WO2020013305A1 - Method for producing clopidogrel sulfate form i crystals - Google Patents

Method for producing clopidogrel sulfate form i crystals Download PDF

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WO2020013305A1
WO2020013305A1 PCT/JP2019/027621 JP2019027621W WO2020013305A1 WO 2020013305 A1 WO2020013305 A1 WO 2020013305A1 JP 2019027621 W JP2019027621 W JP 2019027621W WO 2020013305 A1 WO2020013305 A1 WO 2020013305A1
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weight
clopidogrel
butanol
methyl
butyl ether
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PCT/JP2019/027621
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French (fr)
Japanese (ja)
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俊太 武口
中川　貴洋乃
政臣 押元
美菜子 丸山
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有機合成薬品工業株式会社
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Priority to CN201980046516.0A priority Critical patent/CN112399969B/en
Priority to JP2020530274A priority patent/JP7323876B2/en
Publication of WO2020013305A1 publication Critical patent/WO2020013305A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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  • the present invention relates to a method for producing a clopidogrel sulfate type I crystal. According to the present invention, it is possible to produce clopidogrel sulfate having a low content of monoalkyl sulfate of clopidogrel as an impurity.
  • Clopidogrel sulfate ((+)-(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl sulfate ) has a platelet aggregation inhibitory effect, and is effectively used for treating peripheral arterial diseases such as stroke and thrombus and embolism, and coronary diseases such as myocardial infarction and angina.
  • Patent Document 1 discloses a production method in which n-butanol and concentrated sulfuric acid are added to a mixture of a free base of methyl t-butyl ether and clopidogrel.
  • the inventors of the present invention have conducted intensive studies on a method for producing clopidogrel sulfate that produces less monoalkyl sulfate, and surprisingly found that by adjusting the mixing ratio of methyl t-butyl ether and 1-butanol, monoalkyl sulfate was produced. It has been found that the production of sulfate can be dramatically suppressed. Specifically, by increasing the amount of 1-butanol relative to methyl t-butyl ether, it became possible to suppress the production of monoalkyl sulfate. The present invention is based on these findings.
  • the present invention [1] (1) With respect to (a) 1 part by weight of methyl t-butyl ether, a solvent containing 1.3 parts by weight or more of 1-butanol, or (b) 1 part by weight of methyl t-butyl ether Clopidogrel free base is contacted with concentrated sulfuric acid in the presence of a solvent containing 0.9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water, and the following general formula (1): Obtaining a type I crystal of clopidogrel sulfate represented by the formula: [2] The method for producing a clopidogrel sulfate type I crystal according to [1], wherein the weight ratio of 1-butanol to methyl t-butyl ether of the solvent is 10 parts by weight or less, [3] The method for producing a clopidogrel sulfate I-type crystal according to [1] or [2], further comprising: (2) drying the I-type crystal at
  • the method for producing a clopidogrel sulfate type I crystal of the present invention comprises: (1) (a) a solvent containing 1.3 parts by weight or more of 1-butanol based on 1 part by weight of methyl t-butyl ether, or (b) Concentrated sulfuric acid is contacted with the free base of clopidogrel in the presence of 1 part by weight of methyl tert-butyl ether in a solvent containing 0.9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water.
  • the method for producing the clopidogrel sulfate type I crystal of the present invention preferably includes (2) a step of drying the type I crystal at 50 ° C. or lower.
  • Clopidogrel sulfate ((+)-(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c]) obtainable by the production method of the present invention
  • Pyridin-5-yl) methyl acetate sulfate is an I-type crystal of the compound represented by the general formula (1).
  • the production method of the present invention the production of clopidogrel monoalkyl sulfate is suppressed. Therefore, the clopidogrel sulfate obtained by the production method of the present invention has a low content of clopidogrel monoalkyl sulfate.
  • the monoalkyl sulfate is represented by the formula (2): Is clopidogrel monobutyl sulfate.
  • Clopidogrel sulfate obtained by the production method of the present invention has a small amount of monoalkyl sulfate mixed therein.
  • the content of the monoalkyl sulfate is preferably 0.20% by weight or less, more preferably 0.15% by weight or less, further preferably 0.10% by weight or less, and most preferably 0.05% by weight or less. % By weight or less.
  • Crystallization Step In the step of obtaining the type I crystal of clopidogrel sulfate of the present invention (hereinafter sometimes referred to as the crystallization step), (a) 1.3 parts by weight of 1 part by weight of methyl t-butyl ether. A solvent containing 1 part by weight or more of 1-butanol or (b) a solvent containing 0.9 part by weight or more of 1-butanol and 0.05 part by weight or more of water based on 1 part by weight of methyl t-butyl ether; Contact clopidogrel free base with concentrated sulfuric acid in the presence.
  • clopidogrel free base is dissolved in a solvent containing methyl t-butyl ether and 1-butanol, or a solvent containing methyl t-butyl ether, 1-butanol, and water, but containing methyl t-butyl ether, 1-butanol, water, and
  • the order of mixing clopidogrel free base is not particularly limited.
  • concentrated sulfuric acid is added dropwise to the solution in which clopidogrel free base is dissolved, and seed crystals are added.
  • concentrated sulfuric acid may be added to the solvent, clopidogrel free base may be added thereto, and then a seed crystal may be added.
  • a seed crystal may be added.
  • the temperature of the crystallization step is not particularly limited, but is preferably ⁇ 10 to 30 ° C., and more preferably 0 to 10 ° C.
  • the pressure in the crystallization step is not particularly limited, and may be under pressure, under normal pressure, or under reduced pressure.
  • the seed crystal is not particularly limited as long as it is an I-type crystal.
  • solvent dissolves clopidogrel free base and efficiently performs the reaction between clopidogrel free base and sulfuric acid.
  • the solvent is used as long as it contains 1.3 parts by weight or more of 1-butanol with respect to 1 part by weight of methyl t-butyl ether, or with respect to 1 part by weight of methyl t-butyl ether. It is not particularly limited as long as it contains 0.9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water, and may contain other components.
  • methyl t-butyl ether By using methyl t-butyl ether (hereinafter sometimes referred to as MTBE) as a solvent, the target substance can be efficiently crystallized.
  • the amount of methyl t-butyl ether based on clopidogrel free base is not particularly limited as long as clopidogrel sulfate is produced, but methyl t-butyl ether is preferably used in an amount of 1 to 1 part by weight of clopidogrel free base. It is 10 parts by weight, more preferably 1.2 to 8 parts by weight, even more preferably 1.5 to 6 parts by weight. When the content is within the above range, the production of monoalkyl sulfate can be suppressed, and the type I crystal can be obtained stably and efficiently.
  • the solvent includes 1-butanol.
  • 1-butanol By using 1-butanol as a solvent, a type I crystal can be obtained stably and efficiently.
  • the amount of 1-butanol based on clopidogrel free base is not particularly limited as long as clopidogrel sulfate is formed, but 1-butanol is preferably used per 1 part by weight of clopidogrel free base, preferably 2 to 15 parts by weight. Parts by weight, more preferably 3 to 13 parts by weight, even more preferably 4 to 12 parts by weight. When the content is within the above range, generation of clopidogrel monoalkyl sulfate can be suppressed.
  • Weight ratio of methyl t-butyl ether and 1-butanol (Weight ratio of methyl t-butyl ether and 1-butanol) (A) When 1.3 parts by weight or more of 1-butanol is used with respect to 1 part by weight of methyl t-butyl ether, the weight ratio of methyl t-butyl ether and 1-butanol is 1 to 1 part by weight of methyl t-butyl ether.
  • -Butanol is at least 1.3 parts by weight, preferably at least 1.4 parts by weight, more preferably at least 1.5 parts by weight, most preferably at least 1.6 parts by weight.
  • the upper limit of the weight ratio of 1-butanol to methyl t-butyl ether is not limited, but is preferably 10 parts by weight or less, more preferably 9 parts by weight or less, and most preferably 8 parts by weight or less. is there.
  • the upper and lower limits can be arbitrarily combined as desired.
  • the content is within the above range, the production of monoalkyl sulfate can be suppressed.
  • the upper limit of 1-butanol with respect to methyl t-butyl ether exceeds 10 parts by weight, the production of clopidogrel monoalkyl sulfate can be sufficiently suppressed, but there is a risk of producing type II crystals.
  • the upper limit of 1-butanol relative to methyl t-butyl ether is preferably at most 10 parts by weight.
  • the content of water is not particularly limited, but is preferably 0.5 parts by weight or less, more preferably 0.2 parts by weight or less.
  • the weight ratio of methyl t-butyl ether and 1-butanol is determined by adding methyl t-butyl ether to the solvent when water is added to the solvent.
  • 1-butanol is at least 0.9 part by weight, preferably at least 1.0 part by weight, more preferably at least 1.1 part by weight, most preferably at least 1.2 parts by weight with respect to 1 part by weight of -butyl ether. It is more than weight part.
  • the upper limit of the weight ratio of 1-butanol to methyl t-butyl ether is not limited, but is preferably 10 parts by weight or less, more preferably 9 parts by weight or less, and most preferably 8 parts by weight or less. is there.
  • the weight ratio of water to methyl t-butyl ether is at least 0.05 part by weight, preferably at least 0.06 part by weight, more preferably at least 0.06 part by weight, based on 1 part by weight of methyl t-butyl ether. It is at least 07 parts by weight, most preferably at least 0.08 parts by weight.
  • the upper limit of the weight ratio of water to methyl t-butyl ether is not particularly limited, but is preferably 0.3 part by weight, more preferably 0.25 part by weight or less, and most preferably 0.2 part by weight or less. Not more than parts by weight.
  • the upper and lower limits can be arbitrarily combined as desired. When the content is within the above range, the production of monoalkyl sulfate can be suppressed.
  • the solvent may contain other components other than 1-butanol and methyl t-butyl ether as long as the effects of the present invention can be obtained. That is, other components can be included as long as the formation of clopidogrel monoalkyl sulfate is not increased.
  • Other components include toluene, salts or alcohols. That is, a small amount of an inorganic salt or an organic solvent does not affect the reaction of the present invention.
  • the clopidogrel free base used in the present invention can be prepared, for example, according to the following reaction formula (3). That is, toluene and sodium hydrogen carbonate are added to clopidogrel ⁇ ( ⁇ )-camphorsulfonic acid salt and reacted. Water is added to the organic layer and the mixture is separated and washed, and the organic layer is collected. By evaporating the solvent under reduced pressure, clopidogrel free base can be obtained.
  • concentrated sulfuric acid means one having a sulfuric acid concentration of 90% by weight or more.
  • Commercially available concentrated sulfuric acid generally has a concentration of 96 to 98% by weight, and the production method of the present invention can be carried out using concentrated sulfuric acid at such a concentration.
  • the weight ratio of the solvent, clopidogrel free base and sulfuric acid in the production method of the present invention is not limited as long as clopidogrel sulfate can be obtained.
  • the reaction can be carried out in the following weight ratio.
  • the theoretical ratio of clopidogrel free base to concentrated sulfuric acid is 1: 1, but the reaction can be usually carried out with 0.8 to 2 mol of concentrated sulfuric acid per mol of clopidogrel free base.
  • the ratio of clopidogrel free base to solvent is not limited, but the solvent is preferably 2 to 30 parts by weight, more preferably 4 to 20 parts by weight, per 1 part by weight of clopidogrel free base. , Most preferably 5 to 15 parts by weight.
  • the ratio between the concentrated sulfuric acid and the solvent is not limited, but the solvent is preferably 5 to 100 parts by weight, more preferably 7 to 80 parts by weight, most preferably 1 part by weight of concentrated sulfuric acid. Is from 9 to 70 parts by weight.
  • the type I crystal of clopidogrel sulfate is dried at 50 ° C. or lower to remove residual 1-butanol and methyl t-butyl ether.
  • the drying method is not particularly limited as long as the monoalkyl sulfate of clopidogrel does not excessively increase, and examples of the drying method include a pressureless drying method, a blast drying method, and a drying method using a humidity control gas.
  • a drying method using a humidified gas specifically, an operation of contacting with a gas having a relative humidity of 45 to 99% and a temperature of 0 to 50 ° C. is preferable.
  • the relative humidity is preferably between 50 and 95%, more preferably between 55 and 90%.
  • the temperature is preferably 5 to 45 ° C, more preferably 10 to 40 ° C. With the above relative humidity and temperature, 1-butanol can be efficiently removed.
  • the excess amount of alkyl sulfate can be reduced. It is presumed that the formation is suppressed and the alkyl sulfate is removed, so that the type I crystal can be obtained stably and efficiently.
  • clopidogrel free base (compound 2) was prepared according to the following formula (4).
  • a 1-L reaction flask was charged with Compound 1 (clopidogrel-(-)-camphorsulfonic acid salt; 100 g; 0.18 mol) and toluene (300 g), and an aqueous solution of sodium hydrogencarbonate (16.7 g; 0.20 mol) (300 g) was added. ) was added dropwise. After stirring at room temperature for 30 minutes, the layers were separated. After washing the organic layer with water (300 g), the solvent was distilled off under reduced pressure to obtain Compound 2 (clopidogrel free base; CLOP-FB).
  • Example 1 clopidogrel sulfate was produced.
  • Compound 2 (5.8 g; 18 mmol), 1-butanol (60 g), and methyl t-butyl ether (20 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. .
  • sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. .
  • the mixture was stirred at 15 ° C for 26 hours.
  • the crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 6.1 g).
  • Form I crystal yield 81%, chemical purity 99.96%.
  • Example 2 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (5.8 g; 18 mmol), 1-butanol (50 g), and methyl t-butyl ether (30 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. . After the seed crystal was added, the mixture was stirred at 15 ° C. for 23 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 5.9 g). Form I crystal, 77% yield, 99.96% chemical purity. The content of compound 4 was 0.10%. Table 1 shows the results.
  • Example 3 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (11.6 g; 36 mmol), 1-butanol (60 g), and methyl t-butyl ether (20 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.5 g; 36 mmol) was added dropwise at 10 ° C. or lower. . After adding seed crystals, the mixture was stirred at 5 ° C. for 22 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 12.9 g). Form I crystals, 85% yield, 99.97% chemical purity. The content of compound 4 was 0.02%. Table 1 shows the results.
  • Example 4 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (11.6 g; 36 mmol), 1-butanol (50 g), methyl t-butyl ether (30 g), and water (2 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.7 g; 38 mmol) at 10 ° C. or lower. ) was added dropwise. After adding seed crystals, the mixture was stirred at 5 ° C for 43 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 12.5 g). Form I crystal, yield 82%, chemical purity 99.87%. The content of compound 4 was 0.02%. Table 1 shows the results.
  • Example 5 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (11.6 g; 36 mmol), 1-butanol (72.7 g), and methyl tert-butyl ether (7.3 g) were charged into a 200 mL reaction flask, and sulfuric acid (3.5 g; 35 mmol) at 10 ° C. or lower. Was dropped. After adding seed crystals, the mixture was stirred at 4 ° C for 24 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 5 hours to obtain Compound 3 (clopidogrel sulfate: 13.2 g). Form I crystal, 87% yield, 99.94% chemical purity. The content of compound 4 was 0.02%. Table 1 shows the results.
  • Comparative Example 1 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (5.8 g; 18 mmol), 1-butanol (40 g), and methyl t-butyl ether (40 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. . After adding seed crystals, the mixture was stirred at 15 ° C for 43 hours. The crystals were collected by filtration and dried under reduced pressure to obtain Compound 3 (clopidogrel sulfate: 5.9 g). Form I crystal, 78% yield, 99.93% chemical purity. The content of compound 4 was 0.44%. Table 1 shows the results.
  • Comparative Example 2 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • 1-Butanol (20 g) and methyl t-butyl ether (40 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower.
  • sulfuric acid 1.8 g; 18 mmol
  • a solution of compound 2 (5.8 g; 18 mmol) in methyl t-butyl ether (20 g) was added dropwise at 10 ° C. or lower, and the mixture was stirred at 15 ° C. for 22 hours.
  • Example 6 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (11.6 g; 36 mmol), 1-butanol (40 g), methyl t-butyl ether (40 g), and water (6 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.5 g; 35 mmol) at 10 ° C. or lower. ) was added dropwise. After adding seed crystals, the mixture was stirred at 4 ° C for 24 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C.
  • Example 7 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (11.6 g; 36 mmol), 1-butanol (40 g), methyl t-butyl ether (40 g), and water (4.2 g) were charged into a 200 mL reaction flask, and sulfuric acid (3.5 g) was used at 10 ° C. or lower. ; 35 mmol) was added dropwise. After adding seed crystals, the mixture was stirred at 4 ° C for 24 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 5 hours to obtain Compound 3 (clopidogrel sulfate: 9.8 g). Form I crystals, 65% yield, 99.97% chemical purity. The content of compound 4 was 0.02%. Table 1 shows the results.
  • Comparative Example 3 clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
  • Compound 2 (11.6 g; 36 mmol), 1-butanol (30 g), methyl t-butyl ether (50 g), and water (6 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.5 g; 35 mmol) at 10 ° C. or lower. ) was added dropwise. After the seed crystal was added, the mixture was stirred at 4 ° C. for 24 hours, but oil-out occurred and no crystals were precipitated. That is, if the amount of 1-butanol was too small relative to methyl t-butyl ether, clopidogrel sulfate crystals could not be obtained.
  • Embodiment 8 >> Using 5 g of the crude dry crystal of the compound 3 obtained in Preparation Example 2, it was dried at 30 ° C. under reduced pressure for 3, 6, 9, and 12 hours. After drying for 12 hours, the content of compound 4 was 0.06%, and the residual 1-butanol was 3900 ppm. Table 2 shows the results.
  • Example 9 >> The procedure of Example 8 was repeated except that the pressure-drying temperature was changed to 40 ° C. instead of 30 ° C. to obtain compound 3. After drying for 12 hours, the content of compound 4 was 0.13%, and residual 1-butanol was 3527 ppm. Table 2 shows the results.
  • Example 10 Using 5 g of the crude dry crystal of Compound 3 obtained in Preparation Example 2, dry nitrogen was blown at 30 ° C. for 3, 6, 9, and 12 hours. After ventilation for 12 hours, the content of compound 4 was 0.07%, and the residual 1-butanol was 3899 ppm. Table 2 shows the results.
  • Example 11 >> The procedure of Example 10 was repeated except that the drying temperature was changed to 40 ° C. instead of 30 ° C. to obtain compound 3. After ventilation for 12 hours, the content of compound 4 was 0.11%, and the amount of residual 1-butanol was 3613 ppm. Table 2 shows the results.
  • the wet crystals of the compound 3 were dried under reduced pressure at 30 ° C. for 8 hours to obtain 65.8 g of crude dry crystals of the compound 3.
  • the content of the compound 4 in the roughly dried crystals was 0.06%, and the residual 1-butanol was 5286 ppm.
  • Example 12 >> Using 5 g of the crude dry crystal of Compound 3 obtained in Preparation Example 3, nitrogen at 90% humidity was blown at 30 ° C. for 3, 6, 9, and 12 hours. After ventilation for 12 hours, the content of compound 4 was 0.08%, and the residual 1-butanol was 1,717 ppm. Table 2 shows the results.
  • Example 13 >> The procedure of Example 12 was repeated, except that the drying temperature was changed to 30 ° C. and to 40 ° C., thereby obtaining a compound 3. After ventilation for 12 hours, the content of compound 4 was 0.09%, and the amount of residual 1-butanol was 2330 ppm. Table 2 shows the results.
  • Example 14 >> The procedure of Example 12 was repeated, except that the drying temperature was changed to 30 ° C. and 50 ° C., to obtain compound 3. After ventilation for 12 hours, the content of compound 4 was 0.15%, and residual 1-butanol was 2159 ppm. Table 2 shows the results.
  • the content of 1-butanol can be reduced, and the monoalkyl sulfate (compound 4) generated by 1-butanol and sulfuric acid can be reduced.
  • the 1-butanol content can be reduced by vacuum drying and a dry nitrogen flow, but the 1-butanol content can be reduced more efficiently by drying with a wet nitrogen flow.
  • a type I crystal of clopidogrel sulfate with little contamination of monoalkyl sulfate can be used for production.

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Abstract

The purpose of the present invention is to provide a method for producing clopidogrel sulfate contaminated with little monoalkyl sulfates, and clopidogrel sulfate contaminated with little monoalkyl sulfates. The aforesaid problem can be solved by the method according to the present invention for producing clopidogrel sulfate form I crystals, said method comprising (1) a step for contacting clopidogrel free base with concentrated sulfuric acid in the presence of (a) a solvent that comprises 1.3 part by weight or more of 1-butanol per part by weight of methyl t-butyl ether or (b) a solvent that comprises 0.9 part by weight or more of 1-butanol and 0.05 part by weight or more of water per part by weight of methyl t-butyl ether to thereby give clopidogrel sulfate form I crystals.

Description

クロピドグレル硫酸塩のＩ型結晶の製造方法Method for producing type I crystal of clopidogrel sulfate
　本発明は、クロピドグレル硫酸塩のＩ型結晶の製造方法に関する。本発明によれば、不純物であるクロピドグレルのモノアルキル硫酸塩の含有量が少ないクロピドグレル硫酸塩を製造することができる。 << The present invention relates to a method for producing a clopidogrel sulfate type I crystal. According to the present invention, it is possible to produce clopidogrel sulfate having a low content of monoalkyl sulfate of clopidogrel as an impurity.
　クロピドグレル硫酸塩（（＋）－（Ｓ）－２－（２－クロロフェニル）－２－（４，５，６，７－テトラヒドロチエノ［３，２－ｃ］ピリジン－５－イル）酢酸メチル硫酸塩）は、血小板凝集阻害作用を有しており、脳卒中及び血栓、塞栓などの末梢動脈性疾患、並びに心筋梗塞、及び狭心症などの冠状動脈性疾患の治療に効果的に用いられている。 Clopidogrel sulfate ((+)-(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl sulfate ) Has a platelet aggregation inhibitory effect, and is effectively used for treating peripheral arterial diseases such as stroke and thrombus and embolism, and coronary diseases such as myocardial infarction and angina.
　クロピドグレル硫酸塩のＩ型結晶（フォームＩ結晶）の製造に関して、特許文献１は、メチルｔ－ブチルエーテル及びクロピドグレルの遊離塩基の混合物にｎブタノール及び濃硫酸を添加する製造方法を開示している。 Regarding the production of Form I crystal of clopidogrel sulfate (Form I crystal), Patent Document 1 discloses a production method in which n-butanol and concentrated sulfuric acid are added to a mixture of a free base of methyl t-butyl ether and clopidogrel.
国際公開第２０１１／０４２８０４号International Publication No. 2011/042804
　本発明者らは、クロピドグレル硫酸塩のＩ型結晶（フォームＩ結晶）の製造において、モノアルキル硫酸（ブチル硫酸）が生成され、これがクロピドグレルの遊離塩基と結合し、クロピドグレル硫酸塩の生成物にクロピドグレルのモノアルキル硫酸塩が混入することを確認した。
　従って、本発明の目的は、モノアルキル硫酸塩の混入が少ないクロピドグレル硫酸塩の製造方法、及びモノアルキル硫酸塩の混入が少ないクロピドグレル硫酸塩を提供することである。 In the production of clopidogrel sulfate Form I crystal (form I crystal), the present inventors produced a monoalkyl sulfate (butyl sulfate), which was combined with clopidogrel free base and added to the clopidogrel sulfate product. Was confirmed to be mixed.
Accordingly, it is an object of the present invention to provide a method for producing clopidogrel sulfate with less contamination with monoalkyl sulfate, and a clopidogrel sulfate with less contamination with monoalkyl sulfate.
　本発明者は、モノアルキル硫酸塩の生成が少ないクロピドグレル硫酸塩の製造方法について、鋭意研究した結果、驚くべきことに、メチルｔ－ブチルエーテル及び１－ブタノールの混合比を調整することによって、モノアルキル硫酸塩の生成を劇的に抑制できることを見出した。具体的には、メチルｔ－ブチルエーテルに対する１－ブタノールの量を増加させることによって、モノアルキル硫酸塩の生成を抑制することが可能になった。
　本発明は、こうした知見に基づくものである。
　従って、本発明は、
［１］（１）（ａ）１重量部のメチルｔ－ブチルエーテルに対して、１．３重量部以上の１－ブタノールを含む溶媒、又は（ｂ）１重量部のメチルｔ－ブチルエーテルに対して、０．９重量部以上の１－ブタノール及び０．０５重量部以上の水を含む溶媒、の存在下で、クロピドグレル遊離塩基に濃硫酸を接触させ、下記一般式（１）：
Figure JPOXMLDOC01-appb-C000002
 で表されるクロピドグレル硫酸塩のＩ型結晶を得る工程、を含むクロピドグレル硫酸塩のＩ型結晶の製造方法、
［２］前記溶媒のメチルｔ－ブチルエーテルに対する１－ブタノールの重量比が１０重量部以下である、［１］に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法、
［３］（２）前記Ｉ型結晶を５０℃以下で乾燥する工程、を更に含む［１］又は［２］に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法、
［４］前記乾燥工程（２）が、相対湿度４５～９９％及び温度０～５０℃の気体と接触させる操作を含む、［１］～［３］のいずれかに記載のクロピドグレル硫酸塩のＩ型結晶の製造方法、及び
［５］前記気体が、空気又は窒素である、［４］に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法、
に関する。 The inventors of the present invention have conducted intensive studies on a method for producing clopidogrel sulfate that produces less monoalkyl sulfate, and surprisingly found that by adjusting the mixing ratio of methyl t-butyl ether and 1-butanol, monoalkyl sulfate was produced. It has been found that the production of sulfate can be dramatically suppressed. Specifically, by increasing the amount of 1-butanol relative to methyl t-butyl ether, it became possible to suppress the production of monoalkyl sulfate.
The present invention is based on these findings.
Therefore, the present invention
[1] (1) With respect to (a) 1 part by weight of methyl t-butyl ether, a solvent containing 1.3 parts by weight or more of 1-butanol, or (b) 1 part by weight of methyl t-butyl ether Clopidogrel free base is contacted with concentrated sulfuric acid in the presence of a solvent containing 0.9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water, and the following general formula (1):
Figure JPOXMLDOC01-appb-C000002
 Obtaining a type I crystal of clopidogrel sulfate represented by the formula:
[2] The method for producing a clopidogrel sulfate type I crystal according to [1], wherein the weight ratio of 1-butanol to methyl t-butyl ether of the solvent is 10 parts by weight or less,
[3] The method for producing a clopidogrel sulfate I-type crystal according to [1] or [2], further comprising: (2) drying the I-type crystal at 50 ° C. or lower.
[4] The clopidogrel sulfate I according to any one of [1] to [3], wherein the drying step (2) includes an operation of contacting with a gas having a relative humidity of 45 to 99% and a temperature of 0 to 50 ° C. The method for producing a type I crystal of clopidogrel sulfate according to [4], wherein the method is a method for producing a type crystal, and [5] the gas is air or nitrogen.
About.
　本発明のクロピドグレル硫酸塩のＩ型結晶の製造方法によれば、モノアルキル硫酸塩の混入が少ないクロピドグレル硫酸塩のＩ型結晶を得ることができる。 According to the method for producing a clopidogrel sulfate type I crystal of the present invention, it is possible to obtain a clopidogrel sulfate type I crystal with less contamination of a monoalkyl sulfate.
本発明の製造方法で得られたクロピドグレル硫酸塩のＩ型結晶のＸＲＰＤディフラクトグラムである。1 is an XRPD diffractogram of Form I crystal of clopidogrel sulfate obtained by the production method of the present invention.
　本発明のクロピドグレル硫酸塩のＩ型結晶の製造方法は、（１）（ａ）１重量部のメチルｔ－ブチルエーテルに対して１．３重量部以上の１－ブタノールを含む溶媒、又は（ｂ）１重量部のメチルｔ－ブチルエーテルに対して、０．９重量部以上の１－ブタノール及び０．０５重量部以上の水を含む溶媒、の存在下で、クロピドグレルの遊離塩基に濃硫酸を接触させ、下記一般式（１）：
Figure JPOXMLDOC01-appb-C000003
 で表されるクロピドグレル硫酸塩のＩ型結晶を得る工程、を含む。更に、本発明のクロピドグレル硫酸塩のＩ型結晶の製造方法は、好ましくは（２）前記Ｉ型結晶を５０℃以下で乾燥する工程、を含む。 The method for producing a clopidogrel sulfate type I crystal of the present invention comprises: (1) (a) a solvent containing 1.3 parts by weight or more of 1-butanol based on 1 part by weight of methyl t-butyl ether, or (b) Concentrated sulfuric acid is contacted with the free base of clopidogrel in the presence of 1 part by weight of methyl tert-butyl ether in a solvent containing 0.9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water. And the following general formula (1):
Figure JPOXMLDOC01-appb-C000003
 Obtaining a type I crystal of clopidogrel sulfate represented by the formula: Furthermore, the method for producing the clopidogrel sulfate type I crystal of the present invention preferably includes (2) a step of drying the type I crystal at 50 ° C. or lower.
《クロピドグレル硫酸塩》
　本発明の製造方法によって得ることのできるクロピドグレル硫酸塩（（＋）－（Ｓ）－２－（２－クロロフェニル）－２－（４，５，６，７－テトラヒドロチエノ［３，２－ｃ］ピリジン－５－イル）酢酸メチル硫酸塩）は、前記一般式（１）で表される化合物のＩ型結晶である。 << Clopidogrel sulfate >>
Clopidogrel sulfate ((+)-(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c]) obtainable by the production method of the present invention Pyridin-5-yl) methyl acetate sulfate is an I-type crystal of the compound represented by the general formula (1).
《モノアルキル硫酸塩》
　本発明の製造方法においては、クロピドグレルのモノアルキル硫酸塩の生成が抑制される。従って、本発明の製造方法によって得られるクロピドグレル硫酸塩は、クロピドグレルのモノアルキル硫酸塩の含有量が少ない。
　モノアルキル硫酸塩は、式（２）：
Figure JPOXMLDOC01-appb-C000004
 で表されるクロピドグレルモノブチル硫酸塩である。 《Monoalkyl sulfate》
In the production method of the present invention, the production of clopidogrel monoalkyl sulfate is suppressed. Therefore, the clopidogrel sulfate obtained by the production method of the present invention has a low content of clopidogrel monoalkyl sulfate.
The monoalkyl sulfate is represented by the formula (2):
Figure JPOXMLDOC01-appb-C000004
 Is clopidogrel monobutyl sulfate.
　本発明の製造方法によって得られるクロピドグレル硫酸塩は、モノアルキル硫酸塩の混入量が少ない。モノアルキル硫酸塩の混入量は、好ましくは０．２０重量％以下であり、より好ましくは０．１５重量％以下であり、更に好ましくは０．１０重量％以下であり、最も好ましくは０．０５重量％以下である。 ク ロ Clopidogrel sulfate obtained by the production method of the present invention has a small amount of monoalkyl sulfate mixed therein. The content of the monoalkyl sulfate is preferably 0.20% by weight or less, more preferably 0.15% by weight or less, further preferably 0.10% by weight or less, and most preferably 0.05% by weight or less. % By weight or less.
［１］結晶化工程
　本発明のクロピドグレル硫酸塩のＩ型結晶を得る工程（以下、結晶化工程と称することがある）において、（ａ）１重量部のメチルｔ－ブチルエーテルに対して１．３重量部以上の１－ブタノールを含む溶媒、又は（ｂ）１重量部のメチルｔ－ブチルエーテルに対して、０．９重量部以上の１－ブタノール及び０．０５重量部以上の水を含む溶媒の存在下で、クロピドグレル遊離塩基に濃硫酸を接触させる。例えば、メチルｔ－ブチルエーテル及び１－ブタノールを含む溶媒、又はメチルｔ－ブチルエーテル、１－ブタノール、及び水を含む溶媒にクロピドグレル遊離塩基を溶解するが、メチルｔ－ブチルエーテル、１－ブタノール、水、及びクロピドグレル遊離塩基の混合の順番は特に限定されない。そして、好ましくはクロピドグレル遊離塩基を溶解した溶液に、濃硫酸を滴下し、そして種結晶を添加する。また、濃硫酸とクロピドグレル遊離塩基との接触については、例えば前記溶媒に、濃硫酸を添加し、それにクロピドグレル遊離塩基を添加して、その後に種結晶を添加してもよい。得られた混合物を撹拌することによって、クロピドグレル硫酸塩の結晶を得ることができる。
　結晶化工程の温度は、特に限定されるものではないが、好ましくは－１０～３０℃であり、より好ましくは０～１０℃である。結晶化工程の圧力は、特に限定されるものではなく、加圧下でも、常圧下でもよいし、減圧下でもよい。
　前記種結晶は、Ｉ型結晶である限りにおいて、特に限定されるものではない。 [1] Crystallization Step In the step of obtaining the type I crystal of clopidogrel sulfate of the present invention (hereinafter sometimes referred to as the crystallization step), (a) 1.3 parts by weight of 1 part by weight of methyl t-butyl ether. A solvent containing 1 part by weight or more of 1-butanol or (b) a solvent containing 0.9 part by weight or more of 1-butanol and 0.05 part by weight or more of water based on 1 part by weight of methyl t-butyl ether; Contact clopidogrel free base with concentrated sulfuric acid in the presence. For example, clopidogrel free base is dissolved in a solvent containing methyl t-butyl ether and 1-butanol, or a solvent containing methyl t-butyl ether, 1-butanol, and water, but containing methyl t-butyl ether, 1-butanol, water, and The order of mixing clopidogrel free base is not particularly limited. Then, preferably, concentrated sulfuric acid is added dropwise to the solution in which clopidogrel free base is dissolved, and seed crystals are added. As for the contact between concentrated sulfuric acid and clopidogrel free base, for example, concentrated sulfuric acid may be added to the solvent, clopidogrel free base may be added thereto, and then a seed crystal may be added. By stirring the obtained mixture, crystals of clopidogrel sulfate can be obtained.
The temperature of the crystallization step is not particularly limited, but is preferably −10 to 30 ° C., and more preferably 0 to 10 ° C. The pressure in the crystallization step is not particularly limited, and may be under pressure, under normal pressure, or under reduced pressure.
The seed crystal is not particularly limited as long as it is an I-type crystal.
《溶媒》
　溶媒は、クロピドグレル遊離塩基を溶解し、クロピドグレル遊離塩基と硫酸との反応を効率的に行うものである。本発明の製造方法においては、溶媒は、１重量部のメチルｔ－ブチルエーテルに対して１．３重量部以上の１－ブタノールを含む限りにおいて、又は１重量部のメチルｔ－ブチルエーテルに対して、０．９重量部以上の１－ブタノール及び０．０５重量部以上の水を含む限りにおいて、特に限定されるものではなく、その他の成分を含んでもよい。 "solvent"
The solvent dissolves clopidogrel free base and efficiently performs the reaction between clopidogrel free base and sulfuric acid. In the production method of the present invention, the solvent is used as long as it contains 1.3 parts by weight or more of 1-butanol with respect to 1 part by weight of methyl t-butyl ether, or with respect to 1 part by weight of methyl t-butyl ether. It is not particularly limited as long as it contains 0.9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water, and may contain other components.
（メチルｔ－ブチルエーテル）
　溶媒として、メチルｔ－ブチルエーテル（以下、ＭＴＢＥと称することがある）を用いることにより、効率的に目的物を晶析することができる。
　クロピドグレル遊離塩基に対するメチルｔ－ブチルエーテルの量は、クロピドグレル硫酸塩が生成される限りにおいて、特に限定されるものではないが、クロピドグレル遊離塩基１重量部に対してメチルｔ－ブチルエーテルが、好ましくは１～１０重量部であり、より好ましくは１．２～８重量部であり、更に好ましくは１．５～６重量部である。前記範囲であることにより、モノアルキル硫酸塩の生成を抑制することができ、安定且つ効率的にＩ型結晶を得ることができる。 (Methyl t-butyl ether)
By using methyl t-butyl ether (hereinafter sometimes referred to as MTBE) as a solvent, the target substance can be efficiently crystallized.
The amount of methyl t-butyl ether based on clopidogrel free base is not particularly limited as long as clopidogrel sulfate is produced, but methyl t-butyl ether is preferably used in an amount of 1 to 1 part by weight of clopidogrel free base. It is 10 parts by weight, more preferably 1.2 to 8 parts by weight, even more preferably 1.5 to 6 parts by weight. When the content is within the above range, the production of monoalkyl sulfate can be suppressed, and the type I crystal can be obtained stably and efficiently.
（１－ブタノール）
　前記溶媒は、１－ブタノールを含む。溶媒として、１－ブタノールを用いることにより、安定且つ効率的にＩ型結晶を得ることができる。
　クロピドグレル遊離塩基に対する１－ブタノールの量は、クロピドグレル硫酸塩が生成される限りにおいて、特に限定されるものではないが、クロピドグレル遊離塩基１重量部に対して１－ブタノールが、好ましくは２～１５重量部であり、より好ましくは３～１３重量部であり、更に好ましくは４～１２重量部である。前記範囲であることにより、クロピドグレルモノアルキル硫酸塩の生成を抑制することができる。 (1-butanol)
The solvent includes 1-butanol. By using 1-butanol as a solvent, a type I crystal can be obtained stably and efficiently.
The amount of 1-butanol based on clopidogrel free base is not particularly limited as long as clopidogrel sulfate is formed, but 1-butanol is preferably used per 1 part by weight of clopidogrel free base, preferably 2 to 15 parts by weight. Parts by weight, more preferably 3 to 13 parts by weight, even more preferably 4 to 12 parts by weight. When the content is within the above range, generation of clopidogrel monoalkyl sulfate can be suppressed.
（メチルｔ－ブチルエーテル及び１－ブタノールの重量比）
（ａ）メチルｔ－ブチルエーテル１重量部に対して１－ブタノール１．３重量部以上を使用する場合
　メチルｔ－ブチルエーテル及び１－ブタノールの重量比は、メチルｔ－ブチルエーテル１重量部に対して１－ブタノール１．３重量部以上であり、好ましくは１．４重量部以上であり、さらに好ましくは１．５重量部以上であり、最も好ましくは１．６重量部以上である。メチルｔ－ブチルエーテルに対する１－ブタノールの重量比の上限は、限定されるものではないが、好ましくは１０重量部以下であり、より好ましくは９重量部以下であり、最も好ましくは８重量部以下である。上限と下限とは、所望により任意に組み合わせることができる。前記範囲であることにより、モノアルキル硫酸塩の生成を抑制することができる。メチルｔ－ブチルエーテルに対する１－ブタノールの上限が、１０重量部を超える場合も、十分にクロピドグレルのモノアルキル硫酸塩の生成を抑制することができるが、II型結晶が産生されるリスクがあるので、メチルｔ－ブチルエーテルに対する１－ブタノールの上限は、好ましくは１０重量部以下である。
　また、メチルｔ－ブチルエーテル１重量部に対して１－ブタノール１．３重量部以上を使用する場合は、水を添加せずに本発明の効果を得ることができるが、更に水を添加してもよい。水の含有量は特に限定されないが、好ましくは０．５重量部以下であり、より好ましくは０．２重量部以下である。 (Weight ratio of methyl t-butyl ether and 1-butanol)
(A) When 1.3 parts by weight or more of 1-butanol is used with respect to 1 part by weight of methyl t-butyl ether, the weight ratio of methyl t-butyl ether and 1-butanol is 1 to 1 part by weight of methyl t-butyl ether. -Butanol is at least 1.3 parts by weight, preferably at least 1.4 parts by weight, more preferably at least 1.5 parts by weight, most preferably at least 1.6 parts by weight. The upper limit of the weight ratio of 1-butanol to methyl t-butyl ether is not limited, but is preferably 10 parts by weight or less, more preferably 9 parts by weight or less, and most preferably 8 parts by weight or less. is there. The upper and lower limits can be arbitrarily combined as desired. When the content is within the above range, the production of monoalkyl sulfate can be suppressed. When the upper limit of 1-butanol with respect to methyl t-butyl ether exceeds 10 parts by weight, the production of clopidogrel monoalkyl sulfate can be sufficiently suppressed, but there is a risk of producing type II crystals. The upper limit of 1-butanol relative to methyl t-butyl ether is preferably at most 10 parts by weight.
When 1.3 parts by weight of 1-butanol is used per 1 part by weight of methyl t-butyl ether, the effect of the present invention can be obtained without adding water. Is also good. The content of water is not particularly limited, but is preferably 0.5 parts by weight or less, more preferably 0.2 parts by weight or less.
（ｂ）メチルｔ－ブチルエーテル１重量部に対して１－ブタノール０．９重量部以上を使用する場合
　メチルｔ－ブチルエーテル及び１－ブタノールの重量比は、水を溶媒に添加する場合は、メチルｔ－ブチルエーテル１重量部に対して１－ブタノール０．９重量部以上であり、好ましくは１．０重量部以上であり、さらにこの好ましくは１．１重量部以上であり、最も好ましくは１．２重量部以上である。メチルｔ－ブチルエーテルに対する１－ブタノールの重量比の上限は、限定されるものではないが、好ましくは１０重量部以下であり、より好ましくは９重量部以下であり、最も好ましくは８重量部以下である。また、メチルｔ－ブチルエーテルに対する水の重量比は、メチルｔ－ブチルエーテル１重量部に対して水０．０５重量部以上であり、好ましくは０．０６重量部以上であり、さらにこの好ましくは０．０７重量部以上であり、最も好ましくは０．０８重量部以上である。メチルｔ－ブチルエーテルに対する水の重量比の上限は、特に限定されるものではないが、好ましくは０．３重量部であり、より好ましくは０．２５重量部以下であり、最も好ましくは０．２重量部以下である。上限と下限とは、所望により任意に組み合わせることができる。前記範囲であることにより、モノアルキル硫酸塩の生成を抑制することができる。 (B) When 1 part by weight of methyl t-butyl ether is used in an amount of 0.9 part by weight or more, the weight ratio of methyl t-butyl ether and 1-butanol is determined by adding methyl t-butyl ether to the solvent when water is added to the solvent. 1-butanol is at least 0.9 part by weight, preferably at least 1.0 part by weight, more preferably at least 1.1 part by weight, most preferably at least 1.2 parts by weight with respect to 1 part by weight of -butyl ether. It is more than weight part. The upper limit of the weight ratio of 1-butanol to methyl t-butyl ether is not limited, but is preferably 10 parts by weight or less, more preferably 9 parts by weight or less, and most preferably 8 parts by weight or less. is there. The weight ratio of water to methyl t-butyl ether is at least 0.05 part by weight, preferably at least 0.06 part by weight, more preferably at least 0.06 part by weight, based on 1 part by weight of methyl t-butyl ether. It is at least 07 parts by weight, most preferably at least 0.08 parts by weight. The upper limit of the weight ratio of water to methyl t-butyl ether is not particularly limited, but is preferably 0.3 part by weight, more preferably 0.25 part by weight or less, and most preferably 0.2 part by weight or less. Not more than parts by weight. The upper and lower limits can be arbitrarily combined as desired. When the content is within the above range, the production of monoalkyl sulfate can be suppressed.
（その他の成分）
　前記溶媒は、本発明の効果が得られる限りにおいて、１－ブタノール及びメチルｔ－ブチルエーテル以外のその他の成分を含むことができる。すなわち、クロピドグレルのモノアルキル硫酸塩の生成を増加させない限りにおいて、その他の成分を含むことができる。その他の成分としては、トルエン、塩又はアルコールを挙げることができる。すなわち、少量の無機塩又は有機溶媒は、本発明の反応に影響を与えない。 (Other components)
The solvent may contain other components other than 1-butanol and methyl t-butyl ether as long as the effects of the present invention can be obtained. That is, other components can be included as long as the formation of clopidogrel monoalkyl sulfate is not increased. Other components include toluene, salts or alcohols. That is, a small amount of an inorganic salt or an organic solvent does not affect the reaction of the present invention.
《クロピドグレル遊離塩基》
　本発明に用いるクロピドグレル遊離塩基は、例えば下記の反応式（３）に従って、調製することができる。
Figure JPOXMLDOC01-appb-C000005
 　すなわち、クロピドグレル・（－）－カンファースルホン酸塩に、トルエン及び炭酸水素ナトリウムを添加し、反応させる。有機層に水を加えて分液洗浄し、有機層を回収する。滅圧下で溶媒を留去することによって、クロピドグレル遊離塩基を得ることができる。 《Clopidogrel free base》
The clopidogrel free base used in the present invention can be prepared, for example, according to the following reaction formula (3).
Figure JPOXMLDOC01-appb-C000005
 That is, toluene and sodium hydrogen carbonate are added to clopidogrel · (−)-camphorsulfonic acid salt and reacted. Water is added to the organic layer and the mixture is separated and washed, and the organic layer is collected. By evaporating the solvent under reduced pressure, clopidogrel free base can be obtained.
《濃硫酸》
　本発明の製造方法において、濃硫酸を前記クロピドグレル遊離塩基に接触させることによって、クロピドグレル硫酸塩を得ることができる。本明細書において、濃硫酸とは、硫酸の濃度が９０重量％以上のものを意味する。濃硫酸として市販されているものは、通常９６～９８重量％の濃度であり、このような濃度の濃硫酸を用いて、本発明の製造方法を実施することができる。 << concentrated sulfuric acid >>
In the production method of the present invention, clopidogrel sulfate can be obtained by contacting concentrated sulfuric acid with the clopidogrel free base. In this specification, concentrated sulfuric acid means one having a sulfuric acid concentration of 90% by weight or more. Commercially available concentrated sulfuric acid generally has a concentration of 96 to 98% by weight, and the production method of the present invention can be carried out using concentrated sulfuric acid at such a concentration.
《溶媒、クロピドグレル遊離塩基、及び硫酸の重量比》
　本発明の製造方法における溶媒、クロピドグレル遊離塩基、及び硫酸の重量比は、クロピドグレル硫酸塩が得られる限りにおいて限定されない。通常、以下の重量比で反応を行うことができる。
　クロピドグレル遊離塩基と濃硫酸の比率は、１：１のモル比が理論値であるが、通常はクロピドグレル遊離塩基１モルに対して、濃硫酸０．８～２モルで反応させることができる。
　クロピドグレル遊離塩基と溶媒との比率は、限定されるものではないが、クロピドグレル遊離塩基１重量部に対して、好ましくは溶媒が２～３０重量部であり、より好ましくは４～２０重量部であり、最も好ましくは５～１５重量部である。
　濃硫酸と溶媒との比率も限定されるものではないが、濃硫酸１重量部に対して、好ましくは溶媒が５～１００重量部であり、より好ましくは７～８０重量部であり、最も好ましくは９～７０重量部である。 << Solvent, weight ratio of clopidogrel free base and sulfuric acid >>
The weight ratio of the solvent, clopidogrel free base and sulfuric acid in the production method of the present invention is not limited as long as clopidogrel sulfate can be obtained. Usually, the reaction can be carried out in the following weight ratio.
The theoretical ratio of clopidogrel free base to concentrated sulfuric acid is 1: 1, but the reaction can be usually carried out with 0.8 to 2 mol of concentrated sulfuric acid per mol of clopidogrel free base.
The ratio of clopidogrel free base to solvent is not limited, but the solvent is preferably 2 to 30 parts by weight, more preferably 4 to 20 parts by weight, per 1 part by weight of clopidogrel free base. , Most preferably 5 to 15 parts by weight.
The ratio between the concentrated sulfuric acid and the solvent is not limited, but the solvent is preferably 5 to 100 parts by weight, more preferably 7 to 80 parts by weight, most preferably 1 part by weight of concentrated sulfuric acid. Is from 9 to 70 parts by weight.
［２］乾燥工程
　本発明の乾燥工程において、前記クロピドグレル硫酸塩のＩ型結晶を５０℃以下で乾燥し、残留１－ブタノール及びメチルｔ－ブチルエーテルを除去する。乾燥方法は、クロピドグレルのモノアルキル硫酸塩が過度に増加しない限りにおいて、特に限定されるものではなく、滅圧乾燥法、送風乾燥、又は調湿気体による乾燥法を挙げることができるが、好ましくは調湿気体による乾燥法である。
　調湿気体による乾燥法としては、具体的には、相対湿度４５～９９％及び温度０～５０℃の気体と接触させる操作が好ましい。調湿気体による乾燥は、残存している１－ブタノールを効率良く除去できるため、モノアルキル硫酸塩の生成を抑制することができる。
　相対湿度は、好ましくは５０～９５％であり、更に好ましくは５５～９０％である。また、温度は好ましくは５～４５℃であり、更に好ましくは１０～４０℃である。前記の相対湿度及び温度であることにより、１－ブタノールを効率よく除去することができる。 [2] Drying Step In the drying step of the present invention, the type I crystal of clopidogrel sulfate is dried at 50 ° C. or lower to remove residual 1-butanol and methyl t-butyl ether. The drying method is not particularly limited as long as the monoalkyl sulfate of clopidogrel does not excessively increase, and examples of the drying method include a pressureless drying method, a blast drying method, and a drying method using a humidity control gas. This is a drying method using a humidified gas.
As a drying method using a humidified gas, specifically, an operation of contacting with a gas having a relative humidity of 45 to 99% and a temperature of 0 to 50 ° C. is preferable. Drying using a humidified gas can efficiently remove the remaining 1-butanol, and therefore can suppress the production of monoalkyl sulfate.
The relative humidity is preferably between 50 and 95%, more preferably between 55 and 90%. The temperature is preferably 5 to 45 ° C, more preferably 10 to 40 ° C. With the above relative humidity and temperature, 1-butanol can be efficiently removed.
《作用》
　本発明の製造方法において、クロピドグレルのモノアルキル硫酸塩の生成が抑制される機構は、詳細には解明されていないが、以下のように考えることができる。しかしながら、本発明は、以下の説明によって限定されるものではない。
　本発明で溶媒として用いる１－ブタノールは、硫酸と接触することによりモノアルキル硫酸を生成することがある。このモノアルキル硫酸は、クロピドグレル遊離塩基と結合してクロピドグレルのモノアルキル硫酸塩を生成する。本発明の製造方法においては、１－ブタノールの量を通常よりも増加させ、貧溶媒であるメチルｔ－ブチルエーテルと１－ブタノールとの量を特定の比率とすることにより、アルキル硫酸塩の過度な生成が抑制され、そしてアルキル硫酸塩が除去され、安定且つ効率的にＩ型結晶を得ることができるものと推定される。 《Action》
In the production method of the present invention, the mechanism by which the production of clopidogrel monoalkyl sulfate is suppressed has not been elucidated in detail, but can be considered as follows. However, the present invention is not limited by the following description.
1-Butanol used as a solvent in the present invention may form monoalkyl sulfate upon contact with sulfuric acid. The monoalkyl sulfate combines with the clopidogrel free base to form a clopidogrel monoalkyl sulfate. In the production method of the present invention, by increasing the amount of 1-butanol more than usual and setting the amount of methyl t-butyl ether and 1-butanol, which are poor solvents, to a specific ratio, the excess amount of alkyl sulfate can be reduced. It is presumed that the formation is suppressed and the alkyl sulfate is removed, so that the type I crystal can be obtained stably and efficiently.
　以下、実施例によって本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。 Hereinafter, the present invention will be described specifically with reference to Examples, but these do not limit the scope of the present invention.
《調製例１》
　本調製例では、クロピドグレル遊離塩基（化合物２）を下記式（４）に従って調製した。
Figure JPOXMLDOC01-appb-C000006
 　容量１Ｌの反応フラスコに、化合物１（クロピドグレル・（－）－カンファースルホン酸塩；１００ｇ；０．１８ｍｏｌ）、トルエン（３００ｇ）を仕込み、炭酸水素ナトリウム（１６．７ｇ；０．２０ｍｏｌ）水溶液（３００ｇ）を滴下した。室温で３０分間撹拌後、分液した。有機層を水（３００ｇ）で洗浄後、減圧下、溶媒を留去して、化合物２（クロピドグレル遊離塩基；ＣＬＯＰ－ＦＢ）を得た。 << Preparation Example 1 >>
In this preparation example, clopidogrel free base (compound 2) was prepared according to the following formula (4).
Figure JPOXMLDOC01-appb-C000006
 A 1-L reaction flask was charged with Compound 1 (clopidogrel-(-)-camphorsulfonic acid salt; 100 g; 0.18 mol) and toluene (300 g), and an aqueous solution of sodium hydrogencarbonate (16.7 g; 0.20 mol) (300 g) was added. ) Was added dropwise. After stirring at room temperature for 30 minutes, the layers were separated. After washing the organic layer with water (300 g), the solvent was distilled off under reduced pressure to obtain Compound 2 (clopidogrel free base; CLOP-FB).
《実施例１》
　本実施例では、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（５．８ｇ；１８ｍｍｏｌ）、１－ブタノール（６０ｇ）、及びメチルｔ－ブチルエーテル（２０ｇ）を仕込み、１０℃以下で硫酸（１．８ｇ；１８ｍｍｏｌ）を滴下した。種結晶を添加後、１５℃で２６時間撹拌した。結晶をろ取し、３０℃で７時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：６．１ｇ）を得た。
　フォームＩ結晶、収率８１％、化学純度９９．９６％。
　下記式（２）：
Figure JPOXMLDOC01-appb-C000007
 で表される化合物４（クロピドグレルモノブチル硫酸塩）の含有量は０．０２％であった。結果を表１に示す。 << Example 1 >>
In this example, clopidogrel sulfate was produced.
Compound 2 (5.8 g; 18 mmol), 1-butanol (60 g), and methyl t-butyl ether (20 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. . After adding seed crystals, the mixture was stirred at 15 ° C for 26 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 6.1 g).
Form I crystal, yield 81%, chemical purity 99.96%.
The following equation (2):
Figure JPOXMLDOC01-appb-C000007
 The content of the compound 4 (clopidogrel monobutyl sulfate) represented by the formula was 0.02%. Table 1 shows the results.
《実施例２》
　本実施例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（５．８ｇ；１８ｍｍｏｌ）、１－ブタノール（５０ｇ）、及びメチルｔ－ブチルエーテル（３０ｇ）を仕込み、１０℃以下で硫酸（１．８ｇ；１８ｍｍｏｌ）を滴下した。種結晶を添加後、１５℃で２３時間撹拌した。結晶をろ取し、３０℃で７時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：５．９ｇ）を得た。
　フォームＩ結晶、収率７７％、化学純度９９．９６％。
　化合物４の含有量は０．１０％であった。結果を表１に示す。 << Example 2 >>
In this example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (5.8 g; 18 mmol), 1-butanol (50 g), and methyl t-butyl ether (30 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. . After the seed crystal was added, the mixture was stirred at 15 ° C. for 23 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 5.9 g).
Form I crystal, 77% yield, 99.96% chemical purity.
The content of compound 4 was 0.10%. Table 1 shows the results.
《実施例３》
　本実施例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（１１．６ｇ；３６ｍｍｏｌ）、１－ブタノール（６０ｇ）、及びメチルｔ－ブチルエーテル（２０ｇ）を仕込み、１０℃以下で硫酸（３．５ｇ；３６ｍｍｏｌ）を滴下した。種結晶を添加後、５℃で２２時間撹拌した。結晶をろ取し、３０℃で７時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：１２．９ｇ）を得た。
　フォームＩ結晶、収率８５％、化学純度９９．９７％。
　化合物４の含有量は０．０２％であった。結果を表１に示す。 << Example 3 >>
In this example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (11.6 g; 36 mmol), 1-butanol (60 g), and methyl t-butyl ether (20 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.5 g; 36 mmol) was added dropwise at 10 ° C. or lower. . After adding seed crystals, the mixture was stirred at 5 ° C. for 22 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 12.9 g).
Form I crystals, 85% yield, 99.97% chemical purity.
The content of compound 4 was 0.02%. Table 1 shows the results.
《実施例４》
　本実施例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（１１．６ｇ；３６ｍｍｏｌ）、１－ブタノール（５０ｇ）、メチルｔ－ブチルエーテル（３０ｇ）、水（２ｇ）を仕込み、１０℃以下で硫酸（３．７ｇ；３８ｍｍｏｌ）を滴下した。種結晶を添加後、５℃で４３時間撹拌した。結晶をろ取し、３０℃で７時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：１２．５ｇ）を得た。
　フォームＩ結晶、収率８２％、化学純度９９．８７％。
　化合物４の含有量は０．０２％であった。結果を表１に示す。 << Example 4 >>
In this example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (11.6 g; 36 mmol), 1-butanol (50 g), methyl t-butyl ether (30 g), and water (2 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.7 g; 38 mmol) at 10 ° C. or lower. ) Was added dropwise. After adding seed crystals, the mixture was stirred at 5 ° C for 43 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 7 hours to obtain Compound 3 (clopidogrel sulfate: 12.5 g).
Form I crystal, yield 82%, chemical purity 99.87%.
The content of compound 4 was 0.02%. Table 1 shows the results.
《実施例５》
　本実施例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（１１．６ｇ；３６ｍｍｏｌ）、１－ブタノール（７２．７ｇ）、メチルｔ－ブチルエーテル（７．３ｇ）を仕込み、１０℃以下で硫酸（３．５ｇ；３５ｍｍｏｌ）を滴下した。種結晶を添加後、４℃で２４時間撹拌した。結晶をろ取し、３０℃で５時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：１３．２ｇ）を得た。
　フォームＩ結晶、収率８７％、化学純度９９．９４％。
　化合物４の含有量は０．０２％であった。結果を表１に示す。 << Example 5 >>
In this example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (11.6 g; 36 mmol), 1-butanol (72.7 g), and methyl tert-butyl ether (7.3 g) were charged into a 200 mL reaction flask, and sulfuric acid (3.5 g; 35 mmol) at 10 ° C. or lower. Was dropped. After adding seed crystals, the mixture was stirred at 4 ° C for 24 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 5 hours to obtain Compound 3 (clopidogrel sulfate: 13.2 g).
Form I crystal, 87% yield, 99.94% chemical purity.
The content of compound 4 was 0.02%. Table 1 shows the results.
《比較例１》
　本比較例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（５．８ｇ；１８ｍｍｏｌ）、１－ブタノール（４０ｇ）、及びメチルｔ－ブチルエーテル（４０ｇ）を仕込み、１０℃以下で硫酸（１．８ｇ；１８ｍｍｏｌ）を滴下した。種結晶を添加後、１５℃で４３時間撹拌した。結晶をろ取し、減圧乾燥し、化合物３（クロピドグレル硫酸塩：５．９ｇ）を得た。
　フォームＩ結晶、収率７８％、化学純度９９．９３％。
　化合物４の含有量は０．４４％であった。結果を表１に示す。 << Comparative Example 1 >>
In this comparative example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (5.8 g; 18 mmol), 1-butanol (40 g), and methyl t-butyl ether (40 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. . After adding seed crystals, the mixture was stirred at 15 ° C for 43 hours. The crystals were collected by filtration and dried under reduced pressure to obtain Compound 3 (clopidogrel sulfate: 5.9 g).
Form I crystal, 78% yield, 99.93% chemical purity.
The content of compound 4 was 0.44%. Table 1 shows the results.
《比較例２》
　本比較例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、１－ブタノール（２０ｇ）、メチルｔ－ブチルエーテル（４０ｇ）を仕込み、１０℃以下で硫酸（１．８ｇ；１８ｍｍｏｌ）を滴下した。種結晶を添加後、１０℃以下で化合物２（５．８ｇ；１８ｍｍｏｌ）のメチルｔ－ブチルエーテル（２０ｇ）溶液を滴下し、１５℃で２２時間撹拌した。結晶をろ取し、減圧乾燥し、化合物３（クロピドグレル硫酸塩：７．１ｇ）を得た。
　フォームＩ結晶、収率９３％、化学純度９９．９１％。
　化合物４の含有量は１．２２％であった。結果を表１に示す。 << Comparative Example 2 >>
In this comparative example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
1-Butanol (20 g) and methyl t-butyl ether (40 g) were charged into a 200 mL reaction flask, and sulfuric acid (1.8 g; 18 mmol) was added dropwise at 10 ° C. or lower. After adding seed crystals, a solution of compound 2 (5.8 g; 18 mmol) in methyl t-butyl ether (20 g) was added dropwise at 10 ° C. or lower, and the mixture was stirred at 15 ° C. for 22 hours. The crystals were collected by filtration and dried under reduced pressure to obtain Compound 3 (clopidogrel sulfate: 7.1 g).
Form I crystals, 93% yield, 99.91% chemical purity.
The content of compound 4 was 1.22%. Table 1 shows the results.
《実施例６》
　本実施例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（１１．６ｇ；３６ｍｍｏｌ）、１－ブタノール（４０ｇ）、メチルｔ－ブチルエーテル（４０ｇ）、水（６ｇ）を仕込み、１０℃以下で硫酸（３．５ｇ；３５ｍｍｏｌ）を滴下した。種結晶を添加後、４℃で２４時間撹拌した。結晶をろ取し、３０℃で５時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：８．８ｇ）を得た。ＸＲＰＤディフラクトグラムを図１に示す。９．００、１０．６９、１４．６１、１７．７４、１８．７４、２０．３７、２２．９６、２５．３１（±０．２）°２θ付近に特徴的なピークを有していた。
　フォームＩ結晶、収率５８％、化学純度９９．９８％。
　化合物４の含有量は０．０１％であった。結果を表１に示す。 << Example 6 >>
In this example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (11.6 g; 36 mmol), 1-butanol (40 g), methyl t-butyl ether (40 g), and water (6 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.5 g; 35 mmol) at 10 ° C. or lower. ) Was added dropwise. After adding seed crystals, the mixture was stirred at 4 ° C for 24 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 5 hours to obtain Compound 3 (clopidogrel sulfate: 8.8 g). The XRPD diffractogram is shown in FIG. 9.00, 10.69, 14.61, 17.74, 18.74, 20.37, 22.96, 25.31 (± 0.2) ° 2θ. .
Form I crystal, 58% yield, 99.98% chemical purity.
The content of compound 4 was 0.01%. Table 1 shows the results.
《実施例７》
　本実施例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（１１．６ｇ；３６ｍｍｏｌ）、１－ブタノール（４０ｇ）、メチルｔ－ブチルエーテル（４０ｇ）、水（４．２ｇ）を仕込み、１０℃以下で硫酸（３．５ｇ；３５ｍｍｏｌ）を滴下した。種結晶を添加後、４℃で２４時間撹拌した。結晶をろ取し、３０℃で５時間減圧乾燥し、化合物３（クロピドグレル硫酸塩：９．８ｇ）を得た。
　フォームＩ結晶、収率６５％、化学純度９９．９７％。
　化合物４の含有量は０．０２％であった。結果を表１に示す。 << Example 7 >>
In this example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (11.6 g; 36 mmol), 1-butanol (40 g), methyl t-butyl ether (40 g), and water (4.2 g) were charged into a 200 mL reaction flask, and sulfuric acid (3.5 g) was used at 10 ° C. or lower. ; 35 mmol) was added dropwise. After adding seed crystals, the mixture was stirred at 4 ° C for 24 hours. The crystals were collected by filtration and dried under reduced pressure at 30 ° C. for 5 hours to obtain Compound 3 (clopidogrel sulfate: 9.8 g).
Form I crystals, 65% yield, 99.97% chemical purity.
The content of compound 4 was 0.02%. Table 1 shows the results.
《比較例３》
　本比較例では、１－ブタノール及びメチルｔ－ブチルエーテルの量比を変更して、クロピドグレル硫酸塩を生成した。
　容量２００ｍＬの反応フラスコに、化合物２（１１．６ｇ；３６ｍｍｏｌ）、１－ブタノール（３０ｇ）、メチルｔ－ブチルエーテル（５０ｇ）、水（６ｇ）を仕込み、１０℃以下で硫酸（３．５ｇ；３５ｍｍｏｌ）を滴下した。種結晶を添加後、４℃で２４時間撹拌したが、オイルアウトし、結晶の析出は見られなかった。すなわち、メチルｔ－ブチルエーテルに対して１－ブタノールの量が少なすぎると、クロピドグレル硫酸塩の結晶が得られなかった。 << Comparative Example 3 >>
In this comparative example, clopidogrel sulfate was produced by changing the amount ratio of 1-butanol and methyl t-butyl ether.
Compound 2 (11.6 g; 36 mmol), 1-butanol (30 g), methyl t-butyl ether (50 g), and water (6 g) were charged into a 200-mL reaction flask, and sulfuric acid (3.5 g; 35 mmol) at 10 ° C. or lower. ) Was added dropwise. After the seed crystal was added, the mixture was stirred at 4 ° C. for 24 hours, but oil-out occurred and no crystals were precipitated. That is, if the amount of 1-butanol was too small relative to methyl t-butyl ether, clopidogrel sulfate crystals could not be obtained.
Figure JPOXMLDOC01-appb-T000008
 　１－ブタノール／メチルｔ－ブチルエーテルが１．３０以上である実施例１～４のクロピドグレル硫酸塩は、不純物であるクロピドグレルモノブチル硫酸塩（化合物４）の含有量が０．１０重量％以下に抑制されたが、１－ブタノール／メチルｔ－ブチルエーテルが１．３０未満の比較例１及び２では、化合物４の含有量が多かった。しかし、１－ブタノール／メチルｔ－ブチルエーテルが１：１であっても、溶媒に水を添加することによって、化合物４の含有量を抑制することができた（実施例６及び７）。一方、１－ブタノールの添加量が少なすぎると、クロピドグレル硫酸塩の結晶が得られなかった（比較例３）。
Figure JPOXMLDOC01-appb-T000008
 In the clopidogrel sulfate of Examples 1 to 4 in which 1-butanol / methyl t-butyl ether is 1.30 or more, the content of clopidogrel monobutyl sulfate (compound 4) as an impurity is suppressed to 0.10% by weight or less. However, in Comparative Examples 1 and 2 in which 1-butanol / methyl t-butyl ether was less than 1.30, the content of compound 4 was large. However, even when 1-butanol / methyl t-butyl ether was 1: 1, the content of compound 4 could be suppressed by adding water to the solvent (Examples 6 and 7). On the other hand, when the amount of 1-butanol added was too small, crystals of clopidogrel sulfate could not be obtained (Comparative Example 3).
《調製例２》
　本調製例では、化合物３（クロピドグレル硫酸塩）の粗乾燥結晶を調製した。
　容量１０００ｍＬの反応フラスコに、化合物２（５８．１ｇ；０．１８ｍｏｌ）、１－ブタノール（２５０ｇ）、メチルｔ－ブチルエーテル（１５０ｇ）、水（９ｇ）を仕込み、１０℃以下で硫酸（１８．１ｇ；１８ｍｍｏｌ）を滴下した。種結晶を添加後、５℃で４７時間撹拌した。結晶をろ取し、化合物３の湿結晶７５．１ｇを得た。化合物３の湿結晶を３０℃で４時間減圧乾燥し、化合物３の粗乾燥結晶６７．４ｇを得た。粗乾燥結晶の化合物４の含有量は０．０５％であり、残留１－ブタノールは４７４４ｐｐｍであった。 << Preparation Example 2 >>
In this Preparation Example, crude dry crystals of Compound 3 (clopidogrel sulfate) were prepared.
Compound 2 (58.1 g; 0.18 mol), 1-butanol (250 g), methyl t-butyl ether (150 g), and water (9 g) were charged into a 1000 mL reaction flask, and sulfuric acid (18.1 g) was added at 10 ° C. or lower. ; 18 mmol) was added dropwise. After adding seed crystals, the mixture was stirred at 5 ° C. for 47 hours. The crystals were collected by filtration to obtain 75.1 g of wet crystals of Compound 3. The wet crystals of Compound 3 were dried under reduced pressure at 30 ° C. for 4 hours to obtain 67.4 g of crude dry crystals of Compound 3. The content of the compound 4 in the crude dry crystals was 0.05%, and the residual 1-butanol was 4744 ppm.
《実施例８》
　調製例２で得た化合物３の粗乾燥結晶５ｇを使用し、３０℃で３、６、９、１２時間減圧乾燥した。１２時間乾燥後の化合物４の含有量は０．０６％であり、残留１－ブタノールは３９００ｐｐｍであった。結果を表２に示す。 << Embodiment 8 >>
Using 5 g of the crude dry crystal of the compound 3 obtained in Preparation Example 2, it was dried at 30 ° C. under reduced pressure for 3, 6, 9, and 12 hours. After drying for 12 hours, the content of compound 4 was 0.06%, and the residual 1-butanol was 3900 ppm. Table 2 shows the results.
《実施例９》
　滅圧乾燥の温度を、３０℃に代えて、４０℃とした以外は実施例８の操作を繰り返して、化合物３を得た。１２時間乾燥後の化合物４の含有量は０．１３％であり、残留１－ブタノールは３５２７ｐｐｍであった。結果を表２に示す。 << Example 9 >>
The procedure of Example 8 was repeated except that the pressure-drying temperature was changed to 40 ° C. instead of 30 ° C. to obtain compound 3. After drying for 12 hours, the content of compound 4 was 0.13%, and residual 1-butanol was 3527 ppm. Table 2 shows the results.
《実施例１０》
　調製例２で得た化合物３の粗乾燥結晶５ｇを使用し、３０℃で３、６、９、１２時間、乾燥窒素を通風した。１２時間通風後の化合物４の含有量は０．０７％であり、残留１－ブタノールは３８９９ｐｐｍであった。結果を表２に示す。 << Example 10 >>
Using 5 g of the crude dry crystal of Compound 3 obtained in Preparation Example 2, dry nitrogen was blown at 30 ° C. for 3, 6, 9, and 12 hours. After ventilation for 12 hours, the content of compound 4 was 0.07%, and the residual 1-butanol was 3899 ppm. Table 2 shows the results.
《実施例１１》
　乾燥温度を、３０℃に代えて、４０℃とした以外は実施例１０の操作を繰り返して、化合物３を得た。１２時間通風後の化合物４の含有量は０．１１％であり、残留１－ブタノールは３６１３ｐｐｍであった。結果を表２に示す。 << Example 11 >>
The procedure of Example 10 was repeated except that the drying temperature was changed to 40 ° C. instead of 30 ° C. to obtain compound 3. After ventilation for 12 hours, the content of compound 4 was 0.11%, and the amount of residual 1-butanol was 3613 ppm. Table 2 shows the results.
《調製例３》
　本調製例では、化合物３（クロピドグレル硫酸塩）の粗乾燥結晶を生成した。
　容量１０００ｍＬの反応フラスコに、化合物２（５８．１ｇ；０．１８ｍｏｌ）、１－ブタノール（２５０ｇ）、メチルｔ－ブチルエーテル（１５０ｇ）、水（９ｇ）を仕込み、１０℃以下で硫酸（１８．１ｇ；１８ｍｍｏｌ）を滴下した。種結晶を添加後、５℃で７２時間撹拌した。結晶をろ取し、化合物３の湿結晶７３．０ｇを得た。化合物３の湿結晶を３０℃で８時間減圧乾燥し、化合物３の粗乾燥結晶６５．８ｇを得た。粗乾燥結晶の化合物４の含有量は０．０６％であり、残留１－ブタノールは５２８６ｐｐｍであった。 << Preparation Example 3 >>
In this Preparation Example, crude dry crystals of Compound 3 (clopidogrel sulfate) were produced.
Compound 2 (58.1 g; 0.18 mol), 1-butanol (250 g), methyl t-butyl ether (150 g), and water (9 g) were charged into a 1000 mL reaction flask, and sulfuric acid (18.1 g) was added at 10 ° C. or lower. ; 18 mmol) was added dropwise. After the seed crystals were added, the mixture was stirred at 5 ° C. for 72 hours. The crystals were collected by filtration to obtain 73.0 g of wet crystals of compound 3. The wet crystals of the compound 3 were dried under reduced pressure at 30 ° C. for 8 hours to obtain 65.8 g of crude dry crystals of the compound 3. The content of the compound 4 in the roughly dried crystals was 0.06%, and the residual 1-butanol was 5286 ppm.
《実施例１２》
　調製例３で得た化合物３の粗乾燥結晶５ｇを使用し、３０℃で３、６、９、１２時間、湿度９０％の窒素を通風した。１２時間通風後の化合物４の含有量は０．０８％であり、残留１－ブタノールは１７１７ｐｐｍであった。結果を表２に示す。 << Example 12 >>
Using 5 g of the crude dry crystal of Compound 3 obtained in Preparation Example 3, nitrogen at 90% humidity was blown at 30 ° C. for 3, 6, 9, and 12 hours. After ventilation for 12 hours, the content of compound 4 was 0.08%, and the residual 1-butanol was 1,717 ppm. Table 2 shows the results.
《実施例１３》
　乾燥温度を、３０℃に代えて、４０℃とした以外は実施例１２の操作を繰り返して、化合物３を得た。１２時間通風後の化合物４の含有量は０．０９％であり、残留１－ブタノールは２３３０ｐｐｍであった。結果を表２に示す。 << Example 13 >>
The procedure of Example 12 was repeated, except that the drying temperature was changed to 30 ° C. and to 40 ° C., thereby obtaining a compound 3. After ventilation for 12 hours, the content of compound 4 was 0.09%, and the amount of residual 1-butanol was 2330 ppm. Table 2 shows the results.
《実施例１４》
　乾燥温度を、３０℃に代えて、５０℃とした以外は実施例１２の操作を繰り返して、化合物３を得た。１２時間通風後の化合物４の含有量は０．１５％であり、残留１－ブタノールは２１５９ｐｐｍであった。結果を表２に示す。 << Example 14 >>
The procedure of Example 12 was repeated, except that the drying temperature was changed to 30 ° C. and 50 ° C., to obtain compound 3. After ventilation for 12 hours, the content of compound 4 was 0.15%, and residual 1-butanol was 2159 ppm. Table 2 shows the results.
Figure JPOXMLDOC01-appb-T000009
 　乾燥工程により、１－ブタノールの含有量を低下させることが可能であり、１－ブタノール及び硫酸によって生成されるモノアルキル硫酸（化合物４）を減少させることができる。減圧乾燥、及び乾燥窒素フローによっても、１－ブタノールの含有量を減少させることが可能であるが、湿窒素フローによる乾燥により、より効率的に１－ブタノールの含有量を減少させることができる。
Figure JPOXMLDOC01-appb-T000009
 By the drying step, the content of 1-butanol can be reduced, and the monoalkyl sulfate (compound 4) generated by 1-butanol and sulfuric acid can be reduced. The 1-butanol content can be reduced by vacuum drying and a dry nitrogen flow, but the 1-butanol content can be reduced more efficiently by drying with a wet nitrogen flow.
　本発明の製造方法は、モノアルキル硫酸塩の混入の少ないクロピドグレル硫酸塩のＩ型結晶を製造に用いることができる。 製造 In the production method of the present invention, a type I crystal of clopidogrel sulfate with little contamination of monoalkyl sulfate can be used for production.

Claims (5)

  1. 　（１）（ａ）１重量部のメチルｔ－ブチルエーテルに対して、１．３重量部以上の１－ブタノールを含む溶媒、又は
    （ｂ）１重量部のメチルｔ－ブチルエーテルに対して、０．９重量部以上の１－ブタノール及び０．０５重量部以上の水を含む溶媒、
    の存在下で、クロピドグレル遊離塩基に濃硫酸を接触させ、下記一般式（１）：
    Figure JPOXMLDOC01-appb-C000001
     で表されるクロピドグレル硫酸塩のＩ型結晶を得る工程、
    を含むクロピドグレル硫酸塩のＩ型結晶の製造方法。     (1) (a) a solvent containing 1.3 parts by weight or more of 1-butanol with respect to 1 part by weight of methyl t-butyl ether, or (b) a solvent containing 1 part by weight of methyl t-butyl ether with 0.1 part by weight. A solvent comprising 9 parts by weight or more of 1-butanol and 0.05 parts by weight or more of water,
    Is contacted with concentrated sulfuric acid in the presence of clopidogrel free base in the presence of the following general formula (1):
    Figure JPOXMLDOC01-appb-C000001
     Obtaining a type I crystal of clopidogrel sulfate represented by:
    A method for producing a type I crystal of clopidogrel sulfate, comprising:
  2. 　前記溶媒のメチルｔ－ブチルエーテルに対する１－ブタノールの重量比が１０重量部以下である、請求項１に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法。 The process for producing a clopidogrel sulfate type I crystal according to claim 1, wherein the weight ratio of 1-butanol to methyl t-butyl ether of the solvent is 10 parts by weight or less.
  3. （２）前記Ｉ型結晶を５０℃以下で乾燥する工程、を更に含む請求項１又は２に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法。 The method for producing a clopidogrel sulfate type I crystal according to claim 1 or 2, further comprising: (2) a step of drying the type I crystal at 50 ° C or lower.
  4. 　前記乾燥工程（２）が、相対湿度４５～９９％及び温度０～５０℃の気体と接触させる操作を含む、請求項１～３のいずれか一項に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法。 The clopidogrel sulfate type I crystal according to any one of claims 1 to 3, wherein the drying step (2) includes an operation of contacting with a gas having a relative humidity of 45 to 99% and a temperature of 0 to 50 ° C. Production method.
  5. 　前記気体が、空気又は窒素である、請求項４に記載のクロピドグレル硫酸塩のＩ型結晶の製造方法。 方法 The method for producing a clopidogrel sulfate type I crystal according to claim 4, wherein the gas is air or nitrogen.
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WO2011042804A2 (en) * 2009-10-08 2011-04-14 Jubliant Life Sciences Limited An improved process for the preparation of clopidogrel hydrogen sulfate form i

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