Process for preparing substituted cyclopentane derivatives...

Details Process for preparing substituted cyclopentane derivatives... Process for preparing substituted cyclopentane derivatives...

2001-11-26

2003-06-10

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S121000, C562S504000, C562S503000, C562S498000, C562S500000, C562S501000

Reexamination Certificate

active

06576786

ABSTRACT:

BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates to a process for preparing substituted cyclopentane derivatives represented by the formula (I)
wherein R
1
, R
2
, R
3
, R
4
, X and Y are as described below, and pharmaceutically acceptable salts thereof.
The invention further relates to a process for purifying the compound of formula (Ia) and novel crystalline forms of the compound of formula (Ia).
The compounds of formula (I) are neuraminidase inhibitors, useful for the treatment of influenza and other viral infections.
The compounds of formula (I) and method of making and using compounds of formula (I) are described in pending application PCT US 98/26871, filed Dec. 17, 1997.
The invention relates to a more efficient process of preparing the compounds of formula (I), more particularly a process which permits high yield isolation of the desired stereoisomer, without the need for chromatographic purification.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of formula (I)
wherein
R
1
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
R
2
is selected from the group consisting of hydrogen; alkyl, cycloalkyl, halogen substituted alkyl, aryl and substituted aryl;
R
3
and R
4
are independently selected from the group consisting of hydrogen, alkyl, alkylene, cycloalkyl, aryl and substituted aryl, provided that at least one of R
3
or R
4
is alkyl;
X is NHC(═NH)NH
2
;
Y is selected from the group consisting of hydrogen, fluorine, hydroxy, OR
5
, OCOR
5
, NH
2
, NHCOR
5
and NR
5
R
6
, where R
5
is selected from alkyl, aryl, COR
6
or COOR
6
; and where R
6
is selected from hydrogen, alkyl, alkylene, cycloalkyl, aryl or substituted aryl;
and pharmaceutically acceptable salts thereof;
comprising the steps of:
reacting a compound of formula (II), wherein W is an N-protecting group, with a nitrile oxide of formula (III) by cycloaddition, at a temperature which prevents uncontrolled decomposition of the compound of formula (III), to yield a mixture of two stereoisomers of two regioisomers of the formula (IV) and (IV′), respectively;
reacting the mixture of the compounds of formula (IV) and (IV′) by hydrolyzing to the corresponding alkali metal salts of formula (V) and (V′), where M
+
represents an alkali metal cation or a tetra-alkyl-ammonium cation; reacting the resulting mixture of salts of formula (V) and (V′) with a acid to form the corresponding acids of formula (VI) and (VI′); reacting the acids of formula (VI) and (VI′) with ammonia or an amine, to precipitate the corresponding salt of formula (VII), where Q
+
represents NH
4
+
or substituted ammonium cation; reacting the salt of formula (VII) to yield the compound of formula (IVa);
reducing the compound of formula (IVa) using sodium borohydride and NiCl
2
to yield a mixture of two stereoisomers of the corresponding aminoalcohol of formula (IX); isolating the desired diastereomer of formula (IXa) by recrystallization from an organic solvent or alcohol/water mixture;
reacting the aminoalcohol of formula (IXa) with a compound of formula (X) or a compound of formula (XI), where V is chlorine or bromine, to produce the corresponding compound of formula (XII);
if in the compound of formula I Y is other than hydroxy in the configuration as set forth in formula (XII), the compound of formula (XII) is further converted to the compound of formula (XII′) by known methods, for example as described in pending application PCT US 98/26871, filed Dec. 17, 1997.;
removing the N-protecting group from the compound of formula (XII) or (XII′) to produce the corresponding amine of formula (XIII), or salt thereof; hydrolyzing the compound of formula (XIII) to the corresponding acid salt of formula (XIV); and reacting the compound of formula (XIV) with a guanylating agent, to produce the compound of formula (I).
For the compound of formula (XIII), if Y represents NH
2
or NR
5
R
6
where R
6
is hydrogen, then Y is protected with a protecting group other than W, which protecting group is removed by known methods following the guanylation step.
In another aspect, the invention is directed to a recrystallization procedure for purification and formation of a stable crystalline form of the compound of formula (Ia)
comprising the steps of dissolving the crude compound of formula (Ia) in a mixture of water/methanol at reflux temperature; and cooling to crystallize the pure compound of formula (Ia).
The process of this invention, as described herein, is advantageous over previously disclosed methods in that it does not require chromatographic separation or purification; it does not require the use of highly flammable or toxic solvents such as ether, CH
2
Cl
2
, and the like; and it results in high product yield and purity; making it suitable for large scale production.
The recrystallization as described above may be directed to produce either of two crystalline forms of the compound of formula (Ia), labelled Form A and Form B, or a mixture thereof.
A further aspect of the claimed invention is directed to novel crystalline structures of the compound of formula (Ia), more particularly Form A and Form B, characterized by their respective X-ray powder diffraction patterns.
Form A of the compound of formula (Ia) is more stable to changes in ambient relative humidity.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “alkyl” whether used alone or as part of a substituent group, include straight and branched chains containing one to eight carbon atoms, preferably one to three carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
As used herein, the term “alkylene” whether used alone or as part of a substituent group, include straight, branched or cyclic unsaturated hydrocarbon groups containing two to eight carbon atoms, preferably two to three carbon atoms. Examples of alkylene groups include vinyl, 1-propenyl, allyl, 2-propenyl, 2-methyl-1-propenyl, cyclopentenyl, and the like.
As used herein, unless otherwise noted, “cycloalkyl” shall denote cyclic aliphatic groups containing three to eight carbon atoms in the ring, optionally substituted with alkyl groups typically having one to six carbon atoms. Usually one or two substituent groups are present. Suitable examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
As used herein, unless otherwise noted, “aryl” shall refer to unsubstituted carbocyclic aromatic groups containing six to fourteen carbon atom, such as phenyl, naphthyl, and the like, preferably phenyl.
As used herein, unless otherwise noted, “aralkyl” shall mean any alkyl group substituted with an aryl group. Suitable examples of aralkyl groups include benzyl, phenylethyl, and the like.
As used herein, unless otherwise noted, substituents on the aryl and aralkyl groups are one or more, preferably one or two, of halogen.
As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine.
As used herein, “amine” shall mean a primary, secondary or tertiary amine such as ethylamine, t-butylamine, dimethylamine, diethylamine, triethylamine, piperidine, morpholine, N-methyl morpholine, and the like.
As used herein, “guanylating agent” shall mean an agent which adds a formamidine group to an amine nitrogen. Suitable examples of a guanylating agent include formamidine sulfonic acid, S-methyl iso-thiourea, 1H-pyrazole-1-carboxamidine monohydrochloride, 1H-triazole-1-carboxamidine monohydrochloride, and the like. Preferably, the guanylating agent is 1H-pyrazole-1-carboxamidine monohydrochloride or 1H-triazole-1-carboxamidine monohydrochloride, more preferably 1H-triazole-1-carboxamidine monohydrochloride.
As used herein, unless otherwise noted, an N-protecting group shall mean any functional group that is bonded directly to the N and is capable of preventing reactions at the N. Such protecting groups are known in the

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