JP2008222630A - PRODUCTION METHOD OF R-II TYPE CRYSTAL OF 1-beta-D-RIBOFURANOSYL-1,2,4-TRIAZOLE-3-CARBOXAMIDE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing ribavirin R-II type crystal which is assumed to be an effective ingredient in a ribavirin medicine. <P>SOLUTION: The manufacturing method comprises dissolving ribavirin in an organic solvent and a small amount of water followed by refluxing and subsequent recrystallization. Concretely, the ribavirin R-II type crystal is produced by dissolving 1 pt.wt. of ribavirin in a mixed solvent of at least 20 pts.wt. of a 3C or higher alcohol solvent with at most 25 wt.%, based on the alcohol solvent, of water followed by refluxing under heating, and subsequently cooling the mixed solvent down to 10°C or lower followed by filtration. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for selectively obtaining 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, ie, R-II type crystal of ribavirin.

  Ribavirin is a purine nucleoside analog (nucleic acid structural analog) synthesized by Witkowski et al. In 1972 and exhibits antiviral activity over a wide range of DNA viruses and RNA viruses. In recent years, it has been found that when used in combination with interferon, it exerts a direct antiviral effect.

Ribavirin is a general name for a drug represented by the chemical formula of Chemical Formula 1 such as 1-β-D-ribofuranosyl-1H, 2,4-triazole-3-carboxamide, which has a Japanese chemical name, It is marketed under the names Copegus, Desiken, Rebetol, Ribavin, Ribaviran, Ribavirina, Ribavirinum, Tribavirin, Trivorin, Vilona, Viramid, Virazide, Virazole, Ribavirin, including generic drugs as viral drugs. It is a drug effective against many RNA and DNA viruses such as influenza virus A, B, parainfluenza, adenovirus, and RS virus.

  A study on two polymorphic structures of V1 obtained by slow recrystallization in water using Virazole and V2 obtained by rapid cooling in 50% ethanol-water solution. It belongs to the tetragonal system, and the molecular structure of V1 was analyzed by X-ray analysis, and the structure of V2 was analyzed using the MULTAN program. The molecular structure of V1 and V ″ is illustrated in FIG. 1 and FIG. 2. It can be seen that the twist angle of the glycosyl group is clearly different in the above two crystal forms with respect to the reference orientation relative to the sugar and is a conformer. (Non-Patent Document 1).

  The purchased USP grade ribavirin raw material (R-RW) was dissolved in warm water at 60 ° C., slowly cooled to room temperature, the product obtained was filtered, and dried in a desiccator overnight using phosphorus pentoxide as a desiccant. The obtained crystal (R-II) and a melt (R-I) of R-RW at 169 to 170 ° C. were obtained on a Hot-Stage microscope. Using high-performance liquid chromatography, using purified R-RW, R-I, and R-II samples, confirming that ribavirin contains only the above three components, thermal analysis (TGA / DSC) shows R- RW and purified R-I type and R-II type were used for evaluation, with a heating rate of 2 K / min, melting point of 175.7 ° C for R-I type, and 166.6 ° C for R-II type. R-RW includes R-II type and R-I type, R-II type is stable and is the main component, and R-I is reported to exist in trace amounts as a metastable type. (Non-Patent Document 2).

  As of November 14, 1978, 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide is an antiviral agent exhibiting broad spectrum antiviral activity in vitro and in vivo. It is disclosed in the reissued US patent document (Patent Document 1), and its use for specific viral diseases is disclosed in the US patent document issued on July 8, 1980. In addition, a method for preparing the structural isomer L-ribavirin on an industrial scale including a glycosylation reaction of a 3-substituted triazole in the presence of a Lewis acid and a solvent is known (Patent Document 3).

  As a method for synthesizing ribavirin, 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl-1,2,4-triazole-3-carboxymethyl ester in methanol solution at 0 ° C. After reacting and removing the solvent, recrystallization with ethanol reported that ribavirin with a melting point of 174 to 176 ° C. and recrystallization with water-ethanol yielded 166 to 168 ° C. with ribavirin (Non-patent Document 3). ).

  A pharmaceutical interview form (Schering-Plough shares) that contains information that cannot be obtained with the package inserts of pharmaceuticals, such as product characteristics and stability of active ingredients, provided by pharmaceutical companies to evaluate pharmaceuticals by pharmacists According to the company, Rebetol capsule 200 mg (trade name of ribavirin)), ribavirin is easily soluble in water, hardly soluble in alcohol, hardly soluble in nonpolar solvents, and the melting point is described as 167 to 171 ° C. From this melting point, it is understood that ribavirin is a mixture of R-I type and R-II type.

US 3,798,209 specification US 4,211,771 specification JP-T-2004-538317 Nature New Bioligy Vol.244 July 25, 1973 An improved thermoanalytical approach to quantifying trace levels of polymorphic impurity in drug powders, International Journal of Pharmaceutics 2005, Vol 295 191-199 Journal of Medical Chemistry 1972, Vol 15, No. 11

Judging from the melting point described in the interview form, it can be seen that the main component of ribavirin is R-II type and contains a small amount of metastable R-I type. Ribavirin is difficult to dissolve in ordinary organic solvents, and is recrystallized using a water-ethanol solvent known as the R-II type production method, but it is too expensive on an actual production scale. Not realistic.
The present invention provides a method for producing ribavirin type II crystal capable of mass production.

  The present inventors selectively obtain ribavirin having a crystal structure of R-II type in a high yield by selecting an organic solvent to be used by recrystallizing ribavirin with an organic solvent-aqueous solvent. I found that I can do it.

The present invention is based on the above findings and has the following configuration.
(1) As a guide, 1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of an alcohol solvent having 3 or more carbon atoms and 25% by weight or less of water with respect to the alcohol solvent, and heated to reflux. Thereafter, the mixed solvent is cooled to 10 ° C. or lower and filtered, and a method for producing R-II type crystals of ribavirin,
(2) As a guide, 1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of a ketone solvent and 25% by weight or less of water with respect to the ketone solvent, and after heating under reflux, the mixed solvent Of producing R-II type crystals of ribavirin by cooling and filtering to 10 ° C. or lower.
(3) As a guideline, 1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of an ether solvent and 25% by weight or less of water with respect to the ether solvent, and after heating under reflux, the mixed solvent A method for producing R-2 type crystals of ribavirin by cooling and filtering to 10 ° C. or lower.
(4) As a guideline, 1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of a halogenated solvent and 25% by weight or less of water based on the halogenated solvent, and after heating to reflux, the mixed solvent A method for producing ribavirin R-II type crystals by cooling and filtering to 10 ° C. or lower.
(5) As a guide, 1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of an ester solvent and 25% by weight or less of water with respect to the ester solvent, and after heating to reflux, the mixed solvent Of producing R-II type crystals of ribavirin by cooling and filtering to 10 ° C. or lower.
(6) As a guide, 1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of a nitrile solvent and 25% by weight or less of water with respect to the nitrile solvent, and after heating to reflux, the mixed solvent Of producing R-II type crystals of ribavirin by cooling and filtering to 10 ° C. or lower.
(7) As a guide, 1 part by weight of ribavirin, at least 20 parts by weight of two or more mixed solvents selected from alcohols, ethers, esters, nitriles, and halogen solvents, and 25% by weight or less based on the mixed solvent A process for producing R-II type crystals of ribavirin by dissolving in a mixed solvent with water, heating to reflux, and then cooling and filtering the mixed solvent to 10 ° C. or lower.

  According to the method of the present invention, it is possible to reduce the R-I type, which is considered as an impurity in ribavirin, and therefore it is possible to mass-produce Ribavirin R-II type, which can be expected to have a higher medicinal effect than before, on an industrial scale. it can.

  As a method for synthesizing ribavirin (including R-I type), N- (2,3-3-) obtained by reacting hydrazine cyanoformate with 2,3-O-isopropylidene-D-ribose in US Patents 3798209 and 3976545. It is known that O-isopropylidene-D-ribofuranosyl) -cyanoformamidrazone is cyclized with triethyl-O-formic acid and synthesized by the chemical step 1 by acid hydrolysis of ammonia and isopropylidene group.

Thereafter, a method of chemical formula 2 in which ribavirin (including R-I type) is synthesized by glucosylation of triazole is also known, and various synthetic methods using a specific catalyst have been proposed.

  As a specific method, crude N- (2,3-O-isopropylidene-D-ribofuranosyl) -cyano obtained by dissolving 2,3-O-isopropylidene-D-ribose in triethyl-O-formic acid 1- (2,3-O-isopropylidene-D-ribofuranosyl-1,2,4-) produced by dissolving formamiderazone in ethyl alcohol, adding concentrated aqueous ammonia and heating on a steam bath. Using triazole-3-carboxamide as a developing solvent in a 10% methanol-chloroform solution, the absorbing component is extracted by column chromatography, and the α isomer and the β isomer are separated by crystallization from the solvent. The isomer is reacted with trifluoroacetic acid to give 1-β-D-ribofuranosyl-1H, 2,4-triazole-3-carboxamide (ribavirin << RI Can be synthesized include ") a.

  Also, cyanoformate hydrazide is reacted with 2,3-O-isopropylidene-D-ribose to produce N- (2,3-O-isopropylidene-D-ribofuranosyl) -cyanoformamidrazone. Ring closure with O-formic acid, treatment with ammonia, acid hydrolysis of the isopropylidene group, 1-β-D-ribofuranosyl-1H, 2,4-triazole-3-carboxamide (ribavirin <including R-I type>) Can also be synthesized.

  In the present invention, ribavirin (including R-I type) obtained by the conventional synthesis method as described above may be used as a raw material.

  By the way, regarding the crystal form of ribavirin, a method for obtaining a single crystal of R-I type or R-II type has not been known. The crystal form of ribavirin effective as a drug is the R-II type as described above, and this R-II type is industrially obtained in a high yield from ribavirin obtained by the synthesis method described above. The method is not known.

  In the present invention, ribavirin is very difficult to dissolve in commonly used organic solvents such as ethanol, ester, ether, and hydrogen halide, and has high solubility in water. Ribavirin is recrystallized using a mixed solvent. According to this method, Ribavirin having an R-II type crystal form useful as a drug is industrially produced from ribavirin obtained by a conventional synthesis method. In high yields.

Further, the method for obtaining R-II form by recrystallizing ribavirin in a water-ethanol mixed solvent is described in the non-patent literature, but it is very expensive when performed on an actual production scale, Also, recrystallization with water must be cooled very slowly and the yield is low.
On the other hand, the amount of organic solvent for 1 g of ribavirin is basically 33 ml. This is because ribavirin has a bulky crystal obtained by recrystallization, and therefore, if the amount of the solvent is not 30 times, it is a problem in handling.

In response to such a fact, the present inventors have found that a decrease in yield can be prevented by adding only the amount of dissolved water under reflux.
It has also been found that generation of static electricity can be prevented by adding water in an organic solvent and water mixture system.

  The alcohol solvent in the organic solvent of the present invention has 3 to 15 carbon atoms, for example, isopropanol (3 carbon atoms), butanol (4 carbon atoms), amyl alcohol (5 carbon atoms), hexanol (6 carbon atoms). , Pentanol (carbon number 7), nonyl alcohol (carbon number 9), and the like.

  Examples of the ketone solvent include acetone, methyl ethyl ketone, diethyl ketone, 3-pentanone, cyclopentanone, cyclohexanone, methyl isobutyl ketone, diisobutyl ketone, methyl isobutyl ketone, and DAA (diacetone alcohol).

  Examples of ether solvents include dioxane, butyl ether, tetrahydropyran, ethylene glycol dibutyl ether, methyl cellosolve, cellosolve, butyl cellosolve, MTBE (methyl tertiary butanol), and butyl carbitol.

  Examples of the halogen solvent include methylene chloride, trichloroethylene, perchloroethylene, HCFC-141B, HCFC-225, bromopropane, chloroform and the like.

  Examples of ester solvents include ethyl acetate, butyl acetate, isobutyl acetate, cyclohexyl acetate, hexyl acetate, methyl propionate, butyl acrylate, methoxybutyl acetate, cellosolve acetate, amyl acetate, normal propyl acetate, isopropyl acetate, and butyl lactate. Can be mentioned.

  Examples of the nitrile solvent include acetonitrile and benzonitrile.

Each of the solvents listed above may be used alone or in a mixed solvent of two or more selected from alcohols, ethers, esters, nitriles, and halogen solvents except for ketone solvents. .
None of these solvents have a limited solubility in water and are not mixed in any proportion, and the amount of water may be the minimum amount in which ribavirin dissolves, and is 1 to 5 times the volume of ribavirin. The degree is sufficient. When the amount is small, dissolution is insufficient and it is difficult to obtain uniform crystals. Further, when the amount of solvent is large, the yield is lowered and the production cost is high.

Further, the solvent, water, and ribavirin may be added in any order. When stirring is sufficiently performed on a small scale, the organic solvent may be added to ribavirin, and water may be added gradually.
For large scales where stirring is a problem, there is a method in which an organic solvent and water are placed in a reaction kettle and ribavirin is added little by little later.

  100 g of cyanoformate hydrazide and 230 g of 2,3-O-isopropylidene-D-ribose are added to 5 L of ethanol containing 20 ml of ethanol formate and stirred at room temperature for 23 hours. The solvent was removed and the residue was recrystallized in benzene-ether to give 302 g of 2,3-O-isopropylidene-D-ribose.

The analysis results of 2,3-O-isopropylidene-D-ribose obtained by stirring for 23 hours are as follows.
Calculated values: C10H16N4O4 as C; 46.87, H; 6.29, N; 21.86
Experimental value: C; 46.87, H; 6.47, N; 21.85

  The crude N- (2, obtained by dissolving 50 g of 2,3-O-isopropylidene-D-ribose obtained above and having the above analysis results in 300 ml of triethyl-O-formic acid and removing the solvent after 2 days. 3-O-isopropylidene-D-ribofuranosyl) -cyanoformamidrazone is dissolved in 500 ml of ethyl alcohol, 500 ml of concentrated aqueous ammonia is added, and the mixture is heated on a steam bath for 1 hour to absorb the product onto silica gel. Place 500 g in the column, extract with 10% methanol-chloroform, collect 50 ml fractions, collect 100-200 ml fractions, remove the solvent, recrystallize with methanol-ethanol mixed solvent, 1- (2 , 3-O-isopropylidene-D-ribofuranosyl) -1,2,4-triazole-3-cal 15 g of boxyamide (β isomer, mp: 154-156 ° C.) was obtained.

The analysis results of 1- (2,3-O-isopropylidene-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide are as follows.
Calculated values: C11H16N4O4 C; 46.48, H; 4.57, N; 19.71
Experimental value: C; 46.68, H; 5.97, N; 19.83

  The 1- (2,3-O-isopropylidene-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide obtained above and having the above analysis results (DSC chart of this raw material ribavirin is shown in FIG. 1) is reacted with 100 ml of 80% trifluoroacetic acid for 10 minutes, the solvent is removed, and the residue is recrystallized with ethanol to give 1-β-D-ribofuranosyl-1H, 2,4-triazole-3-carboxamide. 11 g of (ribavirin) (mp: 165 to 167 ° C.) was obtained.

The analysis result of this recrystallized 1-β-D-ribofuranosyl-1H, 2,4-triazole-3-carboxamide (ribavirin) is as follows.
Calculated values: as C8H12N4O4 C; 39.35, H; 4.95, N; 22.94
Experimental value: C; 39.59, H; 4.82, N; 22.82

After adding 33 ml of the organic solvent shown in Table 1 to 1.0 g of ribavirin obtained by the method of Example 1 and heating and refluxing, water was added in an amount shown in Table 1, and after the ribavirin was completely dissolved, After cooling to 10 ° C., the resulting crystals were filtered and dried at 70 ° C. under reduced pressure.
The solvent used, the amount of added water, the yield, and the crystal form confirmed from the obtained DSC analysis are described. The DSC charts of the obtained crystal form are shown in FIGS. In Table 1, the DSC chart of the crystal form obtained in 1 is the DSC chart of the crystal form obtained in FIGS. 3 and 2, and the DSC chart of the crystal form obtained in FIGS. Is a DSC chart, and a broken line is a temperature curve.

In Example 1, only the R-II type can be selectively obtained by the methods (1) and (3) to (11), and the mixture of the R-I type and the R-II type can be obtained only by (2). According to the present invention, it can be seen that the R-II form can be selectively obtained with high yield.
In the cooling method at the time of crystal precipitation, in the organic solvent + water mixed system of the present invention, an R-II type crystal can be selectively obtained even by slow cooling or rapid cooling, and is not affected by the stirring speed, and depends on the organic solvent used. It was found that the crystal form was determined.

  Two kinds of organic solvents (16.5 ml × 2) shown in Table 1 were added to 1.0 g of ribavirin obtained in Example 1, and water was added while heating under reflux. After ribavirin was completely dissolved, 5-10 ° C. The resulting crystals were filtered and dried under reduced pressure at 70 ° C. The solvent used, the amount and yield of added water, and the crystal form confirmed by DSC analysis are described. The obtained crystal form DSC charts are shown in FIGS. In Table 2, the DSC chart of the crystal form obtained in 1 is the DSC chart of the crystal form obtained in FIGS. 15 and 2, and the DSC chart of the crystal form obtained in FIGS. Is a DSC chart, and a broken line is a temperature curve.

  Also in Example 3, as in Example 2, R-II form could be selectively obtained with high yield.

The conformation of the R-II type crystal contained in ribavirin is shown. The conformation of the R-II type crystal contained in ribavirin is shown. DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of crystal form obtained in Example DSC chart of raw ribavirin

Claims (7)

  1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of an alcohol solvent having 3 or more carbon atoms and 25% by weight or less of water with respect to the alcohol solvent. A method for producing R-II type crystals of ribavirin, which is cooled and filtered to 10 ° C or lower.   1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of a ketone solvent and 25% by weight or less of water with respect to the ketone solvent, and after heating to reflux, the mixed solvent is cooled to 10 ° C. or less. -The method of manufacturing R-II type crystal | crystallization of ribavirin by filtering.   1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of an ether solvent and 25% by weight or less of water with respect to the ether solvent, and after heating to reflux, the mixed solvent is cooled to 10 ° C. or less. -The method of manufacturing R-II type crystal | crystallization of ribavirin by filtering.   1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of a halogenated solvent and 25% by weight or less of water with respect to the halogenated solvent, and after heating to reflux, the mixed solvent is cooled to 10 ° C. or lower. A method for producing R-II type crystals of ribavirin by filtration.   1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of an ester solvent and 25% by weight or less of water with respect to the ester solvent, and after heating to reflux, the mixed solvent is cooled to 10 ° C. or less. -The method of manufacturing R-II type crystal | crystallization of ribavirin by filtering.   1 part by weight of ribavirin is dissolved in a mixed solvent of at least 20 parts by weight of a nitrile solvent and 25% by weight or less of water with respect to the nitrile solvent, and after heating to reflux, the mixed solvent is cooled to 10 ° C. or less. -The method of manufacturing R-II type crystal | crystallization of ribavirin by filtering.   1 part by weight of ribavirin is mixed with at least 20 parts by weight of two or more mixed solvents selected from alcohols, ethers, esters, nitriles, and halogen-based solvents and 25% by weight or less of water based on the mixed solvent. A method for producing R-II type crystals of ribavirin by dissolving and heating to reflux and then cooling and filtering the mixed solvent to 10 ° C. or lower.

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