
having a chemical purity of about 98% or greater and an e.e. of
about 98% or greater; wherein the method excludes the use of any
column chromatography.
18. The method of claim 17, wherein the derivatizing reagent
comprises 3,5-dinitrobenzoyl chloride and the alcohol comprises
methanol.
19. A method of purifying a compound of Formula 9 comprising:
##STR00350## xl) reacting a compound of Formula 9, wherein R.sup.1
is C.sub.1-6 alkyl, with 3,5-dinitrobenzoyl chloride to generate a
precipitate comprising a compound of Formula 9A; and ##STR00351##
xli) collecting the precipitate and treating the precipitate with a
base in the presence of an alcohol to generate the compound of
Formula 9 having a chemical purity of about 95% or greater; wherein
the method excludes the use of any column chromatography.
20. The method of claim 19, further comprising the step: xlii)
recrystallizing the precipitate of step xli).
21. A compound of Formula 9a ##STR00352## wherein R.sup.1 is
C.sub.1-6 alkyl.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 15/874,093, filed Jan. 18, 2018, which is a
divisional application of U.S. patent application Ser. No.
15/583,457, filed May 1, 2017, now U.S. Pat. No. 9,908,834, issued
Mar. 6, 2018, which is a divisional application of U.S. patent
application Ser. No. 14/650,234, filed Jun. 5, 2015, which is a 35
U.S.C. .sctn. 371 United States National Phase Application of PCT
Application Serial No. PCT/US2013/073474, filed Dec. 6, 2013, which
claims the benefit of and priority to U.S. provisional application
Ser. No. 61/734,672, filed Dec. 7, 2012, and 61/777,882, filed Mar.
12, 2013. The entire contents of the aforementioned disclosures are
incorporated herein by reference in their entireties.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to processes and intermediates
for the preparation of prostacyclin analog that are useful for
treating hypertension and other diseases.
BACKGROUND
[0003] Prostacyclin derivatives and analogs are useful
pharmaceutical compounds possessing activities such as platelet
aggregation inhibition, gastric secretion reduction, lesion
inhibition, vasodilation, and bronchodilation.
[0004] Treprostinil is a synthetic prostacyclin derivative
currently marketed as an active pharmaceutical ingredient (API) for
its ability to inhibit pulmonary arterial hypertension under the
trade name Remodulin.RTM.. Treprostinil was first described in U.S.
Pat. No. 4,306,075.
[0005] Prostacyclin derivatives are traditionally synthesized using
a variety of methods that are described in J. Org. Chem. 2004, 69,
1890-1902, Drug of the Future, 2001, 26(4), 364-374, U.S. Pat. Nos.
4,306,075; 6,441,245; 6,528,688; 6,700,025; 6,765,117; 6,809,223
and U.S. patent application publication nos. 2009/0163738,
2011/0319641 A1, as well as Canadian patent application publication
no. 2710726 A1. The entire teachings of these documents are
incorporated herein by reference in their entireties. Also
disclosed in these publications are processes and intermediates
useful for the preparation of Treprostinil. However, the methods of
these teachings suffer from one or more problems including toxic
oxidation reagents, reduced yields, elevated levels of impurities,
poor scalability, and numerous chromatography steps to purify
intermediates and final products. Thus, there remains a need for
safe, scalable, efficient, and economical processes for the
preparation of Treprostinil.
SUMMARY OF THE INVENTION
[0006] As described herein, the present invention provides
processes for preparing a prostacyclin analogue of Formula IA:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein R.sup.10 is
a linear or branched C.sub.1-6 alkyl.
[0007] The processes of the present invention comprise steps that
generate improved yields and fewer byproducts than traditional
methods. The processes of the present invention employ reagents
(e.g., the oxidizing reagent) that are less toxic that those used
in the traditional methods (e.g., oxalyl chloride). Many of the
processes of the present invention do not require additional
chromatography for purification of intermediates and generate
intermediates with improved e.e. and chemical purity. And, the
processes of the present invention are scalable to generate
commercial quantities of the final compound.
[0008] One aspect of the present invention provides a method of
generating a compound of Formula I
##STR00003##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent in
the presence of an organic solvent to generate a compound of
Formula 10
##STR00004##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2 or Dess-Martin periodinane; ii) reacting the
compound of Formula 10 with a compound of Formula 5 in the presence
of a base and an organic solvent to generate a compound of Formula
11, wherein each R.sup.2 is independently selected from C.sub.1-6
alkyl or phenyl; and
##STR00005##
iii) converting the compound of Formula 11 to the compound of
Formula I.
[0009] In some implementations, the organic solvent of step i)
comprises a halogenated organic solvent. For example, the organic
solvent of step i) comprises dichloromethane, chloroform, or any
combination thereof.
[0010] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the base of step ii) comprises
sec-butyllithium.
[0011] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0012] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00006##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00007##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00008##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0013] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00009##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: viii) reacting a compound of Formula 11 with an oxidizing agent
in the presence of an organic solvent to generate a compound of
Formula 12
##STR00010##
wherein R.sup.1 is C.sub.1-6 alkyl, each R.sup.2 is independently
selected from C.sub.1-6 alkyl or phenyl, and the oxidizing agent
comprises MnO.sub.2; and ix) converting the compound of Formula 12
to the compound of Formula I.
[0014] In some implementations, each of the --OSi(R.sup.2).sub.3
groups in the compounds of Formulae 11 and 12 is independently
selected from
##STR00011##
[0015] In some implementations, the organic solvent of step viii)
comprises a halogenated organic solvent. In some examples, the
halogenated organic solvent of step viii) comprises
dichloromethane, chloroform, or any combination thereof.
[0016] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent in the presence of an
organic solvent to generate a compound of Formula 10
##STR00012##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2 or Dess-Martin periodinane; and ii) reacting
the compound of Formula 10 with a compound of Formula 5
##STR00013##
in the presence of a base and an organic solvent to generate a
compound of Formula 11.
[0017] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the alkyllithium reagent of step
ii) comprises sec-butyllithium.
[0018] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0019] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00014##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: x) reacting a compound of Formula 12 with a reducing agent in
the presence of an organic solvent to generate a compound of
Formula 13
##STR00015##
wherein the organic solvent comprises THF, R.sup.1 is C.sub.1-6
alkyl, and each R.sup.2 is independently C.sub.1-6 alkyl or phenyl;
and xi) converting the compound of Formula 13 to the compound of
Formula I.
[0020] In some implementations, the reducing agent of step x)
comprises a chiral borane compound. And, in some examples, the
chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,
(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any
combination thereof.
[0021] In some implementations, the organic solvent of step x)
further comprises toluene.
[0022] Some methods further comprise the step of: viii) reacting a
compound of Formula 11 with an oxidizing agent to generate the
compound of Formula 12, wherein the oxidizing agent comprises
MnO.sub.2
##STR00016##
[0023] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00017##
ii) reacting the compound of Formula 10 with a compound of Formula
5 in the presence of a base and an organic solvent to generate a
compound of Formula 11
##STR00018##
[0024] In some implementations, the oxidizing agent comprises
MnO.sub.2 or Dess-Martin periodinane.
[0025] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the alkyllithium reagent of step
ii) comprises sec-butyllithium.
[0026] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0027] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00019##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00020##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00021##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0028] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00022##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xii) hydrogenating a compound of Formula 15 in the presence of
an organic solvent (e.g., an alcohol (e.g., methanol, ethanol, or
any combination thereof), an optionally substituted THF (e.g.,
2-methyl-THF or THF), EtOAc, or any combination thereof) to
generate the compound of Formula 16
##STR00023##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.2 is
independently selected from C.sub.1-6 alkyl or phenyl; and xiii)
converting the compound of Formula 16 to the compound of Formula
I.
[0029] Some methods further comprise the steps of: x) reacting a
compound of Formula 12 with a reducing agent in the presence of an
organic solvent to generate a compound of Formula 13
##STR00024##
wherein the organic solvent comprises THF; and xiv) converting the
compound of Formula 13 to the compound of Formula 15.
[0030] In some implementations, the reducing agent of step x)
comprises a chiral borane compound. And, in some examples, the
chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,
(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any
combination thereof.
[0031] Some methods further comprise the steps of: viii) reacting a
compound of Formula 11 with an oxidizing agent to generate the
compound of Formula 12, wherein the oxidizing agent comprises
MnO.sub.2
##STR00025##
[0032] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00026##
ii) reacting the compound of Formula 10 with a compound of Formula
5 in the presence of a base and an organic solvent to generate a
compound of Formula 11
##STR00027##
[0033] In some implementations, the oxidizing agent of step i)
comprises MnO.sub.2 or Dess-Martin periodinane.
[0034] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the alkyllithium reagent of step
ii) comprises sec-butyllithium.
[0035] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0036] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00028##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00029##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00030##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0037] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00031##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xv) reacting a compound of Formula 21 with n-butyllithium in
the presence of an organic solvent and a transition metal catalyst
to generate a compound of Formula 22
##STR00032##
wherein R.sup.3 is C.sub.1-6 alkyl or phenyl; and xvi) converting
the compound of Formula 22 to the compound of Formula I.
[0038] In some implementations, the transition metal catalyst of
step xv) comprises a compound or complex either of which comprises
Cu having a +1 oxidation state. For example, the transition metal
catalyst of step xv) comprises CuX, wherein X is selected from
halogen, acetate, benzoate, cyanide, hydroxide, nitrate, or any
combination thereof. In other examples, the transition metal
catalyst of step xv) comprises CuI.
[0039] Some methods further comprise the steps of: xvii) reacting a
compound of Formula 19 with R.sup.4-substituted benzenesulfonyl
chloride under basic conditions to generate a compound of Formula
20, wherein each R.sup.4 is independently selected from --H or
C.sub.1-3 alkyl; and
##STR00033##
xviii) reacting the compound of Formula 20 with methanol under
basic conditions to generate the compound of Formula 21.
[0040] Some methods further comprise the steps of: xix) reacting a
compound of Formula 16 with a reducing agent to generate a compound
of Formula 17;
##STR00034##
xx) reacting the compound of Formula 17 with Si(R.sup.3).sub.3Cl
under basic conditions to generate a compound of Formula 18;
and
##STR00035##
xxi) selectively deprotecting the compound of Formula 18 to
generate the compound of Formula 19.
[0041] Some methods further comprise the steps of: xii)
hydrogenating a compound of Formula 15
##STR00036##
in the presence of an organic solvent (e.g., an alcohol (e.g.,
methanol, ethanol, or any combination thereof), an optionally
substituted THF (e.g., 2-methyl-THF or THF), EtOAc, or any
combination thereof) to generate the compound of Formula 16.
[0042] In some implementations, the hydrogenation of the compound
of Formula 15 also occurs in the presence of a base (e.g.,
potassium carbonate or potassium bicarbonate).
[0043] Some methods further comprise the steps of: x) reacting a
compound of Formula 12 with a reducing agent to generate a compound
of Formula 13; and
##STR00037##
xiv) converting the compound of Formula 13 to the compound of
Formula 15.
[0044] In some implementations, the reducing agent of step x)
comprises a chiral borane compound. And, in some examples, the
chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,
(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any
combination thereof.
[0045] Some methods further comprise the step of: viii) reacting a
compound of Formula 11
##STR00038##
with an oxidizing agent to generate the compound of Formula 12,
wherein the oxidizing agent comprises MnO.sub.2.
[0046] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00039##
ii) reacting the compound of Formula 10 with a compound of Formula
5 in the presence of a base and an organic solvent to generate a
compound of Formula 11
##STR00040##
[0047] In some implementations, the oxidizing agent of step i)
comprises MnO.sub.2 or Dess-Martin periodinane.
[0048] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the alkyllithium reagent of step
ii) comprises sec-butyllithium.
[0049] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0050] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having greater than about 99% e.e.;
##STR00041##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00042##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00043##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0051] Some methods further comprise the steps of: xxii) reacting a
compound of Formula 7 with a 3-haloprop-1-ene in the presence of a
base and an organic solvent to generate a compound of Formula 8;
and
##STR00044##
xxiii) deprotecting the compound of Formula 8 to generate the
compound of Formula 9.
[0052] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00045##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xxii) reacting a compound of Formula 7, wherein R.sup.1 is
C.sub.1-6 alkyl and each R.sup.2 is independently selected from
C.sub.1-6 alkyl or phenyl, with a 3-haloprop-1-ene in the presence
of a base and an organic solvent to generate a compound of Formula
8;
##STR00046##
xxiii) deprotecting the compound of Formula 8 to generate the
compound of Formula 9, and
##STR00047##
xxiv) converting the compound of Formula 9 to the compound of
Formula I, wherein the base of step xxii) comprises sec-butyl
lithium.
[0053] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00048##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent in
the presence of an organic solvent to generate a compound of
Formula 10
##STR00049##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2 or Dess-Martin periodinane; ii) reacting the
compound of Formula 10 with a compound of Formula 5a in the
presence of a base and an organic solvent to generate a compound of
Formula 11a; and
##STR00050##
iii) converting the compound of Formula 11a to the compound of
Formula I.
[0054] In some implementations, the organic solvent of step i)
comprises a halogenated organic solvent. For example, the organic
solvent of step i) comprises dichloromethane, chloroform, or any
combination thereof.
[0055] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the base of step ii) comprises
sec-butyllithium.
[0056] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0057] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00051##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00052##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00053##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0058] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00054##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: viii) reacting a compound of Formula 11a with an oxidizing
agent in the presence of an organic solvent to generate a compound
of Formula 12a
##STR00055##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2; and ix) converting the compound of Formula 12a
to the compound of Formula I.
[0059] In some implementations, the organic solvent of step viii)
comprises a halogenated organic solvent. For example, the
halogenated organic solvent of step viii) comprises
dichloromethane, chloroform, or any combination thereof.
[0060] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent in the presence of an
organic solvent to generate a compound of Formula 10
##STR00056##
wherein the oxidizing agent comprises MnO.sub.2 or Dess-Martin
periodinane; and ii) reacting the compound of Formula 10 with a
compound of Formula 5a
##STR00057##
in the presence of a base and an organic solvent to generate a
compound of Formula 11a.
[0061] In some implementations, the organic solvent of step i)
comprises a halogenated organic solvent. For example, the organic
solvent of step i) comprises dichloromethane, chloroform, or any
combination thereof.
[0062] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the base of step ii) comprises
sec-butyllithium.
[0063] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0064] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00058##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: x) reacting a compound of Formula 12a with a reducing agent in
the presence of an organic solvent to generate a compound of
Formula 13a
##STR00059##
wherein the organic solvent comprises THF, R.sup.1 is C.sub.1-6
alkyl, and each R.sup.2 is independently selected from C.sub.1-6
alkyl or phenyl; and xi) converting the compound of Formula 13 to
the compound of Formula I.
[0065] In some implementations, the reducing agent of step x)
comprises a chiral borane compound. And, in some examples, the
chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,
(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any
combination thereof.
[0066] In some implementations, the organic solvent of step x)
comprises THF.
[0067] In some implementations, the organic solvent of step x)
further comprises toluene.
[0068] Some methods further comprise the step of: viii) reacting a
compound of Formula 11a with an oxidizing agent to generate the
compound of Formula 12a, wherein the oxidizing agent comprises
MnO.sub.2
##STR00060##
[0069] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00061##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a
##STR00062##
[0070] In some implementations, the oxidizing agent of step i)
comprises MnO.sub.2 or Dess-Martin periodinane.
[0071] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the alkyllithium reagent of step
ii) comprises sec-butyllithium.
[0072] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0073] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00063##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00064##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00065##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0074] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00066##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xii) hydrogenating a compound of Formula 15a in the presence of
an organic solvent (e.g., an alcohol (e.g., methanol, ethanol, or
any combination thereof), an optionally substituted THF (e.g.,
2-methyl-THF or THF), EtOAc, or any combination thereof) to
generate the compound of Formula 16a
##STR00067##
wherein R.sup.1 is C.sub.1-6 alkyl; and xiii) converting the
compound of Formula 16a to the compound of Formula I.
[0075] In some implementations, the hydrogenation of the compound
of Formula 15a also occurs in the presence of a base (e.g.,
potassium carbonate or potassium bicarbonate).
[0076] Some methods further comprise the steps of: x) reacting a
compound of Formula 12a with a reducing agent in the presence of an
organic solvent to generate a compound of Formula 13a
##STR00068##
wherein the organic solvent comprises THF; and xiv) converting the
compound of Formula 13a to the compound of Formula 15a.
[0077] Some methods further comprise the steps of: viii) reacting a
compound of Formula 11a with an oxidizing agent to generate the
compound of Formula 12a, wherein the oxidizing agent comprises
MnO.sub.2
##STR00069##
[0078] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00070##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a
##STR00071##
[0079] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00072##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00073##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00074##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0080] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00075##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xv) reacting a compound of Formula 21a with n-butyllithium in
the presence of an organic solvent and a transition metal catalyst
to generate a compound of Formula 22a
##STR00076##
wherein R.sup.1 is C.sub.1-6 alkyl; and xvi) converting the
compound of Formula 22a to the compound of Formula I.
[0081] In some implementations, the transition metal catalyst of
step xv) comprises a compound or complex either of which comprises
Cu having a +1 oxidation state. For example, the transition metal
catalyst of step xv) comprises CuX, wherein X is selected from
halogen, acetate, benzoate, cyanide, hydroxide, nitrate, or any
combination thereof. In other examples, the transition metal
catalyst of step xv) comprises CuI.
[0082] Some methods further comprise the steps of: xvii) reacting a
compound of Formula 19a with triisopropylbenzenesulfonyl chloride
under basic conditions to generate a compound of Formula 20a;
and
##STR00077##
xviii) reacting the compound of Formula 20a with methanol under
basic conditions to generate the compound of Formula 21a.
[0083] Some methods further comprise the steps of: xix) reacting a
compound of Formula 16a with a reducing agent to generate a
compound of Formula 17a;
##STR00078##
xx) reacting the compound of Formula 17a with TBDPSCl under basic
conditions to generate a compound of Formula 18a; and
##STR00079##
xxi) selectively deprotecting the compound of Formula 18a to
generate the compound of Formula 19a.
[0084] Some methods further comprise the step of: xii)
hydrogenating a compound of Formula 15a
##STR00080##
in the presence of an organic solvent (e.g., an alcohol (e.g.,
methanol, ethanol, or any combination thereof), an optionally
substituted THF (e.g., 2-methyl-THF or THF), EtOAc, or any
combination thereof) to generate the compound of Formula 16a.
[0085] In some implementations, the organic solvent of step xii) is
anhydrous (e.g., anhydrous methanol or anhydrous THF).
[0086] In some implementations, the hydrogenation of the compound
of Formula 15a occurs in the presence of a base (e.g., potassium
carbonate or potassium bicarbonate).
[0087] Some methods further comprise the steps of: x) reacting a
compound of Formula 12a with a reducing agent to generate a
compound of Formula 13a; and
##STR00081##
xiv) converting the compound of Formula 13a to the compound of
Formula 15a.
[0088] Some methods further comprise the step of: viii) reacting a
compound of Formula 11a
##STR00082##
with an oxidizing agent to generate the compound of Formula 12a,
wherein the oxidizing agent comprises MnO.sub.2.
[0089] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00083##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a
##STR00084##
[0090] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00085##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00086##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00087##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0091] Some methods further comprise the steps of: xxii) reacting a
compound of Formula 7a with a 3-haloprop-1-ene in the presence of a
base and an organic solvent to generate a compound of Formula 8a;
and
##STR00088##
xxiii) deprotecting the compound of Formula 8a to generate the
compound of Formula 9.
[0092] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00089##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent to
generate a compound of Formula 10;
##STR00090##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a;
##STR00091##
iv) refluxing the compound of Formula 1a in the presence of
methanol to generate a compound of Formula 1 having an e.e. of
greater than about 98%;
##STR00092##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00093##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a;
##STR00094##
vii) converting the compound of Formula 3a to the compound of
Formula 5a; viii) reacting a compound of Formula 11a with an
oxidizing agent to generate the compound of Formula 12a, wherein
the oxidizing agent comprises MnO.sub.2;
##STR00095##
x) reacting a compound of Formula 12a with a reducing agent to
generate a compound of Formula 13a;
##STR00096##
xiv) converting the compound of Formula 13a to the compound of
Formula 15a;
##STR00097##
xii) hydrogenating a compound of Formula 15a in the presence of an
organic solvent (e.g., an alcohol (e.g., methanol, ethanol, or any
combination thereof), an optionally substituted THF (e.g.,
2-methyl-THF or THF), EtOAc, or any combination thereof) to
generate the compound of Formula 16a;
##STR00098##
xix) reacting a compound of Formula 16a with a reducing agent to
generate a compound of Formula 17a; xx) reacting the compound of
Formula 17a with TDPSCl under basic conditions to generate a
compound of Formula 18a;
##STR00099##
xxi) selectively deprotecting the compound of Formula 18a to
generate the compound of Formula 19a;
##STR00100##
xvii) reacting a compound of Formula 19a with
triisopropylbenzenesulfonyl chloride under basic conditions to
generate a compound of Formula 20a;
##STR00101##
xviii) reacting the compound of Formula 20a with methanol under
basic conditions to generate the compound of Formula 21a;
##STR00102##
xv) reacting a compound of Formula 21a with n-butyllithium in the
presence of an organic solvent and a transition metal catalyst to
generate a compound of Formula 22a; and
##STR00103##
xvi) converting the compound of Formula 22a to the compound of
Formula I.
[0093] Some methods further comprise the step of: xxiv) reacting
the compound of Formula I with diethanolamine in the presence of an
organic solvent to generate the diethanolamine salt of the compound
of Formula I.
[0094] Another aspect of the present invention provides a compound
of Formula 21
##STR00104##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.3 is
independently C.sub.1-6 alkyl or phenyl.
[0095] In some embodiments, R.sup.1 is methyl, ethyl, propyl,
iso-propyl, butyl, sec-butyl, or tert-butyl.
[0096] In other embodiments, the --OSi(R.sup.3).sub.3 group is
selected from
##STR00105##
[0097] In some embodiments, R.sup.1 is methyl and the
--OSi(R.sup.3).sub.3 group is
##STR00106##
[0098] Another aspect of the present invention provides a compound
of Formula 1a
##STR00107##
[0099] Another aspect of the present invention provides a method of
purifying a compound of Formula 1
##STR00108##
comprising the steps of: xxx) reacting a compound of Formula 1 with
a derivatizing reagent to generate a precipitate that is
substantially insoluble in dichloromethane or mixtures thereof
(e.g., a mixture of dichloromethane and an alkane (e.g., heptane));
xxxi) collecting the precipitate and refluxing the precipitate in a
solvent comprising an alcohol to generate the compound of Formula 1
having a chemical purity of about 98% or greater and an e.e. of
about 98% or greater; wherein the method excludes the use of any
column chromatography.
[0100] In some implementations, the derivatizing reagent comprises
3,5-dinitrobenzoyl chloride and the alcohol comprises methanol.
[0101] Another aspect of the present invention provides a method of
purifying a compound of Formula 9
##STR00109##
comprising the steps of: xl) reacting a compound of Formula 9,
wherein R.sup.1 is C.sub.1-6 alkyl, with 3,5-dinitrobenzoyl
chloride to generate a precipitate comprising a compound of Formula
9A; and
##STR00110##
xli) collecting the precipitate and treating the precipitate with a
base in the presence of an alcohol to generate the compound of
Formula 9 having a chemical purity of about 95% or greater (e.g.,
about 98% or greater, or from about 95% to about 99.9%); wherein
the method excludes the use of any column chromatography.
[0102] Some methods further comprise the step of: xlii)
recrystallizing the precipitate of step xli).
[0103] Another aspect of the present invention provides a method of
generating a compound of Formula 5
##STR00111##
wherein each of R.sup.2 is independently selected from a C.sub.1-6
alkyl or phenyl, comprising the steps of: iv) refluxing the
compound of Formula 1a in the presence of methanol to generate a
compound of Formula 1 having an e.e. of greater than about 98%;
##STR00112##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3,
wherein each R.sup.2 is independently selected from C.sub.1-6 alkyl
or phenyl, under basic conditions to generate the compound of
Formula 2;
##STR00113##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3;
##STR00114##
l) deprotecting the compound Formula 3 under basic condition to
generate a compound of Formula 4, wherein each of R.sup.4 and
R.sup.5 are H or --OSi(R.sup.2).sub.3; and
##STR00115##
li) reacting the compound of Formula 4 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 5,
wherein the compound of Formula 5 has a chemical purity of about
98% or greater and an e.e. of about 98% or greater (e.g., from
about 99% to about 99.99%).
[0104] Another aspect of the present invention provides a method of
generating a compound of Formula 13
##STR00116##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.2 is
independently selected from C.sub.1-6 alkyl or phenyl, comprising
the step of: x) reacting a compound of Formula 12 with
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole
in the presence of an organic solvent comprising THF and toluene to
generate a compound of Formula 13
##STR00117##
wherein the compound of Formula 13 has a chemical purity of about
97% or greater and a d.e. of about 97% or greater.
DETAILED DESCRIPTION OF THE INVENTION
[0105] The present invention provides a method of generating a
compound of Formula I
##STR00118##
or a pharmaceutically acceptable salt thereof.
[0106] The present invention also provides novel intermediates that
are useful for the synthesis of the compound of Formula I.
I. DEFINITIONS
[0107] As used herein, the following definitions shall apply unless
otherwise indicated.
[0108] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed.
Additionally, general principles of organic chemistry are described
in "Organic Chemistry", Thomas Sorrell, University Science Books,
Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed.,
Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York:
2001, the entire contents of which are hereby incorporated by
reference.
[0109] As used herein, the term "Treprostinil" refers to
(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3
S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid having the
chemical structure, illustrated below, of the compound of Formula
I
##STR00119##
[0110] Treprostinil is a synthetic analog of prostacyclin
(PGI.sub.2) that is indicated for the treatment of pulmonary
arterial hypertension and other diseases in patients. Treprostinil
is formulated into a variety of dosage forms including forms suited
for i.v. infusion and inhalation.
[0111] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention.
[0112] As used herein, the term "hydroxyl" or "hydroxy" refers to
an --OH moiety.
[0113] As used herein the term "aliphatic" encompasses the terms
alkyl, alkenyl, alkynyl, each of which being optionally substituted
as set forth below.
[0114] As used herein, an "alkyl" group refers to a saturated
aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or
1-4) carbon atoms. An alkyl group can be straight or branched.
Examples of alkyl groups include, but are not limited to, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be
substituted (i.e., optionally substituted) with one or more
substituents such as halo, phospho, cycloaliphatic [e.g.,
cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g.,
heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy,
aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,
(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl],
nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino,
arylcarbonylamino, aralkyl carbonylamino,
(heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,
aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino],
sulfonyl [e.g., aliphatic-SO.sub.2--], sulfinyl, sulfanyl, sulfoxy,
urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,
cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy,
aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or
hydroxy. Without limitation, some examples of substituted alkyls
include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and
alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl,
acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such
as (alkyl-SO.sub.2-amino)alkyl), aminoalkyl, amidoalkyl,
(cycloaliphatic)alkyl, or haloalkyl.
[0115] As used herein, an "alkenyl" group refers to an aliphatic
carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon
atoms and at least one double bond. Like an alkyl group, an alkenyl
group can be straight or branched. Examples of an alkenyl group
include, but are not limited to allyl, 1- or 2-isopropenyl,
2-butenyl, and 2-hexenyl. An alkenyl group can be optionally
substituted with one or more substituents such as halo, phospho,
cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],
heterocycloaliphatic [e.g., heterocycloalkyl or
heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl,
acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or
(heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g.,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkyl
carbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,
aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or
aliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO.sub.2--,
cycloaliphatic-SO.sub.2--, or aryl-SO.sub.2--], sulfinyl, sulfanyl,
sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy,
carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl,
alkylcarbonyloxy, or hydroxy. Without limitation, some examples of
substituted alkenyls include cyanoalkenyl, alkoxyalkenyl,
acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
(sulfonylamino)alkenyl (such as (alkyl-SO.sub.2-amino)alkenyl),
aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or
haloalkenyl.
[0116] As used herein, an "alkynyl" group refers to an aliphatic
carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon
atoms and has at least one triple bond. An alkynyl group can be
straight or branched. Examples of an alkynyl group include, but are
not limited to, propargyl and butynyl. An alkynyl group can be
optionally substituted with one or more substituents such as aroyl,
heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,
heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy,
sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or
cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or
cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO.sub.2--,
aliphaticamino-SO.sub.2--, or cycloaliphatic-SO.sub.2--], amido
[e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
cycloalkylcarbonyl amino, arylaminocarbonyl, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonyl amino,
(cycloalkylalkyl)carbonylamino, heteroaralkyl carbonyl amino,
heteroarylcarbonylamino or heteroarylaminocarbonyl], urea,
thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy,
cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,
(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino
[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or
(heteroaryl)alkoxy.
[0117] As used herein, an "amido" encompasses both "aminocarbonyl"
and "carbonylamino". These terms when used alone or in connection
with another group refer to an amido group such as
--N(R.sup.X)--C(O)--R.sup.Y or --C(O)--N(R.sup.X).sub.2, when used
terminally, and --C(O)--N(R.sup.X)-- or --N(R.sup.X)--C(O)-- when
used internally, wherein R.sup.X and R.sup.Y can be aliphatic,
cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl
or heteroaraliphatic. Examples of amido groups include alkylamido
(such as alkylcarbonylamino or alkylaminocarbonyl),
(heterocycloaliphatic)amido, (heteroaralkyl)amido,
(heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido,
aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
[0118] As used herein, an "amino" group refers to --NR.sup.XR.sup.Y
wherein each of R.sup.X and R.sup.Y is independently hydrogen,
aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl,
araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic,
heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl,
(aliphatic)carbonyl, (cycloaliphatic)carbonyl,
((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,
(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or
(heteroaraliphatic)carbonyl, each of which being defined herein and
being optionally substituted. Examples of amino groups include
alkylamino, dialkylamino, or arylamino. When the term "amino" is
not the terminal group (e.g., alkylcarbonylamino), it is
represented by --NR.sup.X--, where R.sup.X has the same meaning as
defined above.
[0119] As used herein, an "aryl" group used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers
to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl,
naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic
(e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl,
anthracenyl) ring systems in which the monocyclic ring system is
aromatic or at least one of the rings in a bicyclic or tricyclic
ring system is aromatic. The bicyclic and tricyclic groups include
benzofused 2-3 membered carbocyclic rings. For example, a
benzofused group includes phenyl fused with two or more C.sub.4-8
carbocyclic moieties. An aryl is optionally substituted with one or
more substituents including aliphatic [e.g., alkyl, alkenyl, or
alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl;
heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy;
aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy;
aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring
of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido;
acyl [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl;
((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO.sub.2--
or amino-SO.sub.2--]; sulfinyl [e.g., aliphatic-S(O)-- or
cycloaliphatic-S(O)--]; sulfanyl [e.g., aliphatic-S--]; cyano;
halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl;
sulfamide; or carbamoyl. Alternatively, an aryl can be
unsubstituted.
[0120] Non-limiting examples of substituted aryls include haloaryl
[e.g., mono-, di (such as p, m-dihaloaryl), and (trihalo)aryl];
(carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl
[e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl,
(alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and
(((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];
(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,
(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,
((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl;
(nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl;
((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl;
(cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl;
alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl;
p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or
(m-(heterocycloaliphatic)-o-(alkyl))aryl.
[0121] As used herein, an "araliphatic" such as an "aralkyl" group
refers to an aliphatic group (e.g., a C.sub.1-4 alkyl group) that
is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl"
are defined herein. An example of an araliphatic such as an aralkyl
group is benzyl.
[0122] As used herein, an "aralkyl" group refers to an alkyl group
(e.g., a C.sub.1-4 alkyl group) that is substituted with an aryl
group. Both "alkyl" and "aryl" have been defined above. An example
of an aralkyl group is benzyl. An aralkyl is optionally substituted
with one or more substituents such as aliphatic [e.g., alkyl,
alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or
haloalkyl such as trifluoromethyl], cycloaliphatic [e.g.,
cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonyl amino,
(cycloalkylalkyl)carbonyl amino, aryl carbonyl amino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl alkyl)carbonyl amino, heteroarylcarbonylamino, or
heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0123] As used herein, a "bicyclic ring system" includes 6-12
(e.g., 8-12 or 9, 10, or 11) membered structures that form two
rings, wherein the two rings have at least one atom in common
(e.g., 2 atoms in common). Bicyclic ring systems include
bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl),
bicycloheteroaliphatics, bicyclic aryls, and bicyclic
heteroaryls.
[0124] As used herein, a "cycloaliphatic" group encompasses a
"cycloalkyl" group and a "cycloalkenyl" group, each of which being
optionally substituted as set forth below.
[0125] As used herein, a "cycloalkyl" group refers to a saturated
carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10
(e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl,
bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,
bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or
((aminocarbonyl)cycloalkyl)cycloalkyl.
[0126] A "cycloalkenyl" group, as used herein, refers to a
non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms
having one or more double bonds. Examples of cycloalkenyl groups
include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl,
cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl,
bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.
[0127] A cycloalkyl or cycloalkenyl group can be optionally
substituted with one or more substituents such as phospho,
aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic,
(cycloaliphatic) aliphatic, heterocycloaliphatic,
(heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,
heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,
(cycloaliphati c)carbonyl amino,
((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonyl amino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonyl amino,
((heterocycloaliphatic)aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonyl amino],
nitro, carboxy [e.g., HOOC--, alkoxycarbonyl, or alkylcarbonyloxy],
acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto,
sulfonyl [e.g., alkyl-SO.sub.2-- and aryl-SO.sub.2--], sulfinyl
[e.g., alkyl-S(O)--], sulfanyl [e.g., alkyl-S--], sulfoxy, urea,
thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0128] As used herein, the term "heterocycloaliphatic" encompasses
heterocycloalkyl groups and heterocycloalkenyl groups, each of
which being optionally substituted as set forth below.
[0129] As used herein, a "heterocycloalkyl" group refers to a 3-10
membered mono- or bicylic (fused or bridged) (e.g., 5- to
10-membered mono- or bicyclic) saturated ring structure, in which
one or more of the ring atoms is a heteroatom (e.g., N, O, S, or
combinations thereof). Examples of a heterocycloalkyl group include
piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl,
1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl,
isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl,
octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl,
octahydropyrindinyl, decahydroquinolinyl,
octahydrobenzo[b]thiopheneyl, 2-oxabicyclo[2.2.2]octyl,
1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and
2,6-dioxa-tricyclo[3.3.1.0.sup.3,7]nonyl. A monocyclic
heterocycloalkyl group can be fused with a phenyl moiety to form
structures, such as tetrahydroisoquinoline, which would be
categorized as heteroaryls.
[0130] A "heterocycloalkenyl" group, as used herein, refers to a
mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic)
non-aromatic ring structure having one or more double bonds, and
wherein one or more of the ring atoms is a heteroatom (e.g., N, O,
or S). Monocyclic and bicyclic heterocycloaliphatics are numbered
according to standard chemical nomenclature.
[0131] A heterocycloalkyl or heterocycloalkenyl group can be
optionally substituted with one or more substituents such as
phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl],
cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic,
(heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,
heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,
(cycloaliphati c)carbonylamino, ((cycloaliphatic)
aliphatic)carbonyl amino, (aryl)carbonylamino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonyl amino,
((heterocycloaliphatic) aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino],
nitro, carboxy [e.g., HOOC--, alkoxycarbonyl, or alkylcarbonyloxy],
acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy,
mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl
[e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy,
urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0132] A "heteroaryl" group, as used herein, refers to a
monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring
atoms wherein one or more of the ring atoms is a heteroatom (e.g.,
N, O, S, or combinations thereof) and in which the monocyclic ring
system is aromatic or at least one of the rings in the bicyclic or
tricyclic ring systems is aromatic. A heteroaryl group includes a
benzofused ring system having 2 to 3 rings. For example, a
benzofused group includes benzo fused with one or two 4 to 8
membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophene-yl, quinolinyl, or isoquinolinyl). Some examples
of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl,
pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl,
benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene,
phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,
puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl,
quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl,
benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[0133] Without limitation, monocyclic heteroaryls include furyl,
thiophene-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl,
pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic
heteroaryls are numbered according to standard chemical
nomenclature.
[0134] Without limitation, bicyclic heteroaryls include indolizyl,
indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl,
isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl,
benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl,
isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl,
1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered
according to standard chemical nomenclature.
[0135] A heteroaryl is optionally substituted with one or more
substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl];
cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic;
(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;
heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;
heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or
heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy;
amido; acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl;
((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or
aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,
aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;
urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively,
a heteroaryl can be unsubstituted.
[0136] Non-limiting examples of substituted heteroaryls include
(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];
(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];
cyanoheteroaryl; aminoheteroaryl [e.g.,
((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl];
(amido)heteroaryl [e.g., aminocarbonylheteroaryl,
((alkylcarbonyl)amino)heteroaryl,
((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
(((heteroaryl)amino)carbonyl)heteroaryl,
((heterocycloaliphatic)carbonyl)heteroaryl, and
((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;
(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,
(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,
(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;
(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;
((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;
(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;
((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;
(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl];
(alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g.,
trihaloalkylheteroaryl].
[0137] A "heteroaraliphatic (such as a heteroaralkyl group) as used
herein, refers to an aliphatic group (e.g., a C.sub.1-4 alkyl
group) that is substituted with a heteroaryl group. "Aliphatic,"
"alkyl," and "heteroaryl" have been defined above.
[0138] A "heteroaralkyl" group, as used herein, refers to an alkyl
group (e.g., a C.sub.1-4 alkyl group) that is substituted with a
heteroaryl group. Both "alkyl" and "heteroaryl" have been defined
above. A heteroaralkyl is optionally substituted with one or more
substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,
and haloalkyl such as trifluoromethyl), alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonyl amino,
(cycloalkylalkyl)carbonyl amino, aryl carbonyl amino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl alkyl)carbonyl amino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0139] As used herein, "cyclic moiety" and "cyclic group" refer to
mono-, bi-, and tri-cyclic ring systems including cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, each of which has been
previously defined.
[0140] As used herein, a "bridged bicyclic ring system" refers to a
bicyclic heterocyclicalipahtic ring system or bicyclic
cycloaliphatic ring system in which the rings are bridged. Examples
of bridged bicyclic ring systems include, but are not limited to,
adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,
bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl,
1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and
2,6-dioxa-tricyclo[3.3.1.0.sup.3.degree. 7]nonyl. A bridged
bicyclic ring system can be optionally substituted with one or more
substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,
and haloalkyl such as trifluoromethyl), alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonyl amino,
(cycloalkylalkyl)carbonyl amino, aryl carbonyl amino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl alkyl)carbonyl amino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0141] As used herein, an "acyl" group refers to a formyl group or
R.sup.X--C(O)-- (such as alkyl-C(O)--, also referred to as
"alkylcarbonyl") where R.sup.X and "alkyl" have been defined
previously. Acetyl and pivaloyl are examples of acyl groups.
[0142] As used herein, an "aroyl" or "heteroaroyl" refers to an
aryl-C(O)-- or a heteroaryl-C(O)--. The aryl and heteroaryl portion
of the aroyl or heteroaroyl is optionally substituted as previously
defined.
[0143] As used herein, an "alkoxy" group refers to an alkyl-O--
group where "alkyl" has been defined previously.
[0144] As used herein, a "carbamoyl" group refers to a group having
the structure --O--CO--NR.sup.XR.sup.Y or
--NR.sup.X--CO--O--R.sup.Z, wherein R.sup.X and R.sup.Y have been
defined above and R.sup.Z can be aliphatic, aryl, araliphatic,
heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[0145] As used herein, a "carboxy" group refers to --COOH,
--COOR.sup.X, --OC(O)H, --OC(O)R.sup.X, when used as a terminal
group; or --OC(O)-- or --C(O)O-- when used as an internal
group.
[0146] As used herein, a "haloaliphatic" group refers to an
aliphatic group substituted with 1-3 halogen. For instance, the
term haloalkyl includes the group --CF.sub.3.
[0147] As used herein, a "mercapto" group refers to --SH.
[0148] As used herein, a "sulfo" group refers to --SO.sub.3H or
--SO.sub.3R.sup.X when used terminally or --S(O).sub.3-- when used
internally.
[0149] As used herein, a "sulfamide" group refers to the structure
--NR.sup.X--S(O).sub.2--NR.sup.YR.sup.Z when used terminally and
--NR.sup.X--S(O).sub.2--NR.sup.Y-- when used internally, wherein
R.sup.X, R.sup.Y, and R.sup.Z have been defined above.
[0150] As used herein, a "sulfamoyl" group refers to the structure
--O--S(O).sub.2--NR.sup.YR.sup.Z wherein R.sup.Y and R.sup.Z have
been defined above.
[0151] As used herein, a "sulfonamide" group refers to the
structure --S(O).sub.2--NR.sup.XR.sup.Y or
--NR.sup.X--S(O).sub.2--R.sup.Z when used terminally; or
--S(O).sub.2--NR.sup.X-- or --NR.sup.X--S(O).sub.2-- when used
internally, wherein R.sup.X, R.sup.Y, and R.sup.Z are defined
above.
[0152] As used herein a "sulfanyl" group refers to --S--R.sup.X
when used terminally and --S-- when used internally, wherein
R.sup.X has been defined above. Examples of sulfanyls include
aliphatic-S--, cycloaliphatic-S--, aryl-S--, or the like.
[0153] As used herein a "sulfinyl" group refers to --S(O)--R.sup.X
when used terminally and --S(O)-- when used internally, wherein
R.sup.X has been defined above. Exemplary sulfinyl groups include
aliphatic-S(O)--, aryl-S(O)--, (cycloaliphatic(aliphatic))-S(O)--,
cycloalkyl-S(O)--, heterocycloaliphatic-S(O)--, heteroaryl-S(O)--,
or the like.
[0154] As used herein, a "sulfonyl" group refers to
--S(O).sub.2--R.sup.X when used terminally and --S(O).sub.2-- when
used internally, wherein R.sup.X has been defined above. Exemplary
sulfonyl groups include aliphatic-S(O).sub.2--, aryl-S(O).sub.2--,
(cycloaliphatic(aliphatic))-S(O).sub.2--,
cycloaliphatic-S(O).sub.2--, heterocycloaliphatic-S(O).sub.2--,
heteroaryl-S(O).sub.2--,
(cycloaliphatic(amido(aliphatic)))-S(O).sub.2-- or the like.
[0155] As used herein, a "sulfoxy" group refers to
--O--S(O)--R.sup.X or --S(O)--O--R.sup.X, when used terminally and
--O--S(O)-- or --S(O)--O-- when used internally, where R.sup.X has
been defined above.
[0156] As used herein, a "halogen" or "halo" group refers to
fluorine, chlorine, bromine or iodine.
[0157] As used herein, an "alkoxycarbonyl," which is encompassed by
the term carboxy, used alone or in connection with another group
refers to a group such as alkyl-O--C(O)--.
[0158] As used herein, an "alkoxyalkyl" refers to an alkyl group
such as alkyl-O-alkyl-, wherein alkyl has been defined above.
[0159] As used herein, a "carbonyl" refers to --C(O)--.
[0160] As used herein, an "oxo" refers to .dbd.O.
[0161] As used herein, the term "phospho" refers to phosphinates
and phosphonates. Examples of phosphinates and phosphonates include
--P(O)(R.sup.P).sub.2, wherein R.sup.P is aliphatic, alkoxy,
aryloxy, heteroaryloxy, (cycloaliphatic)oxy,
(heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or
amino.
[0162] As used herein, an "aminoalkyl" refers to the structure
(R.sup.X).sub.2N-alkyl-.
[0163] As used herein, a "cyanoalkyl" refers to the structure
(NC)-alkyl-.
[0164] As used herein, a "urea" group refers to the structure
--NR.sup.X--CO--NR.sup.YR.sup.Z and a "thiourea" group refers to
the structure --NR.sup.X--CS--NR.sup.YR.sup.Z when used terminally
and --NR.sup.X--CO--NR.sup.Y-- or --NR.sup.X--CS--NR.sup.Y-- when
used internally, wherein R.sup.X, R.sup.Y, and R.sup.Z have been
defined above.
[0165] As used herein, a "guanidine" group refers to the structure
--N.dbd.C(N(R.sup.XR.sup.Y))N(R.sup.XR.sup.Y) or
--NR.sup.X--C(.dbd.NR.sup.X)NR.sup.XR.sup.Y wherein R.sup.X and
R.sup.Y have been defined above.
[0166] As used herein, the term "amidino" group refers to the
structure --C.dbd.(NR.sup.X)N(R.sup.XR.sup.Y) wherein R.sup.X and
R.sup.Y have been defined above.
[0167] In general, the term "vicinal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to adjacent carbon atoms.
[0168] In general, the term "geminal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to the same carbon atom.
[0169] The terms "terminally" and "internally" refer to the
location of a group within a substituent. A group is terminal when
the group is present at the end of the substituent not further
bonded to the rest of the chemical structure. Carboxyalkyl, i.e.,
R.sup.XO(O)C-alkyl is an example of a carboxy group used
terminally. A group is internal when the group is present in the
middle of a substituent of the chemical structure. Alkylcarboxy
(e.g., alkyl-C(O)O-- or alkyl-OC(O)--) and alkylcarboxyaryl (e.g.,
alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy
groups used internally.
[0170] As used herein, an "aliphatic chain" refers to a branched or
straight aliphatic group (e.g., alkyl groups, alkenyl groups, or
alkynyl groups). A straight aliphatic chain has the structure
--[CH.sub.2].sub.v--, where v is 1-12. A branched aliphatic chain
is a straight aliphatic chain that is substituted with one or more
aliphatic groups. A branched aliphatic chain has the structure
--[CQQ].sub.v- where Q is independently a hydrogen or an aliphatic
group; however, Q shall be an aliphatic group in at least one
instance. The term aliphatic chain includes alkyl chains, alkenyl
chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are
defined above.
[0171] As used herein, "Dess-Martin periodinane" and its
abbreviation "DMP" are used interchangeably. DMP refers to
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one having the
structure
##STR00120##
[0172] The phrase "optionally substituted" is used interchangeably
with the phrase "substituted or unsubstituted." As described
herein, compounds of the invention can optionally be substituted
with one or more substituents, such as are illustrated generally
above, or as exemplified by particular classes, subclasses, and
species of the invention. As described herein, the variables
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.10, and other variables
contained in Formulae IA and I described herein encompass specific
groups, such as alkyl and aryl. Unless otherwise noted, each of the
specific groups for the variables R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.10, and other variables contained therein can be
optionally substituted with one or more substituents described
herein. Each substituent of a specific group is further optionally
substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy,
amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic,
heteroaryl, haloalkyl, and alkyl. For instance, an alkyl group can
be substituted with alkylsulfanyl and the alkylsulfanyl can be
optionally substituted with one to three of halo, cyano, oxo,
alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an
additional example, the cycloalkyl portion of a
(cycloalkyl)carbonylamino can be optionally substituted with one to
three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
When two alkoxy groups are bound to the same atom or adjacent
atoms, the two alkxoy groups can form a ring together with the
atom(s) to which they are bound.
[0173] In general, the term "substituted," whether preceded by the
term "optionally" or not, refers to the replacement of hydrogen
atoms in a given structure with the radical of a specified
substituent. Specific substituents are described above in the
definitions and below in the description of compounds and examples
thereof. Unless otherwise indicated, an optionally substituted
group can have a substituent at each substitutable position of the
group, and when more than one position in any given structure can
be substituted with more than one substituent selected from a
specified group, the substituent can be either the same or
different at every position. A ring substituent, such as a
heterocycloalkyl, can be bound to another ring, such as a
cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings
share one common atom. As one of ordinary skill in the art will
recognize, combinations of substituents envisioned by this
invention are those combinations that result in the formation of
stable or chemically feasible compounds.
[0174] The phrase "stable or chemically feasible," as used herein,
refers to compounds that are not substantially altered when
subjected to conditions to allow for their production, detection,
and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a
stable compound or chemically feasible compound is one that is not
substantially altered when kept at a temperature of 40.degree. C.
or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0175] As used herein, "chemical purity" refers to the degree to
which a substance, i.e., the desired product or intermediate, is
undiluted or unmixed with extraneous material such as chemical
byproducts.
[0176] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays, or as therapeutic
agents.
[0177] Chemical structures and nomenclature are derived from
ChemDraw, version 11.0.1, Cambridge, Mass.
[0178] It is noted that the use of the descriptors "first",
"second", "third", or the like is used to differentiate separate
elements (e.g., solvents, reaction steps, processes, reagents, or
the like) and may or may not refer to the relative order or
relative chronology of the elements described.
II. COMMONLY USED ABBREVIATIONS
[0179] The following abbreviations are used: [0180] PG protecting
group [0181] LG leaving group [0182] DCM dichloromethane [0183] Ac
acetyl [0184] THF tetrohydrofuran [0185] TMS trimethylsilyl [0186]
TBS tert-butyldimethyl silyl [0187] TIPS tri-iso-propylsilyl [0188]
TBDPS tert-butyldiphenylsilyl [0189] TOM tri-iso-propyl
silyloxymethyl [0190] DMP Dess-Martin periodinane [0191] IBX
2-iodoxybenzoic acid [0192] DMF dimethylformamide [0193] MTBE
methyl-tert-butylether [0194] TBAF tetra-n-butylammonium fluoride
[0195] d.e. diastereomeric excess [0196] e.e. enantiomeric excess
[0197] EtOAc ethyl acetate [0198] DMSO dimethyl sulfoxide [0199]
MeCN acetonitrile [0200] TCA trichloroacetic acid [0201] ATP
adenosine triphosphate [0202] EtOH ethanol [0203] Ph phenyl [0204]
Me methyl [0205] Et ethyl [0206] Bu butyl [0207] iPr isopropyl
[0208] tBu tertbutyl [0209] DEAD diethylazodicarboxylate [0210]
HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [0211] DTT
dithiothreitol [0212] MOPS 4-morpholinepropanesulfonic acid [0213]
NMR nuclear magnetic resonance [0214] HPLC high performance liquid
chromatography [0215] LCMS liquid chromatography-mass spectrometry
[0216] TLC thin layer chromatography [0217] Rt retention time
[0218] HOBt hydroxybenzotriazole [0219] Ms mesyl [0220] Ts tosyl
[0221] Tf triflyl [0222] Bs besyl [0223] Ns nosyl [0224] Cbz
carboxybenzyl [0225] Moz p-methoxybenzyl carbonyl [0226] Boc
tert-butyloxycarbonyl [0227] Fmoc 9-fluorenylmethyloxycarbonyl
[0228] Bz benzoly [0229] Bn benzyl [0230] PMB p-methoxybenzyl
[0231] DMPM 3,4-dimethoxybenzyl [0232] PMP p-methoxyphenyl
III. METHODS OF SYNTHESIS
[0233] One aspect of the present invention provides a method of
generating a compound of Formula
##STR00121##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent in
the presence of an organic solvent to generate a compound of
Formula 10
##STR00122##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2 or Dess-Martin periodinane; ii) reacting the
compound of Formula 10 with a compound of Formula 5 in the presence
of a base and an organic solvent to generate a compound of Formula
11, wherein each R.sup.2 is independently selected from C.sub.1-6
alkyl or phenyl; and
##STR00123##
iii) converting the compound of Formula 11 to the compound of
Formula I.
[0234] A. Step i)
[0235] Step i) comprises reacting a compound of Formula 9 with an
oxidizing agent in the presence of an organic solvent to generate a
compound of Formula 10
##STR00124##
wherein R.sup.1 is C.sub.1-6 alkyl.
[0236] In some implementations, R.sup.1 is methyl, ethyl, propyl,
iso-propyl, butyl, sec-butyl, or tert-butyl. For example, R.sup.1
is methyl.
[0237] In some implementations, the oxidizing agent of step i)
comprises manganese(IV)oxide, i.e., MnO.sub.2, DMP, or IBX. For
example, the oxidizing agent comprises MnO.sub.2 or DMP. And, in
some instances, the oxidizing agent comprises MnO.sub.2.
[0238] The organic solvent of step i) is any suitable solvent that
is capable of substantially dissolving the compound of Formula 9
and is substantially inert when combined with the oxidizing agent
and the compound of Formula 9. In some implementations, the organic
solvent of step i) comprises a halogenated organic solvent. For
example, the halogenated organic solvent comprises dichloromethane,
i.e., methylene chloride, chloroform, or any combination thereof.
In other implementations, the organic solvent (e.g.,
dichloromethane) is anhydrous.
[0239] In some implementations, the reaction of step i) is
performed at a temperature from about 10.degree. C. to about
40.degree. C. For example, the reaction of step i) is performed at
room temperature.
[0240] In other implementations, the reaction of step i) is
performed under agitation, e.g., stirring.
[0241] In some implementations, the reaction of step i) is
performed under an inert gas (e.g., nitrogen gas).
[0242] In other implementations, the reaction of step i) is about
99% complete (e.g., from about 95% to about 99.9% complete after
about 15 hrs (e.g. from about 14 to about 18 hrs).
[0243] In some implementations, step i) generates the compound of
Formula 10, having a yield of greater than about 95% (e.g., from
about 95% to about 99.9% or about 99%).
[0244] B. Step ii)
[0245] Step ii) comprises reacting the compound of Formula 10 with
a compound of Formula 5 in the presence of a base and an organic
solvent to generate a compound of Formula 11, wherein each R.sup.2
is independently selected from C.sub.1-6 alkyl or phenyl.
##STR00125##
[0246] In some implementations, the base comprises an alkyllithium
reagent. Examples of alkyllithium reagents include butyllithium,
hexyllithium, sec-butyllithium, and methyllithium. In some
instances, the base comprises sec-butyllithium.
[0247] Organic solvents that are useful in the reaction of step ii)
comprise alkanes, cyclic alkanes, heterocycles (e.g., THF,
1,4-dioxane, or any combination thereof), ethers, or any
combination thereof.
[0248] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, THF, 1,4-dioxane,
diethyl ether, petro ether, MTBE, or any combination thereof. For
example, the organic solvent of step ii) comprises MTBE.
[0249] In other implementations, the organic solvent of step ii) is
anhydrous (e.g., anhydrous MTBE).
[0250] And, in some implementations, the base of step ii) comprises
sec-butyllithium, and the organic solvent of step ii) comprises
MTBE.
[0251] In some implementations, the compound of Formula 5 has an
e.e. of about 98% or greater (e.g., from about 98.0% to about
99.9%). In other implementations, the compound of Formula 5 has a
chemical purity of about 95% or greater (e.g., from about 97% to
about 99.9%).
[0252] In some implementations, the reaction of step ii) is
performed at a temperature from about -80.degree. C. to about
30.degree. C. (e.g., from about -78.degree. C. to about room
temperature).
[0253] In other implementations, the reaction of step ii) is
performed under agitation, e.g., stirring.
[0254] In some implementations, the reaction of step ii) is
performed under an inert gas (e.g., nitrogen gas).
[0255] C. Additional Steps
[0256] Steps iv)-vii) may optionally be performed with other steps
described herein to generate the compound of Formula I.
[0257] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00126##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00127##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00128##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0258] Step iv) is an efficient stereoselective method for
generating the compound of Formula 1 having an e.e. of greater than
98% that does not require additional chromatography. Moreover, in
some implementations, step iv) generates the compound of Formula 1
with a yield of at least about 90% (e.g., at least about 91%, or
about 92%).
[0259] In some implementations, the refluxing of the compound of
Formula 1a occurs in the presence of an alcohol (e.g., methanol,
ethanol, or any combination thereof). In other implementations, the
compound of Formula 1a undergoes reflux in the presence of methanol
(e.g., anhydrous methanol).
[0260] In other implementations, the compound of Formula 1a is
heated to reflux under an inert gas (e.g., nitrogen).
[0261] And, in some implementations, the compound of Formula 1a is
heated to reflux for a period of about 1 to about 3 hrs (e.g.,
about 2 hrs).
[0262] Step v) comprises the protection of the hydroxy functional
group of the compound of Formula 1 under basic conditions to
generate the alkylsilyl ether compound of Formula 2.
[0263] In some implementations, the base of step v) comprises a
nitrogen base. In some examples, the nitrogen base comprises
Et.sub.3N, imidazole, piperidine, piperazine, any combination
thereof, or the like. For instance, the base of step v) comprises
imidazole.
[0264] In some implementations, the SiCl(R.sup.2).sub.3 reagent of
step v) comprises chloro-tert-butyldimethylsilane (TBS-Cl),
tert-butylchlorodiphenyl silane (TBDPS-Cl), chlorotrimethyl silane
(TMS-Cl), triisopropylsilyloxymethyl chloride (TOM-Cl), or
chlorotriisopropylsilane (TIPS-Cl).
[0265] In some implementations, the 1-TMS-1-propyne of step vi) is
first reacted with an alkyllithium reagent followed by the reaction
with the compound of Formula 2.
[0266] The present invention provides a method of generating a
compound of Formula 5
##STR00129##
wherein each R.sup.2 is independently selected from a C.sub.1-6
alkyl or phenyl, comprising the steps of: iv) refluxing the
compound of Formula 1a in the presence of methanol to generate a
compound of Formula 1 having an e.e. of greater than about 98%
(e.g., greater than about 98.5%, greater than about 99% or from
about 98.5% to about 99.9%);
##STR00130##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3,
wherein each R.sup.2 is independently selected from C.sub.1-6 alkyl
or phenyl, under basic conditions to generate the compound of
Formula 2;
##STR00131##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3;
##STR00132##
l) deprotecting the compound Formula 3 under basic condition to
generate a compound of Formula 4, wherein each of R.sup.4 and
R.sup.5 are H or --OSi(R.sup.2).sub.3; and
##STR00133##
li) reacting the compound of Formula 4 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 5,
wherein the compound of Formula 5 has a chemical purity of about
98% or greater (e.g., greater than about 98.5%, greater than about
99% or from about 98.5% to about 99.9%) and an e.e. of about 98% or
greater (e.g., from about 99% to about 99.99%).
[0267] In implementations, the compound of Formula 5 has a chemical
purity of about 95% or greater (e.g., from about 97% to about 99.9%
or about 99% or greater) and an e.e. of about 98% or greater (e.g.,
about 99% or greater). In some implementations, the compound of
Formula 5 has an e.e. of .about.100%, e.g., about 98% or greater,
about 99% or greater, or greater than 99%.
[0268] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00134##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: viii) reacting a compound of Formula 11 with an oxidizing agent
in the presence of an organic solvent to generate a compound of
Formula 12
##STR00135##
wherein R.sup.1 is C.sub.1-6 alkyl, each R.sup.2 is independently
selected from C.sub.1-6 alkyl or phenyl, and the oxidizing agent
comprises MnO.sub.2; and ix) converting the compound of Formula 12
to the compound of Formula I.
[0269] D. Step viii)
[0270] The reaction of step viii) accomplishes the oxidation of the
compound of Formula 11 to generate the compound of Formula 12 using
an oxidizing agent that possesses a reduced toxicity than
traditional chromium based oxidation agents (e.g., PCC).
[0271] In some implementations, each of the --OSi(R.sup.2).sub.3
groups in the compounds of Formulae 11 and 12 is independently
selected from
##STR00136##
[0272] In some implementations, the organic solvent of step viii)
comprises a halogenated organic solvent. In some examples, the
halogenated organic solvent of step viii) comprises
dichloromethane, chloroform, or any combination thereof. In other
examples, the organic solvent of step viii) (e.g., dichloromethane)
is anhydrous.
[0273] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent in the presence of an
organic solvent to generate a compound of Formula 10
##STR00137##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2 or Dess-Martin periodinane; and ii) reacting
the compound of Formula 10 with a compound of Formula 5
##STR00138##
in the presence of a base and an organic solvent to generate a
compound of Formula 11.
[0274] Steps i) and ii) are described, in detail, above.
[0275] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00139##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: x) reacting a compound of Formula 12 with a reducing agent in
the presence of an organic solvent to generate a compound of
Formula 13
##STR00140##
wherein the organic solvent comprises THF, R.sup.1 is C.sub.1-6
alkyl, and R.sup.2 is independently selected from C.sub.1-6 alkyl
or phenyl; and xi) converting the compound of Formula 13 to the
compound of Formula I.
[0276] E. Step x)
[0277] In some implementations, the reducing agent of step x)
comprises a chiral borane compound. In some implementations, the
chiral borane compound of step x) reacts with the compound of
Formula 12 to generate the compound of Formula 13 with a d.e. of
about 97% or greater (e.g., about 97.5% of greater). In other
implementations, the chiral borane reducing agent is formed in situ
or ex situ. And, in some examples, the chiral borane compound is
selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,
(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any
combination thereof.
[0278] In some implementations, the organic solvent of step x)
further comprises toluene.
[0279] And, in some implementations, the organic solvent of step x)
is anhydrous.
[0280] Some methods further comprise the step of: viii) reacting a
compound of Formula 11 with an oxidizing agent to generate the
compound of Formula 12, wherein the oxidizing agent comprises
MnO.sub.2
##STR00141##
[0281] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00142##
ii) reacting the compound of Formula 10 with a compound of Formula
5 in the presence of a base and an organic solvent to generate a
compound of Formula 11
##STR00143##
[0282] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00144##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00145##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00146##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0283] Each of steps i), ii), and iv)-viii) is discussed above.
[0284] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00147##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xii) hydrogenating a compound of Formula 15 in the presence of
an organic solvent (e.g., an alcohol (e.g., methanol, ethanol, or
any combination thereof), an optionally substituted THF (e.g.,
2-methyl-THF or THF), EtOAc, or any combination thereof) to
generate the compound of Formula 16
##STR00148##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.2 is
independently selected from C.sub.1-6 alkyl or phenyl; and xiii)
converting the compound of Formula 16 to the compound of Formula
I.
[0285] F. Step xii)
[0286] Step xii) comprises the improved hydrogenation of the
compound of Formula 15 to generate the compound of Formula 16. Some
implementations comprise the hydrogenation of the compound of
Formula 15 in the presence of an alcohol (e.g., methanol or
ethanol), optionally substituted THF (e.g., THF or 2-Me-THF), or
any combination thereof to generate the compound of Formula 16. In
other implementations, the hydrogenation of the compound of Formula
15 occurs in the presence of an alcohol (e.g., methanol or
ethanol), optionally substituted THF (e.g., THF or 2-Me-THF), or
any combination thereof and a base (e.g., potassium carbonate or
potassium bicarbonate).
[0287] The substitution of methanol for the traditional ethanol in
step xii) produces an improved yield (e.g., at least about 88%) and
improved chemical purity for the compound of Formula 16.
[0288] Some methods further comprise the steps of: x) reacting a
compound of Formula 12 with a reducing agent in the presence of an
organic solvent to generate a compound of Formula 13
##STR00149##
wherein the organic solvent comprises THF; and xiv) converting the
compound of Formula 13 to the compound of Formula 15.
[0289] Some methods further comprise the steps of: viii) reacting a
compound of Formula 11 with an oxidizing agent to generate the
compound of Formula 12, wherein the oxidizing agent comprises
MnO.sub.2
##STR00150##
[0290] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00151##
ii) reacting the compound of Formula 10 with a compound of Formula
5 in the presence of a base and an organic solvent to generate a
compound of Formula 11
##STR00152##
[0291] In some implementations, the oxidizing agent of step i)
comprises MnO.sub.2 or Dess-Martin periodinane.
[0292] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00153##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00154##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00155##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0293] Each of steps i), ii), iv), v)-viii), x), and xiv) is
discussed above.
[0294] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00156##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xv) reacting a compound of Formula 21 with n-butyllithium in
the presence of an organic solvent and a transition metal catalyst
to generate a compound of Formula 22
##STR00157##
wherein R.sup.3 is C.sub.1-6 alkyl or phenyl; and xvi) converting
the compound of Formula 22 to the compound of Formula I.
[0295] G. Step xv)
[0296] Step xv) generates a yield of at least about 70% (e.g., at
least about 75%, at least about 80%, or about 82%) for the compound
of Formula 22.
[0297] In some implementations, the reaction of step xv) is
conducted at a temperature of from about -80.degree. C. to about
-20.degree. C. (e.g., from about -78.degree. C. to about
-30.degree. C.).
[0298] In some implementations, the transition metal catalyst of
step xv) comprises copper having a +1 oxidation state. For example,
the transition metal catalyst comprises a copper compound or a
copper complex wherein the Cu has a +1 oxidation state. In other
examples, the transition metal catalyst of step xv) comprises CuX,
wherein X is selected from halogen, acetate, benzoate, cyanide,
hydroxide, nitrate, or any combination thereof. In other examples,
the transition metal catalyst of step xv) comprises CuI.
[0299] Some methods further comprise the steps of: xvii) reacting a
compound of Formula 19 with R.sup.4-substituted benzenesulfonyl
chloride under basic conditions to generate a compound of Formula
20, wherein each R.sup.4 is independently selected from --H or
C.sub.1-3 alkyl; and
##STR00158##
xviii) reacting the compound of Formula 20 with methanol under
basic conditions to generate the compound of Formula 21.
[0300] In some implementations, the R.sup.4-substituted
benzenesulfonyl chloride of step xvii) is 2-mesitylenesulfonyl
chloride (2,4,6-trimethylbenzenesulfonyl chloride) or tosyl
chloride (TsCl).
[0301] Some methods further comprise the steps of: xix) reacting a
compound of Formula 16 with a reducing agent to generate a compound
of Formula 17;
##STR00159##
xx) reacting the compound of Formula 17 with Si(R.sup.3).sub.3Cl
under basic conditions to generate a compound of Formula 18;
and
##STR00160##
xxi) selectively deprotecting the compound of Formula 18 to
generate the compound of Formula 19.
[0302] Some methods further comprise the steps of: xii)
hydrogenating a compound of Formula 15
##STR00161##
in the presence of an organic solvent (e.g., an alcohol (e.g.,
methanol, ethanol, or any combination thereof), an optionally
substituted THF (e.g., 2-methyl-THF or THF), EtOAc, or any
combination thereof) to generate the compound of Formula 16.
[0303] In some implementations, the hydrogenation of the compound
of Formula 15 occurs in the presence of a base (e.g., potassium
carbonate or potassium bicarbonate).
[0304] Some methods further comprise the steps of: x) reacting a
compound of Formula 12 with a reducing agent to generate a compound
of Formula 13; and
##STR00162##
xiv) converting the compound of Formula 13 to the compound of
Formula 15.
[0305] Some methods further comprise the step of: viii) reacting a
compound of Formula 11
##STR00163##
with an oxidizing agent to generate the compound of Formula 12,
wherein the oxidizing agent comprises MnO.sub.2.
[0306] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00164##
ii) reacting the compound of Formula 10 with a compound of Formula
5 in the presence of a base and an organic solvent to generate a
compound of Formula 11
##STR00165##
[0307] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having greater than about 99% e.e.;
##STR00166##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of Formula 2;
##STR00167##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3; and
##STR00168##
vii) converting the compound of Formula 3 to the compound of
Formula 5.
[0308] Steps i), ii), iv)-viii), x), xii), and xiv) are discussed
above.
[0309] The present invention also provides a method of generating a
compound of Formula I
##STR00169##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xxii) reacting a compound of Formula 7, wherein R.sup.1 is
C.sub.1-6 alkyl and R.sup.2 is independently selected from
C.sub.1-6 alkyl or phenyl, with a 3-haloprop-1-ene in the presence
of a base and an organic solvent to generate a compound of Formula
8;
##STR00170##
xxiii) deprotecting the compound of Formula 8 to generate the
compound of Formula 9, and
##STR00171##
xxiv) converting the compound of Formula 9 to the compound of
Formula I, wherein the base of step xxii) comprises sec-butyl
lithium.
[0310] H. Step xxii)
[0311] The reaction of step xxii) generates the compound of Formula
8 with improved chemical purity without additional chromatography
steps.
[0312] In some implementations, the reaction of step xxii) is
conducted at room temperature (e.g., from about 20.degree. C. to
about 30.degree. C.) for a period of about 2 hrs (e.g., from about
1.5 to about 2.5 hrs) then cooled to a temperature of about
0.degree. C. (e.g., from about -5.degree. C. to about 5.degree. C.)
under stirring.
[0313] In some implementations, the organic solvent of step xxii)
comprises one or more alkanes. For example, the organic solvent of
step xxii) comprises heptanes, cyclohexane, or any combination
thereof. In other implementations, the organic solvent of step
xxii) comprises MTBE.
[0314] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00172##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent in
the presence of an organic solvent to generate a compound of
Formula 10
##STR00173##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2 or Dess-Martin periodinane; ii) reacting the
compound of Formula 10 with a compound of Formula 5a in the
presence of a base and an organic solvent to generate a compound of
Formula 11a; and
##STR00174##
iii) converting the compound of Formula 11a to the compound of
Formula I.
[0315] Steps i) and ii) are discussed in detail above.
[0316] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00175##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00176##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00177##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0317] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00178##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: viii) reacting a compound of Formula 11a with an oxidizing
agent in the presence of an organic solvent to generate a compound
of Formula 12a
##STR00179##
wherein R.sup.1 is C.sub.1-6 alkyl and the oxidizing agent
comprises MnO.sub.2; and ix) converting the compound of Formula 12a
to the compound of Formula I.
[0318] Step viii) is discussed above.
[0319] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent in the presence of an
organic solvent to generate a compound of Formula 10
##STR00180##
wherein the oxidizing agent comprises MnO.sub.2 or Dess-Martin
periodinane; and ii) reacting the compound of Formula 10 with a
compound of Formula 5a
##STR00181##
in the presence of a base and an organic solvent to generate a
compound of Formula 11a.
[0320] Steps i) and ii) are discussed in detail above.
[0321] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00182##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: x) reacting a compound of Formula 12a with a reducing agent in
the presence of an organic solvent to generate a compound of
Formula 13a
##STR00183##
wherein the organic solvent comprises THF, R.sup.1 is C.sub.1-6
alkyl, and each R.sup.2 is independently selected from C.sub.1-6
alkyl or phenyl; and xi) converting the compound of Formula 13 to
the compound of Formula I.
[0322] Steps x) and xi) are discusses in detail above.
[0323] Some methods further comprise the step of: viii) reacting a
compound of Formula 11a with an oxidizing agent to generate the
compound of Formula 12a, wherein the oxidizing agent comprises
MnO.sub.2
##STR00184##
[0324] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00185##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 1a
##STR00186##
[0325] In some implementations, the oxidizing agent of step i)
comprises MnO.sub.2 or Dess-Martin periodinane.
[0326] In some implementations, the base of step ii) comprises an
alkyllithium reagent. For example, the alkyllithium reagent of step
ii) comprises sec-butyllithium.
[0327] In some implementations, the organic solvent of step ii)
comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran,
1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or
any combination thereof. For example, the organic solvent of step
ii) comprises methyl-tert-butylether.
[0328] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00187##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00188##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00189##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0329] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00190##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xii) hydrogenating a compound of Formula 15a in the presence of
an organic solvent (e.g., an alcohol (e.g., methanol, ethanol, or
any combination thereof), an optionally substituted THF (e.g.,
2-methyl-THF or THF), EtOAc, or any combination thereof) to
generate the compound of Formula 16a
##STR00191##
wherein R.sup.1 is C.sub.1-6 alkyl; and xiii) converting the
compound of Formula 16a to the compound of Formula I.
[0330] In some implementations, the hydrogenation of the compound
of Formula 15a occurs in the presence of a base (e.g., potassium
carbonate or potassium bicarbonate).
[0331] Some methods further comprise the steps of: x) reacting a
compound of Formula 12a with a reducing agent in the presence of an
organic solvent to generate a compound of Formula 13a
##STR00192##
wherein the organic solvent comprises THF; and xiv) converting the
compound of Formula 13a to the compound of Formula 15a.
[0332] Some methods further comprise the steps of: viii) reacting a
compound of Formula 11a with an oxidizing agent to generate the
compound of Formula 12a, wherein the oxidizing agent comprises
MnO.sub.2
##STR00193##
[0333] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00194##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a
##STR00195##
[0334] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00196##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00197##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00198##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0335] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00199##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: xv) reacting a compound of Formula 21a with n-butyllithium in
the presence of an organic solvent and a transition metal catalyst
to generate a compound of Formula 22a
##STR00200##
wherein R.sup.1 is C.sub.1-6 alkyl; and xvi) converting the
compound of Formula 22a to the compound of Formula I.
[0336] In some implementations, the transition metal catalyst of
step xv) comprises a compound or complex either of which comprises
Cu having a +1 oxidation state. For example, the transition metal
catalyst of step xv) comprises CuX, wherein X is selected from
halogen, acetate, benzoate, cyanide, hydroxide, nitrate, or any
combination thereof. In other examples, the transition metal
catalyst of step xv) comprises CuI.
[0337] Some methods further comprise the steps of: xvii) reacting a
compound of Formula 19a with triisopropylbenzenesulfonyl chloride
under basic conditions to generate a compound of Formula 20a;
and
##STR00201##
xviii) reacting the compound of Formula 20a with methanol under
basic conditions to generate the compound of Formula 21a.
[0338] Some methods further comprise the steps of: xix) reacting a
compound of Formula 16a with a reducing agent to generate a
compound of Formula 17a;
##STR00202##
xx) reacting the compound of Formula 17a with TBDPSCl under basic
conditions to generate a compound of Formula 18a; and
##STR00203##
xxi) selectively deprotecting the compound of Formula 18a to
generate the compound of Formula 19a.
[0339] Some methods further comprise the step of: xii)
hydrogenating a compound of Formula 15a
##STR00204##
in the presence of an organic solvent (e.g., an alcohol (e.g.,
methanol, ethanol, or any combination thereof), an optionally
substituted THF (e.g., 2-methyl-THF or THF), EtOAc, or any
combination thereof) to generate the compound of Formula 16a.
[0340] In some implementations, the hydrogenation of the compound
of Formula 15a occurs in the presence of a base (e.g., potassium
carbonate or potassium bicarbonate).
[0341] Some methods further comprise the steps of: x) reacting a
compound of Formula 12a with a reducing agent to generate a
compound of Formula 13a; and
##STR00205##
xiv) converting the compound of Formula 13a to the compound of
Formula 15a.
[0342] Some methods further comprise the step of: viii) reacting a
compound of Formula 11a
##STR00206##
with an oxidizing agent to generate the compound of Formula 12a,
wherein the oxidizing agent comprises MnO.sub.2.
[0343] Some methods further comprise the steps of: i) reacting a
compound of Formula 9 with an oxidizing agent to generate a
compound of Formula 10; and
##STR00207##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a
##STR00208##
[0344] Some methods further comprise the steps of: iv) refluxing
the compound of Formula 1a in the presence of methanol to generate
a compound of Formula 1 having an e.e. of greater than about
98%;
##STR00209##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00210##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a; and
##STR00211##
vii) converting the compound of Formula 3a to the compound of
Formula 5a.
[0345] Some methods further comprise the steps of: xxii) reacting a
compound of Formula 7a with a 3-haloprop-1-ene in the presence of a
base and an organic solvent to generate a compound of Formula 8a;
and
##STR00212##
xxiii) deprotecting the compound of Formula 8a to generate the
compound of Formula 9.
[0346] Another aspect of the present invention provides a method of
generating a compound of Formula I
##STR00213##
or a pharmaceutically acceptable salt thereof, comprising the steps
of: i) reacting a compound of Formula 9 with an oxidizing agent to
generate a compound of Formula 10;
##STR00214##
ii) reacting the compound of Formula 10 with a compound of Formula
5a in the presence of a base and an organic solvent to generate a
compound of Formula 11a;
##STR00215##
iv) refluxing the compound of Formula 1a in the presence of
methanol to generate a compound of Formula 1 having an e.e. of
greater than about 98%;
##STR00216##
v) reacting the compound of Formula 1 with TBSCl under basic
conditions to generate the compound of Formula 2a;
##STR00217##
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to
generate the compound of Formula 3a;
##STR00218##
vii) converting the compound of Formula 3a to the compound of
Formula 5a; viii) reacting a compound of Formula 11a with an
oxidizing agent to generate the compound of Formula 12a, wherein
the oxidizing agent comprises MnO.sub.2;
##STR00219##
x) reacting a compound of Formula 12a with a reducing agent to
generate a compound of Formula 13a;
##STR00220##
xiv) converting the compound of Formula 13a to the compound of
Formula 15a;
##STR00221##
xii) hydrogenating a compound of Formula 15a in the presence of an
organic solvent (e.g., an alcohol (e.g., methanol, ethanol, or any
combination thereof), an optionally substituted THF (e.g.,
2-methyl-THF or THF), EtOAc, or any combination thereof) to
generate the compound of Formula 16a;
##STR00222##
xix) reacting a compound of Formula 16a with a reducing agent to
generate a compound of Formula 17a; xx) reacting the compound of
Formula 17a with TDPSCl under basic conditions to generate a
compound of Formula 18a;
##STR00223##
xxi) selectively deprotecting the compound of Formula 18a to
generate the compound of Formula 19a;
##STR00224##
xvii) reacting a compound of Formula 19a with
triisopropylbenzenesulfonyl chloride under basic conditions to
generate a compound of Formula 20a;
##STR00225##
xviii) reacting the compound of Formula 20a with methanol under
basic conditions to generate the compound of Formula 21a;
##STR00226##
xv) reacting a compound of Formula 21a with n-butyllithium in the
presence of an organic solvent and a transition metal catalyst to
generate a compound of Formula 22a; and
##STR00227##
xvi) converting the compound of Formula 22a to the compound of
Formula I.
[0347] In some implementations, the hydrogenation of the compound
of Formula 15a occurs in the presence of a base (e.g., potassium
carbonate or potassium bicarbonate).
[0348] Some methods further comprise the step of: xxiv) reacting
the compound of Formula I with diethanolamine in the presence of an
organic solvent to generate the diethanolamine salt of the compound
of Formula I.
[0349] Some methods further comprise the step of: xxva) treating
the compound of Formula I with an alkali metal hydroxide (e.g.,
NaOH, KOH, or like, or any combination thereof) in the presence of
an alcohol (e.g., ethanol, methanol, iso-propanol, or any
combination thereof) to generate the alkali metal salt (e.g., Na
salt) of the compound of Formula I.
[0350] In some implementations, the alkali metal hydroxide
comprises NaOH.
[0351] In other implementations, the alcohol comprises ethanol.
[0352] Alternatively, some methods further comprise the step of:
xxvi) treating the compound of Formula 25
##STR00228##
wherein R.sup.2 is defined above, with an alkali metal hydroxide
(e.g., NaOH, KOH, or like, or any combination thereof), in the
presence of an alcohol and water to generate the alkali metal salt
(e.g., Na salt) of the compound of Formula I.
[0353] In some implementations, the alcohol comprises methanol.
[0354] Some methods further comprise the step of: xxvii)
recrystallizing the diethanolamine salt of the compound of Formula
I to generate a first pure form of the diethanolamine salt of the
compound of Formula I. (e.g., about 90% or greater chemical purity,
about 95% or greater chemical purity, or about 97.5% or greater
chemical purity). Some methods further comprise the step of:
xxviii) reacting the first pure form of the diethanolamine salt of
the compound of Formula I with an acid to generate a second pure
form of the compound of Formula I (e.g., about 98% or greater
chemical purity, about 98.5% or greater chemical purity, or about
99% or greater chemical purity). And, some methods further comprise
the step of: xxvb) converting the second pure form of the compound
of Formula I to an alkali metal salt.
[0355] Another aspect of the present invention provides a compound
of Formula 21
##STR00229##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.3 is
independently C.sub.1-6 alkyl or phenyl.
[0356] In some embodiments, R.sup.1 is methyl, ethyl, propyl,
iso-propyl, butyl, sec-butyl, or tert-butyl.
[0357] In other embodiments, the --OSi(R.sup.3).sub.3 group is
selected from
##STR00230##
[0358] In some embodiments, R.sup.1 is methyl and the
--OSi(R.sup.3).sub.3 group is
##STR00231##
[0359] Another aspect of the present invention provides a compound
of Formula 1a
##STR00232##
[0360] Another aspect of the present invention provides a compound
of Formula 5
##STR00233##
wherein each of R.sup.2 is independently selected from a C.sub.1-6
alkyl or phenyl.
[0361] Another aspect of the present invention provides a compound
of Formula 9a
##STR00234##
wherein R.sup.1 is C.sub.1-6 alkyl.
[0362] Another aspect of the present invention provides a compound
of Formula 13
##STR00235##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.2 is
independently selected from C.sub.1-6 alkyl or phenyl.
[0363] Another aspect of the present invention provides a method of
purifying a compound of Formula 1
##STR00236##
comprising the steps of: xxx) reacting a compound of Formula 1 with
a derivatizing reagent to generate a precipitate that is
substantially insoluble in dichloromethane or mixture thereof
(e.g., a mixture comprising dicloromethane and an alkane (e.g.,
heptane) (e.g., a mixture comprising dichloromethane and about 50%
or more by volume heptane)); xxxi) collecting the precipitate and
refluxing the precipitate in a solvent comprising an alcohol to
generate the compound of Formula 1 having a chemical purity of
about 98% or greater (e.g., about 98.5% or greater, about 99% or
greater, or about 99.5% or greater) and an e.e. of about 98% or
greater (e.g., about 98.5% or greater, about 99% or greater, or
about 99.5% or greater); wherein the method excludes the use of any
column chromatography (e.g., HPLC).
[0364] In some implementations, the derivatizing reagent comprises
3,5-dinitrobenzoyl chloride and the alcohol comprises methanol.
[0365] Another aspect of the present invention provides a method of
purifying a compound of
##STR00237##
comprising the steps of: xl) reacting a compound of Formula 9,
wherein R.sup.1 is C.sub.1-6 alkyl, with 3,5-dinitrobenzoyl
chloride to generate a precipitate comprising a compound of Formula
9A; and
##STR00238##
xli) collecting the precipitate and treating the precipitate with a
base in the presence of an alcohol to generate the compound of
Formula 9 having a chemical purity of about 95% or greater (e.g.,
about 98% or greater, about 99% or greater, or about 99.5% or
greater); wherein the method excludes the use of any column
chromatography (e.g., HPLC).
[0366] Some methods further comprise the step of: xlii)
recrystallizing the precipitate of step xli).
[0367] Another aspect of the present invention provides a method of
generating a compound of Formula 5
##STR00239##
wherein each of R.sup.2 is independently selected from a C.sub.1-6
alkyl or phenyl, comprising the steps of: iv) refluxing the
compound of Formula 1a in the presence of methanol to generate a
compound of Formula 1 having an e.e. of greater than about 98%;
##STR00240##
v) reacting the compound of Formula 1 with SiCl(R.sup.2).sub.3,
wherein each R.sup.2 is independently C.sub.1-6 alkyl or phenyl,
under basic conditions to generate the compound of Formula 2;
##STR00241##
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to
generate the compound of Formula 3;
##STR00242##
l) deprotecting the compound Formula 3 under basic condition to
generate a compound of Formula 4, wherein each of R.sup.4 and
R.sup.5 are H or --OSi(R.sup.2).sub.3; and
##STR00243##
li) reacting the compound of Formula 4 with SiCl(R.sup.2).sub.3
under basic conditions to generate the compound of formula 5,
wherein the compound of Formula 5 has a chemical purity of about
98% or greater (e.g., about 98.5% or greater, about 99% or greater,
or about 99.5% or greater) and an e.e. of about 98% or greater
(e.g., about 98.5% or greater, about 99% or greater, or about 99.5%
or greater).
[0368] Steps iv)-vi) are discussed above.
[0369] Another aspect of the present invention provides a method of
generating a compound of Formula 13
##STR00244##
wherein R.sup.1 is C.sub.1-6 alkyl and each R.sup.2 is
independently selected from C.sub.1-6 alkyl or phenyl, comprising
the step of: x) reacting a compound of Formula 12 with
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole
in the presence of an organic solvent comprising THF and toluene to
generate a compound of Formula 13
##STR00245##
wherein the compound of Formula 13 has a chemical purity of greater
than about 97% (e.g., about 97.5% or greater, about 98% or greater)
and a d.e. of greater than about 97% (e.g., about 97.5% or greater,
about 98% or greater, or about 98.5% or greater).
[0370] Step x) is described in detail above.
IV. GENERAL SYNTHETIC SCHEME
[0371] General schemes for generating compounds of Formula I and
salts thereof are provided below.
##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250##
##STR00251## ##STR00252##
[0372] In the general schemes above, R.sup.1, R.sup.2, and R.sup.3
are as defined above.
[0373] Some methods of the present invention comprise one or more
of the following reaction conditions: [0374] Step xxx): 1.
3,5-dinitrobenzoyl chloride, DMAP, NEt.sub.3, CH.sub.2Cl.sub.2,
0.degree. C. to rt [0375] 2. recrystallization [0376] Step iv):
MeOH, reflux [0377] Step v): TBSCl, imidazole, DMF, 0.degree. C.
[0378] Step vi): 1-TMS-1-propyne, sec-BuLi, CuI, MTBE, -78.degree.
C. [0379] Step l): KOH, EtOH [0380] Step li): TBSCl, imidazole,
DMF, 0.degree. C. [0381] Step xxii): 3-bromoprop-1-ene, sec-BuLi,
Heptanes, 0.degree. C. [0382] Step xxiii): 1N aq. HCl, MeOH [0383]
Step xl): 1. 3,5-dinitrobenzoyl chloride, DMAP, NEt.sub.3,
CH.sub.2Cl.sub.2, 0.degree. C. to r.t. [0384] 2. recrystallization
[0385] Step xli): KOH, MeOH [0386] Step i): MnO.sub.2,
CH.sub.2Cl.sub.2 [0387] Step ii): compound of Formula 5, sec-BuLi,
THF, -78.degree. C. to r.t. [0388] Step viii): MnO.sub.2,
CH.sub.2Cl.sub.2 [0389] Step x):
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,
BH.sub.3, DMS, toluene/THF [0390] Step a): TBSCl, imidazole, DMF,
0.degree. C. [0391] Step b): 1. Co.sub.2(CO).sub.8,
CH.sub.2Cl.sub.2, rt [0392] 2. CH.sub.3CN, reflux [0393] Step xii):
H.sub.2, 10% Pd/C, K.sub.2CO.sub.3, MeOH or THF [0394] Step xix):
NaBH.sub.4, aq. NaOH, EtOH, -10.degree. C. [0395] Step xx):
TBDPSCl, imidazole, DMF, 50.degree. C. [0396] Step xxi): Aq. HCl,
THF/MeOH or TBAF, THF, 0.degree. C. [0397] Step xvii):
triisopropylbenzene-sulfonyl chloride, Et.sub.3N, DMAP,
CH.sub.2Cl.sub.2, 0.degree. C. to r.t. [0398] Step xviii):
K.sub.2CO.sub.3, MeOH [0399] Step xv): nBuLi, CuI, THF, -78.degree.
C. to r.t. [0400] Step c): Ph.sub.2PH, nBuLi, THF, -20.degree. C.
to reflux [0401] Step d): TBAF, THF, 50.degree. C. [0402] Step e):
R.sup.2 substituted 2-bromoacetate, K.sub.2CO.sub.3, KI, acetone
[0403] Step f): KOH, MeOH [0404] Step xxiv): diethanolamine, EtOAc,
EtOH, reflux to r.t. [0405] Step xxva): NaOH, EtOH [0406] Step
xxvb): NaOH, EtOH [0407] Step xxvi): NaOH, H.sub.2O, MeOH [0408]
Step xxvii): 3N aq. HCl, H.sub.2O
VI. ALTERNATIVE STEPS
[0409] The present invention also provides the following synthetic
steps, wherein one or more of the following steps may be optionally
substituted for one or more steps described above.
[0410] Step A1):
##STR00253##
[0411] Step A2):
##STR00254##
[0412] Steps A3) and A4):
##STR00255##
[0413] Steps A5)-A7):
##STR00256##
[0414] Steps A8)-A11):
##STR00257## ##STR00258##
[0415] Steps A12)-A23):
##STR00259## ##STR00260## ##STR00261##
[0416] Steps A24)-A30):
##STR00262## ##STR00263##
[0417] Steps A31) and A32)
##STR00264## ##STR00265##
[0418] Steps A37) and A38)
##STR00266##
VII. EXAMPLES
[0419] The following examples are not intended to limit the scope
of the present invention.
Example 1: (R)-oxiran-2-ylmethyl 3,5-dinitrobenzoate (1a)
##STR00267##
[0421] Triethylamine (8.52 g/mL, 84.2 mmol, 1.25 equiv) and
4-dimethylaminopyridine (100 mg, 0.818 mmol, 0.01 equiv) were added
to a solution of (S)-(-)-glycidol 1 (5.00 g, 67.5 mmol, 1.0 equiv,
99.5% ee) in anhydrous methylene chloride (100 mL) while stirring
under nitrogen. The reaction was then warmed to 30.degree. C. and
3,5-dinitrobenzoyl chloride (16.3 g, 70.9 mmol, 1.05 equiv) added
drop-wise over 20 minutes as a solution in anhydrous methylene
chloride (50 mL). After stirring at this temperature for 30
minutes, the reaction was quenched with addition of 10% aqueous
potassium bicarbonate (50 mL) and cooled to room temperature while
stirring for an additional 30 minutes. The two phases were
separated and the organic phase washed with 10% aqueous citric acid
(50 mL). The organic phase was then purified by filtration through
a plug of silica gel giving 14.69 g of a white solid that was shown
to be 99.4% e.e. by chiral HPLC. Recrystallization (180 mL of 3:2
v/v heptane-dichloromethane) afforded 11.5 g (64%) of the title
compound as a white solid. Data for 1a: R.sub.f=0.43 (100%
methylene chloride); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.25-9.28 (m, 1H), 9.21 (d, J=2.20 Hz, 2H), 4.82 (dd, J=2.93, 12.45
Hz, 1H), 4.20-4.33 (m, 1H), 3.42 (tdd, J=2.61, 4.07, 6.82 Hz, 1H),
2.92-3.04 (m, 1H), 2.77 (dd, J=2.75, 4.58 Hz, 1H); MS (ESI+) m/z
291.0 (M+Na.sup.+). HPLC, ChiralPak IA column (4.6.times.250
mm.sup.2), 5 mm; flow rate 1.0 mL/min; 210 nm; mobile phase heptane
(80%): ethanol (20%); retention time, 27.0 min, purity
(100.0%).
Example 2: (S)-(-)-glycidol (1, .about.100% ee)
##STR00268##
[0423] A solution of dinitrobenzoate 1a (30.06 g, 112.1 mmol, 1.0
equiv) in anhydrous methanol (190 mL) was heated to reflux for 2
hours while stirring, under nitrogen. The reaction was then cooled
to 0.degree. C. in an ice bath causing formation of a crystalline
solid that was removed by filtration and rinsed with ice cold
methanol (15 mL). The filtrate was concentrated under reduced
pressure resulting in formation of a white slurry that was
dissolved in tert-butyl methyl ether (20 mL) and concentrated to
dryness. The residue was again slurried in methanol (15 mL), the
solid removed by filtration and rinsed with more methanol (5 mL).
The filtrate was concentrated to give 7.6 g (92%) of the title
compound as a pale yellow oil. Data for 1: R.sub.f=0.12 (20%
EtOAc/heptane).
Example 3: (R)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane
(2a)
##STR00269##
[0425] To a 0.degree. C. solution of
tert-butyl(chloro)dimethylsilane (26.540 g, 176.21 mmol, 1.3 equiv)
and imidazole (14.786 g, 217.19 mmol, 1.6 equiv) in
dimethylformamide (80 mL) was added (S)-oxiran-2-yl methanol
(10.013 g, 135.16 mmol, 1.0 equiv) drop-wise and the resulting
mixture stirred at that temperature under nitrogen for 30 minutes.
The reaction was then quenched with addition of saturated aqueous
ammonium chloride (200 mL) and water (200 mL). The resulting
mixture was extracted with heptane (5.times.200 mL) and the
combined organic phases were washed with brine, dried (MgSO.sub.4)
and concentrated to give 25.142 g (99%) of the title compound as a
yellow oil. This material was used in the next step without
purification. Data for 2a: R.sub.f=0.64 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.85 (dd, J=3.22, 12.01
Hz, 1H), 3.66 (dd, J=4.69, 12.01 Hz, 1H), 3.05-3.12 (m, 1H), 2.76
(dd, J=4.25, 5.13 Hz, 1H), 2.63 (dd, J=2.64, 4.98 Hz, 1H), 0.90 (s,
9H), 0.08 (s, 3H), 0.07 (s, 3H).
Example 4:
(R)-1-((tert-butyldimethylsilyl)oxy)-6-(trimethylsilyl)hex-5-yn-
-2-ol (3a)
##STR00270##
[0427] To a 3-neck flask fitted with a mechanical stirrer, a
thermocouple and addition funnel was charged
1-(trimethylsilyl)-1-propyne (120.0 g, 1.07 mol, 2.2 equiv)
followed by tert-butyl methyl ether (600 mL) while being kept under
nitrogen. The solution was cooled to 0.+-.5.degree. C. while
stirring and sec-butyllithium (696 mL, mmol, 2.0 equiv, 2 M in
cyclohexane) was added slowly while maintaining the reaction
temperature below 5.degree. C. After complete addition, the
resulting mixture was stirred at 0.+-.5.degree. C. under nitrogen
for three hours. In a separate 3-neck flask fitted with a
mechanical stirrer, a thermocouple, and addition funnel was charged
epoxide 2a (92.5 g, 0.49 mol, 1.0 equiv) followed by tert-butyl
methyl ether (1800 mL) and copper iodide (18.6 g, 0.1 mol, 0.2
equiv) while being kept under nitrogen. The resulting mixture was
cooled to -78.degree. C..+-.5.degree. C. and then the
1-(trimethylsilyl)-1-propyne solution was cannulated into the
epoxide reaction mixture. The resulting reaction mixture was
allowed to slowly warm to room temperature. After stirring for 18
hours, the reaction was judged complete by TLC. The reaction was
quenched with addition of 5% aqueous citric acid (1500 mL), the
layers were separated and the lower aqueous layer was extracted
with heptane (1000 mL). The combined organic phases were filtered
through a pad of celite (150 g) and the filtrate was concentrated
under reduced pressure to give 147 g (.about.100%) of the title
compound as a dark yellow/brown oil. This material was used in the
next step without purification. Data for 3a: R.sub.f=0.55 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.72-3.82
(m, 1H), 3.65 (dd, J=3.81, 9.96 Hz, 1H), 3.45 (dd, J=7.03, 9.96 Hz,
1H), 2.47 (d, J=3.81 Hz, 1H), 2.34-2.42 (m, 2H), 1.63 (q, J=7.13
Hz, 2H), 0.91 (s, 9H), 0.14 (s, 9H), 0.08 (s, 6H); MS (ESI+) m/z
324.4 (M+Na.sup.+).
Example 5: (R)-1-((tert-butyldimethylsilyl)oxy)hex-5-yn-2-ol
(4a)
##STR00271##
[0429] To a 3-neck flask fitted with a mechanical stirrer and
thermocouple was charged
(R)-1-((tert-butyldimethylsilyl)oxy)-6-(trimethylsilyl)hex-5-yn-2-ol
3a (147 g, 489 mmol, 1 equiv) dissolved in ethanol (1200 mL) under
nitrogen. Solid potassium hydroxide pellets (55 g, 980 mmol, 2.0
equiv) was added and the resulting solution was stirred at room
temperature for 2 hours. After completion of the reaction as judged
by TLC, the reaction mixture was concentrated under reduced
pressure. The crude residue was treated with heptane (1000 mL) and
10% citric acid solution (1700 mL) and the resulting mixture was
stirred for 5 minutes. The layers were separated and the lower
aqueous layer was extracted with heptane (700 mL). The combined
organic phases were filtered through a pad of celite (120 g) and
concentrated under reduced pressure to give 85 g (77%) of the title
compound as a light brown oil. This material was an unquantified
mixture of regioisomers due to migration of the silyl protecting
group that was used in the next step without further purification.
Purification of a small amount of crude 4a by chromatography (0% to
25% ethyl acetate/heptane gradient) provided analytically pure
samples of 4b and 4c. Data for 4b: R.sub.f=0.50 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.73-3.84
(m, 1H), 3.60-3.68 (m, 1H), 3.44 (dd, J=7.14, 10.07 Hz, 1H), 2.45
(br. s., 1H), 2.35 (dt, J=2.56, 7.14 Hz, 2H), 1.95 (t, J=2.56 Hz,
1H), 1.59-1.67 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (ESI+) m/z
229.2 (M+H+). Data for 4c: R.sub.f=0.40 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 3.84-3.97 (m, 1H),
3.56-3.66 (m, 1H), 3.43-3.54 (m, 1H), 2.25 (dt, J=2.56, 7.14 Hz,
2H), 1.96 (t, J=2.75 Hz, 1H), 1.89 (br. s., 1H), 1.65-1.81 (m, 2H),
0.78-0.98 (m, 9H), 0.12 (s, 3H), 0.10 (s, 3H); MS (ESI+) m/z 229.2
(M+H+).
Example 6:
(R)-5-(but-3-yn-1-yl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8--
disiladecane (5a)
##STR00272##
[0431] To a 3-neck flask fitted with a mechanical stirrer, a
thermocouple and addition funnel was charged
tert-butyldimethylsilyl chloride (59.0 g, 391 mmol, 1.05 equiv) and
imidazole (40.5 g, 595 mmol, 1.6 equiv) in dimethylformamide (1100
mL). The solution was cooled to 0.+-.5.degree. C. while stirring.
Then, a solution of
(R)-1-((tert-butyldimethylsilyl)oxy)hex-5-yn-2-ol 4a (85 g, 372
mmol, 1.0 equiv) dissolved in dimethylformamide (200 mL) and added
slowly to the reaction while maintaining the temperature below
5.degree. C. Upon complete addition, the resulting mixture was
stirred at 0.+-.5.degree. C. under nitrogen for three hours and
then was slowly warmed up to room temperature and stir under
nitrogen for at least 15 hrs. The reaction mixture was then diluted
with methyl tert-butyl ether (1500 mL) and quenched with 5% aqueous
citric acid (1500 mL). The layers were separated and the lower
aqueous layer was extracted with methyl tert-butyl ether
(3.times.1000 mL). The combined organic phases were washed with 14%
aqueous sodium chloride, and concentrated under reduced pressure to
give an orange oil. Chromatography (1% to 10% ethyl acetate/heptane
gradient) afforded 114 g (90%) of the title compound as a yellow
oil. Data for 5a: R.sub.f=0.89 (20% EtOAc/heptane); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 3.72-3.84 (m, 1H), 3.56 (dd, J=5.13,
10.25 Hz, 1H), 3.41 (dd, J=6.59, 9.89 Hz, 1H), 2.19-2.35 (m, 2H),
1.90-1.95 (m, 1H), 1.75-1.89 (m, 1H), 1.54-1.66 (m, 1H), 0.90 (s,
9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 6H); MS
(ESI+) m/z 343.2 (M+H.sup.+). Chiral GC, Restek bDEXm column (30
m.times.0.32 mm), 65.degree. C. for 40 min, 10.degree. C./min to
130.degree. C., 20.degree. C./min to 200.degree. C., 1 mL
injection; retention time, 43.49 min (.about.100% 5a); Chemical
Purity GC, Restek Stabilwax column (30 m.times.0.32 mm), 60.degree.
C. for 2 min, 10.degree. C./min to 230.degree. C., 1 mL injection;
retention time, 10.82 min (90.0% 5a).
Example 7: tert-butyl((3-methoxybenzyl)oxy)dimethylsilane (7b)
##STR00273##
[0433] To a solution of 3-methoxybenzyl alcohol 6 (2500 g, 18.09
mol, 1.0 equiv) in dichloromethane (20 L, 8 volumes) was added
imidazole (1466 g, 21.53 mol, 1.19 equiv) and the solution cooled
to 15.degree. C. while stirring under nitrogen. Once cooled, the
solution was charged with tert-butyl(chloro)dimethyl-silane (3164
g, 20.99 mol, 1.16 equiv) over the next 9 minutes during which time
an exotherm of 42.9.degree. C. was observed. The reaction was then
cooled to room temperature while stirring for 17 hours. The
reaction was then quenched with 5% aqueous citric acid (20 L, 8
volumes) and the lower organic phase concentrated to give 4958 g of
a pale yellow oil. Vacuum distillation done in two batches (bp
ranges 115-120.degree. C., 132-135.degree. C. at 5 torr) afforded
2336 g and 1964 g of a clear colorless oil, which totaled 4300 g
(94%) of the title compound. Data for 7b: R.sub.f=0.27 (1%
EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.25 (t,
J=8.1 Hz, 1H), 6.91 (m, 1H), 6.79 (dd, J=2.4, 8.2 Hz, 2H), 4.74 (s,
2H), 3.82 (s, 3H), 0.96 (s, 9H), 0.11 (s, 6H); MS (ESI+) m/z 275.2
(M+Na.sup.+).
Example 8: ((2-allyl-3-methoxybenzyl)oxy)(tert-butyl)dimethylsilane
(8b)
##STR00274##
[0435] A solution of silane 7b (2660 g, 10.54 mol, 1.0 equiv) in
heptane (13.30 L, 5 volumes) was treated drop-wise with
sec-butyllithium (15.81 L, 22.13 mol, 2.1 equiv, 1.4 M in
cyclohexane) over a period of 2 hours. The reaction was stirred at
room temperature for 2 additional hours before cooling to 0.degree.
C. Once cooled, the reaction was treated drop-wise with allyl
bromide (2805 g, 23.18 mol, 2.2 equiv) over the next 70 minutes. An
exotherm of 17.6.degree. C. was observed, and the reaction warmed
to room temperature over the next 38 minutes. The reaction was
stirred at room temperature for 20 hours and was then quenched with
20% aqueous ammonium chloride (13.30 L, 5 volumes). The organic
phase was washed with 14% aqueous sodium chloride (5.32 L, 2
volumes) and was concentrated to give 3274 g of yellow oil. This
material was deemed sufficiently pure to be carried forward. Data
for 8b: R.sub.f=0.64 (5% EtOAc/heptane); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.22 (t, J=8.1 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H),
6.82 (d, J=8.4 Hz, 1H), 5.92 (m, 1H), 4.93 (m, 2H), 4.74 (s, 2H),
3.82 (s, 3H), 3.41 (dt, J=1.6, 6.0 Hz, 2H), 0.95 (s, 9H), 0.10 (s,
6H); MS (ESI+) m/z 315.2 (M+Na.sup.+).
Example 9: (2-allyl-3-methoxyphenyl)methanol (9b)
##STR00275##
[0437] To a solution of silane 8b (3082 g, 10.54 mol, 1.0 equiv,
theoretical weight) in methanol (30.82 L, 10 volumes) was added 6N
aqueous hydrochloric acid (8.43 L, 8.431 mol, 0.8 equiv) and the
reaction stirred at room temperature for 2 hours. The reaction was
quenched with drop-wise addition of 10% aqueous potassium
bicarbonate (15.41 L, 5 volumes) and then evaporated until
approximately 10 volumes of methanol were removed. The resulting
aqueous solution was extracted with ethyl acetate (15.41 L, 10
volumes). The combined organic phases were washed with 7% sodium
chloride (15.41 L, 5 volumes) and concentrated to give 2582 g of a
brown oil. Vacuum distillation (bp range 132-135.degree. C. at 5
torr) afforded 1558 g (83%, 2 steps) of the title compound as a
yellow oil. This material was deemed sufficiently pure to be
carried forward. Data for 9b: R.sub.f=0.36 (30% EtOAc/heptane);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.24 (t, J=8.1 Hz, 1H),
7.03 (d, J=7.7 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.01 (m, 1H), 4.97
(dq, J=1.8, 10.0 Hz, 1H), 4.92 (dq, J=1.9, 17.1 Hz, 1H), 4.70 (s,
2H), 3.84 (s, 3H), 3.52 (dt, J=1.7, 5.9 Hz, 2H); MS (ESI+) m/z
201.1 (M+Na.sup.+).
Example 10: 2-allyl-3-methoxybenzyl 3,5-dinitrobenzoate (9c)
##STR00276##
[0439] To a 0.degree. C. solution of alcohol 9b (1558 g, 11.28 mol,
1.0 equiv) in dichloromethane (7.789 L, 5 volumes) was added
3,5-dinitrobenzoyl chloride (2860 g, 12.40 mol, 1.1 equiv) and
4-dimethylamino-pyridine (206.6 g, 1.690 mol, 0.15 equiv) resulting
in an exotherm of 12.6.degree. C. The reaction was cooled back to
0.degree. C. and triethylamine (1.729 L, 12.40 mol, 1.1 equiv) was
added drop-wise over the next 57 minutes, during which time an
exotherm of 17.6.degree. C. was observed. Upon completion of the
triethylamine addition, the reaction was quenched with 10% aqueous
potassium bicarbonate (7.789 L, 5 volumes) which generated an
exotherm of 19.8.degree. C. The lower organic layer was washed with
10% aqueous citric acid (7.789 L, 5 volumes) and concentrated to
give 4118 g of a light brown amorphous solid. The crude solid was
suspended in methanol (41.18 L, 10 volumes based on crude quantity)
and was heated to 65.degree. C. over 94 minutes to fully dissolve
the solid. The solution was then cooled back to room temperature
and the precipitated solid was isolated by filtration. The solid
was vacuum dried at 40.degree. C. for 20 hours to afford 2131 g
(65%) of the title compound as a light yellow solid. This material
was deemed sufficiently pure to be carried forward. Data for 9c:
R.sub.f=0.45 (30% EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.22 (t, J=2.2 Hz, 1H), 9.16 (d, J=2.2 Hz, 2H), 7.28 (t,
J=8.1 Hz, 1H), 7.08 (dd, J=0.9, 7.5 Hz, 1H), 6.97 (d, J=8.1 Hz,
1H), 5.99 (ddt, J=5.8, 10.1, 17.2 Hz, 1H), 5.49 (s, 2H), 4.98 (dq,
J=1.8, 17.2 Hz, 1H), 4.89 (dq, J=1.7, 10.1 Hz, 1H), 3.87 (s, 3H),
3.57 (dt, J=1.8, 5.9 Hz, 2H); MS (ESI+) m/z 395.1 (M+Na.sup.+).
Example 11: (2-allyl-3-methoxyphenyl)methanol (9b)
[0440] To a slurry of dinitrobenzoate 9c (3463 g, 9.302 mol, 1.0
equiv) in methanol (17.32 L, 5 volumes) was added potassium
hydroxide (719.9 g, 11.16 mol, 1.2 equiv) and water (3.463 L, 1
volume), generating an exotherm of 37.7.degree. C. The reaction was
cooled to room temperature while stirring over 1 hour and was then
concentrated until 5 volumes of methanol was removed. The resulting
slurry was dissolved in 10% aqueous citric acid (17.32 L, 5
volumes) and extracted with dichloromethane (17.32 L, 5 volumes).
The solid dinitrobenzoic acid byproduct was removed by filtration
and the filtrate was washed with 10% aqueous potassium carbonate
(9.02 L, 5 volumes) and concentrated to afford 1464 g (88%) of the
title compound as a dark green oil. This material was deemed
sufficiently pure to be carried forward. Data for 9b: R.sub.f=0.36
(30% EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.24
(t, J=8.1 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H),
6.01 (m, 1H), 4.96 (m, 2H), 4.70 (s, 2H), 3.84 (s, 3H), 3.52 (dt,
J=1.6, 6.0 Hz, 2H); MS (ESI+) m/z 201.1 (M+Na.sup.+).
Example 12: 2-Allyl-3-Methoxybenzaldehyde (10b)
##STR00277##
[0442] Manganese (IV) oxide (85.00 g, 977.6 mmol, 10.0 equiv) was
added to a solution of alcohol 9b (17.424 g, 97.761 mmol, 1.0
equiv) in anhydrous methylene chloride (5 mL) and the mixture
stirred under nitrogen for 16 hours. The reaction was then filtered
through celite, the solids washed with heptane and the filtrate
concentrated to give 534 mg (99%) of the title compound as a pale
oil. Data for 10b: R.sub.f=0.64 (30% EtOAc/heptane); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 10.28 (s, 1H), 7.49 (dd, J=1.1, 7.7
Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.13 (dd, J=0.9, 8.2 Hz, 1H), 6.02
(ddt, J=5.9, 10.0, 17.1 Hz, 1H), 5.02 (dq, J=1.6, 10.1, 5.0 Hz,
1H), 4.93 (dq, J=1.7, 17.2, 4.9 Hz, 1H), 3.88 (s, 3H), 3.86 (dt,
J=1.8, 5.9 Hz, 2H); MS (ESI+) m/z 199.1 (M+Na.sup.+).
Example 13:
(6R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)hep-
t-2-yn-1-ol (11c)
##STR00278##
[0444] A solution of alkyne 5a (1.070 g, 3.121 mmol, 1.1 equiv) in
anhydrous MTBE (11 mL) that had been cooled to -78.degree. C. was
treated drop-wise with sec-butyllithium (2.20 mL, 3.12 mmol, 1.1
equiv, 1.4 M solution in cyclohexane) and the resulting mixture
stirred at that temperature under nitrogen for 30 minutes. Then,
aldehyde 10b (500 mg, 2.83 mmol, 1.0 equiv) was added drop-wise as
a solution in MTBE (4 mL) and the reaction allowed to slowly warm
to room temperature. After stirring for 17 hours, the reaction was
quenched with addition of 10% aqueous citric acid (30 mL) and
extracted with heptane (3.times.30 mL). The combined organic phases
were then washed with brine and concentrated to give 1.6 g of a
yellow oil. Chromatography (0% to 15% ethyl acetate/heptane
gradient) afforded 1.340 g (91%) of the title compound as a pale
yellow oil. Data for 11c: R.sub.f=0.60 (20% EtOAc/heptane); .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.35 (d, J=7.91 Hz, 1H),
7.19-7.29 (m, 1H), 6.87 (dd, J=0.88, 8.20 Hz, 1H), 5.93-6.08 (m,
1H), 5.64 (s, 1H), 4.90-5.03 (m, 2H), 3.83 (s, 3H), 3.71-3.80 (m,
1H), 3.60-3.70 (m, 1H), 3.50-3.60 (m, 2H), 3.40 (dd, J=6.74, 9.96
Hz, 1H), 2.25-2.44 (m, 2H), 2.04 (br. s., 1H), 1.76-1.90 (m, 1H),
1.60 (dtd, J=6.30, 7.67, 13.81 Hz, 1H), 0.90 (s, 9H), 0.88 (s, 9H),
0.05 (s, 12H); MS (ESI+) m/z 541.4 (M+Na.sup.+).
Example 14:
(R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)hept-
-2-yn-1-one (12b)
##STR00279##
[0446] Manganese (IV) oxide (869 mg, 10.0 mmol, 10.0 equiv) was
added to a solution of alcohol 11c (540 mg, 1.04 mmol, 1.0 equiv)
in anhydrous methylene chloride (5 mL) and the mixture stirred
under nitrogen for 16 hours. The reaction was then filtered through
celite, the solids washed with heptane and the filtrate
concentrated to give 534 mg (99%) of the title compound as a pale
oil. Data for 12b: R.sub.f=0.62 (normal phase, 20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (dd, J=1.17, 7.81
Hz, 1H), 7.24-7.35 (m, 1H), 7.07 (dd, J=0.78, 8.20 Hz, 1H),
5.90-6.06 (m, 1H), 4.86-5.09 (m, 2H), 3.86 (s, 3H), 3.75-3.84 (m,
3H), 3.58 (dd, J=5.27, 9.96 Hz, 1H), 3.41 (dd, J=6.84, 9.96 Hz,
1H), 2.44-2.66 (m, 2H), 1.87-2.01 (m, 1H), 1.72 (dtd, J=5.86, 7.81,
13.67 Hz, 1H), 0.90 (s, 9H), 0.89 (s, 9H), 0.08 (s, 6H), 0.06 (s,
6H); MS (ESI+) m/z 517.2 (M+H.sup.+).
Example 15:
(1S,6R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)-
hept-2-yn-1-ol (13c)
##STR00280##
[0448] Aryl ketone 12b (95.7 g, 185 mmol, 1.0 equiv) was dissolved
in THF (1900 mL) under nitrogen.
(R)-(+)-2-methyl-CBS-oxazaborolidine (222 mL, 222 mmol, 1.2 equiv,
1 M solution in toluene) was added and the resulting mixture cooled
to -50.degree. C..+-.5.degree. C. Borane-methyl sulfide complex
(370 mL, 370 mmol, 4.0 equiv, 2.0 M solution in THF) was then added
drop-wise over 20 minutes. After stirring at -50.degree. C. for 75
minutes, the mixture was cautiously quenched with drop-wise
addition of methanol (600 mL) and subsequently warmed to room
temperature while stirring overnight. The quenched mixture was
cooled to 0.degree. C., diluted with ethyl acetate (2000 mL) and
treated with 5% aqueous citric acid (1500 mL). The layers were
separated and the aqueous phase was further extracted with ethyl
acetate (2.times.1500 mL). The combined organic phases were washed
with 14% sodium chloride solution (1500 mL) and concentrated under
reduced pressure. The crude oil was chased with heptane
(2.times.500 mL) to afford 96.35 g of a pale oil. This material was
deemed sufficiently pure to be carried forward crude. Data for 13c:
Rf=0.58 (20% EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.35 (dd, J=1.03, 7.76 Hz, 1H), 7.20-7.29 (m, 1H), 6.87
(dd, J=0.88, 8.20 Hz, 1H), 6.00 (tdd, J=5.64, 10.18, 17.21 Hz, 1H),
5.63 (br. s., 1H), 4.87-5.06 (m, 2H), 3.83 (s, 3H), 3.75 (dddd,
J=4.25, 5.27, 6.66, 7.84 Hz, 1H), 3.61-3.69 (m, 1H), 3.51-3.61 (m,
2H), 3.40 (dd, J=6.74, 9.96 Hz, 1H), 2.26-2.42 (m, 2H), 2.06 (br.
s., 1H), 1.78-1.90 (m, 1H), 1.60 (dtd, J=5.86, 7.95, 13.70 Hz, 1H),
0.90 (s, 9H), 0.88 (s, 9H), 0.05 (s, 12H); MS (ESI+) m/z 541.2
(M+Na+); HPLC, ChiralPak IA column (4.6.times.250 mm2), 5 mm; flow
rate 1.0 mL/min; 210 nm; mobile phase heptane (99%): 2-propanol
(1%): trifluoroacetic acid (0.1%); retention time, 8.66 min (1.2%,
(1R,6R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsil-
yl)oxy)hept-2-yn-1-ol), retention time, 9.48 min (98.8%, 13c).
Example 16:
(5S,10R)-5-(2-allyl-3-methoxyphenyl)-10-((tert-butyldimethylsilyl)oxy)-2,-
2,3,3,13,13,14,14-octamethyl-4,12-dioxa-3,13-disilapentadec-6-yne
(14c)
##STR00281##
[0450] Imidazole (1.732 g, 25.44 mmol, 1.2 equiv) and
tert-butyl(chloro)dimethylsilane (3.545 g, 23.32 mmol, 1.1 equiv)
were added to a stirred, 0.degree. C. solution of alkynol 13c
(11.002 g, 21.20 mmol, 1.0 equiv) in anhydrous DMF under nitrogen
and the mixture was then warmed to room temperature. The reaction
was then quenched with addition of saturated aqueous ammonium
chloride (100 mL) and water (100 mL). The resulting mixture was
extracted with heptane (3.times.200 mL) and the combined organic
phases were washed with water, brine, dried (MgSO.sub.4) and
concentrated to give 13.351 g (99%) of the title compound as a pale
yellow oil. This material was deemed sufficiently pure to be
carried forward. Data for 14c: R.sub.f=0.82 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CDCL.sub.3) .delta. 7.25-7.32 (m, 1H),
7.18-7.25 (m, 1H), 6.82 (d, J=8.20 Hz, 1H), 5.88-6.04 (m, 1H), 5.58
(s, 1H), 4.88-5.03 (m, 2H), 3.82 (s, 3H), 3.67-3.76 (m, 1H),
3.57-3.66 (m, 1H), 3.46-3.57 (m, 2H), 3.37 (dd, J=6.45, 9.96 Hz,
1H), 2.16-2.34 (m, 2H), 1.70-1.85 (m, 1H), 1.47-1.60 (m, 1H), 0.91
(s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H),
0.04 (s, 12H); MS (ESI+) m/z 655.5 (M+Na.sup.+).
Example 17:
(4R,9aS)-3-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-4-((tert-buty-
ldimethylsilyl)oxy)-8-methoxy-9,9a-dihydro-1H-cyclopenta[b]naphthalen-2(4H-
)-one (15d)
##STR00282##
[0452] Cobalt carbonyl (7.197 g, 21.05 mmol, 1.0 equiv) was added
to a solution of compound 14c (13.326 g, 21.05 mmol, 1.0 equiv) in
anhydrous methylene chloride and the reaction stirred at room
temperature under nitrogen for 2 hours to allow for formation of
the cobalt-alkyne complex. The reaction was then concentrated by
rotary evaporation, the residue dissolved in anhydrous acetonitrile
and the mixture heated to reflux with stirring for 18 hours. The
reaction was then cooled to room temperature, filtered through
celite, and the precipitate washed with several portions of
acetone. The filtrate was concentrated to give 14.9 g of an amber
oil. Chromatography (0% to 20% ethyl acetate/heptane gradient)
afforded 13.803 g (99%) of the title compound as a colorless oil.
Data for 15d: R.sub.f=0.57 (20% EtOAc/heptane); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.24 (t, J=7.91 Hz, 1H), 6.91 (d, J=7.62
Hz, 1H), 6.79 (d, J=7.91 Hz, 1H), 5.51 (s, 1H), 3.83 (s, 3H),
3.61-3.71 (m, 1H), 3.30-3.59 (m, 4H), 2.70 (dd, J=6.45, 18.75 Hz,
1H), 2.35-2.48 (m, 1H), 2.10-2.32 (m, 3H), 1.57 (td, J=7.58, 15.01
Hz, 2H), 0.91 (s, 9H), 0.88 (s, 9H), 0.82 (s, 9H), 0.00-0.14 (m,
18H); MS (ESI+) m/z 683.4 (M+Na.sup.+).
Example 18a:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00283##
[0454] To a solution of tricyclic enone 15d (14.86 g, 22.48 mmol,
1.0 equiv) in absolute methanol (225 mL) was added anhydrous
potassium bicarbonate (743 mg, 5% w/w) and 10% Pd/C (3.715 g, 50%
wet, 25% w/w) and the mixture was hydrogenated with a balloon of
hydrogen gas while stirring at room temperature for 64 hours. The
reaction mixture was then filtered through celite, the residue
washed with several portions of ethanol, and the filtrate
concentrated to give a yellow oil. Triteration with heptane caused
formation of a small amount of precipitate that was filtered off,
and the filtrate concentrated to give 12.5 g of a viscous, yellow
oil. Chromatography (0% to 10% ethyl acetate/heptane gradient)
afforded 10.998 g (92%) of the title compound as a pale oil. Data
for 16d: R.sub.f=0.47 (20% EtOAc/heptane); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz,
2H), 3.84 (s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd,
J=6.84, 9.96 Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91
(d, J=8.98 Hz, 18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2
(M+H.sup.+).
Example 18b:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00284##
[0456] To a solution of tricyclic enone 15d (1.0 g, mmol, 1.0
equiv) in methanol (10 mL) was added anhydrous potassium carbonate
(53 mg, 5% w/w) and 10% Pd/C (100 mg, 50% wet, 10% w/w) and the
mixture was hydrogenated under 10 psi hydrogen gas while stirring
at room temperature for about 18 hours. The reaction mixture was
then filtered through celite, the residue was washed with several
portions of MTBE, and the filtrate concentrated to give a yellow
oil. Triteration with MTBE caused formation of a small amount of
precipitate that was filtered off, and the filtrate concentrated to
give 0.98 g of viscous, yellow oil. This material was deemed
sufficiently pure to be carried forward, but was purified for
analytical characterization. Chromatography (0% to 2.5% ethyl
acetate/heptane) afforded 0.711 g (88%) of the title compound as a
viscous, colorless oil. Data for 16d: R.sub.f=0.64 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.11 (t,
J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H), 3.62-3.76
(m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz, 1H),
2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H),
0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H.sup.+).
Example 18c:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00285##
[0458] To a solution of tricyclic enone 15d (500 mg, 0.756 mmol,
1.0 equiv) in ethyl acetate (7.5 mL) was added anhydrous potassium
carbonate (25 mg, 5% w/w) and 10% Pd/C (75 mg, 50% wet, 15% w/w).
The mixture was hydrogenated under 10 psi hydrogen gas while
shaking in a Parr flask at room temperature for 24 hours. The
reaction was then charged with additional 10% Pd/C (75 mg, 50% wet,
15% w/w), and hydrogenated under 10 psi hydrogen gas while shaking
in a Parr flask at room temperature for 24 more hours. At this
point the reaction was shown to be complete by TLC and was filtered
through celite, the residue was washed with several portions of
ethyl acetate, and the filtrate concentrated to give 404 mg of a
light yellow oil. Chromatography (0% to 5% ethyl acetate/heptane
gradient) afforded 290 mg (72%) of the title compound as a viscous,
colorless oil. Data for 16d: R.sub.f=0.47 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.11 (t, J=7.81 Hz,
1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H), 3.62-3.76 (m, 1H),
3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz, 1H), 2.10-3.08 (m,
8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H), 0.01-0.18 (m,
12H); MS (ESI+) m/z 533.2 (M+H.sup.+).
Example 18d:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00286##
[0460] To a solution of tricyclic enone 15d (1.000 g, 1.513 mmol,
1.0 equiv) in 2-methyltetrahydrofuran (15 mL) was added anhydrous
potassium carbonate (50 mg, 5% w/w) and 10% Pd/C (150 mg, 50% wet,
10% w/w) and the mixture was hydrogenated under 10 psi hydrogen gas
while stirring at room temperature for about 18 hours. The reaction
was then charged with additional 10% Pd/C (150 mg, 50% wet, 15%
w/w), and hydrogenated under 10 psi hydrogen gas while stirring at
room temperature for about 23 hours. At this point the reaction was
shown to be complete by TLC and was filtered through celite, the
residue was washed with several portions of ethyl acetate, and the
filtrate concentrated to give 984 mg of a light yellow oil.
Chromatography (0% to 5% ethyl acetate/heptane gradient) afforded
507 mg (63%) of the title compound as a viscous, colorless oil.
Data for 16d: R.sub.f=0.47 (20% EtOAc/heptane); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20
Hz, 2H), 3.84 (s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43
(dd, J=6.84, 9.96 Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H),
0.91 (d, J=8.98 Hz, 18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2
(M+H.sup.+).
Example 18e:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00287##
[0462] To a solution of tricyclic enone 15d (1.465 g, 2.216 mmol,
1.0 equiv) in absolute ethanol (225 mL) was added anhydrous
potassium carbonate (126 mg, 8.5% w/w) and 10% Pd/C (225 mg, 50%
wet, 15% w/w) and the mixture was hydrogenated at atmospheric
pressure of hydrogen gas while stirring at room temperature
overnight. The reaction mixture was then filtered through celite,
the residue washed with several portions of ethanol, and the
filtrate concentrated to give yellow oil. Triteration with heptane
caused formation of a small amount of precipitate that was filtered
off, and the filtrate was concentrated to give a viscous, yellow
oil. The crude oil was dissolved in ethanol (15 mL) and DI water (7
mL) was added slowly to the stirred solution. The white solid was
filtered and washed with a 1:1 mixture of ethanol and DI water. The
solid was dried under vacuum overnight to afford 985 mg (83%) of
the title compound as a white solid. Data for 16d: R.sub.f=0.47
(20% EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H),
3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz,
1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,
18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H.sup.+).
Example 18f:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00288##
[0464] To a solution of tricyclic enone 15d (1.425 g, 2.155 mmol,
1.0 equiv) in absolute ethanol (225 mL) was added anhydrous
potassium carbonate (116 mg, 8% w/w) and 10% Pd/C (220 mg, 50% wet,
15% w/w) and the mixture was hydrogenated under 10 psi of hydrogen
gas while stirring at room temperature overnight. The reaction
mixture was then filtered through celite, the residue washed with
several portions of ethanol, and the filtrate concentrated to give
a yellow oil. Triteration with heptane caused formation of a small
amount of precipitate that was filtered off, and the filtrate was
concentrated to give a viscous, yellow oil. The crude oil was
dissolved in ethanol (15 mL) and DI water (7 mL) was added slowly
to the stirred solution. The white solid was filtered and washed
with a 1:1 mixture of ethanol and DI water. The solid was dried
under vacuum overnight to afford 1.51 g (91%) of the title compound
as a white solid. Data for 16d: R.sub.f=0.47 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.11 (t, J=7.81 Hz,
1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H), 3.62-3.76 (m, 1H),
3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz, 1H), 2.10-3.08 (m,
8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H), 0.01-0.18 (m,
12H); MS (ESI+) m/z 533.2 (M+H.sup.+).
Example 18g:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00289##
[0466] To a solution of tricyclic enone 15d (2.0 g, 3.0 mmol, 1.0
equiv) in methanol (15 mL) was added anhydrous potassium carbonate
(141 mg, 7% w/w) and 10% Pd/C (294 mg, 50% wet, 15% w/w) and the
mixture was hydrogenated at atmospheric pressure of hydrogen gas
while stirring at room temperature overnight. The reaction was then
filtered through celite, the residue washed with several portions
of methanol, and the filtrate concentrated to give a yellow oil.
Triteration with heptane caused formation of a small amount of
precipitate that was filtered off. The filtrate was concentrated to
give a viscous, yellow oil. Chromatography (0% to 3% ethyl
acetate/heptane gradient) afforded 1.51 g (94%) of the title
compound as white solid. Data for 16d: R.sub.f=0.47 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.11
(t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H),
3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz,
1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,
18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H.sup.+).
Example 18h:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
##STR00290##
[0468] To a solution of tricyclic enone 15d (1.42 g, 2.15 mmol, 1.0
equiv) in methanol (15 mL) was added anhydrous potassium
bicarbonate (110 mg, 8% w/w) and 10% Pd/C (220 mg, 50% wet, 15%
w/w) and the mixture was hydrogenated at 10 psi of hydrogen gas
while stirring at room temperature for 24 hours. The reaction was
then charged with additional anhydrous potassium bicarbonate (110
mg, 8% w/w) and 10% Pd/C (220 mg, 50% wet, 15% w/w) and
hydrogenated under 10 psi hydrogen gas while stirring at room
temperature for about 24 hours. The reaction was then filtered
through celite, the residue washed with several portions of
methanol, and the filtrate concentrated to give a yellow oil.
Triteration with heptane caused formation of a small amount of
precipitate that was filtered off, and the filtrate concentrated to
give 12.5 g of a viscous, yellow oil. Chromatography (0% to 10%
ethyl acetate/heptane gradient) afforded 722 mg (63%) of the title
compound as a pale oil. Data for 16d: R.sub.f=0.47 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.11
(t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H),
3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz,
1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,
18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H.sup.+).
Examples 18i-18s:
(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a-
,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one (16d)
[0469] The hydrogenation of tricyclic enone 15d to generate ketone
16d was performed using a 10% Pd/C (50% wet) catalyst and other
reaction conditions provided in Table 1:
TABLE-US-00001 TABLE 1 Reaction conditions for the hydrogenation of
tricyclic enone 15d. H.sub.2 % yield Ex. # Catalyst Base (wt %)
Solvent pressure 16d i 15 wt % K.sub.2CO.sub.3 (5) MeOH 10 psi 76 j
15 wt % K.sub.2CO.sub.3 (5) EtOAc 10 psi 72 (x2) k 15 wt %
K.sub.2CO.sub.3 (5) THF 10 psi 102 (x2) l 15 wt % K.sub.2CO.sub.3
(5) THF 10 psi 100 (x2) m 15 wt % KHCO.sub.3 (2 .times. MeOH 10 psi
63 7.7) n 15 wt % KHCO.sub.3 (2 .times. MeOH atm 79 7.7) o 15 wt %
KHCO.sub.3 (8.2) EtOH 10 psi 83 p 15 wt % KHCO.sub.3 (7.4) EtOH atm
54 q 15 wt % K.sub.2CO.sub.3 (5) 2-Me- 10 psi 63 (x2) THF r 15 wt %
K.sub.2CO.sub.3 (5) EtOH 10 psi 64 s 15 wt % KHCO.sub.3 (5) EtOH 10
psi 87 (x2)
Example 19a:
(1R,2R,3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-meth-
oxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol
(17c)
##STR00291##
[0471] Sodium hydroxide (5.492 g in 28 mL of water, 20% solution in
water, 10 equiv) was added to a -10.degree. C. solution of ketone
16d (7.318 g, 13.73 mmol, 1.0 equiv) in absolute ethanol and the
reaction was stirred under nitrogen for 30 minutes. Then, sodium
borohydride (545 mg, 14.42 mmol, 1.05 equiv) was added in one
portion and the reaction maintained at -10.degree. C. for 1 hour
with stirring. At that point, an additional portion of sodium
borohydride (545 mg, 14.42 mmol, 1.05 equiv) was added and the
reaction stirred at -10.degree. C. for 17 hours. The reaction was
then cautiously quenched with addition of glacial acetic acid (10
mL), resulting in a pH of 6. This was diluted with brine (200 mL)
and warmed to room temperature. The mixture was extracted with
heptane (3.times.200 mL), the combined organic phases dried
(MgSO.sub.4) and concentrated to give a yellow oil. Chromatography
(0% to 15% ethyl acetate/heptane gradient) afforded 5.359 g (73%)
of the title compound as a viscous, colorless oil. Data for 17c:
R.sub.f=0.53 (20% EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.11 (t, J=7.91 Hz, 1H), 6.76 (dd, J=2.78, 7.76 Hz, 2H),
3.82 (s, 3H), 3.62-3.78 (m, 2H), 3.51-3.60 (m, 1H), 3.39-3.49 (m,
1H), 2.70-2.87 (m, 2H), 2.48 (ddd, J=6.59, 11.35, 14.57 Hz, 2H),
2.12-2.31 (m, 2H), 1.84-1.97 (m, 1H), 1.44-1.80 (m, 5H), 1.22-1.32
(m, 1H), 1.10-1.22 (m, 1H), 0.91 (s, 18H), 0.01-0.16 (m, 12H); MS
(ESI+) m/z 557.5 (M+Na.sup.+).
Example 19b:
(R)-4-((1R,2R,3aS,9aS)-2-hydroxy-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyc-
lopenta[b]naphthalen-1-yl)butane-1,2-diol (17d)
##STR00292##
[0473] Sodium hydroxide (648 mg in 3.2 mL of water, 20% solution in
water, 16.2 mmol, 10 equiv) was added to a -10.degree. C. solution
of ketone 16d (864 mg, 1.62 mmol, 1.0 equiv) in absolute ethanol
and the reaction was stirred under nitrogen for 30 minutes. Then,
sodium borohydride (68 mg, 1.80 mmol, 1.1 equiv) was added in one
portion and the reaction maintained at -10.degree. C. for 1 hour
with stirring. At that point, an additional portion of sodium
borohydride (68 mg, 1.80 mmol, 1.1 equiv) was added and the
reaction stirred at -10.degree. C. for 17 hours. The reaction was
then cautiously quenched with addition of 3 N aqueous HCl (10 mL)
until the pH was about 1, the reaction was warmed to room
temperature and stirred 2 hours until homogenous. This was
concentrated by rotary evaporation to remove the ethanol, diluted
with brine (10 mL) and the resulting white slurry extracted with a
solution of 10% ethanol/isopropyl acetate (3.times.20 mL). The
combined organic phases were dried (Na.sub.2SO.sub.4) and
concentrated to give 530 mg of an off-white solid. The crude
product was recrystallized by dissolving in refluxing ethyl acetate
(10 mL) and cooling back to room temperature giving 432 mg (87%) of
the title compound as a white solid. Data for 17d: R.sub.f=0.18
(100% EtOAc); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.07 (t,
J=7.87 Hz, 1H), 6.80 (d, J=8.42 Hz, 1H), 6.74 (d, J=7.32 Hz, 1H),
4.48 (d, J=5.49 Hz, 1H), 4.44 (t, J=5.31 Hz, 1H), 4.37 (d, J=4.39
Hz, 1H), 3.74 (s, 3H), 3.40-3.53 (m, 1H), 3.36-3.40 (m, 1H),
3.22-3.32 (m, 2H), 2.64 (ddd, J=6.59, 8.51, 14.56 Hz, 2H),
2.32-2.47 (m, 2H), 2.03-2.19 (m, 1H), 1.87-2.00 (m, 1H), 1.71-1.84
(m, 1H), 1.60-1.71 (m, 1H), 1.46-1.60 (m, 1H), 1.22-1.40 (m, 2H),
1.01-1.14 (m, 1H), 0.84-1.01 (m, 1H); MS (ESI+) m/z 329.2
(M+Na.sup.+).
Example 20a:
(R)-5-(2-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)ethyl)-2,2,3,3,8,8,9,9-
-octamethyl-4,7-dioxa-3,8-disiladecane (18d)
##STR00293##
[0475] Imidazole (1.017 g, 14.94 mmol, 1.5 equiv) and
tert-butyl(chloro)diphenylsilane (3.557 g, 12.94 mmol, 1.3 equiv)
were added to a stirred solution of alcohol 17c (5.326 g, 9.957
mmol, 1.0 equiv) in anhydrous DMF, under nitrogen, and the mixture
was then warmed to 50.degree. C. for 40 hours. The reaction was
then quenched with addition of saturated aqueous ammonium chloride
(100 mL) and extracted with heptane (3.times.100 mL). The combined
organic phases were washed with water, brine and concentrated to
give a pale yellow oil. Chromatography (0% to 10% ethyl
acetate/heptane gradient) afforded 7.186 g (93%) of the title
compound as a viscous, colorless oil. Data for 18d: R.sub.f=0.74
(20% EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.67
(dd, J=6.77, 14.46 Hz, 4H), 7.30-7.49 (m, 6H), 7.11 (t, J=7.69 Hz,
1H), 6.69-6.83 (m, 2H), 3.73-3.88 (m, 4H, contains s, 3H, 3.79),
3.53-3.65 (m, 1H), 3.43-3.52 (m, 1H), 3.32-3.43 (m, 1H), 2.92 (dd,
J=6.23, 14.65 Hz, 1H), 2.77 (dd, J=5.86, 14.28 Hz, 1H), 2.52 (dd,
J=8.79, 14.28 Hz, 1H), 2.28 (dd, J=8.42, 14.65 Hz, 1H), 1.96 (sxt,
J=8.06 Hz, 1H), 1.48-1.83 (m, 5H), 1.14-1.45 (m, 3H), 1.03 (s, 9H),
0.90 (d, J=4.03 Hz, 18H), 0.06 (t, J=3.30 Hz, 12H).
Example 20b:
(1R,2R,3aS,9aS)-1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-methoxy-
-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol (18e)
##STR00294##
[0477] PTSA.H.sub.2O (15 mg, 0.082 mmol, 0.05 equiv) was added to a
solution of 17d (500 mg, 1.53 mmol, 1.0 equiv) and
2,2-dimethoxypropane (0.40 mL, 3.2 mmol, 2.0 equiv) in anhydrous
DMF (5 mL), under nitrogen, and the mixture was stirred at room
temperature for 22 hours. The reaction was then quenched with
addition of saturated aqueous sodium bicarbonate (5 mL), diluted
with water (5 mL) and extracted with ethyl acetate (3.times.10 mL).
The combined organic phases were washed with brine, dried
(MgSO.sub.4) and concentrated to give 997 mg of a light brown oil.
Chromatography (25% to 60% ethyl acetate/heptane gradient) afforded
529 mg (94%) of the title compound as a colorless oil. Data for
18a: R.sub.f=0.32 (50% EtOAc/heptane); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.10 (t, J=7.87 Hz, 1H), 6.76 (t, J=8.24 Hz,
2H), 3.96-4.17 (m, 2H), 3.80 (s, 3H), 3.64-3.75 (m, 1H), 3.53 (t,
J=7.51 Hz, 1H), 2.76 (ddd, J=6.23, 12.27, 14.46 Hz, 2H), 2.41-2.59
(m, 2H), 2.19-2.33 (m, 1H), 2.09-2.19 (m, 1H), 2.05 (s, 1H),
1.56-1.95 (m, 4H), 1.44-1.55 (m, 1H), 1.42 (s, 3H), 1.37 (s, 3H),
1.21-1.32 (m, 1H), 1.06-1.19 (m, 1H); MS (ESI+) m/z 369.1
(M+Na.sup.+).
Example 20c:
Tert-butyl(((1R,2R,3aS,9aS)-1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethy-
l)-5-methoxy-2,3,3a,4,9,9a-hexahydro-H-cyclopenta[b]naphthalen-2-yl)oxy)di-
phenylsilane (18f)
##STR00295##
[0479] Imidazole (145 mg, 2.13 mmol, 1.4 equiv) and
tert-butyl(chloro)diphenylsilane (501 mg, 1.82 mmol, 1.2 equiv)
were added to a stirred solution of alcohol 18e (526 mg, 1.52 mmol,
1.0 equiv) in anhydrous DMF (7.5 mL), under nitrogen, and the
mixture was then warmed to 50.degree. C. for 19 hours. The reaction
was then quenched with water (10 mL) and extracted with heptane
(3.times.10 mL). The combined organic phases were washed with 14%
aqueous sodium chloride and concentrated to give 989 mg of a pale
yellow oil. Chromatography (0% to 10% ethyl acetate/heptane
gradient) afforded 882 mg (99%) of the title compound as a
colorless oil. Data for 18f: R.sub.f=0.55 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.69 (dt, J=6.59, 17.21
Hz, 4H), 7.32-7.49 (m, 6H), 7.12 (t, J=7.69 Hz, 1H), 6.77 (t,
J=8.06 Hz, 2H), 3.89-3.99 (m, 2H), 3.72-3.84 (m, 4H), 3.25-3.43 (m,
1H), 2.89 (dd, J=6.23, 14.65 Hz, 1H), 2.75 (dd, J=6.23, 14.28 Hz,
1H), 2.51 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=8.06, 14.65 Hz,
1H), 1.48-2.08 (m, 7H), 1.24-1.46 (m, 7H), 1.18 (td, J=4.94, 9.89
Hz, 1H), 1.04 (s, 9H).
Example 21a:
(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol
(19d)
##STR00296##
[0481] Aqueous 3N hydrochloric acid (10 mL) was added to a solution
of TBDMS ether 18d (4.411 g, 5.704 mmol, 1.0 equiv) in THF (30 mL)
and MeOH (10 mL) and the reaction stirred at room temperature for
27 hours. The reaction was then concentrated to remove the organic
solvents, diluted with water (50 mL), and extracted with EtOAc
(3.times.100 mL). The combined organic phases were washed with
saturated aqueous sodium bicarbonate, brine, dried
(Na.sub.2SO.sub.4) and concentrated to give a foamy oil.
Chromatography (20% to 80% ethyl acetate/heptane gradient) afforded
1.982 g (64%) of the title compound as a fluffy white solid. Data
for 19d: R.sub.f=0.26 (40% EtOAc/heptane); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.60-7.76 (m, 4H), 7.32-7.49 (m, 6H), 7.12 (t,
J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz, 2H), 3.72-3.85 (m, 4H, contains
s, 3H, 3.80), 3.48-3.59 (m, 2H), 3.27-3.39 (m, 1H), 2.90 (dd,
J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04, 14.10 Hz, 1H), 2.50 (dd,
J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74 Hz, 1H), 1.84-2.08
(m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz, 1H), 1.48-1.62
(m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H); MS (ESI+) m/z 567.5
(M+Na.sup.+).
Example 21b:
(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol
(19d)
##STR00297##
[0483] Tetra-n-butylammonium fluoride (2.75 mL, 2.75 mmol, 2.0
equiv, 1.0 M solution in THF) was added to an ice-cold solution of
TBDMS ether 18d (1.053 g, 1.362 mmol, 1.0 equiv) in THF (10 mL) and
the reaction stirred at 0.degree. C. for 3 hours. The reaction was
then quenched with saturated aqueous ammonium chloride (10 mL),
diluted with water (10 mL) and extracted with ethyl acetate
(3.times.20 mL). The combined organic phases were dried
(Na.sub.2SO.sub.4) and concentrated to give 1.03 g of a yellow oil.
Chromatography (30% to 100% ethyl acetate/heptane gradient)
afforded 616 mg (83%) of the title compound as a white, foamy
solid. Data for 19d: R.sub.f=0.26 (40% EtOAc/heptane); .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.60-7.76 (m, 4H), 7.32-7.49 (m,
6H), 7.12 (t, J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz, 2H), 3.72-3.85
(m, 4H, contains s, 3H, 3.80), 3.48-3.59 (m, 2H), 3.27-3.39 (m,
1H), 2.90 (dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04, 14.10 Hz,
1H), 2.50 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74 Hz,
1H), 1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz,
1H), 1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H); MS (ESI+)
m/z 567.3 (M+Na.sup.+).
Example 21c:
(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol
(19d)
##STR00298##
[0485] Aqueous hydrochloric acid (10 mL, 1 N solution) was added to
a solution of acetonide 18f (1.015 g, 1.735 mmol, 1.0 equiv) in THF
(10 mL) and the reaction stirred at room temperature for 46 hours.
It was then diluted with 14% aqueous sodium chloride (20 mL) and
extracted with isopropyl acetate (3.times.20 mL). The combined
organic phases were washed with saturated aqueous sodium
bicarbonate (40 mL), 14% aqueous sodium chloride (40 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give 1.066 g of a colorless
oil. Chromatography (40% to 100% ethyl acetate/heptane gradient)
afforded 670 mg (71%) of the title compound as a foamy white solid.
Data for 19d: R.sub.f=0.31 (50% EtOAc/heptane); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 7.58-7.81 (m, 4H), 7.31-7.51 (m, 6H),
7.11 (t, J=7.91 Hz, 1H), 6.77 (t, J=7.62 Hz, 2H), 3.73-3.85 (m, 4H,
contains s, 3H, 3.80), 3.47-3.62 (m, 2H), 3.27-3.40 (m, 1H), 2.90
(dd, J=6.15, 14.65 Hz, 1H), 2.74 (dd, J=6.15, 14.06 Hz, 1H), 2.50
(dd, J=8.20, 14.06 Hz, 1H), 2.34 (dd, J=7.91, 14.65 Hz, 1H),
1.83-2.09 (m, 2H), 1.64-1.82 (m, 3H), 1.48-1.62 (m, 2H), 1.14-1.46
(m, 4H), 0.96-1.11 (m, 9H); MS (ESI+) m/z 567.2 (M+Na.sup.+).
Example 21d:
(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol
(19d)
##STR00299##
[0487] Triethylamine trihydrofluoride (0.16 mL, 0.98 mmol, 3.0
equiv) was added to an ice-cold solution of TBDMS ether 18d (253
mg, 0.327 mmol, 1.0 equiv) in THF (2 mL) with stirring, under
nitrogen. The reaction was then warmed to 50.degree. C. for 18
hours at which point it was shown to be complete by TLC. The
reaction was quenched with saturated aqueous ammonium chloride (2
mL), diluted with water (2 mL) and extracted with ethyl acetate
(3.times.4 mL). The combined organic phases were dried
(Na.sub.2SO.sub.4) and concentrated to give 172 mg of a yellow oil.
Chromatography (30% to 100% ethyl acetate/heptane gradient)
afforded 99 mg (58%) of the title compound as a white, foamy solid.
Data for 19d: R.sub.f=0.26 (40% EtOAc/heptane); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 7.60-7.76 (m, 4H), 7.32-7.49 (m, 6H),
7.12 (t, J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz, 2H), 3.72-3.85 (m, 4H,
contains s, 3H, 3.80), 3.48-3.59 (m, 2H), 3.27-3.39 (m, 1H), 2.90
(dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04, 14.10 Hz, 1H), 2.50
(dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74 Hz, 1H),
1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz, 1H),
1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H).
Example 21e:
(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol
(19d)
##STR00300##
[0489] Pyridinium p-toluene sulfonate (5.52 g, 220 mmol) was added
to a solution of TBDMS ether 18d (17 g, 221 mmol, 1.0 equiv) in
ethanol (170 mL) and the reaction stirred at 40.degree. C. for 56
hours. The reaction was then quenched with 2 mL of pyridine, and
the resulting mixture concentrated to remove the organic solvents.
Chromatography (15% to 40% ethyl acetate/heptane gradient) afforded
9.48 g (78%) of the title compound as a fluffy white solid. Data
for 19d: R.sub.f=0.26 (40% EtOAc/heptane); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.60-7.76 (m, 4H), 7.32-7.49 (m, 6H),
7.12 (t, J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz, 2H), 3.72-3.85 (m, 4H,
contains s, 3H, 3.80), 3.48-3.59 (m, 2H), 3.27-3.39 (m, 1H), 2.90
(dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04, 14.10 Hz, 1H), 2.50
(dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74 Hz, 1H),
1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz, 1H),
1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H); MS (ESI+) m/z
567.3 (M+Na.sup.+).
Example 22:
(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-2-hydroxybutyl
2,4,6-triisopropylbenzenesulfonate (20d)
##STR00301##
[0491] Triethylamine (3.80 mL, 27.5 mmol, 4.0 equiv) and
4-dimethylaminopyridine (168 mg, 1.374 mmol, 0.2 equiv) were added
to a solution of diol 19d (3.744 g, 6.872 mmol, 1.0 equiv) in
anhydrous methylene chloride (30 mL) while stirring under nitrogen.
The reaction was then cooled to 0.degree. C. and
2,4,6-triisopropylbenzenesulfonyl chloride (2.498 g, 8.247 mmol,
1.2 equiv) added drop-wise as a solution in anhydrous methylene
chloride (10 mL). After stirring at this temperature for 15 hours,
the reaction was quenched with addition of saturated aqueous
ammonium chloride (50 mL) and warmed to room temperature. The two
phases were separated and the aqueous phase extracted with
methylene chloride (3.times.50 mL). The combined organics were
dried (MgSO.sub.4) and concentrated to give a dark yellow oil.
Chromatography (0% to 20% ethyl acetate/heptane gradient) afforded
4.797 g (86%) of the title compound as a white, foamy solid. Data
for 20d: R.sub.f=0.46 (20% EtOAc/heptane); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.55-7.73 (m, 4H), 7.29-7.46 (m, 6H), 7.22 (s,
2H), 7.11 (t, J=7.87 Hz, 1H), 6.75 (d, J=8.42 Hz, 2H), 4.15 (quin,
J=6.68 Hz, 2H), 3.92 (dd, J=2.56, 9.89 Hz, 1H), 3.58-3.84 (m, 6H,
contains s, 3H, 3.80), 2.81-3.03 (m, 2H), 2.71 (dd, J=6.23, 14.28
Hz, 1H), 2.46 (dd, J=8.06, 14.28 Hz, 1H), 2.26-2.40 (m, 1H),
1.81-2.09 (m, 3H), 1.69 (td, J=8.06, 16.11 Hz, 1H), 1.46-1.61 (m,
2H), 1.28 (m, 22H), 1.01 (s, 9H); MS (ESI+) m/z 828.8
(M+NH.sub.4.sup.+).
Example 23a:
tert-butyl(((1R,2R,3aS,9aS)-5-methoxy-1-(2-((R)-oxiran-2-yl)ethyl)-2,3,3a-
,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)oxy)diphenylsilane
(21c)
##STR00302##
[0493] Anhydrous potassium carbonate (1.592 g, 11.52 mmol, 2.0
equiv) was added to a solution of alcohol 20d (4.674 g, 5.762 mmol,
1.0 equiv) in anhydrous methanol (30 mL) and the mixture stirred
under nitrogen for 1 hour. The reaction was then concentrated, the
residue triterated in methylene chloride and filtered to remove the
precipitate. The filtrate was concentrated, and the residue
triterated in heptane, filtered to remove the precipitate and the
filtrate concentrated to give 3.032 g (99%) of the title compound
as a colorless oil. This material was deemed sufficiently pure to
be carried forward. Data for 21c: R.sub.f=0.50 (20% EtOAc/heptane);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.59-7.77 (m, 4H),
7.32-7.49 (m, 6H), 7.11 (t, J=7.69 Hz, 1H), 6.76 (t, J=8.24 Hz,
2H), 3.72-3.86 (m, 4H, contains s, 3H, 3.80), 2.89 (dd, J=6.23,
14.65 Hz, 1H), 2.66-2.84 (m, 3H), 2.50 (dd, J=8.06, 14.28 Hz, 1H),
2.35-2.44 (m, 1H), 2.32 (dd, J=8.06, 15.01 Hz, 1H), 1.92-2.05 (m,
1H), 1.79-1.90 (m, 1H), 1.22-1.77 (m, 7H), 1.04 (s, 9H); MS (ESI+)
m/z 549.5 (M+Na.sup.+).
Example 23b:
tert-butyl(((1R,2R,3aS,9aS)-5-methoxy-1-(2-((R)-oxiran-2-yl)ethyl)-2,3,3a-
,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)oxy)diphenylsilane
(21c)
##STR00303##
[0495] Anhydrous potassium carbonate (14.14 g, 102.3 mmol, 2.0
equiv) was added to a solution of alcohol 20d (41.5 g, 51.2 mmol,
1.0 equiv) in anhydrous methanol (415 mL) and the mixture stirred
under nitrogen for 24 hours. The reaction was then quenched with
14% aqueous sodium chloride solution (800 mL) and extracted with
heptane (3.times.800 mL). The combined organic phases were washed
with 14% aqueous sodium chloride solution (800 mL), dried
(MgSO.sub.4) and concentrated to give 26.3 g of a white waxy solid.
Chromatography (0% to 10% ethyl acetate/heptane gradient) afforded
24.1 g (89%) of the title compound (21c) as a white waxy solid. The
24.1 g of 21c obtained above was warmed to a gentle reflux in
heptane (240 mL, 10 volumes) until dissolved, cooled first to room
temperature and then to -20.degree. C. After standing at that
temperature overnight, white crystals had formed that were filtered
and dried under high vacuum to give 22.003 g of 21c (91% recovery).
HPLC analysis showed that the white waxy solid 21c material had a
purity of 91.07%, while the recrystallized 21c material had a
purity of 96.59%. This recrystallization process was repeated again
with 220 mL heptane giving 20.240 g (92% recovery) of 21c as a
white crystalline product. HPLC analysis showed further enrichment
to a purity of 97.46%. The 20.240 g of 21c obtained above was
warmed to a gentle reflux in heptane (200 mL, 10 volumes) until
dissolved, cooled first to room temperature and then to -20.degree.
C. After standing at that temperature overnight, white crystals had
formed which were filtered and dried at 40.degree. C. under high
vacuum to give 19.308 g of 21c (95% recovery). HPLC analysis showed
further enrichment to a purity of 98.19%. Data for 21c:
R.sub.f=0.50 (20% EtOAc/heptane); mp=78.5-79.5.degree. C.; .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 7.59-7.77 (m, 4H), 7.32-7.49
(m, 6H), 7.11 (t, J=7.69 Hz, 1H), 6.76 (t, J=8.24 Hz, 2H),
3.72-3.86 (m, 4H, contains s, 3H, 3.80), 2.89 (dd, J=6.23, 14.65
Hz, 1H), 2.66-2.84 (m, 3H), 2.50 (dd, J=8.06, 14.28 Hz, 1H),
2.35-2.44 (m, 1H), 2.32 (dd, J=8.06, 15.01 Hz, 1H), 1.92-2.05 (m,
1H), 1.79-1.90 (m, 1H), 1.22-1.77 (m, 7H), 1.04 (s, 9H); IR (KBr
pellet) 3427.7 (s), 3071.0 (m), 3049.8 (m), 2959.6 (s), 2928.6 (s),
2858.7 (m), 1797.0 (w), 1584.5 (s), 1473.4 (s), 1454.6 (m), 1428.1
(m), 1264.4 (s), 1109.4 (s), 1022.0 (m), 822.6 (w), 783.1 (w),
743.9 (w), 703.8 (s), 613.5 (w) cm.sup.-1; MS (ESI+) m/z 549.5
(M+Na.sup.+); HPLC, Regis (S,S) Whelk-01 column (4.6.times.250
mm.sup.2), 5 .mu.m; flow rate 1.0 mL/min; 210 nm; mobile phase
90:10 heptane/MTBE, 21c retention time: 20.14 min.
Example 24a:
(S)-1-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)heptan-3-ol
(22b)
##STR00304##
[0497] A slurry of epoxide 21c (56 mg, 0.11 mmol, 1.0 equiv) and
copper(I) iodide (4.0 mg, 0.021 mmol, 0.2 equiv) in anhydrous ether
(1.0 mL) that had been cooled to -78.degree. C. was treated
drop-wise with n-butyllithium (0.28 mL, 0.70 mmol, 6.6 equiv, 2.5 M
in hexanes) and the resulting mixture slowly warmed to -40.degree.
C. over 30 minutes while stirring under nitrogen. The cloudy yellow
mixture turned almost black in color during this time and the
reaction was shown to be complete by TLC. This was then quenched
with addition of saturated aqueous ammonium chloride (5 mL) and
warmed to room temperature. The deep blue aqueous layer was
extracted with ethyl acetate (3.times.5 mL). The combined organic
phases were washed with brine, dried (MgSO.sub.4) and concentrated
to give 60 mg of a colorless oil. Chromatography (0% to 20% ethyl
acetate/heptane gradient) afforded 52 mg (84%) of the title
compound as a colorless oil. Data for 22b: R.sub.f=0.42 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.59-7.77
(m, 4H), 7.31-7.51 (m, 6H), 7.11 (t, J=7.81 Hz, 1H), 6.71-6.81 (m,
2H), 3.73-3.85 (m, 4H, contains s, 3H, 3.80), 3.44 (br. s., 1H),
2.91 (dd, J=6.25, 14.45 Hz, 1H), 2.75 (dd, J=6.25, 14.45 Hz, 1H),
2.50 (dd, J=8.20, 14.06 Hz, 1H), 2.32 (dd, J=8.01, 14.65 Hz, 1H),
1.82-2.05 (m, 2H), 1.65-1.77 (m, 1H), 1.50-1.62 (m, 2H), 1.15-1.47
(m, 13H), 1.04 (s, 9H), 0.92 (t, J=7.03 Hz, 3H); MS (ESI+) m/z
607.2 (M+Na.sup.+).
Example 24b:
(S)-1-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,-
4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)hexan-3-yl acetate
(22c)
##STR00305##
[0499] A slurry of epoxide 21c (3.3 g, 6.3 mmol, 1.0 equiv) and
copper(I) iodide (148 mg, 0.78 mmol, 0.013 equiv) in methyl
tert-butyl ether (35.0 mL) that had been cooled to -40.degree. C.
was treated drop-wise with n-butyllithium (11.4 mL, 17.1 mmol, 2.74
equiv, 1.5 M solution in hexanes) and the resulting mixture stirred
under nitrogen. The cloudy yellow mixture turned almost black in
color during this time and the reaction was shown to be complete by
TLC. This was then treated with addition of ethyl acetate and
warmed to room temperature then quenched with aqueous ammonium
chloride (75 mL). The deep blue aqueous layer was extracted with
ethyl acetate (2.times.75 mL). The combined organic phases were
concentrated to give a colorless oil. Chromatography (0% to 2%
ethyl acetate/heptane gradient) afforded 3.3 g (88%) of the title
compound as a colorless oil. Data for 22c: R.sub.f=0.64 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.60-7.73 (m, 4H), 7.31-7.48 (m, 6H), 7.11 (t, J=7.69 Hz, 1H), 6.77
(dd, J=7.87, 16.30 Hz, 2H), 4.80 (d, J=5.86 Hz, 1H), 3.68-3.83 (m,
4H), 2.87 (dd, J=6.23, 14.65 Hz, 1H), 2.73 (dd, J=6.23, 13.92 Hz,
1H), 2.48 (dd, J=8.24, 14.10 Hz, 1H), 2.30 (dd, J=8.06, 15.01 Hz,
1H), 1.89-2.06 (m, 4H), 1.74-1.87 (m, 1H), 1.61-1.74 (m, 1H),
1.13-1.60 (m, 14H), 1.03 (s, 9H), 0.84-0.94 (m, 3H); MS (ESI+) m/z
649.4 (M+Na.sup.+).
Example 24c:
S)-1-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4-
,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)heptan-3-ol
(22b)
##STR00306##
[0501] To a solution of acetate 22c (3.3 g, 5.3 mmol, 1 equiv) in
methanol (90 mL) was added anhydrous potassium carbonate (3.5 g,
25.4 mmol, 4.8 equiv) and DI water (10 mL). The reaction was
stirred at 60.degree. C. for three hours and then cooled to room
temperature overnight. At that point the reaction was deemed
complete by TLC and the solvent was removed under reduced pressure.
The crude residue was extracted with dichloromethane (100 mL), the
organic layer passed through filter paper to remove the resulting
white solid, and the filtrate was concentrated to give 3.12 g of a
pale yellow solid (quantitative). Data for 22c: R.sub.f=0.42 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.59-7.77 (m, 4H), 7.31-7.51 (m, 6H), 7.11 (t, J=7.81 Hz, 1H),
6.71-6.81 (m, 2H), 3.73-3.85 (m, 4H, contains s, 3H, 3.80), 3.44
(br. s., 1H), 2.91 (dd, J=6.25, 14.45 Hz, 1H), 2.75 (dd, J=6.25,
14.45 Hz, 1H), 2.50 (dd, J=8.20, 14.06 Hz, 1H), 2.32 (dd, J=8.01,
14.65 Hz, 1H), 1.82-2.05 (m, 2H), 1.65-1.77 (m, 1H), 1.50-1.62 (m,
2H), 1.15-1.47 (m, 13H), 1.04 (s, 9H), 0.92 (t, J=7.03 Hz, 3H).
Example 25:
(1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-1-((S)-3-hydroxyoctyl)-2-
,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-ol (23a)
##STR00307##
[0503] A solution of n-butyllithium (6.80 mL, 17.0 mmol, 8.2 equiv,
2.5 M in hexanes) was added drop-wise to a -20.degree. C. solution
of diphenylphosphine (2.714 g, 14.58 mmol, 7.0 equiv) in THF (25
mL), under nitrogen, and stirred at that temperature for 30
minutes. Then, approximately 2/3 of this solution was cannulated
into a solution of methyl ether 22b in THF (5 mL) at room
temperature and the resultant mixture was heated to reflux for 2
hours while stirring, under nitrogen. The reaction was then cooled
to room temperature, the remainder of the
n-butyllithium/diphenylphosphine solution was cannulated over and
the reaction was heated back to reflux for 17 hours. At this point,
the reaction was cooled in an ice bath and cautiously quenched with
addition of 3 M aqueous hydrochloric acid until the pH is acidic.
The organic layer was separated and the aqueous phase extracted
with ethyl acetate (3.times.30 mL). The combined organic phases
were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated
to give 4.3 g of a colorless oil. Chromatography (0% to 40% ethyl
acetate/heptane gradient) afforded 1.101 g (93%) of the title
compound as a white, foamy solid. Data for 23a: R.sub.f=0.29 (20%
EtOAc/heptane); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.70 (dd,
J=7.32, 17.94 Hz, 4H), 7.32-7.51 (m, 6H), 6.96-7.06 (m, 1H), 6.75
(d, J=7.32 Hz, 1H), 6.67 (d, J=8.06 Hz, 1H), 3.82 (q, J=6.84 Hz,
1H), 3.49 (br. s., 1H), 2.84 (dd, J=6.23, 14.65 Hz, 1H), 2.75 (dd,
J=5.86, 14.28 Hz, 1H), 2.51 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd,
J=7.87, 14.46 Hz, 1H), 2.02 (dd, J=7.87, 15.93 Hz, 1H), 1.91 (td,
J=6.36, 12.54 Hz, 1H), 1.73 (quin, J=8.06 Hz, 1H), 1.50-1.65 (m,
2H), 1.15-1.49 (m, 13H), 1.07 (s, 9H), 0.87-0.97 (m, 3H); MS (ESI+)
m/z 593.3 (M+H.sup.+).
Example 26a:
(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclope-
nta[b]naphthalene-2,5-diol (24a)
##STR00308##
[0505] Tetra-n-butylammonium fluoride (2.90 mL, 2.90 mmol, 1.5
equiv, 1.0 M solution in THF) was added to a solution of
TBDPS-ether 23a (1.083 g, 1.897 mmol, 1.0 equiv) in anhydrous THF,
under nitrogen, and the mixture stirred at room temperature for 22
hours. Analysis by TLC indicated that the reaction was not
complete, so it was fitted with a water-cooled condenser and heated
to 50.degree. C. for 3.5 hours. The reaction was then quenched with
14% aqueous sodium chloride (20 mL) and extracted with ethyl
acetate (3.times.15 mL). The combined organic phases were dried
(Na.sub.2SO.sub.4) and concentrated to give 1.375 g of an amber
oil. Chromatography (12% to 100% ethyl acetate/heptane gradient)
afforded 484 mg (77%) of the title compound as a white foam. Data
for 24a: R.sub.f=0.12 (50% EtOAc/heptane); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.95 (t, J=7.51 Hz, 1H), 6.66 (dd, J=7.69,
13.55 Hz, 2H), 6.59 (br. s., 1H), 3.61-3.77 (m, 1H), 3.57 (br. s.,
1H), 3.02 (br. s., 1H), 2.58-2.76 (m, 2H), 2.34-2.56 (m, 3H),
2.17-2.30 (m, 1H), 2.03-2.14 (m, 1H), 1.79-1.93 (m, 1H), 1.64 (d,
J=7.32 Hz, 2H), 1.38-1.56 (m, 4H), 1.16-1.37 (m, 7H), 1.10 (q,
J=10.62 Hz, 1H), 0.85-0.96 (m, 3H); MS (ESI+) m/z 355.2
(M+Na.sup.+).
Example 26b:
(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclope-
nta[b]naphthalene-2,5-diol (24a)
##STR00309##
[0507] Triethylamine Trihydrofluoride (4.57 g, 28.3 mmol, 3.7
equiv) was added in portions to a solution of TBDPS-ether 23a (4.4
g, 7.7 mmol, 1.0 equiv) in anhydrous THF (45 mL), under nitrogen,
and the mixture stirred at 62.degree. C. for 5 days. Analysis by
TLC indicated that the reaction was complete. The reaction was then
quenched with 10% aqueous potassium bicarbonate (35 mL) and
extracted with ethyl acetate (2.times.35 mL). The combined organic
phases were concentrated to give 5.37 g of oil. Chromatography (25%
to 100% ethyl acetate/heptane gradient) afforded 1.84 g (72%) of
the title compound as white foam. Data for 24a: R.sub.f=0.12 (50%
EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.95
(t, J=7.51 Hz, 1H), 6.66 (dd, J=7.69, 13.55 Hz, 2H), 6.59 (br. s.,
1H), 3.61-3.77 (m, 1H), 3.57 (br. s., 1H), 3.02 (br. s., 1H),
2.58-2.76 (m, 2H), 2.34-2.56 (m, 3H), 2.17-2.30 (m, 1H), 2.03-2.14
(m, 1H), 1.79-1.93 (m, 1H), 1.64 (d, J=7.32 Hz, 2H), 1.38-1.56 (m,
4H), 1.16-1.37 (m, 7H), 1.10 (q, J=10.62 Hz, 1H), 0.85-0.96 (m,
3H); MS (ESI+) m/z 355.2 (M+Na.sup.+).
Example 26c:
(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclope-
nta[b]naphthalene-2,5-diol (24a)
##STR00310##
[0509] Hydrochloric acid (12 mL, 3 N) was added to a solution of
TBDPS-ether 23a (4.4 g, 7.7 mmol) in methanol (40 mL) and the
mixture stirred at 62.degree. C. for 22 hrs. Analysis by TLC
indicated that the reaction was complete. The reaction was
concentrated to give 4.95 g of colorless oil. Chromatography (5% to
40% ethyl acetate/heptane gradient) afforded 1.48 g (58%) of the
title compound as white foam. Data for 24a: R.sub.f=0.12 (50%
EtOAc/heptane); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
6.91-6.99 (m, 1H), 6.66-6.72 (m, 1H), 6.61-6.66 (m, 1H), 3.63-3.73
(m, 1H), 3.53-3.63 (m, 1H), 2.57-2.75 (m, 2H), 2.33-2.51 (m, 2H),
2.16-2.30 (m, 1H), 2.05-2.15 (m, 1H), 1.79-1.92 (m, 1H), 1.18-1.71
(m, 13H), 1.04-1.15 (m, 1H), 0.83-0.93 (m, 3H); MS (ESI+) m/z 355.2
(M+Na.sup.+).
Example 27: ethyl
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetate (25a)
##STR00311##
[0511] Ethyl bromoacetate was added drop-wise to a slurry of
benzindene triol 24a (500 mg, 1.504 mmol, 1.0 equiv), anhydrous
potassium carbonate (312 mg, 2.26 mmol, 1.5 equiv) and anhydrous
potassium iodide (25 mg, 0.15 mmol, 0.1 equiv) in acetone (20 mL)
and the reaction was heated to reflux while stirring, under
nitrogen for 16 hours. The reaction was then cooled to room
temperature, diluted with heptane (10 mL) and filtered through
celite. The celite was rinsed with ethyl acetate (3.times.30 mL)
and the filtrate was concentrated to give a pale oil.
Chromatography (10% to 80% ethyl acetate/heptane gradient) afforded
610 mg (96%) of the title compound as a colorless oil. Data for
25a: R.sub.f=0.15 (50% EtOAc/heptane); .sup.1H NMR .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.07 (t, J=7.87 Hz, 1H), 6.81 (d, J=7.32
Hz, 1H), 6.64 (d, J=7.69 Hz, 1H), 4.62 (s, 2H), 4.27 (q, J=7.32 Hz,
2H), 3.76 (dt, J=6.04, 9.61 Hz, 1H), 3.55-3.70 (m, J=4.40 Hz, 1H),
2.89 (dd, J=5.86, 14.65 Hz, 1H), 2.76 (dd, J=6.23, 14.28 Hz, 1H),
2.56 (dd, J=6.59, 15.01 Hz, 1H), 2.46 (dd, J=6.59, 14.28 Hz, 1H),
2.11-2.34 (m, 4H), 1.89 (tt, J=6.50, 9.98 Hz, 1H), 1.24-1.75 (m,
16H), 1.12-1.23 (m, 1H), 0.84-0.99 (m, 3H); MS (ESI+) m/z 419.3
(M+H.sup.+).
Example 28:
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I)
##STR00312##
[0513] Potassium hydroxide (5.623 g in 19 mL water, 30% solution in
water, 100.2 mmol, 5.0 equiv) was added to a solution of ethyl
ester 25a (8.390 g, 20.04 mmol, 1.0 equiv) in ethanol (100 mL) and
stirred at room temperature, under nitrogen for 90 minutes. The
reaction was then concentrated under reduced pressure to remove the
ethanol, diluted with water (50 mL) and extracted with ethyl
acetate (50 mL) to remove organic impurities. The aqueous layer was
acidified to pH 2-3 by addition of 3 N aqueous hydrochloric acid
and extracted with ethyl acetate (3.times.100 mL). The combined
organic phases were treated with activated charcoal (800 mg) and
heated to reflux for 1 hour, cooled to room temperature, filtered
through celite and concentrated to give 8.2 g of the title compound
as an off-white solid. This material was moved forward to the next
step crude and was not characterized further. Data for I:
R.sub.f=0.27 (90:10:1 methylene chloride/methanol/acetic acid).
Example 29:
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid diethanolamine
salt (I, Diethanolamine Salt)
##STR00313##
[0515] A solution of treprostinil I (7.83 g, 20.1 mmol, 1.0 equiv)
in ethyl acetate (250 mL) was treated with a solution of
diethanolamine (2.11 g, 20.1 mmol, 1.0 equiv) in anhydrous ethanol
(32 mL) and the resulting slurry heated to reflux for 15 minutes,
at which point everything went into solution. This was allowed to
slowly cool to room temperature over 18 hours resulting in
formation of a white crystalline solid. The solid was filtered,
rinsed with ethyl acetate (2.times.100 mL), and dried for 24 hours
at 50.degree. C. under vacuum to give 7.552 g (76%) of the title
compound as a white powder.
Example 30:
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I)
[0516] A solution of the diethanolamine salt of Formula I (5.775 g,
11.65 mmol, 1.0 equiv) in water (60 mL) was treated with aqueous
hydrochloric acid (2.11 g, 20.1 mmol, 1.0 equiv) in anhydrous
ethanol (32 mL) and the resulting slurry heated to reflux for 15
minutes, at which point everything went into solution. This was
allowed to slowly cool to room temperature over 18 hours resulting
in formation of a white crystalline solid. The solid was filtered,
rinsed with ethyl acetate (2.times.100 mL), and dried for 24 hours
at 50.degree. C. under vacuum to give 7.552 g (76%) of the title
compound as a white powder. Data for I: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.07 (t, J=7.88 Hz, 1H), 6.82 (d, J=7.69 Hz,
1H), 6.68 (d, J=8.43 Hz, 1H), 4.58-4.72 (m, 2H), 4.40 (br. s., 3H),
3.73 (dt, J=6.23, 9.34 Hz, 1H), 3.64 (d, J=3.66 Hz, 1H), 2.76 (ddd,
J=6.23, 14.20, 19.87 Hz, 2H), 2.61 (dd, J=6.04, 14.84 Hz, 1H), 2.48
(dd, J=6.23, 14.29 Hz, 1H), 2.20-2.36 (m, 1H), 2.10-2.20 (m, 1H),
1.82-1.98 (m, 1H), 1.52-1.76 (m, 4H), 1.40-1.52 (m, 3H), 1.21-1.40
(m, 6H), 1.08-1.21 (m, 1H), 0.92 (t, J=6.60 Hz, 3H); MS (ESI+) m/z
413.2 (M+Na.sup.+); HPLC, Synergi Hydro RP column (4.6.times.250
mm2), 5 mm; flow rate 2.0 mL/min; 277 nm; mobile phase water
(60%):acetonitrile (40%): trifluoroacetic acid (0.1%); retention
time, 39.12 min (98.0%, I), retention time, 41.05 min (1.2%,
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((R)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid).
Example 31a:
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid sodium salt (I,
Sodium Salt)
##STR00314##
[0518] A solution of the compound of Formula I (1 equiv) will be
dissolved in distilled ethanol at 30-50.degree. C. and then cooled
to 15-25.degree. C. The solution will then be neutralized with a
solution of sodium hydroxide (1 molar solution in ethanol) using a
glass electrode to detect the point of equivalence (to pH value
9.8-10.2). The solution will be filtered, and the filtrate
concentrated to give the crude sodium salt of the compound of
Formula I. This may optionally be recrystallized from acetone/water
or another appropriate solvent system to furnish a pure form of the
title compound.
Example 31b:
2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid sodium salt (I,
Sodium Salt)
##STR00315##
[0520] A solution of ethyl ester 25a (1 equiv.) will be dissolved
in distilled methanol and aq. NaOH (1 equiv., 1 molar solution)
will be added and stirred at an appropriate temperature until the
salt formation is complete. The reaction will then be concentrated
to give crude sodium salt of the compound of Formula I. This may
optionally be recrystallized from acetone/water or another
appropriate solvent system to furnish a pure form of the title
compound.
Other Embodiments
[0521] It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims.
* * * * *