WO2009081608A1 - Procédé de production d'hydrochlorure amide de l'acide n-cyclopropyl-3-amino-2-hydroxyhéxanoïque - Google Patents

Procédé de production d'hydrochlorure amide de l'acide n-cyclopropyl-3-amino-2-hydroxyhéxanoïque 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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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

On soumet des cristaux d'hydrochlorure amide de l'acide n-cyclopropyl-3-amino-2-hydroxyhéxanoïque à un processus de cristallisation en utilisant un solvant organique donné. On peut ainsi produire un hydrochlorure amide de l'acide n-cyclopropyl-3-amino-2-hydroxyhéxanoïque ayant atteint le contrôle du polymorphisme des cristaux.
PCT/JP2008/063362 2007-12-21 2008-07-25 Procédé de production d'hydrochlorure amide de l'acide n-cyclopropyl-3-amino-2-hydroxyhéxanoïque WO2009081608A1 (fr)

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JP2007330190A JP2011051896A (ja) 2007-12-21 2007-12-21 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

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CN109734682B (zh) * 2019-02-18 2022-10-21 三峡大学 一类环状烯基亚胺类医药中间体，制备方法及其作为抑制癌细胞生长的药物上的应用

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JPS61129159A (ja) * 1984-11-28 1986-06-17 Nippon Zeon Co Ltd 保護化アミノ酸アミド化合物の精製法
JP2007504251A (ja) * 2003-09-05 2007-03-01 バーテックス　ファーマシューティカルズ　インコーポレイテッド セリンプロテアーゼ、特にｈｃｖｎｓ３‐ｎｓ４ａの阻害剤
JP2007513971A (ja) * 2003-12-11 2007-05-31 シェーリング　コーポレイション Ｃ型肝炎ウイルスｎｓ３／ｎｓ４ａプロテアーゼの阻害剤
WO2007083620A1 (fr) * 2006-01-20 2007-07-26 Kaneka Corporation PROCÉDÉ DE PRODUCTION D'UN DÉRIVÉ DE β-AMINO-α-HYDROXYACIDE DE TYPE AMIDE
WO2007105729A1 (fr) * 2006-03-13 2007-09-20 Ajinomoto Co., Inc. Procédé de synthèse d'un cyclopropylamide
WO2007138928A1 (fr) * 2006-05-26 2007-12-06 Kaneka Corporation Procédé de production de dérivés optiquement actifs de cyclopropylamide d'acide 3-amino-2-hydroxypropionique et de leurs sels

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JPS61129159A (ja) * 1984-11-28 1986-06-17 Nippon Zeon Co Ltd 保護化アミノ酸アミド化合物の精製法
JP2007504251A (ja) * 2003-09-05 2007-03-01 バーテックス　ファーマシューティカルズ　インコーポレイテッド セリンプロテアーゼ、特にｈｃｖｎｓ３‐ｎｓ４ａの阻害剤
JP2007513971A (ja) * 2003-12-11 2007-05-31 シェーリング　コーポレイション Ｃ型肝炎ウイルスｎｓ３／ｎｓ４ａプロテアーゼの阻害剤
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WO2007105729A1 (fr) * 2006-03-13 2007-09-20 Ajinomoto Co., Inc. Procédé de synthèse d'un cyclopropylamide
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CN101691338B (zh) * 2009-08-26 2013-08-14 凯莱英生命科学技术(天津)有限公司 一种手性环氧化合物的合成方法及其中间产物与最终产物

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