WO2009081608A1 - Process for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride - Google Patents

Process for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride Download PDF

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WO2009081608A1
WO2009081608A1 PCT/JP2008/063362 JP2008063362W WO2009081608A1 WO 2009081608 A1 WO2009081608 A1 WO 2009081608A1 JP 2008063362 W JP2008063362 W JP 2008063362W WO 2009081608 A1 WO2009081608 A1 WO 2009081608A1
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crystal
amino
cyclopropyl
crystallization
acid amide
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PCT/JP2008/063362
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French (fr)
Japanese (ja)
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Narumi Kishimoto
Ken Uekita
Hiroaki Yasukouchi
Toshihiro Takeda
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Kaneka Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the present invention relates to a method for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride which is useful as an intermediate for pharmaceuticals.
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) obtained by the production method of the present invention Is an important intermediate compound for producing pharmaceuticals such as antiviral agents (Patent Document 1).
  • Patent Document 1 WO02 / 018639
  • Patent Document 2 WO05 / 058821
  • Patent Document 3 WO05 / 035525
  • the crystalline polymorph may affect the physical properties of the substance, for example, stability and form (appearance), hygroscopicity of the crystalline solid, and the residual solvent remaining in the drying process of the crystal. is there. Therefore, controlling the crystal polymorphism of a substance is an important issue in producing the substance stably industrially.
  • the above Patent Documents 1 to 3 include not only information on the powder X-ray (Cu-K ⁇ ) of crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) to be obtained, There is no description of the shape.
  • the object of the present application is to control the crystal polymorph of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) to produce industrially advantageous N-cyclopropyl-3.
  • the object is to provide a method for obtaining amino-2-hydroxyhexanoic acid amide hydrochloride (1).
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) has at least four crystal polymorphs (crystal A, Crystal B, Crystal C, and Crystal D) exist, and their crystal polymorphs have a difference in the hygroscopicity of the crystal solid, and there is a difference in the residual solvent remaining in the crystal drying process. I found out. Furthermore, the present inventors have found a process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) that controls at least four kinds of crystal polymorphs.
  • the present invention relates to a process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), characterized in that any crystal having a peak at a diffraction angle (2 ⁇ ⁇ 0.1) of .
  • crystal polymorph refers to the same compound and different crystal structures, but in the present invention, what are called “pseudopolymorphs” such as hydrates and solvates are widely used as crystal polymorphs. To be included.
  • the obtained crystal polymorph is not a complete crystal, and a part thereof may contain amorphous.
  • the peak of the powder X-ray may be broad, or it may be difficult to confirm a part of the peak. Even if it is difficult to confirm a part of the X-ray peak, substantially the same peak is included in the crystalline solid.
  • this crystalline solid may be simply referred to as a crystal.
  • P 1 and P 2 each independently represent a hydrogen atom or an amino-protecting group, or together represent a phthaloyl group.
  • the other preferably represents a hydrogen atom.
  • the amino-protecting group is a group that protects the amino group in the reaction, and a group that can be generally used is PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2nd. Ed. , A protecting group described in John Wiley & Sons (1991).
  • Preferred examples of the protecting group in the general formula (2) include carbamate-type protecting groups such as methyloxycarbonyl group, ethyloxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group; acetyl group, trifluoroacetyl group And acyl groups such as phthaloyl group and benzoyl group; aralkyl groups such as benzyl group and dibenzyl group; sulfonyl groups such as tosyl group and mesyl group; and silyl groups such as trimethylsilyl group. More preferred is a carbamate type protecting group or an acyl group, and even more preferred is a carbamate type protecting group. Of these, a tert-butyloxycarbonyl group is preferably used.
  • Deprotection can be performed, for example, by treatment with hydrochloric acid.
  • P 1 and P 2 are protecting groups that cannot be deprotected with hydrochloric acid
  • N-cyclopropyl-3-amino-2-hydroxy is appropriately removed by treating with hydrochloric acid after deprotecting according to the type of protecting group.
  • Hexanoic acid amide hydrochloride (1) can be obtained.
  • P 1 and P 2 are both hydrogen, they may be treated with hydrochloric acid.
  • R 1 in the general formula (3) represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group having 2 to 20 carbon atoms which may have a substituent, or a substituent. It represents an aryl group having 6 to 20 carbon atoms which may have, or an aralkyl group having 7 to 20 carbon atoms which may have a substituent.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the number of substituents is not particularly limited, but is usually 0 to 5, and preferably 0 to 3.
  • R 1 is preferably an unsubstituted C 1-6 alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and the like.
  • a halogenated C 1-3 alkyl group such as a chloromethyl group, a dichloromethyl group or a trichloromethyl group); a C 2-5 alkenyl group such as a vinyl group or an allyl group; a C 6-10 aryl group such as a phenyl group, or A C 7-10 aralkyl group such as a benzyl group, more preferably a methyl group, an ethyl group, an isopropyl group, a chloromethyl group, a phenyl group, or a benzyl group, still more preferably a methyl group, an isopropyl group, or A phenyl group is mentioned.
  • the absolute configuration of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) used in this step is not particularly limited, but is preferably (2S, 3S) or (2R, 3R). .
  • Crystal B is subjected to diffraction angles (2 ⁇ ⁇ 0.1) of 11.5 °, 21.3 °, 24.5 °, and 27.6 ° in powder X-ray (Cu-K ⁇ ) diffraction. Has a peak.
  • the dried form of this crystal (Crystal B) is stable at room temperature and normal pressure, and changes to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. There is nothing. Further, there is an advantage that the residual solvent can be easily removed in the crystal drying step.
  • Crystal B can be obtained, for example, by dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in an organic solvent in the presence of water, and from the solution or slurry solution. It can be obtained by analyzing.
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
  • the crystallization method is not particularly limited.
  • a reaction crystallization method a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or
  • commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination.
  • seed crystals can be added as necessary.
  • organic solvent used for crystallization examples include solvents that are compatible with water other than amides such as alcohol solvents, ketone solvents, and nitrile solvents.
  • the alcohol solvent is not particularly limited, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butanol.
  • ketone solvent examples include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone.
  • the nitrile solvent is not particularly limited, and examples thereof include acetonitrile and propionitrile.
  • solvents may be used independently and may be used together 2 or more types.
  • water may be added to an organic solvent in advance, or water may be added to a solution or suspension of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). It may be added.
  • the mixing ratio (mass ratio) of water and the organic solvent is not particularly limited, but usually the water content of the crystallization solvent is preferably 0.1% or more, more preferably 1% or more, more preferably 3 % Or more.
  • the amount of the organic solvent to be used is not particularly limited, but the lower limit is usually 0.1 times weight, preferably 0, with respect to N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). .5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight.
  • the upper limit is not particularly limited, but is preferably 100 times weight, more preferably 30 times weight, and even more preferably 10 times weight.
  • an auxiliary solvent may be used as necessary.
  • the auxiliary solvent is used for the purpose of improving at least one of, for example, yield, impurity removal property, and crystallization liquid fluidity.
  • the auxiliary solvent is not particularly limited, and examples thereof include hydrocarbon solvents, ether solvents, and ester solvents.
  • the hydrocarbon solvent is not particularly limited, but petroleum ether, pentane, neopentane, hexane, cyclohexane, methylcyclohexane, heptane, cycloheptane, octane, isooctane, nonane, decane, benzene, toluene, ethylbenzene, n-butylbenzene, Examples include o-xylene, m-xylene, p-xylene, cumene, 1,3,5-mesitylene, and preferably toluene and hexane.
  • the ether solvent is not particularly limited, and examples thereof include t-butyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and the like.
  • ester solvent examples include, but are not limited to, ethyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, and the like, preferably ethyl acetate.
  • auxiliary solvents may be used alone or in combination of two or more. When an auxiliary solvent is used, it may be mixed with an organic solvent in advance, but if necessary, it may be added as appropriate after crystals are precipitated.
  • the volume ratio of the organic solvent to the auxiliary solvent is preferably 30 or less, more preferably 10 or less, as the ratio of the organic solvent / auxiliary solvent.
  • Crystal B The crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) thus obtained (Crystal B) are obtained from common solid liquids such as centrifugal separation, pressure separation, and vacuum filtration. Crystals can be collected using separation methods. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
  • the cooling rate may be appropriately set, for example, in the range of more than 5 ° C./hour, preferably 10 ° C./hour or more.
  • Crystal A has a diffraction angle (2 ⁇ ⁇ 0.1) of 6.5 °, 11.9 °, 19.5 °, 23.9 ° in powder X-ray (Cu-K ⁇ ) diffraction, It has peaks at 26.1 °, 28.0 ° and 39.5 °.
  • the dried form of this crystal (Crystal A) is stable at normal temperature and pressure, and changes to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. It has no advantage. Further, the crystal A has a low hygroscopic property and further has excellent filterability in crystal separation.
  • Crystal A can be obtained by using any of i) a system in which water does not coexist in the organic solvent (water non-coexisting system) and ii) a system in which water coexists in the organic solvent (water coexisting system). be able to.
  • ii) water coexisting system crystal A can be obtained by extending the stirring time in cooling crystallization or slowing the cooling rate.
  • Crystal A can be obtained by, for example, dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in an organic solvent and crystallization from the solution or slurry solution. be able to.
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
  • the crystallization method is not particularly limited.
  • a reaction crystallization method a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or
  • commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination.
  • seed crystals can be added as necessary.
  • organic solvent used for crystallization examples include solvents that are compatible with water other than amides such as alcohol solvents, ketone solvents, and nitrile solvents.
  • solvents may be used independently and may be used together 2 or more types.
  • the amount of the organic solvent to be used is not particularly limited, but the lower limit is usually 0.1 times weight, preferably 0, with respect to N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). .5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight.
  • the upper limit is preferably 100 times the weight, more preferably 30 times the weight, and even more preferably 10 times the weight.
  • an auxiliary solvent may be used as necessary.
  • the auxiliary solvent is used for the purpose of improving at least one of, for example, yield, impurity removal property, and crystallization liquid fluidity.
  • the auxiliary solvent is not particularly limited, and examples thereof include hydrocarbon solvents, ether solvents, and ester solvents.
  • hydrocarbon solvent the ether solvent, and the ester solvent are all the same as those exemplified in the method for producing crystal B.
  • auxiliary solvents may be used alone or in combination of two or more.
  • an auxiliary solvent it may be mixed with an organic solvent in advance, but if necessary, it may be added as appropriate after crystals are precipitated.
  • the volume ratio of the organic solvent to the auxiliary solvent is preferably 30 or less, more preferably 10 or less, as the ratio of the organic solvent / auxiliary solvent.
  • Crystal A can also be obtained by coexisting water in the organic solvent described in i) as a crystallization solvent.
  • water may be added to an organic solvent in advance, or water may be added to a solution or suspension of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). It may be added.
  • a water content of 10% or less is preferable.
  • stirring time it is usually effective to set it to 0.5 hours or longer, preferably 1 hour or longer, more preferably 2 hours or longer, particularly preferably 4 hours or longer.
  • the crystal A can be obtained by cooling slowly.
  • the cooling rate is not particularly limited, but usually the upper limit is less than 10 ° C./hour, preferably 5 ° C./hour or less, more preferably 2 ° C./hour or less, particularly preferably 1 ° C./hour or less. Yes, the lower limit is 0.1 ° C./hour or more.
  • the crystal A can be obtained even when water coexists in the organic solvent.
  • the crystal of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) obtained by the method i) or ii) is subjected to centrifugal separation, pressure separation, Crystals can be collected using a general solid-liquid separation method such as vacuum filtration.
  • the obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
  • Crystal C was measured at diffraction angles (2 ⁇ ⁇ 0.1) of 11.9 °, 20.0 °, 21.1 °, and 23.9 ° in powder X-ray (Cu-K ⁇ ) diffraction. Has a peak.
  • the dried form of this crystal (Crystal C) is stable at room temperature and normal pressure, and changes to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. There is nothing. Further, the crystal C has a feature that the crystal grain size is small. In general, a crystal having a small particle size is excellent in solubility in a solvent. Therefore, when the crystal is dissolved in the production process, the dissolution time is shortened and the productivity can be improved.
  • Crystal C can be crystallized, for example, by dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in an amide-based solvent, or a solution thereof or a slurry solution. Can be obtained at
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
  • the crystallization method is not particularly limited.
  • a reaction crystallization method a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or
  • commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination.
  • seed crystals can be added as necessary.
  • the amide solvent used for crystallization is not particularly limited, and examples thereof include dimethylacetamide, dimethylformamide, acetamide, formamide, and preferably dimethylacetamide.
  • amide solvents may be used alone or in combination of two or more. Further, water may coexist in the amide solvent. In the case of coexisting water, an amide solvent to which water has been added in advance may be used, a solution of an amide solvent of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), or Water may be added to the suspension. Moreover, there is no restriction
  • the amount of the amide solvent used is not particularly limited, but the lower limit is usually 0.1 times the weight of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), preferably 0.5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight.
  • the upper limit is not particularly limited, but is preferably 100 times weight, more preferably 30 times weight, and even more preferably 10 times weight.
  • an auxiliary solvent may be used as necessary.
  • the auxiliary solvent is used for the purpose of improving at least one of, for example, yield, impurity removal property, and crystallization liquid fluidity.
  • the auxiliary solvent is not particularly limited, and examples thereof include hydrocarbon solvents, ether solvents, and ester solvents, with hydrocarbon solvents being preferred.
  • hydrocarbon solvent the ether solvent, and the ester solvent are all the same as those exemplified in the method for producing crystal B.
  • auxiliary solvents may be used alone or in combination of two or more.
  • an auxiliary solvent it may be mixed with an organic solvent in advance, but if necessary, it may be added as appropriate after crystals are precipitated.
  • the volume ratio of the amide solvent to the auxiliary solvent is preferably 30 or less, more preferably 10 or less, as the ratio of the amide solvent / auxiliary solvent.
  • crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) thus obtained are obtained by general solid-liquid such as centrifugation, pressure separation, and vacuum filtration. Crystals can be collected using separation methods. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
  • Crystal D is obtained by powder X-ray (Cu-K ⁇ ) diffraction with diffraction angles (2 ⁇ ⁇ 0.1) of 10.7 °, 11.9 °, 23.9 ° and 24.5 °. Has a peak.
  • This crystal (dried crystal D) is stable at room temperature and normal pressure, and can be converted to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. There is no. Further, the crystal D has a feature that the crystal grain size is relatively small. In general, a crystal having a small particle size is excellent in solubility in a solvent. Therefore, when the crystal is dissolved in the production process, the dissolution time is shortened and the productivity can be improved.
  • Crystal D is obtained, for example, by dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in a halogen-based solvent in the presence of water, and from the solution or slurry solution. It can be obtained by crystallization.
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
  • the crystallization method is not particularly limited.
  • a reaction crystallization method a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or
  • commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination.
  • seed crystals can be added as necessary.
  • the halogen solvent is not particularly limited, and examples thereof include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, and the like, preferably methylene chloride.
  • halogen-type solvents may be used independently and may be used together 2 or more types.
  • a halogen solvent to which water has been added in advance may be used, or a solution of a halogen solvent of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be used. Water may be added. Further, the mixing ratio (mass ratio) of water and the halogen-based solvent is not particularly limited, but usually the water content of the crystallization solvent is preferably 0.1% or more, more preferably 1% or more, more preferably. Is 3% or more.
  • the amount of the halogen-based solvent used is not particularly limited, but the lower limit is usually 0.1 times the weight of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), preferably 0.5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight.
  • the upper limit is not particularly limited, but is preferably 100 times weight, more preferably 30 times weight, and even more preferably 10 times weight.
  • Crystal D The crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) thus obtained (Crystal D) are obtained from common solid liquids such as centrifugal separation, pressure separation, and vacuum filtration. Crystals can be collected using separation methods. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) having a crystalline polymorph can be produced industrially and stably. This makes it possible to control physical properties such as crystal stability and hygroscopicity and improve handling properties according to the purpose.
  • Example 1 (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) production method (2S, 3S) -N-cyclopropyl-3-amino- 2-hydroxyhexanoic acid amide hydrochloride (5.05 g) and 2-propanol (50.00 g) were mixed, and the mixture was stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 6 hours, the crystals were separated by filtration.
  • the flowability of the crystallization slurry was good, and the crystal filterability was also good (Kiriyama funnel having a diameter of 4 cm, filter paper pore diameter of 4 ⁇ m, and mother liquor separation time of about 30 seconds).
  • the crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 4.35 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals.
  • the measurement result of powder X-ray diffraction (Cu-K ⁇ ) diffraction of the obtained crystal is shown in FIG. 1, and the result of NMR analysis is shown below.
  • Example 2 (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) production method (2S, 3S) -N-cyclopropyl-3-amino- 1.00 g of 2-hydroxyhexanoic acid amide hydrochloride and 4.00 g of 2-propanol were mixed, 5.00 g of hexane was added thereto, and the mixture was stirred at 60 ° C. for 1 hour. Thereafter, after cooling to 0 ° C. at a constant rate for about 6 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good.
  • Example 3 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) (2S, 3S) -N-cyclopropyl-3-amino- 2-0.00 g of 2-hydroxyhexanoic acid amide hydrochloride, 200.00 g of 2-propanol, and 5.00 g of water were mixed and stirred at 60 ° C. for 1 hour. Then, it cooled from 60 degreeC to 20 degreeC over 12 hours, cooled from 20 degreeC to 15 degreeC in 5 hours, and also cooled to 2 degreeC over 3 hours.
  • Example 4 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) (2S, 3S) -N-cyclopropyl-3-amino- 1.05 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.00 g of acetone and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good. The crystals separated by filtration were vacuum-dried overnight at 40 ° C.
  • Example 5 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) (2S, 3S) -N-cyclopropyl-3-amino- 0.50 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.26 g of acetonitrile and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good. The crystals separated by filtration were vacuum-dried overnight at 40 ° C.
  • Example 6 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal B) (2S, 3S) -N-cyclopropyl-3-amino- 2.00 g of 2-hydroxyhexanoic acid amide hydrochloride, 20.00 g of 2-propanol, and 0.50 g of water were mixed and stirred at 60 ° C. for 1 hour. Thereafter, it was cooled to 0 ° C. at a constant rate over about 6 hours, and the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C.
  • Example 7 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal B) (2S, 3S) -N-cyclopropyl-3-amino- 1.01 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.00 g of acetone and 0.74 g of water, and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C.
  • Example 8 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal B) (2S, 3S) -N-cyclopropyl-3-amino- 1.01 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.03 g of acetonitrile and 0.74 g of water, and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C.
  • Example 9 Moisture absorption measurement of crystals A and B Crystals A and B were each placed in separate containers of about 3 g, and left in an open state under conditions of a temperature of about 20 ° C and a relative humidity of about 60%. did. When 3 hours and 17 hours had passed after standing, the respective water contents were measured with a Karl Fischer moisture meter.
  • Example 10 (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal C) production method (2S, 3S) -N-cyclopropyl-3-amino- 1.03 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 10.20 g of dimethylacetamide and stirred at 60 ° C. for 1 hour. Thereafter, after cooling to 10 ° C. at a constant rate for about 2 hours, 10.00 g of toluene was added dropwise over about 10 minutes.
  • Example 11 Production Method of (2S, 3S) -N-Cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (Crystal C) (2S, 3S) -N-cyclopropyl-3-amino- 1.00 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 5.00 g of dimethylacetamide and 0.26 g of water, and stirred at 60 ° C. for 1 hour. Then, after cooling to 10 degreeC at a constant speed over about 2 hours, 5.00 g of toluene was dripped over about 10 minutes. The crystals were separated by filtration and vacuum dried at 40 ° C.
  • Example 12 Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal D) (2S, 3S) -N-cyclopropyl-3-amino- 1.00 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.00 g of methylene chloride and 0.76 g of water and stirred at 40 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C.
  • N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) obtained by the production method of the present invention is an important intermediate compound for producing pharmaceuticals such as antiviral agents.

Abstract

Crystal of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride is subjected to a crystallization process using a given organic solvent. Accordingly, there can be produced N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride having attained control of crystal polymorphism.

Description

Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩の製造方法Process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride
　本発明は、医薬品の中間体として有用なＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩の製造方法に関する。 The present invention relates to a method for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride which is useful as an intermediate for pharmaceuticals.
　本発明の製造方法により得られるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）：
Figure JPOXMLDOC01-appb-I000004
は、抗ウィルス剤等の医薬品を製造するための重要な中間化合物である（特許文献１）。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) obtained by the production method of the present invention:
Figure JPOXMLDOC01-appb-I000004
Is an important intermediate compound for producing pharmaceuticals such as antiviral agents (Patent Document 1).
　従来、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）、或いはＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミドを得る方法としては、
（ｉ）（２Ｓ）－２－Ｎ－カルバメート保護アミノ－２－アルキル－エタナール誘導体にシクロプロピルイソニトリルを作用させて、（３Ｓ）－３－Ｎ－カルバメート保護アミノ－２－アシロキシプロパン酸シクロプロピルアミドに変換した後、２位の水酸基を脱保護し、さらに４Ｎ－塩酸／ジオキサンを用いて脱Ｂｏｃ化した後、溶媒を留去して（３Ｓ）Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩を合成する方法（特許文献２）、
（ｉｉ）Ｌ－Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－ノルバリン由来のアルデヒドにＨＣＮを付加させ、次にｔｅｒｔ－ブトキシカルボニル基の脱保護とシアノ基の加水分解を行って、３－アミノ－２－ヒドロキシ－ヘキサン酸とし、窒素上をベンジロキシカルボニル保護した後に、縮合剤を用いてシクロプロピルアミンと縮合させ、加水素分解することにより、（２Ｓ，３Ｓ）－３－アミノ－２－ヒドロキシ－ヘキサン酸シクロプロピルアミドを合成する方法（特許文献３）、
等が知られている。 Conventionally, as a method of obtaining N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) or N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide,
(I) (3S) -3-N-carbamate protected amino-2-acyloxypropanoic acid cyclopropyl by reacting (2S) -2-N-carbamate protected amino-2-alkyl-ethanal derivative with cyclopropylisonitrile After conversion to an amide, the hydroxyl group at the 2-position was deprotected and further debocated using 4N-hydrochloric acid / dioxane, and then the solvent was distilled off to remove (3S) N-cyclopropyl-3-amino-2- A method of synthesizing hydroxyhexanoic acid amide hydrochloride (Patent Document 2),
(Ii) HCN is added to an aldehyde derived from LN- (tert-butoxycarbonyl) -norvaline, followed by deprotection of the tert-butoxycarbonyl group and hydrolysis of the cyano group to give 3-amino-2- Hydroxy-hexanoic acid, protected on benzyloxycarbonyl on nitrogen, condensed with cyclopropylamine using a condensing agent, and hydrogenolyzed to give (2S, 3S) -3-amino-2-hydroxy-hexane Method for synthesizing acid cyclopropylamide (Patent Document 3),
Etc. are known.
　　特許文献１：ＷＯ０２／０１８６３９
　　特許文献２：ＷＯ０５／０５８８２１
　　特許文献３：ＷＯ０５／０３５５２５ Patent Document 1: WO02 / 018639
Patent Document 2: WO05 / 058821
Patent Document 3: WO05 / 035525
　一般に、結晶多形はその物質の物性、例えば、安定性や形態（外観）、更には結晶固体の吸湿性や、結晶の乾燥工程における残留溶媒の残りやすさ、等にも影響を与える場合がある。そのため、物質の結晶多形を制御することは、その物質を工業的に安定的に製造する上で重要な課題である。しかしながら、上記特許文献１～３には、取得するＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の結晶の粉末エックス線（Ｃｕ－Ｋα）に関する情報はもとより、結晶多形については何ら記載されていない。 In general, the crystalline polymorph may affect the physical properties of the substance, for example, stability and form (appearance), hygroscopicity of the crystalline solid, and the residual solvent remaining in the drying process of the crystal. is there. Therefore, controlling the crystal polymorphism of a substance is an important issue in producing the substance stably industrially. However, the above Patent Documents 1 to 3 include not only information on the powder X-ray (Cu-Kα) of crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) to be obtained, There is no description of the shape.
　本願の目的は、上記課題を鑑み、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の結晶多形を制御して、工業的に有利なＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を得る方法を提供することにある。 In view of the above-mentioned problems, the object of the present application is to control the crystal polymorph of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) to produce industrially advantageous N-cyclopropyl-3. The object is to provide a method for obtaining amino-2-hydroxyhexanoic acid amide hydrochloride (1).
　本発明者らは前記課題を解決すべく鋭意検討した結果、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）には、少なくとも４種類の結晶多形（結晶Ａ、結晶Ｂ、結晶Ｃ、及び結晶Ｄ）が存在し、それらの結晶多形には結晶固体の吸湿性に違いがあることや、結晶の乾燥工程において、残留溶媒の残りやすさにも違いがあること等を見出した。更には、それら少なくとも４種類の結晶多形を制御する、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法を見出した。 As a result of intensive studies to solve the above problems, the present inventors have found that N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) has at least four crystal polymorphs (crystal A, Crystal B, Crystal C, and Crystal D) exist, and their crystal polymorphs have a difference in the hygroscopicity of the crystal solid, and there is a difference in the residual solvent remaining in the crystal drying process. I found out. Furthermore, the present inventors have found a process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) that controls at least four kinds of crystal polymorphs.
　すなわち、本発明は、下記式（１）：
Figure JPOXMLDOC01-appb-I000005
で表されるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶を、有機溶剤を用いた晶析工程に付す事により、粉末エックス線（Ｃｕ－Ｋα）回折において
Ａ）６．５°、１１．９°、１９．５°、２３．９°、２６．１°、２８．０°、及び３９．５°、
Ｂ）１１．５°、２１．３°、２４．５°、及び２７．６°、
Ｃ）１１．９°、２０．０°、２１．１°、及び２３．９°、
又は
Ｄ）１０．７°、１１．９°、２３．９°、及び２４．５°
の回折角（２θ±０．１）にピークを有するいずれかの結晶を得ることを特徴とする、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法に関する。 That is, the present invention provides the following formula (1):
Figure JPOXMLDOC01-appb-I000005
N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride represented by the formula (A) in powder X-ray (Cu-Kα) diffraction is subjected to a crystallization step using an organic solvent. 5 °, 11.9 °, 19.5 °, 23.9 °, 26.1 °, 28.0 °, and 39.5 °,
B) 11.5 °, 21.3 °, 24.5 °, and 27.6 °,
C) 11.9 °, 20.0 °, 21.1 °, and 23.9 °,
Or D) 10.7 °, 11.9 °, 23.9 °, and 24.5 °.
The present invention relates to a process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), characterized in that any crystal having a peak at a diffraction angle (2θ ± 0.1) of .
結晶Ａの代表的な粉末エックス線回折データである。It is representative powder X-ray diffraction data of crystal A. 結晶Ｂの代表的な粉末エックス線回折データである。It is representative powder X-ray diffraction data of Crystal B. 結晶Ｃの代表的な粉末エックス線回折データである。3 is representative powder X-ray diffraction data of Crystal C. 結晶Ｄの代表的な粉末エックス線回折データである。2 is representative powder X-ray diffraction data of Crystal D.
　本来、「結晶多形」は同一の化合物で結晶構造の異なるものを指すが、本発明においては、水和物や溶媒和物といった「擬多形」と呼ばれるものも広く結晶多形としてその中に含めることとする。また、得られた結晶多形は完全な結晶体ではなく、その一部に非晶質（アモルファス）を含むことがある。その場合、粉末エックス線のピークがブロードになったり、或いは一部のピークの確認が困難であったりする場合があるが、ここでは非晶質を一部含むものも合わせて結晶性固体とし、粉末エックス線の一部のピークの確認が困難であっても、実質上同等なものについては、その結晶性固体に含まれるものとする。またこの結晶性固体を単に結晶と記述することがある。 Originally, “crystal polymorph” refers to the same compound and different crystal structures, but in the present invention, what are called “pseudopolymorphs” such as hydrates and solvates are widely used as crystal polymorphs. To be included. In addition, the obtained crystal polymorph is not a complete crystal, and a part thereof may contain amorphous. In that case, the peak of the powder X-ray may be broad, or it may be difficult to confirm a part of the peak. Even if it is difficult to confirm a part of the X-ray peak, substantially the same peak is included in the crystalline solid. In addition, this crystalline solid may be simply referred to as a crystal.
　以下、本発明を詳述する。 Hereinafter, the present invention will be described in detail.
　Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法について説明する。 A method for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) will be described.
　本発明にかかる方法で用いられるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）：
Figure JPOXMLDOC01-appb-I000006
は、Ｎ－シクロプロピル－（Ｎ－保護）アミノ－α－ヒドロキシヘキサン酸アミド（２）：
Figure JPOXMLDOC01-appb-I000007
を必要に応じて脱保護して取得しても良いし、オキサゾリンアミド誘導体（３）：
Figure JPOXMLDOC01-appb-I000008
のオキサゾリン環を、加水分解、又は加アルコール分解して取得しても良いし、別途公知な方法で合成したものであっても良い。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) used in the method according to the present invention:
Figure JPOXMLDOC01-appb-I000006
N-cyclopropyl- (N-protected) amino-α-hydroxyhexanoic acid amide (2):
Figure JPOXMLDOC01-appb-I000007
May be obtained by deprotection as necessary, or an oxazolinamide derivative (3):
Figure JPOXMLDOC01-appb-I000008
The oxazoline ring may be obtained by hydrolysis or alcoholysis, or may be synthesized by a known method.
　上記一般式（２）における、Ｐ1及びＰ2は、それぞれ独立して水素原子又はアミノ基の保護基を表すか、又は、一緒になってフタロイル基を表す。Ｐ1及びＰ2のうちいずれか一方がアミノ基の保護基を表す場合は、他方は水素原子を表すことが好ましい。 In the above general formula (2), P 1 and P 2 each independently represent a hydrogen atom or an amino-protecting group, or together represent a phthaloyl group. When one of P 1 and P 2 represents an amino-protecting group, the other preferably represents a hydrogen atom.
　アミノ基の保護基とは、反応においてアミノ基を保護する基であり、一般に使用しうる基は、プロテクティヴ・グループス・イン・オーガニックシンセシス第２版（ＰＲＯＴＥＣＴＩＶＥ　ＧＲＯＵＰＳ　ＩＮ　ＯＲＧＡＮＩＣ　ＳＹＮＴＨＥＳＩＳ　２ｎｄ．　Ｅｄ．）、ジョン・ウィリー・アンド・サンズ（ＪＯＨＮ　ＷＩＬＥＹ＆ＳＯＮＳ）出版（１９９１年）に記載されている保護基である。上記一般式（２）において保護基として好ましいものは、例えば、メチルオキシカルボニル基、エチルオキシカルボニル基、ベンジルオキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基等のカルバメート型保護基；アセチル基、トリフルオロアセチル基、フタロイル基、ベンゾイル基等のアシル基；ベンジル基、ジベンジル基等のアラルキル基；トシル基、メシル基等のスルホニル基；トリメチルシリル基等のシリル基が挙げられる。より好ましくは、カルバメート型保護基、又はアシル基であり、さらに好ましくはカルバメート型保護基である。なかでも、ｔｅｒｔ－ブチルオキシカルボニル基が好適に用いられる。 The amino-protecting group is a group that protects the amino group in the reaction, and a group that can be generally used is PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2nd. Ed. , A protecting group described in John Wiley & Sons (1991). Preferred examples of the protecting group in the general formula (2) include carbamate-type protecting groups such as methyloxycarbonyl group, ethyloxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group; acetyl group, trifluoroacetyl group And acyl groups such as phthaloyl group and benzoyl group; aralkyl groups such as benzyl group and dibenzyl group; sulfonyl groups such as tosyl group and mesyl group; and silyl groups such as trimethylsilyl group. More preferred is a carbamate type protecting group or an acyl group, and even more preferred is a carbamate type protecting group. Of these, a tert-butyloxycarbonyl group is preferably used.
　脱保護は、例えば塩酸で処理することにより行うことができる。Ｐ1，Ｐ2が塩酸で脱保護されない保護基の場合は、適宜、保護基の種類に応じて脱保護を行った後、塩酸処理することによりＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を得ることができる。Ｐ1、Ｐ2がいずれも水素である場合は、塩酸で処理すればよい。 Deprotection can be performed, for example, by treatment with hydrochloric acid. In the case where P 1 and P 2 are protecting groups that cannot be deprotected with hydrochloric acid, N-cyclopropyl-3-amino-2-hydroxy is appropriately removed by treating with hydrochloric acid after deprotecting according to the type of protecting group. Hexanoic acid amide hydrochloride (1) can be obtained. When P 1 and P 2 are both hydrogen, they may be treated with hydrochloric acid.
　上記一般式（３）におけるＲ1は、置換基を有していてもよい炭素数１～２０のアルキル基、置換基を有していてもよい炭素数２～２０のアルケニル基、置換基を有していてもよい炭素数６～２０のアリール基、又は置換基を有していてもよい炭素数７～２０のアラルキル基を表す。 R 1 in the general formula (3) represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group having 2 to 20 carbon atoms which may have a substituent, or a substituent. It represents an aryl group having 6 to 20 carbon atoms which may have, or an aralkyl group having 7 to 20 carbon atoms which may have a substituent.
　上記置換基としては、例えば、フッ素原子、塩素原子、臭素原子、又はヨウ素原子等のハロゲン原子が挙げられる。置換基の数は、特に限定されないが、普通０～５個が挙げられ、好ましくは０～３個が挙げられる。 Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The number of substituents is not particularly limited, but is usually 0 to 5, and preferably 0 to 3.
　上記一般式（３）において、Ｒ1として好ましいものは、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｔｅｒｔ－ブチル基などの無置換Ｃ1-6アルキル基；クロロメチル基、ジクロロメチル基、トリクロロメチル基などのハロゲン化Ｃ1-3アルキル基）；ビニル基、アリル基などのＣ2-5アルケニル基；フェニル基などのＣ6-10アリール基、又はベンジル基などのＣ7-10アラルキル基が挙げられ、より好ましくはメチル基、エチル基、イソプロピル基、クロロメチル基、フェニル基、又はベンジル基が挙げられ、更に好ましくはメチル基、イソプロピル基、又はフェニル基が挙げられる。 In the general formula (3), R 1 is preferably an unsubstituted C 1-6 alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and the like. A halogenated C 1-3 alkyl group such as a chloromethyl group, a dichloromethyl group or a trichloromethyl group); a C 2-5 alkenyl group such as a vinyl group or an allyl group; a C 6-10 aryl group such as a phenyl group, or A C 7-10 aralkyl group such as a benzyl group, more preferably a methyl group, an ethyl group, an isopropyl group, a chloromethyl group, a phenyl group, or a benzyl group, still more preferably a methyl group, an isopropyl group, or A phenyl group is mentioned.
　本工程に用いるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の絶対配置は、特に限定されないが、好ましくは（２Ｓ，３Ｓ）、又は（２Ｒ，３Ｒ）である。 The absolute configuration of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) used in this step is not particularly limited, but is preferably (2S, 3S) or (2R, 3R). .
　以下に、各結晶多形（結晶Ａ、結晶Ｂ、結晶Ｃ、及び結晶Ｄ）の製造法について説明する。 Hereinafter, a method for producing each crystal polymorph (crystal A, crystal B, crystal C, and crystal D) will be described.
　まず、結晶Ｂの製造法について説明する。 First, a method for producing crystal B will be described.
　１）結晶Ｂの製造方法
　結晶Ｂは粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）１１．５°、２１．３°、２４．５°、及び２７．６°にピークを有している。この結晶（結晶Ｂ）の乾燥体は、常温常圧下安定であり、直射日光や高温多湿を避ける等の一般的な配慮のもとでは、長期間保管しても他の結晶性形体に変化することはない。又、結晶の乾燥工程で残留溶媒を容易に除去できる利点がある。 1) Production Method of Crystal B Crystal B is subjected to diffraction angles (2θ ± 0.1) of 11.5 °, 21.3 °, 24.5 °, and 27.6 ° in powder X-ray (Cu-Kα) diffraction. Has a peak. The dried form of this crystal (Crystal B) is stable at room temperature and normal pressure, and changes to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. There is nothing. Further, there is an advantage that the residual solvent can be easily removed in the crystal drying step.
　結晶Ｂは、例えば、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を、水共存下、有機溶剤に溶解、又は懸濁させ、その溶液、又はスラリー溶液から晶析することで得ることができる。 Crystal B can be obtained, for example, by dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in an organic solvent in the presence of water, and from the solution or slurry solution. It can be obtained by analyzing.
　Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）は、上述した方法で合成すればよい。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
　本晶析方法としては、特に限定されないが、例えば、反応晶析法、冷却晶析法、濃縮晶析法、溶剤置換を用いる晶析法、貧溶剤を混合することによる晶析法、及び／又は塩析法等の一般に用いられる晶析法を、単独又は適宜組み合わせて実施する事ができる。なお、本晶析では必要に応じて種晶を添加することもできる。 The crystallization method is not particularly limited. For example, a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or Alternatively, commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination. In this crystallization, seed crystals can be added as necessary.
　晶析に用いる有機溶剤としては、例えば、アルコール系溶剤や、ケトン系溶剤、ニトリル系溶剤などの、アミド系以外の水と相溶性のある溶剤が挙げられる。 Examples of the organic solvent used for crystallization include solvents that are compatible with water other than amides such as alcohol solvents, ketone solvents, and nitrile solvents.
　アルコール系溶剤としては、特に限定されないが、例えばメタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、ｔ－ブタノール等が挙げられる。 The alcohol solvent is not particularly limited, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butanol.
　ケトン系溶剤としては、特に限定されないが、アセトン、メチルエチルケトン、ジエチルケトン、メチルイソブチルケトン等が挙げられる。 Examples of the ketone solvent include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone.
　ニトリル系溶剤としては、特に限定されないが、アセトニトリル、プロピオニトリル等が挙げられる。 The nitrile solvent is not particularly limited, and examples thereof include acetonitrile and propionitrile.
　尚、これらの溶剤は、単独で用いてもよく、２種以上併用してもよい。 In addition, these solvents may be used independently and may be used together 2 or more types.
　水を共存させる方法としては、予め有機溶剤に水を加えても良いし、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の溶液、又は懸濁液に水を添加しても良い。また、水と有機溶剤の混合比（質量比）は特に制限されないが、通常、晶析溶剤の水分含量が０．１％以上であるのが好ましく、更に好ましくは１％以上、より好ましくは３％以上である。 As a method for coexisting water, water may be added to an organic solvent in advance, or water may be added to a solution or suspension of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). It may be added. Further, the mixing ratio (mass ratio) of water and the organic solvent is not particularly limited, but usually the water content of the crystallization solvent is preferably 0.1% or more, more preferably 1% or more, more preferably 3 % Or more.
　有機溶剤の使用量としては、特に制限されないが、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）に対して、下限は通常、０．１倍重量、好ましくは０．５倍重量、より好ましくは１倍重量、さらに好ましくは３倍重量である。上限は、特に制限されないが、好ましくは１００倍重量、より好ましくは３０倍重量、さらに好ましくは１０倍重量である。 The amount of the organic solvent to be used is not particularly limited, but the lower limit is usually 0.1 times weight, preferably 0, with respect to N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). .5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight. The upper limit is not particularly limited, but is preferably 100 times weight, more preferably 30 times weight, and even more preferably 10 times weight.
　本晶析において、必要に応じて、補助的な溶剤を使用しても良い。補助的な溶剤とは、例えば、収率、不純物除去性、晶析液の流動性などの内、少なくとも一つを改善する目的で使用されるものである。 In this crystallization, an auxiliary solvent may be used as necessary. The auxiliary solvent is used for the purpose of improving at least one of, for example, yield, impurity removal property, and crystallization liquid fluidity.
　補助的な溶剤としては、特に制限されないが、炭化水素系溶剤、エーテル系溶剤、エステル系溶剤を挙げることができる。 The auxiliary solvent is not particularly limited, and examples thereof include hydrocarbon solvents, ether solvents, and ester solvents.
　炭化水素系溶剤としては、特に限定されないが、石油エーテル、ペンタン、ネオペンタン、ヘキサン、シクロヘキサン、メチルシクロヘキサン、ヘプタン、シクロヘプタン、オクタン、イソオクタン、ノナン、デカン、ベンゼン、トルエン、エチルベンゼン、ｎ－ブチルベンゼン、ｏ－キシレン、ｍ－キシレン、ｐ－キシレン、クメン、１，３，５－メシチレン等が挙げられ、好ましくはトルエン、ヘキサンである。 The hydrocarbon solvent is not particularly limited, but petroleum ether, pentane, neopentane, hexane, cyclohexane, methylcyclohexane, heptane, cycloheptane, octane, isooctane, nonane, decane, benzene, toluene, ethylbenzene, n-butylbenzene, Examples include o-xylene, m-xylene, p-xylene, cumene, 1,3,5-mesitylene, and preferably toluene and hexane.
　エーテル系溶剤としては、特に限定されないが、ｔ－ブチルメチルエーテル、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン等が挙げられる。 The ether solvent is not particularly limited, and examples thereof include t-butyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and the like.
　エステル系溶剤としては、特に限定されないが、ギ酸エチル、酢酸メチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ブチル、プロピオン酸メチル、プロピオン酸エチル等が挙げられ、好ましくは酢酸エチルである。尚、これらの補助的な溶剤は、単独で用いてもよく、２種以上併用してもよい。補助的な溶剤を使用する場合、あらかじめ有機溶剤と混合して用いてもよいが、必要に応じて、結晶が析出した後で適宜添加しても良い。 Examples of the ester solvent include, but are not limited to, ethyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, and the like, preferably ethyl acetate. These auxiliary solvents may be used alone or in combination of two or more. When an auxiliary solvent is used, it may be mixed with an organic solvent in advance, but if necessary, it may be added as appropriate after crystals are precipitated.
　上記有機溶剤と上記補助的な溶剤の容量比は、上記有機溶剤／補助的な溶剤の比として、３０以下が好ましく、より好ましくは１０以下である。 The volume ratio of the organic solvent to the auxiliary solvent is preferably 30 or less, more preferably 10 or less, as the ratio of the organic solvent / auxiliary solvent.
　このようにして得られるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の結晶（結晶Ｂ）は、遠心分離、加圧分離、減圧濾過等の一般的な固液分離方法を用いて結晶を採取する事ができる。得られた結晶は、更に、必要に応じて、例えば、減圧乾燥（真空乾燥）することにより乾燥結晶として取得することができる。 The crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) thus obtained (Crystal B) are obtained from common solid liquids such as centrifugal separation, pressure separation, and vacuum filtration. Crystals can be collected using separation methods. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
　なお、後述するように、攪拌時間を長くしたり、冷却速度を遅くした場合、結晶Ａが得られることとなるため、結晶Ｂを得る場合には、撹拌時間や冷却速度に留意する必要がある。冷却速度は、例えば、５℃／時間超、好ましくは１０℃／時間以上の範囲から適宜設定してもよい。 As will be described later, when the stirring time is lengthened or the cooling rate is slowed, crystal A is obtained. Therefore, when obtaining crystal B, it is necessary to pay attention to the stirring time and the cooling rate. . The cooling rate may be appropriately set, for example, in the range of more than 5 ° C./hour, preferably 10 ° C./hour or more.
　次に結晶Ａの製造法について説明する。 Next, a method for producing crystal A will be described.
　２）結晶Ａの製造方法
　結晶Ａは、粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）６．５°、１１．９°、１９．５°、２３．９°、２６．１°、２８．０°及び３９．５°にピークを有している。この結晶（結晶Ａ）の乾燥体は、常温常圧下安定であり、直射日光や高温多湿を避ける等の一般的な配慮のもとでは、長期間保管しても他の結晶性形体に変化することはない利点を有する。又、結晶Ａは、吸湿性が小さく、更には結晶分離におけるろ過性に優れている。 2) Method for Producing Crystal A Crystal A has a diffraction angle (2θ ± 0.1) of 6.5 °, 11.9 °, 19.5 °, 23.9 ° in powder X-ray (Cu-Kα) diffraction, It has peaks at 26.1 °, 28.0 ° and 39.5 °. The dried form of this crystal (Crystal A) is stable at normal temperature and pressure, and changes to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. It has no advantage. Further, the crystal A has a low hygroscopic property and further has excellent filterability in crystal separation.
　結晶Ａは、晶析溶剤として、ｉ）有機溶剤中に水が共存しない系（水非共存系）、ｉｉ）有機溶剤中に水が共存する系（水共存系）、いずれを用いても得ることができる。尚、ｉｉ）水共存系では、冷却晶析において攪拌時間の延長、或いは冷却速度を遅くすることにより、結晶Ａを得ることができる。 Crystal A can be obtained by using any of i) a system in which water does not coexist in the organic solvent (water non-coexisting system) and ii) a system in which water coexists in the organic solvent (water coexisting system). be able to. In ii) water coexisting system, crystal A can be obtained by extending the stirring time in cooling crystallization or slowing the cooling rate.
　まず、ｉ）水非共存系で結晶Ａを取得する方法について説明する。 First, i) A method for obtaining crystal A in a water non-coexisting system will be described.
　結晶Ａは、例えば、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を有機溶剤に溶解、又は懸濁させ、その溶液、又はスラリー溶液から晶析することで得ることができる。 Crystal A can be obtained by, for example, dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in an organic solvent and crystallization from the solution or slurry solution. be able to.
　Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）は、上述した方法で合成すればよい。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
　本晶析方法としては、特に限定されないが、例えば、反応晶析法、冷却晶析法、濃縮晶析法、溶剤置換を用いる晶析法、貧溶剤を混合することによる晶析法、及び／又は塩析法等の一般に用いられる晶析法を、単独又は適宜組み合わせて実施する事ができる。なお、本晶析では必要に応じて種晶を添加することもできる。 The crystallization method is not particularly limited. For example, a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or Alternatively, commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination. In this crystallization, seed crystals can be added as necessary.
　晶析に用いる有機溶剤としては、例えば、アルコール系溶剤や、ケトン系溶剤、ニトリル系溶剤などの、アミド系以外の水と相溶性のある溶剤が挙げられる。 Examples of the organic solvent used for crystallization include solvents that are compatible with water other than amides such as alcohol solvents, ketone solvents, and nitrile solvents.
　アルコール系溶剤、ケトン系溶剤、ニトリル系溶剤の具体例は、いずれも結晶Ｂの製造方法で例示したものと同じである。 Specific examples of the alcohol solvent, ketone solvent, and nitrile solvent are the same as those exemplified in the method for producing crystal B.
　尚、これらの溶剤は、単独で用いてもよく、２種以上併用してもよい。 In addition, these solvents may be used independently and may be used together 2 or more types.
　有機溶剤の使用量としては、特に制限されないが、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）に対して、下限は通常、０．１倍重量、好ましくは０．５倍重量、より好ましくは１倍重量、さらに好ましくは３倍重量である。上限は、好ましくは１００倍重量、より好ましくは３０倍重量、さらに好ましくは１０倍重量である。 The amount of the organic solvent to be used is not particularly limited, but the lower limit is usually 0.1 times weight, preferably 0, with respect to N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). .5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight. The upper limit is preferably 100 times the weight, more preferably 30 times the weight, and even more preferably 10 times the weight.
　本晶析においては、必要に応じて、補助的な溶剤を使用しても良い。補助的な溶剤とは、例えば、収率、不純物除去性、晶析液の流動性などの内、少なくとも一つを改善する目的で使用されるものである。 In this crystallization, an auxiliary solvent may be used as necessary. The auxiliary solvent is used for the purpose of improving at least one of, for example, yield, impurity removal property, and crystallization liquid fluidity.
　補助的な溶剤としては、特に制限されないが、炭化水素系溶剤、エーテル系溶剤、エステル系溶剤を挙げることができる。 The auxiliary solvent is not particularly limited, and examples thereof include hydrocarbon solvents, ether solvents, and ester solvents.
　炭化水素系溶剤、エーテル系溶剤、エステル系溶剤の具体例は、いずれも結晶Ｂの製造方法で例示したものと同じである。 Specific examples of the hydrocarbon solvent, the ether solvent, and the ester solvent are all the same as those exemplified in the method for producing crystal B.
　尚、これらの補助的な溶剤は、単独で用いてもよく、２種以上併用してもよい。補助的な溶剤を使用する場合、あらかじめ有機溶剤と混合して用いてもよいが、必要に応じて、結晶が析出した後で適宜添加しても良い。 These auxiliary solvents may be used alone or in combination of two or more. When an auxiliary solvent is used, it may be mixed with an organic solvent in advance, but if necessary, it may be added as appropriate after crystals are precipitated.
　上記有機溶剤と上記補助的な溶剤の容量比は、上記有機溶剤／補助的な溶剤の比として、３０以下が好ましく、より好ましくは１０以下である。 The volume ratio of the organic solvent to the auxiliary solvent is preferably 30 or less, more preferably 10 or less, as the ratio of the organic solvent / auxiliary solvent.
　次にｉｉ）水共存系で結晶Ａを取得する方法について説明する。 Next, ii) A method for obtaining crystal A in a water coexisting system will be described.
　結晶Ａは、晶析溶剤としてｉ）で記載した有機溶剤に水を共存させても取得できる。 Crystal A can also be obtained by coexisting water in the organic solvent described in i) as a crystallization solvent.
　水を共存させる方法としては、予め有機溶剤に水を加えても良いし、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の溶液、又は懸濁液に水を添加しても良い。また、水と有機溶剤の混合比（質量比）に特に制限はないが、水分含量１０％以下が好ましい。 As a method for coexisting water, water may be added to an organic solvent in advance, or water may be added to a solution or suspension of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1). It may be added. Moreover, although there is no restriction | limiting in particular in the mixing ratio (mass ratio) of water and an organic solvent, A water content of 10% or less is preferable.
　水共存下、結晶Ａを製造するには、冷却晶析において、攪拌時間の延長、或いは冷却速度を遅くすることが有効である。 In order to produce crystal A in the presence of water, it is effective to extend the stirring time or slow down the cooling rate in cooling crystallization.
　攪拌時間に関しては、普通、０．５時間以上、好ましくは、１時間以上、更に好ましくは２時間以上、特に好ましくは４時間以上に設定することが有効である。 Regarding the stirring time, it is usually effective to set it to 0.5 hours or longer, preferably 1 hour or longer, more preferably 2 hours or longer, particularly preferably 4 hours or longer.
　冷却速度に関しては、ゆっくり冷却することで結晶Ａを取得することができる。冷却速度に関して、特に制限されないが、普通、上限は１０℃／時間未満、好ましくは５℃／時間以下、さらに好ましくは２℃／時間以下、特に好ましくは１℃／時間以下に保つことが有効であり、下限は０．１℃／時間以上である。 Regarding the cooling rate, the crystal A can be obtained by cooling slowly. The cooling rate is not particularly limited, but usually the upper limit is less than 10 ° C./hour, preferably 5 ° C./hour or less, more preferably 2 ° C./hour or less, particularly preferably 1 ° C./hour or less. Yes, the lower limit is 0.1 ° C./hour or more.
　上記のように、攪拌時間を延長するか、或いは冷却速度を遅くすることで、有機溶剤中に水を共存させても結晶Ａを取得することができる。 As described above, by extending the stirring time or slowing the cooling rate, the crystal A can be obtained even when water coexists in the organic solvent.
　このように、ｉ）、或いはｉｉ）の方法で得られるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の結晶（結晶Ａ）は、遠心分離、加圧分離、減圧濾過等の一般的な固液分離方法を用いて結晶を採取する事ができる。得られた結晶は、更に、必要に応じて、例えば、減圧乾燥（真空乾燥）することにより乾燥結晶として取得することができる。 Thus, the crystal of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) obtained by the method i) or ii) (crystal A) is subjected to centrifugal separation, pressure separation, Crystals can be collected using a general solid-liquid separation method such as vacuum filtration. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
　次に結晶Ｃの製造法について説明する。 Next, a method for producing crystal C will be described.
　３）結晶Ｃの製造方法
　結晶Ｃは粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）１１．９°、２０．０°、２１．１°、及び２３．９°にピークを有している。この結晶（結晶Ｃ）の乾燥体は、常温常圧下安定であり、直射日光や高温多湿を避ける等の一般的な配慮のもとでは、長期間保管しても他の結晶性形体に変化することはない。また、結晶Ｃは、結晶粒径が小さい特徴を有する。一般に粒径が小さい結晶は、溶剤への溶解性に優れている為、製造工程における結晶溶解に際し、溶解時間の短縮に繋がり、生産性を向上させることが可能になる。 3) Method for producing crystal C Crystal C was measured at diffraction angles (2θ ± 0.1) of 11.9 °, 20.0 °, 21.1 °, and 23.9 ° in powder X-ray (Cu-Kα) diffraction. Has a peak. The dried form of this crystal (Crystal C) is stable at room temperature and normal pressure, and changes to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. There is nothing. Further, the crystal C has a feature that the crystal grain size is small. In general, a crystal having a small particle size is excellent in solubility in a solvent. Therefore, when the crystal is dissolved in the production process, the dissolution time is shortened and the productivity can be improved.
　結晶Ｃは、例えば、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を、アミド系溶剤に溶解、又は懸濁させ、その溶液、又はスラリー溶液から晶析することで得ることができる。 Crystal C can be crystallized, for example, by dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in an amide-based solvent, or a solution thereof or a slurry solution. Can be obtained at
　Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）は、上述した方法で合成すればよい。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
　本晶析方法としては、特に限定されないが、例えば、反応晶析法、冷却晶析法、濃縮晶析法、溶剤置換を用いる晶析法、貧溶剤を混合することによる晶析法、及び／又は塩析法等の一般に用いられる晶析法を、単独又は適宜組み合わせて実施する事ができる。なお、本晶析では必要に応じて種晶を添加することもできる。 The crystallization method is not particularly limited. For example, a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or Alternatively, commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination. In this crystallization, seed crystals can be added as necessary.
　晶析に用いるアミド系溶剤としては、特に限定されないが、例えば、ジメチルアセトアミド、ジメチルホルムアミド、アセトアミド、ホルムアミド等が挙げられ、好ましくはジメチルアセトアミドが挙げられる。 The amide solvent used for crystallization is not particularly limited, and examples thereof include dimethylacetamide, dimethylformamide, acetamide, formamide, and preferably dimethylacetamide.
　尚、これらアミド系溶剤は、単独で用いてもよく、２種以上併用してもよい。また、アミド系溶剤に水を共存させても良い。水を共存させる場合は、予め水を加えたアミド系溶剤を用いても良いし、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）のアミド系溶剤の溶液、又は懸濁液に水を添加しても良い。また、水とアミド系溶剤の混合比に特に制限はない。 These amide solvents may be used alone or in combination of two or more. Further, water may coexist in the amide solvent. In the case of coexisting water, an amide solvent to which water has been added in advance may be used, a solution of an amide solvent of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), or Water may be added to the suspension. Moreover, there is no restriction | limiting in particular in the mixing ratio of water and an amide-type solvent.
　アミド系溶剤の使用量としては、特に制限されないが、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）に対して、下限は普通、０．１倍重量、好ましくは０．５倍重量、より好ましくは１倍重量、さらに好ましくは３倍重量である。上限は、特に制限されないが、好ましくは１００倍重量、より好ましくは３０倍重量、さらに好ましくは１０倍重量である。 The amount of the amide solvent used is not particularly limited, but the lower limit is usually 0.1 times the weight of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), preferably 0.5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight. The upper limit is not particularly limited, but is preferably 100 times weight, more preferably 30 times weight, and even more preferably 10 times weight.
　本晶析において、必要に応じて、補助的な溶剤を使用しても良い。補助的な溶剤とは、例えば、収率、不純物除去性、晶析液の流動性などの内、少なくとも一つを改善する目的で使用されるものである。 In this crystallization, an auxiliary solvent may be used as necessary. The auxiliary solvent is used for the purpose of improving at least one of, for example, yield, impurity removal property, and crystallization liquid fluidity.
　補助的な溶剤としては、特に制限されないが、例えば、炭化水素系溶剤、エーテル系溶剤、エステル系溶剤が挙げられ、好ましくは、炭化水素系溶剤である。 The auxiliary solvent is not particularly limited, and examples thereof include hydrocarbon solvents, ether solvents, and ester solvents, with hydrocarbon solvents being preferred.
　炭化水素系溶剤、エーテル系溶剤、エステル系溶剤の具体例は、いずれも結晶Ｂの製造方法で例示したものと同じである。 Specific examples of the hydrocarbon solvent, the ether solvent, and the ester solvent are all the same as those exemplified in the method for producing crystal B.
　尚、これらの補助的な溶剤は、単独で用いてもよく、２種以上併用してもよい。補助的な溶剤を使用する場合、あらかじめ有機溶剤と混合して用いてもよいが、必要に応じて、結晶が析出した後で適宜添加しても良い。 These auxiliary solvents may be used alone or in combination of two or more. When an auxiliary solvent is used, it may be mixed with an organic solvent in advance, but if necessary, it may be added as appropriate after crystals are precipitated.
　上記アミド系溶剤と上記補助的な溶剤の容量比は、上記アミド系溶剤／補助的な溶剤の比として、３０以下が好ましく、より好ましくは１０以下である。 The volume ratio of the amide solvent to the auxiliary solvent is preferably 30 or less, more preferably 10 or less, as the ratio of the amide solvent / auxiliary solvent.
　このようにして得られるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の結晶（結晶Ｃ）は、遠心分離、加圧分離、減圧濾過等の一般的な固液分離方法を用いて結晶を採取する事ができる。得られた結晶は、更に、必要に応じて、例えば、減圧乾燥（真空乾燥）することにより乾燥結晶として取得することができる。 The crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) thus obtained (crystal C) are obtained by general solid-liquid such as centrifugation, pressure separation, and vacuum filtration. Crystals can be collected using separation methods. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
　次に結晶Ｄの製造法について説明する。 Next, a method for producing crystal D will be described.
　４）結晶Ｄの製造方法
　結晶Ｄは、粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）１０．７°、１１．９°、２３．９°、及び２４．５°にピークを有している。この結晶（結晶Ｄ乾燥体）は、常温常圧下安定であり、直射日光や高温多湿を避ける等の一般的な配慮のもとでは、長期間保管しても他の結晶性形体に変化することはない。また、結晶Ｄは、結晶粒径が比較的小さい特徴を有する。一般に粒径が小さい結晶は、溶剤への溶解性に優れている為、製造工程における結晶溶解に際し、溶解時間の短縮に繋がり、生産性を向上させることが可能になる。 4) Method for producing crystal D Crystal D is obtained by powder X-ray (Cu-Kα) diffraction with diffraction angles (2θ ± 0.1) of 10.7 °, 11.9 °, 23.9 ° and 24.5 °. Has a peak. This crystal (dried crystal D) is stable at room temperature and normal pressure, and can be converted to other crystalline forms even after long-term storage under general considerations such as avoiding direct sunlight and high temperature and humidity. There is no. Further, the crystal D has a feature that the crystal grain size is relatively small. In general, a crystal having a small particle size is excellent in solubility in a solvent. Therefore, when the crystal is dissolved in the production process, the dissolution time is shortened and the productivity can be improved.
　結晶Ｄは、例えば、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を、水共存下、ハロゲン系溶剤に溶解、又は懸濁させ、その溶液、又はスラリー溶液から晶析することで得ることができる。 Crystal D is obtained, for example, by dissolving or suspending N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) in a halogen-based solvent in the presence of water, and from the solution or slurry solution. It can be obtained by crystallization.
　Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）は、上述した方法で合成すればよい。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be synthesized by the method described above.
　本晶析方法としては、特に限定されないが、例えば、反応晶析法、冷却晶析法、濃縮晶析法、溶剤置換を用いる晶析法、貧溶剤を混合することによる晶析法、及び／又は塩析法等の一般に用いられる晶析法を、単独又は適宜組み合わせて実施する事ができる。なお、本晶析では必要に応じて種晶を添加することもできる。 The crystallization method is not particularly limited. For example, a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or Alternatively, commonly used crystallization methods such as a salting-out method can be carried out alone or in appropriate combination. In this crystallization, seed crystals can be added as necessary.
　ハロゲン系溶剤としては、特に限定されないが、例えば、塩化メチレン、クロロホルム、四塩化炭素、１，２－ジクロロエタン、クロロベンゼン等が挙げられ、好ましくは塩化メチレンである。 The halogen solvent is not particularly limited, and examples thereof include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, and the like, preferably methylene chloride.
　尚、これらハロゲン系溶剤は、単独で用いてもよく、２種以上併用してもよい。 In addition, these halogen-type solvents may be used independently and may be used together 2 or more types.
　水を共存させるタイミングとしては、予め水を加えたハロゲン系溶剤を用いても良いし、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）のハロゲン系溶剤の溶液に水を添加しても良い。また、水とハロゲン系溶剤の混合比（質量比）に特に制限はないが、通常、晶析溶剤の水分含量が０．１％以上であるのが好ましく、更に好ましくは１％以上、より好ましくは３％以上である。 As the timing of coexisting water, a halogen solvent to which water has been added in advance may be used, or a solution of a halogen solvent of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) may be used. Water may be added. Further, the mixing ratio (mass ratio) of water and the halogen-based solvent is not particularly limited, but usually the water content of the crystallization solvent is preferably 0.1% or more, more preferably 1% or more, more preferably. Is 3% or more.
　ハロゲン系溶剤の使用量としては、特に制限されないが、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）に対して、下限は普通、０．１倍重量、好ましくは０．５倍重量、より好ましくは１倍重量、さらに好ましくは３倍重量である。上限は、特に制限されないが、好ましくは１００倍重量、より好ましくは３０倍重量、さらに好ましくは１０倍重量である。 The amount of the halogen-based solvent used is not particularly limited, but the lower limit is usually 0.1 times the weight of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), preferably 0.5 times the weight, more preferably 1 times the weight, still more preferably 3 times the weight. The upper limit is not particularly limited, but is preferably 100 times weight, more preferably 30 times weight, and even more preferably 10 times weight.
　このようにして得られるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の結晶（結晶Ｄ）は、遠心分離、加圧分離、減圧濾過等の一般的な固液分離方法を用いて結晶を採取する事ができる。得られた結晶は、更に、必要に応じて、例えば、減圧乾燥（真空乾燥）することにより乾燥結晶として取得することができる。 The crystals of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) thus obtained (Crystal D) are obtained from common solid liquids such as centrifugal separation, pressure separation, and vacuum filtration. Crystals can be collected using separation methods. The obtained crystal can be further obtained as a dried crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.
　本発明にかかる方法によれば、結晶多形を有するＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）を工業的に安定的に製造することができる。これにより、目的に応じて、結晶の安定性や吸湿性などの物性を制御したり、取り扱い性を向上させることが可能になる。 According to the method of the present invention, N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) having a crystalline polymorph can be produced industrially and stably. This makes it possible to control physical properties such as crystal stability and hygroscopicity and improve handling properties according to the purpose.
　以下、実施例を示して本発明を詳細に説明する。これらの実施例は無論本発明を何ら限定するものではない。 Hereinafter, the present invention will be described in detail with reference to examples. Of course, these examples do not limit the present invention in any way.
　（実施例１）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ａ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩５．０５ｇと２－プロパノール５０．００ｇを混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約６時間かけて冷却した後に、結晶を濾過により分離した。晶析スラリーの流動性はよく、結晶のろ過性も良好であった（直径４ｃｍの桐山ロート、濾紙孔径４μｍで母液分離時間約３０秒）。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶４．３５ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定結果を図１に、ＮＭＲ解析の結果を以下に示す。 (Example 1) (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) production method (2S, 3S) -N-cyclopropyl-3-amino- 2-hydroxyhexanoic acid amide hydrochloride (5.05 g) and 2-propanol (50.00 g) were mixed, and the mixture was stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 6 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good (Kiriyama funnel having a diameter of 4 cm, filter paper pore diameter of 4 μm, and mother liquor separation time of about 30 seconds). The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 4.35 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. The measurement result of powder X-ray diffraction (Cu-Kα) diffraction of the obtained crystal is shown in FIG. 1, and the result of NMR analysis is shown below.
　粉末エックス線（Ｃｕ－Ｋα）回折における主な回折角（２θ±０．１）：６．５°、１１．９°、１９．５°、２３．９°、２６．１°、２８．０°、３９．５°
　[1Ｈ－ＮＭＲ（ＣＤ3）2ＳＯ，４００ＭＨｚ／ｐｐｍ）；０．５２（２Ｈ，ｍ）、０．６３（２Ｈ，ｍ）、０．８６（３Ｈ，ｔ）、１．２５－１．５０（４Ｈ，ｍ）、２．６９（１Ｈ，ｍ）、３．３９（１Ｈ，ｂｓ）、４．２２（１Ｈ，ｂｓ）、６．２７（１Ｈ，ｂｓ）、８．０４（４Ｈ，ｂｓ）] Main diffraction angles (2θ ± 0.1) in powder X-ray (Cu—Kα) diffraction: 6.5 °, 11.9 °, 19.5 °, 23.9 °, 26.1 °, 28.0 ° , 39.5 °
[ 1 H-NMR (CD 3 ) 2 SO, 400 MHz / ppm); 0.52 (2H, m), 0.63 (2H, m), 0.86 (3H, t), 1.25-1. 50 (4H, m), 2.69 (1H, m), 3.39 (1H, bs), 4.22 (1H, bs), 6.27 (1H, bs), 8.04 (4H, bs) )]
　（実施例２）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ａ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．００ｇと２－プロパノール４．００ｇを混合し、そこにヘキサン５．００ｇを加え、６０℃にて１時間攪拌した。その後、０℃まで一定速度で約６時間かけて冷却した後に、結晶を濾過により分離した。晶析スラリーの流動性はよく、結晶のろ過性も良好であった。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．９４ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ａであることを確認した。 (Example 2) (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) production method (2S, 3S) -N-cyclopropyl-3-amino- 1.00 g of 2-hydroxyhexanoic acid amide hydrochloride and 4.00 g of 2-propanol were mixed, 5.00 g of hexane was added thereto, and the mixture was stirred at 60 ° C. for 1 hour. Thereafter, after cooling to 0 ° C. at a constant rate for about 6 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 0.94 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. As a result of powder X-ray (Cu—Kα) diffraction measurement and NMR analysis of the obtained crystal, it was confirmed that it was crystal A.
　（実施例３）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ａ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩２０．００ｇ、２－プロパノール２００．００ｇ、及び水５．００ｇを混合し、６０℃にて１時間攪拌した。その後、６０℃から２０℃まで１２時間かけて冷却、２０℃から１５℃までを５時間で冷却、さらに２℃まで３時間かけて冷却した。析出した結晶を分離後（晶析スラリーの流動性はよく、結晶のろ過性も良好）、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶１６．５３ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ａであることを確認した。 (Example 3) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) (2S, 3S) -N-cyclopropyl-3-amino- 2-0.00 g of 2-hydroxyhexanoic acid amide hydrochloride, 200.00 g of 2-propanol, and 5.00 g of water were mixed and stirred at 60 ° C. for 1 hour. Then, it cooled from 60 degreeC to 20 degreeC over 12 hours, cooled from 20 degreeC to 15 degreeC in 5 hours, and also cooled to 2 degreeC over 3 hours. After separating the precipitated crystals (crystallization slurry has good fluidity and crystal filterability), vacuum drying is performed overnight at 40 ° C., and N-cyclopropyl-3-amino-2-hydroxyhexanoic acid hydrochloride 16.53 g of salt crystals were obtained. As a result of powder X-ray (Cu—Kα) diffraction measurement and NMR analysis of the obtained crystal, it was confirmed that it was crystal A.
　（実施例４）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ａ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．０５ｇを、アセトン１５．００ｇと混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、結晶を濾過により分離した。晶析スラリーの流動性はよく、結晶のろ過性も良好であった。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶１．０２ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ａであることを確認した。 (Example 4) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) (2S, 3S) -N-cyclopropyl-3-amino- 1.05 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.00 g of acetone and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 1.02 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. As a result of powder X-ray (Cu—Kα) diffraction measurement and NMR analysis of the obtained crystal, it was confirmed that it was crystal A.
　（実施例５）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ａ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩０．５０ｇを、アセトニトリル１５．２６ｇと混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、結晶を濾過により分離した。晶析スラリーの流動性はよく、結晶のろ過性も良好であった。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．４９ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ａであることを確認した。 (Example 5) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal A) (2S, 3S) -N-cyclopropyl-3-amino- 0.50 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.26 g of acetonitrile and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The flowability of the crystallization slurry was good, and the crystal filterability was also good. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 0.49 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. As a result of powder X-ray (Cu—Kα) diffraction measurement and NMR analysis of the obtained crystal, it was confirmed that it was crystal A.
 （実施例６）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ｂ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩２．００ｇ、２－プロパノール２０．００ｇ、及び水０．５０ｇを混合し、６０℃にて１時間攪拌した。その後、０℃まで一定速度で約６時間かけて冷却、結晶を濾過により分離した。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶１．８３ｇを得た（２－プロパノール含量：０．０２ｗｔ％）。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定結果を図２に、ＮＭＲ解析の結果を以下に示す。 (Example 6) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal B) (2S, 3S) -N-cyclopropyl-3-amino- 2.00 g of 2-hydroxyhexanoic acid amide hydrochloride, 20.00 g of 2-propanol, and 0.50 g of water were mixed and stirred at 60 ° C. for 1 hour. Thereafter, it was cooled to 0 ° C. at a constant rate over about 6 hours, and the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 1.83 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals (2-propanol content: 0.02 wt%). ). The measurement result of powder X-ray (Cu-Kα) diffraction of the obtained crystal is shown in FIG. 2, and the result of NMR analysis is shown below.
　粉末エックス線（Ｃｕ－Ｋα）回折における主な回折角（２θ±０．１）：１１．５°、２１．３°、２４．５°、２７．６°
　[1Ｈ－ＮＭＲ（ＣＤ3）2ＳＯ，４００ＭＨｚ／ｐｐｍ）；０．５３（２Ｈ，ｍ）、０．６３（２Ｈ，ｍ）、０．８６（３Ｈ，ｔ）、１．２５－１．５０（４Ｈ，ｍ）、２．６９（１Ｈ，ｍ）、３．３９（１Ｈ，ｂｓ）、４．２２（１Ｈ，ｂｓ）、６．２７（１Ｈ，ｂｓ）、８．０４（４Ｈ，ｂｓ）] Main diffraction angles (2θ ± 0.1) in powder X-ray (Cu—Kα) diffraction: 11.5 °, 21.3 °, 24.5 °, 27.6 °
[ 1 H-NMR (CD 3 ) 2 SO, 400 MHz / ppm); 0.53 (2H, m), 0.63 (2H, m), 0.86 (3H, t), 1.25-1. 50 (4H, m), 2.69 (1H, m), 3.39 (1H, bs), 4.22 (1H, bs), 6.27 (1H, bs), 8.04 (4H, bs) )]
　（実施例７）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ｂ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．０１ｇを、アセトン１５．００ｇ、水０．７４ｇと混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、結晶を濾過により分離した。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．９７ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ｂであることを確認した。 (Example 7) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal B) (2S, 3S) -N-cyclopropyl-3-amino- 1.01 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.00 g of acetone and 0.74 g of water, and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 0.97 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. As a result of measurement of powder X-ray (Cu-Kα) diffraction and NMR analysis of the obtained crystal, it was confirmed that it was crystal B.
　（実施例８）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ｂ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．０１ｇを、アセトニトリル１５．０３ｇ、水０．７４ｇと混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、結晶を濾過により分離した。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．９８ｇを得た。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ｂであることを確認した。 (Example 8) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal B) (2S, 3S) -N-cyclopropyl-3-amino- 1.01 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.03 g of acetonitrile and 0.74 g of water, and stirred at 60 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 0.98 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. As a result of measurement of powder X-ray (Cu-Kα) diffraction and NMR analysis of the obtained crystal, it was confirmed that it was crystal B.
 （実施例９）　結晶Ａと結晶Ｂの吸湿測定
　結晶Ａ、及び結晶Ｂを各々約３ｇ別々の容器に入れ、温度：約２０℃、相対湿度：約６０％の条件下、開放状態で静置した。静置後、３時間、及び１７時間経過した時点でそれぞれの水分含量をカールフィッシャー水分計で測定した。 (Example 9) Moisture absorption measurement of crystals A and B Crystals A and B were each placed in separate containers of about 3 g, and left in an open state under conditions of a temperature of about 20 ° C and a relative humidity of about 60%. did. When 3 hours and 17 hours had passed after standing, the respective water contents were measured with a Karl Fischer moisture meter.
Figure JPOXMLDOC01-appb-I000009
Figure JPOXMLDOC01-appb-I000009
　（実施例１０）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ｃ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．０３ｇを、ジメチルアセトアミド１０．２０ｇと混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、トルエン１０．００ｇを約１０分かけて滴下した。結晶を濾過により分離後（晶析スラリーの流動性はよく、結晶のろ過性も良好）、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．９７ｇを得た。この結晶をデジタルマイクロスコープで観察したところ、数μｍ程度の微粉末結晶であった。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定結果を図３に、ＮＭＲ解析の結果を以下に示す。 (Example 10) (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal C) production method (2S, 3S) -N-cyclopropyl-3-amino- 1.03 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 10.20 g of dimethylacetamide and stirred at 60 ° C. for 1 hour. Thereafter, after cooling to 10 ° C. at a constant rate for about 2 hours, 10.00 g of toluene was added dropwise over about 10 minutes. After separation of the crystals by filtration (crystallization slurry has good fluidity and crystal filtration properties are good), vacuum drying is performed overnight at 40 ° C., and N-cyclopropyl-3-amino-2-hydroxyhexanoic acid hydrochloride 0.97 g of salt crystals were obtained. When this crystal was observed with a digital microscope, it was a fine powder crystal of about several μm. The measurement result of powder X-ray (Cu-Kα) diffraction of the obtained crystal is shown in FIG. 3, and the result of NMR analysis is shown below.
　粉末エックス線（Ｃｕ－Ｋα）回折における主な回折角（２θ±０．１）：１１．９°、２０．０°、２１．１°、２３．９°
　[1Ｈ－ＮＭＲ（ＣＤ3）2ＳＯ，４００ＭＨｚ／ｐｐｍ）；０．５３（２Ｈ，ｍ）、０．６４（２Ｈ，ｍ）、０．８５（３Ｈ，ｔ）、１．２５－１．５０（４Ｈ，ｍ）、２．６９（１Ｈ，ｍ）、３．３９（１Ｈ，ｂｓ）、４．２２（１Ｈ，ｂｓ）、６．３１（１Ｈ，ｂｓ）、８．１０（４Ｈ，ｂｓ）] Main diffraction angles (2θ ± 0.1) in powder X-ray (Cu—Kα) diffraction: 11.9 °, 20.0 °, 21.1 °, 23.9 °
[ 1 H-NMR (CD 3 ) 2 SO, 400 MHz / ppm); 0.53 (2H, m), 0.64 (2H, m), 0.85 (3H, t), 1.25-1. 50 (4H, m), 2.69 (1H, m), 3.39 (1H, bs), 4.22 (1H, bs), 6.31 (1H, bs), 8.10 (4H, bs) )]
　（実施例１１）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ｃ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．００ｇを、ジメチルアセトアミド５．００ｇ、水０．２６ｇと混合し、６０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、トルエン５．００ｇを約１０分かけて滴下した。結晶を濾過により分離して、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．７３ｇを得た。この結晶をデジタルマイクロスコープで観察したところ、数μｍ程度の微粉末結晶であった。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定、及びＮＭＲ解析の結果、結晶Ｃであることを確認した。 Example 11 Production Method of (2S, 3S) -N-Cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (Crystal C) (2S, 3S) -N-cyclopropyl-3-amino- 1.00 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 5.00 g of dimethylacetamide and 0.26 g of water, and stirred at 60 ° C. for 1 hour. Then, after cooling to 10 degreeC at a constant speed over about 2 hours, 5.00 g of toluene was dripped over about 10 minutes. The crystals were separated by filtration and vacuum dried at 40 ° C. overnight to obtain 0.73 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. When this crystal was observed with a digital microscope, it was a fine powder crystal of about several μm. As a result of measurement of powder X-ray (Cu-Kα) diffraction and NMR analysis of the obtained crystal, it was confirmed that it was crystal C.
 （実施例１２）　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（結晶Ｄ）の製造法
　（２Ｓ，３Ｓ）－Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩１．００ｇを、塩化メチレン１５．００ｇ、水０．７６ｇと混合し、４０℃にて１時間攪拌した。その後、１０℃まで一定速度で約２時間かけて冷却した後に、結晶を濾過により分離した。濾別した結晶を、４０℃で１晩真空乾燥を行い、Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶０．７２ｇを得た。この結晶をデジタルマイクロスコープで観察したところ、１０μｍ程度の微細な針状結晶であった。得られた結晶の粉末エックス線（Ｃｕ－Ｋα）回折の測定結果を図４に、ＮＭＲ解析の結果を以下に示す。 (Example 12) Production method of (2S, 3S) -N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (crystal D) (2S, 3S) -N-cyclopropyl-3-amino- 1.00 g of 2-hydroxyhexanoic acid amide hydrochloride was mixed with 15.00 g of methylene chloride and 0.76 g of water and stirred at 40 ° C. for 1 hour. After cooling to 10 ° C. at a constant rate for about 2 hours, the crystals were separated by filtration. The crystals separated by filtration were vacuum-dried overnight at 40 ° C. to obtain 0.72 g of N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride crystals. When this crystal was observed with a digital microscope, it was a fine needle crystal of about 10 μm. The measurement result of powder X-ray (Cu-Kα) diffraction of the obtained crystal is shown in FIG. 4, and the result of NMR analysis is shown below.
　粉末エックス線（Ｃｕ－Ｋα）回折における主な回折角（２θ±０．１）：１０．７°、１１．９°、２３．９°、２４．５°
　[1Ｈ－ＮＭＲ（ＣＤ3）2ＳＯ，４００ＭＨｚ／ｐｐｍ）；０．５３（２Ｈ，ｍ）、０．６４（２Ｈ，ｍ）、０．８５（３Ｈ，ｔ）、１．２４－１．５０（４Ｈ，ｍ）、２．６９（１Ｈ，ｍ）、３．３９（１Ｈ，ｂｓ）、４．２２（１Ｈ，ｂｓ）、６．３１（１Ｈ，ｂｓ）、８．１０（４Ｈ，ｂｓ）] Main diffraction angles (2θ ± 0.1) in powder X-ray (Cu-Kα) diffraction: 10.7 °, 11.9 °, 23.9 °, 24.5 °
[ 1 H-NMR (CD 3 ) 2 SO, 400 MHz / ppm); 0.53 (2H, m), 0.64 (2H, m), 0.85 (3H, t), 1.24-1. 50 (4H, m), 2.69 (1H, m), 3.39 (1H, bs), 4.22 (1H, bs), 6.31 (1H, bs), 8.10 (4H, bs) )]
　本発明の製造方法により得られるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）は、抗ウィルス剤等の医薬品を製造するための重要な中間化合物である。 N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) obtained by the production method of the present invention is an important intermediate compound for producing pharmaceuticals such as antiviral agents.

Claims (18)

  1. 　　下記式（１）：
    Figure JPOXMLDOC01-appb-I000001
    で表されるＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩結晶を、有機溶剤を用いた晶析工程に付す事により、粉末エックス線（Ｃｕ－Ｋα）回折において
    Ａ）６．５°、１１．９°、１９．５°、２３．９°、２６．１°、２８．０°、及び３９．５°、
    Ｂ）１１．５°、２１．３°、２４．５°、及び２７．６°、
    Ｃ）１１．９°、２０．０°、２１．１°、及び２３．９°、
    又は
    Ｄ）１０．７°、１１．９°、２３．９°、及び２４．５°
    の回折角（２θ±０．１）にピークを有するいずれかの結晶を得ることを特徴とするＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法。     Following formula (1):
    Figure JPOXMLDOC01-appb-I000001
    N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride represented by the formula (A) in powder X-ray (Cu-Kα) diffraction is subjected to a crystallization step using an organic solvent. 5 °, 11.9 °, 19.5 °, 23.9 °, 26.1 °, 28.0 °, and 39.5 °,
    B) 11.5 °, 21.3 °, 24.5 °, and 27.6 °,
    C) 11.9 °, 20.0 °, 21.1 °, and 23.9 °,
    Or D) 10.7 °, 11.9 °, 23.9 °, and 24.5 °.
    A process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1), characterized in that any crystal having a peak at the diffraction angle (2θ ± 0.1) is obtained.
  2. 　前記晶析工程後の結晶が、粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）６．５°、１１．９°、１９．５°、２３．９°、２６．１°、２８．０°及び３９．５°にピークを有する結晶Ａであることを特徴とする、請求項１に記載のＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法。 The crystals after the crystallization step were subjected to diffraction angles (2θ ± 0.1) of 6.5 °, 11.9 °, 19.5 °, 23.9 °, 26.26 in powder X-ray (Cu-Kα) diffraction. N-cyclopropyl-3-amino-2-hydroxyhexanoic acid hydrochloride (1) according to claim 1, characterized in that it is a crystal A having peaks at 1 °, 28.0 ° and 39.5 °. The production method of 1).
  3. 　晶析に用いる有機溶剤が、アルコール系溶剤、ケトン系溶剤、及びニトリル系溶剤からなる群より選択された少なくとも一種である請求項１又は２に記載の製造法。 The process according to claim 1 or 2, wherein the organic solvent used for crystallization is at least one selected from the group consisting of alcohol solvents, ketone solvents, and nitrile solvents.
  4. 　冷却速度を０．１℃以上／時間以上、１０℃／時間未満として冷却晶析を行うことを特徴とする、請求項１～３のいずれかに記載の製造法。 4. The production method according to claim 1, wherein cooling crystallization is performed at a cooling rate of 0.1 ° C./hour or more and less than 10 ° C./hour.
  5. 　前記晶析工程後の結晶が、粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）１１．５°、２１．３°、２４．５°、及び２７．６°にピークを有する結晶Ｂであることを特徴とする、請求項１に記載のＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法。 Crystals after the crystallization step have peaks at diffraction angles (2θ ± 0.1) of 11.5 °, 21.3 °, 24.5 °, and 27.6 ° in powder X-ray (Cu—Kα) diffraction. The process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) according to claim 1, characterized in that it is a crystal B having the following.
  6. 　水の共存下に晶析を行うことを特徴とする、請求項１又は５に記載の製造法。 6. The process according to claim 1 or 5, wherein crystallization is performed in the presence of water.
  7. 　晶析に用いる有機溶剤が、アルコール系溶剤、ケトン系溶剤、及びニトリル系溶剤からなる群より選択された少なくとも一種である請求項１、５、又は６に記載の製造法。 The production method according to claim 1, 5 or 6, wherein the organic solvent used for crystallization is at least one selected from the group consisting of alcohol solvents, ketone solvents, and nitrile solvents.
  8. 　冷却速度を５℃／時間超とする請求項１及び５～７のいずれかに記載の製造法。 The production method according to any one of claims 1 and 5 to 7, wherein the cooling rate is more than 5 ° C / hour.
  9. 　前記晶析工程後の結晶が、粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）１１．９°、２０．０°、２１．１°、及び２３．９°にピークを有する結晶Ｃであることを特徴とする、請求項１に記載のＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法。 The crystal after the crystallization step has peaks at diffraction angles (2θ ± 0.1) of 11.9 °, 20.0 °, 21.1 °, and 23.9 ° in powder X-ray (Cu—Kα) diffraction. The process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) according to claim 1, characterized in that it is a crystal C having the following formula.
  10. 　アミド系溶剤を用いて晶析することを特徴とする、請求項１又は９に記載の製造法。 The method according to claim 1 or 9, wherein crystallization is performed using an amide solvent.
  11. 　前記晶析工程後の結晶が、粉末エックス線（Ｃｕ－Ｋα）回折において、回折角（２θ±０．１）１０．７°、１１．９°、２３．９°、及び２４．５°にピークを有する結晶Ｄであることを特徴とする、請求項１に記載のＮ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）の製造法。 The crystals after the crystallization step have peaks at diffraction angles (2θ ± 0.1) of 10.7 °, 11.9 °, 23.9 °, and 24.5 ° in powder X-ray (Cu—Kα) diffraction. The process for producing N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) according to claim 1, characterized in that it is a crystal D having the following formula.
  12. 　水共存下、ハロゲン系溶剤を用いて晶析することを特徴とする、請求項１又は１１に記載の製造法。 The method according to claim 1 or 11, wherein crystallization is performed using a halogen-based solvent in the presence of water.
  13. 　結晶化及び晶量増加は、反応晶析法、冷却晶析法、濃縮晶析法、溶剤置換を用いる晶析法、及び貧溶剤を混合することによる晶析法のうち、少なくとも一つの方法を用いて行われる、請求項１～１２のいずれかに記載の製造法。 The crystallization and the increase in the crystal amount are performed by at least one of a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, and a crystallization method by mixing a poor solvent. The production method according to any one of claims 1 to 12, which is carried out using
  14. 　前記Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）が、下記一般式（２）：
    Figure JPOXMLDOC01-appb-I000002
    （式中、Ｐ1及びＰ2は、それぞれ独立して、水素原子又はアミノ基の保護基を表すか、
    又は、一緒になってフタロイル基を表す。）で表されるＮ－シクロプロピル－３－（Ｎ－保護）アミノ－２－ヒドロキシヘキサン酸アミドを必要に応じて脱保護することにより得たものであることを特徴とする請求項１～１３のいずれかに記載の製造法。     The N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) is represented by the following general formula (2):
    Figure JPOXMLDOC01-appb-I000002
    (Wherein P 1 and P 2 each independently represent a hydrogen atom or an amino-protecting group,
    Or together, it represents a phthaloyl group. 14. An N-cyclopropyl-3- (N-protected) amino-2-hydroxyhexanoic acid amide represented by formula (1) is obtained by deprotecting as necessary. The manufacturing method in any one of.
  15. 　前記Ｎ－シクロプロピル－３－アミノ－２－ヒドロキシヘキサン酸アミド塩酸塩（１）が、下記一般式（３）：
    Figure JPOXMLDOC01-appb-I000003
    （式中、Ｒ1は置換基を有していてもよい炭素数１～２０のアルキル基、置換基を有していてもよい炭素数２～２０のアルケニル基、置換基を有していてもよい炭素数６～２０のアリール基、又は置換基を有していてもよい炭素数７～２０のアラルキル基を表す。）で表されるオキサゾリンアミド誘導体を加水分解又は加アルコール分解することにより得たものであることを特徴とする請求項１～１３のいずれかに記載の製造法。     The N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (1) is represented by the following general formula (3):
    Figure JPOXMLDOC01-appb-I000003
    (Wherein R 1 has an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, and a substituent. An oxazoline amide derivative represented by the following formula: an aryl group having 6 to 20 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms which may have a substituent. The production method according to any one of claims 1 to 13, which is obtained.
  16. 　Ｐ1及びＰ2は、一方が水素原子、もう一方がｔｅｒｔ－ブトキシカルボニル基である請求項１４に記載の製造方法。 P 1 and P 2, one of a hydrogen atom, a manufacturing method according to claim 14 which is the other is tert- butoxycarbonyl group.
  17. 　Ｒ1が、メチル基、イソプロピル基、またはフェニル基である請求項１５に記載の製造方法。 The production method according to claim 15, wherein R 1 is a methyl group, an isopropyl group, or a phenyl group.
  18. 　前記式（１）で表される化合物の２位と３位の絶対配置が、（２Ｓ，３Ｓ）または、（２Ｒ，３Ｒ）である、請求項１～１６のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 16, wherein the absolute configuration of the 2-position and the 3-position of the compound represented by the formula (1) is (2S, 3S) or (2R, 3R).
PCT/JP2008/063362 2007-12-21 2008-07-25 Process for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride WO2009081608A1 (en)

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