WO2020013305A1 - クロピドグレル硫酸塩のｉ型結晶の製造方法 - Google Patents

クロピドグレル硫酸塩のｉ型結晶の製造方法 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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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/zh
Priority to JP2020530274A priority patent/JP7323876B2/ja
Publication of WO2020013305A1 publication Critical patent/WO2020013305A1/ja

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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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PCT/JP2019/027621 2018-07-12 2019-07-12 クロピドグレル硫酸塩のｉ型結晶の製造方法 WO2020013305A1 (ja)

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US20040132765A1 (en) * 2002-10-21 2004-07-08 Dinamite Dipharma S.P.A. Clopidogrel salts with alkyl-sulphuric acids
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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