JP2003146988A - Method for producing famciclovir, and method for producing and crystallization of intermediate thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing famciclovir known as an antiviral agent, and a method for efficiently producing and crystallizing an intermediate compound of the same. SOLUTION: An N-9 position alkylated form of a 2-amino-6-halopurine is selectively crystallized by bringing a mixture containing the N-9 position alkylated form and an N-7 position alkylated form of the 2-amino-6-halopurine to a crystallization operation using a mixed solvent of an organic solvent and water. Famciclovir is efficiently produced by further reducing the N-9 position alkylated form.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an industrial production and crystallization method of famciclovir and its intermediate compound known as antiviral agents.

[0002]

2. Description of the Related Art General formula (3)

[0003]

[Chemical 6]

[X represents a chlorine atom, a bromine atom or an iodine atom, and Ac represents an acetyl group. The 2-amino-6-halopurine derivative represented by the general formula (4) is known as an antiviral agent.

[0005]

[Chemical 7]

It is known as an important intermediate compound of famciclovir represented by

2-amino-6-represented by the general formula (3)
The halopurine derivative (hereinafter, also referred to as an N-9-position alkylated product) is represented by the general formula (1) as shown in the following formula.
It can be obtained by reacting amino-6-halopurine with a compound represented by the general formula (2).

[0008]

[Chemical 8]

However, depending on the reaction, the general formula (5)
2-amino-6-halopurine derivative represented by (hereinafter,
(Also referred to as N-7-position alkylated product) is by-produced as an impurity. The impurities are difficult to separate, and conventionally, tetrahedron, Vol. 46, 1990, 6903 was used for separation.
Silica gel chromatography was used, as also shown on page (Tetrahedron, 46, 1990, 6903).

Also known is a method for producing famciclovir by passing through another compound without using silica gel chromatography. For example, Nucleosize and Nucleotides, Volume 15, 19
1996, page 981 (Nucleosides & Nucleotides, 15, 19
96, 981), Tetrahedron, Volume 56, 2000, 4
589 (Tetrahedron, 56, 2000, 4589), Tetrahedron Letters, Volume 42, 2001, 1781 (T
etrahedron letters, 42, 2001, 1781), EP0728.
757A, EP0827960A and the like. However, each method requires a large number of steps, and thus a more efficient manufacturing method has been demanded.

[0011]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an efficient method for producing famciclovir and its intermediate compound known as antiviral agents.

[0012]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a mixture containing an N-7-position alkylated product and an N-9-position alkylated product is treated with an organic solvent and water. By subjecting it to a crystallization operation using a mixed solvent of
The desired N-9-position alkylated product is selectively precipitated,
It was found that the -7-position alkylated product can be highly removed,
The present invention has been completed.

That is, the present invention includes the following contents.

[1] General formula:

[0015]

[Chemical 9]

[In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, and Ac represents an acetyl group. ] The mixture containing the 2-amino-6-halopurine derivative represented by the above is subjected to a crystallization operation using a mixed solvent of an organic solvent and water, and selectively represented by the general formula (3) A general formula (3), characterized in that an amino-6-halopurine derivative is deposited.
A method for producing a 2-amino-6-halopurine derivative represented by: [2] General formula (1):

[0017]

[Chemical 10]

[In the formula, X has the same meaning as in the above [1]. ]
2-amino-6-halopurine represented by the general formula (2):

[0019]

[Chemical 11]

[In the formula, Y represents a leaving group, and Ac has the same meaning as in the above [1]. ] The compound represented by general formula (3) and (5) is reacted with 2-amino-
A mixture containing a 6-halopurine derivative is obtained, [1] above.
Manufacturing method. [3] The above [1] or [2], wherein X is a chlorine atom.
Manufacturing method. [4] The leaving group represented by Y is a chlorine atom, a bromine atom,
The production method of the above-mentioned [2], which is a group selected from an iodine atom, a paratoluenesulfonyloxy group, a mesyloxy group, a trifluoromethanesulfonyloxy group, an alkyl carbonate group, a phenyl carbonate group and a saturated or unsaturated acyloxy group. . [5] The 2-amino-6-halopurine represented by the general formula (1) and the compound represented by the general formula (2) are reacted in the same solvent as the organic solvent used in the crystallization operation. Manufacturing method of [2]. [6] The above-mentioned [1] to [5], wherein the organic solvent is one or more selected from the group consisting of dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide. One of the manufacturing method of. [7] The production method of the above-mentioned [2], wherein the 2-amino-6-halopurine represented by the general formula (1) and the compound represented by the general formula (2) are reacted in the presence of a base. [8] The production method of the above-mentioned [7], wherein after completion of the reaction, the reaction solution is neutralized with an acid. [9] The above-mentioned [1] to crystallization operation is cooling crystallization.
The manufacturing method according to any one of [8]. [10] After obtaining the 2-amino-6-halopurine derivative represented by the general formula (3) according to the method of any of the above-mentioned [1] to [9], the 2-amino-6-halopurine derivative is reduced. General formula (4):

[0021]

[Chemical 12]

[In the formula, Ac represents an acetyl group. ] The manufacturing method of famciclovir represented by these. [11] General formula:

[0023]

[Chemical 13]

[In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, and Ac represents an acetyl group. ] The mixture containing the 2-amino-6-halopurine derivative represented by the above is subjected to a crystallization operation using a mixed solvent of an organic solvent and water, represented by the general formula (3) 2 -Amino-6-
Method for selective crystallization of halopurine derivative. [12] The crystallization method according to the above [11], wherein X is a chlorine atom. [13] The crystallization method according to [11] above, wherein the organic solvent is one or more selected from the group consisting of dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide. . [14] The crystallization method according to [11] above, wherein the crystallization operation is cooling crystallization.

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
In the general formula (1), the general formula (3) and the general formula (5) in the present invention, X represents a chlorine atom, a bromine atom or an iodine atom, and a chlorine atom is most preferable.

In the general formula (2) in the present invention, Y represents a leaving group. The leaving group is not particularly limited, and examples thereof include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), sulfonyloxy group (eg, paratoluenesulfonyloxy group, mesyloxy group, trifluoromethanesulfonyloxy group, etc.), Acyloxy group (preferably a saturated or unsaturated acyloxy group having 1 to 8 carbon atoms, for example, R—C (═O) —O— (in the formula, R is an aryl group which may be substituted with an alkyl group). (Preferable total carbon number is 6-8, for example, phenyl group, p-tolyl group, etc.), aryloxy group optionally substituted with alkyl group (Preferable total carbon number is 6-8, for example, phenoxy group) , P-tolyloxy group, etc.), aralkyl group (preferably having 7 to 9 total carbon atoms, for example, benzyl group), arylalkenyl (Preferable total carbon number is 8 or 9, for example, cinnamyl group, etc.), aralkyloxy group (total carbon number 7 to 15, for example, benzyloxy group, 9-fluorenylmethyloxy group, etc.), alkoxy group (carbon number) 1 to 8 straight-chain or branched-chain alkoxy groups, for example, groups represented by methoxy, ethoxy, t-butoxy, etc.), etc., among which, chlorine atom, bromine atom, iodine atom, Paratoluenesulfonyloxy group, mesyloxy group, trifluoromethanesulfonyloxy group, alkyl carbonate group, phenyl carbonate group, saturated or unsaturated acyloxy group and the like are preferable, and bromine atom and mesyloxy group are particularly preferable.

First, the N-7-position alkylated product and N-9
The step of crystallizing a mixture containing a position-alkylated product (hereinafter, also simply referred to as “mixture”) will be described. In the crystallization step of the present invention, not only an organic solvent but also water, which is a poor solvent for the mixture containing the N-7-position alkylated product and the N-9-position alkylated product, is used as the crystallization solvent. The N-9-position alkylated product is selectively precipitated by subjecting the mixture containing the N-7-position alkylated product and the N-9-position alkylated product to a crystallization operation.

Crystallization in the present invention means (1) an operation of evaporating a solvent from a solution in which a crystalline substance (N-9-position alkylated product) is dissolved to concentrate and precipitate crystals.
(2) An operation (also called cooling crystallization) of precipitating crystals from a solution in which a crystalline substance (N-9-position alkylated product) is dissolved by lowering the temperature to make the concentration higher than the saturated solubility.
(3) An operation of adding an appropriate amount of water, which is a poor solvent, to a solution in which a crystalline substance (N-9-position alkylated product) is dissolved to make the concentration higher than the saturated solubility and precipitate crystals. Refers to normal operation. In the present invention, the cooling crystallization is N-
It is preferable from the viewpoint of improving the purity of the 9-position alkylated product. The crystallization is preferably carried out with stirring.

The solvent used in the crystallization step is a mixed solvent of an organic solvent and water, and the amount of water used is preferably 0.5 to 1.5 times the volume of the organic solvent, more preferably the volume ratio of the organic solvent. Can be 0.7 to 1.1 times.

The organic solvent in the mixed solvent used in the crystallization step is an amide solvent (eg, dimethylformamide (DMF), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, etc.). ,
Examples thereof include dimethylsulfoxide (DMSO) and acetonitrile, preferably amide solvents, more preferably DMF, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide. Among them, DMF is particularly preferable. These organic solvents may be used alone or in combination of two or more.

The amount of the mixed solvent may be appropriately changed depending on the mixing ratio and the crystallization conditions. For example, water and D
Mixed solvent with MF (water: DMF (volume ratio) = 1: 1 to 1
When performing crystallization under the above crystallization conditions according to 6: 7), N-
It is preferable to use an amount in the range of 6 to 15 ml per 1 mmol of the mixture containing the 7-position alkylated product and the N-9-position alkylated product.

The crystallization in the present invention will be described below by taking a preferred embodiment (cooling crystallization) as an example, but the present invention is not limited to this. N-7-position alkylated product and N
The N-9-position alkylated product is selectively precipitated by heating and dissolving the mixture containing the -9-position alkylated product in a mixed solvent of water and an organic solvent, and then cooling. The addition order of the compound and the solvent is not particularly limited, and for example, a mixture containing an N-7-position alkylated product and an N-9-position alkylated product is dissolved in an organic solvent, and then water is added thereto. There are various methods such as adding the mixture containing the alkylated product and the N-9-positioned alkylated product to the previously prepared mixed solvent of the organic solvent and water.

The temperature at the time of dissolution by heating is not particularly limited as long as it is a temperature at which the mixture dissolves in the mixed solvent, and it varies depending on the mixed solvent used, but it is usually 50 ° C. or higher, preferably 50.
If heated to -80 ° C, more preferably 50-60 ° C,
The mixture can be completely dissolved.

After the mixture was heated and dissolved, it was cooled and the desired N-
The 9-position alkylated product is precipitated. The cooling temperature at this time is not particularly limited as long as it is a temperature at which a desired compound precipitates, and is preferably 0 to 30 ° C, more preferably 10 to 20 ° C. Cooling can be performed at a cooling rate of preferably 1 to 10 ° C./hour, more preferably 2 to 5 ° C./hour.

The crystals precipitated by cooling are preferably aged for a certain period of time. Aging can be performed at a cooling temperature, preferably 1 to 24 hours, more preferably 2 to 12 hours.

Crystallization methods other than the cooling crystallization, for example, the above methods (1) and (3) can also be carried out by appropriately determining the conditions based on the description of the cooling crystallization.
For example, in the method (1), from the solution to the organic solvent, each condition such as the mixing ratio of the organic solvent and water and the amount of the mixed solvent used with respect to the N-9-position alkylated product falls within the above range. You can distill off. Also in the method (3), N-9 is added to a solution of an organic solvent by adding water while adjusting the mixing ratio of the above organic solvent and water, and further adjusting the temperature appropriately. The alkylated product can be crystallized.

The obtained crystals can be separated by a conventional method such as filtration. In order to increase the crystal purity, washing may be performed with, for example, a mixed solvent of DMF and water, or water. Moreover, the purity of the crystal can be further increased by subjecting the obtained crystal to the same crystallization step again.

Thus, crystals of the N-9-position alkylated product, in which the impurity N-7-position alkylated product is highly removed, can be obtained. That is, the mixture of the N-9-position alkylated product and the N-7-position alkylated product is subjected to a crystallization operation using a mixed solvent of an organic solvent and water to selectively produce N. It became possible to obtain crystals of the -9-position alkylated form.

The crystallization step in the present invention comprises the N-7-position alkylated product and the N-9-position alkylated product obtained from the reaction in which the N-7-position alkylated product and the N-9-position alkylated product are simultaneously produced. Is especially useful for mixtures containing. This is because it is difficult to separate the N-7-position alkylated form and the N-9-position alkylated form, and it is easy to separate the N-9-position alkylated form by the crystallization step of the present invention. You can As a method for producing the mixture to be subjected to the crystallization step, a method of simultaneously producing an N-7-position alkylated product and an N-9-position alkylated product will be described below as one embodiment, but the mixture of the present invention will be described. The manufacturing method is not limited to this.

The mixture containing the N-7-position alkylated product and the N-9-position alkylated product to be subjected to the crystallization step can be produced by a known method. For example, tetrahedron, 46, 1990, p. 6903 (Tetrahedron,
46, 1990, 6903), that is, the general formula (1)
2-amino-6-halopurine represented by the general formula (2)
It can be produced by reacting with a compound represented by The reaction is usually performed in a reaction solvent.

The amount of the compound represented by the general formula (2) used is usually 0.5 to 2 times the mol of the 2-amino-6-halopurine represented by the general formula (1). You can
It can be preferably 1 to 1.5 times mol.

Examples of the reaction solvent include amide solvents (eg, DMF, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, etc.), acetonitrile, DMSO, etc., preferably An amide solvent, more preferably DM
F, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide and the like. DMF is particularly preferable. These organic solvents may be used alone or in combination of two or more.

The amount of the reaction solvent used is such that the concentration of 2-amino-6-halopurine represented by the general formula (1) in the reaction solvent is
The amount is preferably 0.05 to 1 mol / liter, and more preferably 0.2 to 0.5 mol / liter.

The mixture is usually prepared in the presence of a base. Preferred bases include inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate, and quaternary ammonium salts such as tetrabutylammonium hydroxide. The amount of the base used can be preferably 0.5 to 2 times, and more preferably 1 to 1.5 times the mol of 2-amino-6-halopurine represented by the general formula (1). be able to.

The reaction temperature is usually 0 to 80 ° C., preferably 20 to 50 ° C. The reaction time can be usually 2 to 48 hours, preferably 5 to 25 hours. If necessary, in order to complete the reaction, the reaction may be further carried out at 50 to 100 ° C. for 1 to 5 hours.

After the completion of the reaction, the reaction solution may be optionally removed by concentration or the like to remove the reaction solvent. However, if the reaction solvent is a solvent that can be used in the crystallization step, the above-mentioned crystals are usually used without concentration. It can be subjected to a precipitation step. Thus, it is preferable that the reaction solvent and the organic solvent in the crystallization step are the same, which is economical, can reduce the number of steps, and is industrially useful.

When the reaction is carried out in the presence of a base,
The reaction solution may be neutralized with an acid and subjected to the next crystallization step.
Examples of the acid used for neutralization include organic acids such as acetic acid and citric acid, and inorganic acids such as hydrochloric acid and sulfuric acid, with organic acids being preferred. When neutralizing, the reaction solution may be adjusted to pH 5-9, preferably pH 6-8.

When the mixture containing the N-7-position alkylated product and the N-9-position alkylated product obtained by the above method is subjected to a crystallization operation using a solvent that can be used in the crystallization step as a reaction solvent, For example, if water is added to the reaction solution in excess, N-9
Although crystals of the alkylated compound can be precipitated, it is preferable to add an appropriate amount of water to the reaction solution to form a mixed solvent, heat to an appropriate temperature, and then perform cooling crystallization. The appropriate amount of water and the appropriate heating temperature are the same as those described in the above crystallization step. When water is added to the reaction solution to form a mixed solvent, crystals are usually precipitated, but when cooling crystallization is performed, it is preferable that the precipitated crystals are once dissolved by heating to an appropriate temperature.

The resulting 2-amino-6-halopurine derivative (alkylated N-9 position) was subjected to reduction to give
It can be induced to famciclovir, which is known as an antiviral agent. For example, Nucleosize and Nucleotides, Vol. 15, 1996, p. 981 (Nu
cleosides & Nucleotides, 1
5, 1996, 981),
The 2-amino-6-halopurine derivative (N-9-position alkylated form) is subjected to catalytic reduction reaction using palladium carbon as a catalyst in a solvent such as ethyl acetate in the presence of a base such as triethylamine to give famciclovir. Can be induced.

[0050]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0051]

[Chemical 14]

<Example 1> 2-acetoxymethyl-4-
Methanesulfonoxy-1-butyl acetate (b)
DM of (3.74 g, 83.0 wt%, 11 mmol)
2-Amino-6-chloropurine (a) (1.70 g, 10 mmol) and potassium carbonate (2.07 g, 15 mmol) were added to the F (35 ml) solution, and the mixture was reacted at 30 ° C for 22 hours and at 70 ° C for 2 hours. did. N- at the end of the reaction
9-position alkylated product (c) and N-7-position alkylated product (d)
Ratio is 5.55: 1 and the total amount of reaction products is 3.5.
g (calculated by HPLC). After the reaction, the mixture was cooled to 20 ° C, acetic acid (1.2 ml, 21 mmol) and water (30 ml) were added to adjust the pH to 7.0, and then the mixture was heated to 50 ° C to dissolve the crystals. This solution is 2 at 5 ° C / hour
After gradually cooling to 0 ° C and stirring at 20 ° C for 12 hours, water (5
ml) was added and the mixture was further stirred at 20 ° C. for 2 hours. The obtained crystals were filtered, washed with 50 v / v% DMF aqueous solution (6 ml) and water (6 ml), and dried under reduced pressure at 50 ° C. overnight to give 2-acetoxymethyl-4- (2-amino-6). -Chloropurin-9-yl) -1-butyl acetate (c) (2.27 g, yield 63.8%) was obtained as white crystals. The ratio of (c) to (d) in the obtained crystal was 1144: 1.

¹ H-NMR (CDCl ₃ ): 7.81
(S, 1H, H-8), 5.18 (brs, 2H, NH
₂ ) 4.21 (t, 2H, J = 7.0 Hz, H-
1 '), 4.15 (d, 4H, J = 5.4Hz, H-
4 '), 2.07 (s, 6H, 2Ac), 2.03-
1.90 (m, 3H, H-2 ', 3')

<Example 2> 2-acetoxymethyl-4-
Methanesulfonoxy-1-butyl acetate (b)
(4.08 g, 83.0 wt%, 12 mmol) of 1,
2-Amino-6-chloropurine (a) (1.70) was added to a solution of 3-dimethyl-2-imidazolidinone (21 ml).
g, 10 mmol) and potassium carbonate (2.07 g, 15
mmol) was added, and the mixture was reacted at 40 ° C. for 22 hours and at 70 ° C. for 2 hours. The ratio of the N-9-position alkylated product (c) to the N-7-position alkylated product (d) at the end of the reaction was 5.13:
1 and the total amount of reaction products was 3.26 g (calculated by HPLC). After the reaction, after cooling to 20 ° C, 1
M hydrochloric acid aqueous solution (6 ml, 6 mmol), water (15 ml)
Was added to adjust the pH to 7.0, and then the mixture was stirred at 20 ° C. for 4 hours. The obtained crystals are filtered, washed with 50 v / v% 1,3-dimethyl-2-imidazolidinone aqueous solution (10 ml) and water (10 ml), and dried at 50 ° C. for 12 hours to give 2-acetoxymethyl. -4- (2-Amino-6-chloropurin-9-yl) -1-butyl acetate (c) (1.86 g, yield 52.3%) was obtained as white crystals. The ratio of (c) to (d) in the obtained crystal was 189.5: 1.

[0055]

INDUSTRIAL APPLICABILITY According to the present invention, the 2-amino-6-halopurine derivative (N-9-position alkylated product) represented by the general formula (3) can be selectively crystallized, and the Famciclovir and its intermediate compounds known as viral agents can be efficiently produced.

Continued front page    (72) Inventor Kunisuke Izawa             1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa             Inside the corporation

Claims (14)

[Claims] 1. A general formula: [In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, and Ac represents an acetyl group. ] The mixture containing the 2-amino-6-halopurine derivative represented by the above is subjected to a crystallization operation using a mixed solvent of an organic solvent and water, and selectively represented by the general formula (3) A method for producing a 2-amino-6-halopurine derivative represented by the general formula (3), which comprises depositing an amino-6-halopurine derivative. 2. General formula (1): [In the formula, X has the same meaning as in claim 1. ] 2-
Amino-6-halopurine and general formula (2): [In the formula, Y represents a leaving group, and Ac has the same meaning as in claim 1. ] The manufacturing method of Claim 1 which reacts with the compound represented by these and obtains the mixture containing the 2-amino-6-halo purine derivative represented by General formula (3) and (5). 3. The method according to claim 1, wherein X is a chlorine atom.
The manufacturing method described. 4. The leaving group represented by Y is a chlorine atom, a bromine atom, an iodine atom, a paratoluenesulfonyloxy group,
The production method according to claim 2, which is a group selected from a mesyloxy group, a trifluoromethanesulfonyloxy group, an alkyl carbonate group, a phenyl carbonate group, and a saturated or unsaturated acyloxy group. 5. 2-amino-6 represented by the general formula (1):
-Reacting the halopurine and the compound represented by the general formula (2) in the same solvent as the organic solvent used in the crystallization operation.
The manufacturing method according to claim 2. 6. The organic solvent is dimethylformamide, N
-The production method according to any one of claims 1 to 5, which is at least one selected from the group consisting of methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide. 7. 2-Amino-6 represented by the general formula (1):
-The production method according to claim 2, wherein the halopurine and the compound represented by the general formula (2) are reacted in the presence of a base. 8. After completion of the reaction, the reaction solution is neutralized with an acid,
The manufacturing method according to claim 7. 9. The method according to claim 1, wherein the crystallization operation is cooling crystallization.
8. The manufacturing method according to any one of 8. 10. A 2-amino-6-halopurine derivative represented by the general formula (3) is obtained according to the method according to any one of claims 1 to 9, and then the 2-amino-6-halopurine derivative is obtained. General formula (4) characterized by reduction: embedded image [In the formula, Ac represents an acetyl group. ] The manufacturing method of famciclovir represented by these. 11. A general formula: [In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, and Ac represents an acetyl group. ] The mixture containing the 2-amino-6-halopurine derivative represented by the above is subjected to a crystallization operation using a mixed solvent of an organic solvent and water, represented by the general formula (3) 2 -Selective crystallization method of amino-6-halopurine derivative. 12. The crystallization method according to claim 11, wherein X is a chlorine atom. 13. The organic solvent is dimethylformamide,
The crystallization method according to claim 11, which is one or more selected from the group consisting of N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethylacetamide. 14. The crystallization operation is cooling crystallization.
1. The crystallization method according to 1.