Single-crystal – oriented-crystal – and epitaxy growth processes; – Processes of growth from liquid or supercritical state – Having growth from a solution comprising a solvent which is...
Reexamination Certificate
2002-08-30
2004-07-13
Hiteshew, Felisa (Department: 1765)
Single-crystal, oriented-crystal, and epitaxy growth processes;
Processes of growth from liquid or supercritical state
Having growth from a solution comprising a solvent which is...
C117S070000
Reexamination Certificate
active
06761767
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to industrial production and crystallization methods of famciclovir known as an antiviral agent and an intermediate compound therefor.
BACKGROUND OF THE INVENTION
A 2-amino-6-halopurine derivative of the formula (3)
wherein X is a chlorine atom, a bromine atom or an iodine atom and Ac is an acetyl group, is known as an important intermediate compound for famciclovir of the formula (4)
known as an antiviral agent.
The 2-amino-6-halopurine derivative (hereinafter to be also referred to as an N-9-position alkylated form) of the formula (3) can be obtained by reacting 2-amino-6-halopurine of the formula (1) with a compound of the formula (2) as shown in the following formulas:
Depending on the reaction, however, a 2-amino-6-halopurine derivative of the formula (5) (hereinafter to be also referred to as an N-7-position alkylated form) is by-produced as an impurity. This impurity is difficult to separate, and the separation has conventionally required silica gel chromatography, as taught in Tetrahedron, 46, page 6903 (1990).
In addition, a produce method of famciclovir through a different compound, which is free of silica gel chromatography, has been known. For example, Nucleosides & Nucleotides, 15, page 981 (1996), Tetrahedron, 56, page 4589 (2000), Tetrahedron letters, 42, page 1781 (2001), EP0728757A, EP0827960A and the like can be mentioned. However, since these methods require a number of steps, a more efficient production method has been demanded.
Accordingly, the present invention aims at providing an efficient production method of famciclovir known as an antiviral agent and an intermediate compound therefor.
SUMMARY OF THE INVENTION
As a result of the intensive investigation of the present inventors, it has been found according to the present invention that, by subjecting a mixture containing an N-7-position alkylated form and an N-9-position alkylated form to a crystallization step using a mixed solvent of an organic solvent and water, the objective N-9-position alkylated form precipitates selectively and the N-7-position alkylated form can be removed highly.
Accordingly, the present invention provides the following.
[1] A production method of a 2-amino-6-halopurine derivative represented by the formula (3), which comprises subjecting a mixture containing 2-amino-6-halopurine derivatives represented by the formulas:
wherein X is a chlorine atom, a bromine atom or an iodine atom and Ac is an acetyl group, to a crystallizing step using a mixed solvent of an organic solvent and water to selectively precipitate the 2-amino-6-halopurine derivative represented by the formula (3).
[2] The production method of the above-mentioned [1], wherein the mixture containing the 2-amino-6-halopurine derivatives represented by the formulas (3) and (5) is obtained by reacting 2-amino-6-halopurine represented by the formula (1):
wherein X is as defined in the above-mentioned [1], with a compound represented by the formula (2):
wherein Y is a leaving group and Ac is as defined in the above-mentioned [1].
[3] The production method of the above-mentioned [1] or [2], wherein X is a chlorine atom.
[4] The production method of the above-mentioned [2], wherein the leaving group represented by Y is a group selected from the group consisting of a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a mesyloxy group, a trifluoromethanesulfonyloxy group, an alkylcarbonate group, a phenylcarbonate group and a saturated or unsaturated acyloxy group.
[5] The production method of the above-mentioned [2], wherein the 2-amino-6-halopurine represented by the formula (1) is reacted with the compound represented by the formula (2) in the same organic solvent as used for crystallization.
[6] The production method of any of the above-mentioned [1] to [5], wherein the organic solvent is at least one selected from the group consisting of dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide.
[7] The production method of the above-mentioned [2], wherein the 2-amino-6-halopurine represented by the formula (1) is reacted with the compound represented by the formula (2) in the presence of a base.
[8] The production method of the above-mentioned [7], further comprising neutralization of a reaction mixture by using an acid after completion of the reaction.
[9] The production method of any of the above-mentioned [1] to
[8], wherein the crystallization is cooling crystallization.
[10] A production method of famciclovir represented by the formula (4):
wherein Ac is an acetyl group, which comprises obtaining the 2-amino-6-halopurine derivative represented by the formula (3) according to any of the above-mentioned [1] to [9], and then reducing the 2-amino-6-halopurine derivative.
[11] A method of selectively crystallizing a 2-amino-6-halopurine derivative represented by the formula (3), which comprises subjecting a mixture containing 2-amino-6-halopurine derivatives represented by the formulas:
wherein X is a chlorine atom, a bromine atom or an iodine atom and Ac is an acetyl group, to a crystallization step using a mixed solvent of an organic solvent and water.
[12] The crystallization method of the above-mentioned [11], wherein X is a chlorine atom.
[13] The crystallization method of the above-mentioned [11], wherein the organic solvent is at least a member selected from the group consisting of dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide.
[14] The crystallization method of the above-mentioned [11], wherein the crystallization is cooling crystallization.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail in the following.
In the formula (1), the formula (3) and the formula (5) in the present invention, X represents a chlorine atom, a bromine atom or an iodine atom, with most preference given to a chlorine atom.
In the formula (2) of the present invention, Y represents a leaving group. The leaving group is not particularly limited and is, for example, a halogen atom (e.g., chlorine atom, bromine atom, iodine atom), a sulfonyloxy group (e.g., p-toluenesulfonyloxy group, mesyloxy group, trifluoromethanesulfonyloxy group and the like), an acyloxy group (preferably saturated or unsaturated acyloxy group having 1 to 8 carbon atoms in total, such as a group represented by R—C(═O)—O— wherein R is an aryl group optionally substituted by alkyl group (preferably having 6 to 8 carbon atoms in total, such as phenyl group, p-tolyl group and the like), an aryloxy group optionally substituted by alkyl group (preferably having 6 to 8 carbon atoms in total such as phenoxy group, p-tolyloxy group and the like), aralkyl group (preferably having 7 to 9 carbon atoms in total such as benzyl group and the like), arylalkenyl group (preferably having 8 or 9 carbon atoms in total such as cinnamyl group and the like), aralkyloxy group (having 7 to 15 carbon atoms in total such as benzyloxy group, 9-fluorenylmethyloxy group and the like), or alkoxy group (linear or branched chain alkoxy group having 1 to 8 carbon atoms such as methoxy, ethoxy, t-butoxy and the like), and the like. Of these, chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, mesyloxy group, trifluoromethanesulfonyloxy group, alkylcarbonate group, phenylcarbonate group and saturated or unsaturated acyloxy group and the like are preferable, particularly preferably bromine atom and mesyloxy group.
First, a step for crystallizing a mixture containing an N-7-position alkylated form and an N-9-position alkylated form (hereinafter to be also simply referred to as a mixture) is explained.
In the crystallization step of
Hijiya Toyoto
Izawa Kunisuke
Torii Takayoshi
Ajinomoto Co. Inc.
Hiteshew Felisa
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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