Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-01
2003-04-01
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06541634
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to an improved process for preparing compounds of Formula II comprising coupling a compound of Formula IV with a compound of Formula V. This invention also relates to an improved process for preparing compounds of Formula III by coupling a compound of Formula IV with a compound of Formula V and subsequent deprotection of the resulting Prt-protected compound of Formula II.
Commonly assigned International Patent Application Publication No. WO97/24369, hereinafter referred to as the '369 application, which is incorporated herein by reference, discloses certain growth hormone secretagogue compounds of Formula I,
wherein the definitions of the variables are disclosed therein. Said compounds are disclosed in the '369 application to have utility in treating, inter alia, osteoporosis.
Compounds of Formula II,
are disclosed in the '369 application as intermediates in a process to prepare the compounds of Formula III,
which are within the scope of the disclosure of said international application.
The process disclosed in the '369 application requires coupling a compound of Formula IV with a compound of Formula V. The first step in the coupling reaction is the reaction of a compound of Formula IV below with an organic amine to form the free base of the compound of Formula IV and the organic amine salt of tartaric acid. The next step in the disclosed process is a filtration step to remove the organic amine salt of tartaric acid. This was thought to be necessary to eliminate the possibility of reaction of tartaric acid with the compound of Formula IV under the coupling conditions. Due to the racemization of the 3a position of the pyrazolo[4,3-c]pyridine which occurs at room temperature, this filtration had to be performed cryogenically, i.e., at reduced temperatures. When operating the coupling reaction on a bulk scale, cryogenic filtration presents technical problems, e.g., entrainment, slow filtration, a need to use additional equipment and extra handling. This results in reduced yields of product. In the process of this invention, the cryogenic filtration is avoided, resulting in a more streamlined process and an improved chemical and optical yield.
SUMMARY OF THE INVENTION
This invention is directed to a process, designated Process A, of preparing a compound of Formula II,
wherein:
R
1
is —(C
1
-C
10
)alkyl optionally substituted with up to three fluoro atoms;
R
2
is phenylmethyl or 2-pyridylmethyl;
R
3
is —(C
1
-C
5
)alkyl-O—(C
0
-C
5
)alkylphenyl, where the phenyl substituent in the definition of R
3
is optionally substituted with up to three fluoro atoms; and
Prt is an amine protecting group, comprising:
a) mixing an appropriate chiral tartrate salt having the structure of Formula IV,
wherein R
1
and R
2
are as defined above, and an organic amine in a reaction inert solvent at a temperature of about −68° C. to about −40° C. to form a slurry;
b) adding a compound of the Formula V,
wherein R
3
and Prt are as defined above, to said slurry to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of the formula V; and
c) adding a coupling reagent to said reaction mixture to form a compound of Formula II.
A preferred process within Process A, designated Process B, is a process wherein said compound of Formula IV is suspended in said solvent prior to the addition of said organic amine.
A preferred process within Process B, designated Process C, is a process wherein said slurry is warmed to about −50° C. prior to step b.
Another preferred process within Process A, designated Process D, is the process wherein: in step a, said organic amine is triethylamine; in step b, R
3
is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process of Process D, designated Process E, is a process wherein R
1
is methyl or 2,2,2-trifluoroethyl and R
2
is phenylmethyl or 2-pyridylmethyl.
A preferred process of Process E is a process wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared.
Another preferred process of Process E is a process wherein a compound of Formula IIA,
is prepared.
Another preferred process of Process E is the process wherein a compound of Formula IIB,
is prepared.
Another preferred process within Process B, designated Process F, is the process wherein: in step a, said organic amine is triethylamine; in step b, R
3
is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process F, designated Process G, is a process wherein R
1
is methyl or 2,2,2-trifluoroethyl and R
2
is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process F is a process wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared.
Another preferred process within Process F is a process wherein a compound of Formula IIA,
is prepared.
Another preferred process within Process F is a process wherein a compound of Formula IIB,
is prepared.
Another preferred process within Process C, designated Process H, is a process wherein: in step a, said organic amine is triethylamine; in step b, R
3
is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process H, designated Process I, wherein R
1
is methyl or 2,2,2-trifluoroethyl and R
2
is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process I is a process wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared.
Another preferred process within Process I is a process wherein a compound of Formula IIA,
is prepared.
Another preferred process within Process I is a process wherein a compound of Formula IIB,
is prepared.
This invention is also directed to a process, designated Process J, for preparing a compound of Formula III,
wherein:
R
1
is —(C
1
-C
10
)alkyl optionally substituted with up to three fluoro atoms;
R
2
is phenylmethyl or 2-pyridylmethyl; and
R
3
is —(C
1
-C
5
)alkyl-O—(C
0
-C
5
)alkylphenyl, where the phenyl substituent in the definition of R
3
is optionally substituted with up to three fluoro atoms, comprising:
a) mixing an appropriate chiral tartrate salt of the Formula IV,
wherein R
1
and R
2
are as defined above, and an organic amine in a reaction inert solvent at a temperature of about −68° C. to about −45° C. to form a slurry;
b) adding a compound of the Formula V,
wherein R
3
and Prt are as defined above, to said slurry to form a reaction mixture comprising the tartrat
Busch Frank R.
Chiu Charles K.
Meltz Clifford N.
Post Ronald J.
Rose Peter R.
Benson Gregg C.
Dentz Bernard
Pfizer Inc.
Richardson Peter C.
Wichtowski John A.
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