JP2007039413A - Crystal composed of (2s)-2-propenyloctanoic acid or (2s)-2-propynyloctanoic acid and amine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a crystal composed of a compound usable as a synthetic intermediate for (2R)-2-propyloctanoic acid and an amine. <P>SOLUTION: The invention provides a crystal composed of (2S)-2-propenyloctanoic acid or (2S)-2-propynyloctanoic acid and an amine, keeping the pharmacological effect of (2R)-2-propyloctanoic acid and usable as a synthetic intermediate for a solid medicinal preparation for oral administration. The crystal gives (2R)-2-propyloctaoic acid having excellent handling property and strong pharmacological activity in high optical purity and chemical yield. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a crystal composed of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine, which is useful as a pharmaceutical intermediate.

  In the production of a compound that is an active ingredient of a pharmaceutical product, it is desired that the target compound is obtained in a high yield. Not only the yield of the manufacturing process itself but also the physical properties of the intermediate obtained in the middle greatly affect the yield of the target compound.

  For example, the powder is easier to handle in weighing and the like than the oily compound. Even in the powder form, crystals are more chemically stable than amorphous, and are advantageous in terms of handling such as purification.

  On the other hand, (2R) -2-propyloctanoic acid is a compound that exerts a strong pharmacological action on the central nervous system, but since this compound has an asymmetric carbon atom, its production is difficult. Various production methods have been reported.

  For example, for the production of (2R) -2-propyloctanoic acid, a method obtained by subjecting (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid to a catalytic reduction reaction is known. (See Patent Document 1).

  However, (2S) -2-propenyloctanoic acid and (2S) -2-propynyloctanoic acid are both oily substances and are difficult to handle. In order to obtain (2R) -2-propyloctanoic acid with high optical purity, the raw materials (2S) -2-propenyloctanoic acid and (2S) -2-propynyloctanoic acid are also desired to have high optical purity. . If these compounds are crystals, they can be purified by recrystallization, and their optical purity can be further increased by repeating recrystallization.

  (2S) -2-propenyloctanoic acid is known as a raw material of (2R) -propyloctanoic acid having strong pharmacological activity against the central nervous system (Patent Documents 1, 3, 5 to 6 and Non-Patent Document 1). To 2). Similarly, (2S) -2-propynyloctanoic acid is known as a raw material for (2R) -2-propyloctanoic acid (see Patent Documents 1 to 4 and Non-Patent Documents 1 to 2).

  These references specifically disclose free forms of (2S) -2-propenyloctanoic acid and (2S) -2-propynyloctanoic acid, but for these amine salts, (2S) -2-propenyl The cyclohexylamine salt of octanoic acid is obtained as crystals (see Patent Document 1), and the (R)-(+)-1-phenylethylamine salt of (2R) -2-propynyloctanoic acid is obtained as crystals. It is known (see Patent Document 4).

  However, it was unclear whether these compounds formed crystals with other amines.

  Moreover, since (2S) -2-propenyloctanoic acid has a double bond, the transfer of the double bond may occur under basic conditions or acidic conditions. When the double bond of (2S) -2-propenyloctanoic acid is transferred, there is a concern that (2R) -2-propyloctanoic acid obtained by reduction causes a decrease in optical purity. Therefore, in order to obtain (2R) -2-propyloctanoic acid having a high optical purity, it is desired to form a stable crystal so as not to cause a double bond transition of (2S) -2-propenyloctanoic acid.

International Publication No. 2000/48982 Pamphlet International Publication No. 2005/05366 Pamphlet International Publication No. 99/58513 Pamphlet JP-A-8-291106 International Publication No. 2004/92113 Pamphlet International Publication No. 2003/51852 Pamphlet Bulletin of the Chemical Society of Japan 2000, Vol. 73, No. 2, pages 423-428 Sinlet 1998, No. 8, 882-884

  An object of the present invention is to provide (2S) -2-propenyloctanoic acid or (2S) -2 as a synthetic intermediate for obtaining (2R) -2-propyloctanoic acid used as a pharmaceutical product with high optical purity and chemical yield. -To provide crystals comprising propynyloctanoic acid and an amine.

  In general, whether or not a salt formed from an acid and a base crystallizes depends on the combination of the acid and the base, and the solvent used for the crystallization. In other words, whether or not crystallization is possible does not depend on the nature of the acid itself or the base itself, so just because a crystal is obtained with a combination of an acid and a base, the acid can be combined with any base. However, it does not crystallize.

  Therefore, as a result of studies to make crystals easier to handle, surprisingly, when certain amines are used, (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctane is used. The present invention was completed by finding the formation of crystals with acid.

  According to the present invention, (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine are synthetic intermediates of (2R) -2-propyloctanoic acid having strong pharmacological activity on the central nervous system The crystal | crystallization consisting of can be provided.

That is, the present invention provides a crystal comprising [1] (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine (provided that (2S) -2-propenyloctanoic acid and cyclohexylamine And the crystals of (2S) -2-propynyloctanoic acid and (R)-(+)-1-phenylethylamine).
[2] The crystal according to [1], which is (2S) -2-propenyloctanoic acid,
[3] The crystal according to [1], which is (2S) -2-propynyloctanoic acid,
[4] The amine is (+)-dehydroabiethylamine, (R)-(+)-1- (p-tolyl) ethylamine, (S)-(−)-1- (1-naphthyl) ethylamine, (+) -Cis-2-benzylaminocyclohexanemethanol, (-)-cis-2-benzylaminocyclohexanemethanol, (R)-(+)-1-phenylethylamine, dibenzylamine, 1,2-diphenylethylamine or benzhydrylamine The crystal according to item [2], wherein
[5] The amine is (S)-(−)-1-phenylethylamine, (1S, 2R)-(+)-2-amino-1,2-diphenylethanol, L-arginine, dibenzylamine, 1,2 -The crystal according to [3] above, which is diphenylethylamine, benzhydrylamine, or cyclohexylamine;
[6] (2S) -2-propenyloctanoic acid having a diffraction angle 2θ in the powder X-ray diffraction spectrum of 11.99, 14.63, 17.48, 19.02, 22.89, 23.48, 24.13, 25.49, 26.66, 33.22 (degrees) and ( Crystals with (R)-(+)-1-phenylethylamine and [7] The diffraction angle 2θ in the powder X-ray diffraction spectrum is 15.87, 16.77, 17.87, 19.78, 20.36, 21.19, 23.41, 24.19, 25.05, 25.69, 32.01. 36.11 (degrees) of (2S) -2-propenyloctanoic acid and dibenzylamine.

  In the present invention, (2S) -2-propynyloctanoic acid is a compound of the formula (IA)

(Where

Represents β arrangement (upward on the paper surface). (2S) -2-propenyloctanoic acid is a compound represented by the formula (IB)

The compound shown by these is represented.

  In the present invention, (2S) -2-propynyloctanoic acid is not limited to a substantially pure and single substance, and (2S) -2-propynyloctanoic acid and formula (II-A)

(Where

Represents the α arrangement (downward on the paper). Even if it is a mixture of (2R) -2-propynyloctanoic acid represented by (2R) -2-propynyloctanoic acid, it is referred to as (2S) -2-propynyloctanoic acid if it contains predominantly (2S) -2-propynyloctanoic acid.

  Similarly, (2S) -2-propenyloctanoic acid is not limited to a substantially pure and single substance, (2S) -2-propenyloctanoic acid and formula (II-B)

Even if it is a mixture of (2R) -2-propenyloctanoic acid represented by the formula (2S) -2-propenyloctanoic acid, it is referred to as (2S) -2-propenyloctanoic acid as long as it contains (2S) -2-propenyloctanoic acid. In addition, (2S) -2-propynyloctanoic acid and (2S) -2-propenyloctanoic acid may contain impurities such as by-products, solvents, raw materials, or decomposition products derived from the production process. .

  The “amine” in the present invention may be any amine as long as it forms a crystal with (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid. Are preferably used.

  The amine that forms crystals with (2S) -2-propenyloctanoic acid is as follows.

  An optically active amine, that is, a chiral amine, is preferably (+)-dehydroabiethylamine, (R)-(+)-1- (p-tolyl) ethylamine, (S)-(−)-1- (1-naphthyl) ethylamine, (+)-cis-2-benzylaminocyclohexanemethanol, (−)-cis-2-benzylaminocyclohexanemethanol, (R)-(+)-1-phenylethylamine, and the like.

  Preferred examples of the optically inactive amine, that is, an achiral amine, include dibenzylamine, 1,2-diphenylethylamine, benzhydrylamine, and the like.

  The amine that forms crystals with (2S) -2-propynyloctanoic acid is preferably (S)-(−)-1-phenylethylamine, (1S, 2R)-(+)-2-amino-1, 2-diphenylethanol, L-arginine, dibenzylamine, 1,2-diphenylethylamine, benzhydrylamine and cyclohexylamine.

  Among these amines, particularly preferred are crystals of (2S) -2-propynyloctanoic acid and cyclohexylamine, crystals of (2S) -2-propenyloctanoic acid and (1R) -1-phenylethylamine, and It is a crystal of (2S) -2-propenyloctanoic acid and dibenzylamine.

  Examples of amines in the present invention include low-toxic amines that form salts with active ingredients in pharmaceuticals approved by the US Food and Drug Administration (FDA).

As preferable amines in the present invention, for example, in addition to the above, all amines that form crystals with (2S) -propenyloctanoic acid or (2S) -propynyloctanoic acid are included in the present invention.
[Method for Producing Crystal of the Present Invention]
The crystals of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine of the present invention (hereinafter abbreviated as crystals of the present invention) are the methods described below, these Or by the method described in the examples. The crystals of the present invention comprise (2S) -2-propenyloctanoic acid known as CAS # 213914-70-6 or (2S) -2-propynyloctanoic acid known as CAS # 185463-37-0 with water and / or Alternatively, an organic solvent (for example, an alcohol solvent (for example, methanol, ethanol, isopropyl alcohol, etc.), an ether solvent (for example, diethyl ether, methyl t-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether (diglyme), tetrahydrofuran, 1,4- Dioxane, etc.), ketone solvents (eg, acetone, 2-butanone, etc.), ester solvents (eg, ethyl acetate, diethyl carbonate, etc.), nitrile solvents (eg, acetonitrile, etc.), aliphatic hydrocarbon solvents (eg, , N-hexane, n-heptane, cyclohexane, etc.), aroma This mixture is dissolved in a hydrocarbon solvent (for example, benzene, toluene, xylene, etc., or a mixture of these in any proportion) and further added with about 0.5 to about 1.1 equivalents of the amine. The solution can be precipitated by stirring at about 40 to about 100 ° C. for about 5 to about 60 minutes, cooling to about −20 to about 20 ° C., and then stirring or standing for about 5 to about 60 minutes. The precipitated crystal is collected by filtration, washed with the organic solvent, and dried to isolate the target crystal of the present invention.

  In addition, (2S) -2-propenyloctanoic acid and (2S) -2-propynyloctanoic acid are oily, so the above amine is mixed in the absence of a solvent and subjected to the same treatment as above. The crystal of the present invention can be obtained.

  Note that (2S) -2-propynyloctanoic acid and (2S) -2-propenyloctanoic acid as raw materials used in the production of the crystal of the present invention are known substances, and thus are known methods such as WO2000 / 48982 No., WO2005 / 05366, WO99 / 58513, JP-A-8-291106, WO2004 / 92113, WO2003 / 51852, Bulletin of the Chemical Society of Japan, 2000, Vol. 73, No. No. 2, pages 423-428, Sinlet 1998, No. 8, pages 882-884 and the like.

  Moreover, the optical purity can be increased by subjecting the crystal of the present invention to recrystallization as required.

  In the development of pharmaceuticals with asymmetric carbon atoms, it is very important to obtain compounds with high optical purity (the drug substance). To provide safe pharmaceuticals, the optical purity must be as close to 100% as possible. It has been demanded. Therefore, finding a method for increasing optical purity and an intermediate used in the method is an important issue in drug development.

In the present invention, (2S) -2-propenyloctanoic acid is WO2000 / 48982 using N- (2S)-(2-propenyl) octanoyl)-(1S)-(−)-2,10-camphorsultam. It can be produced by the method described in Reference Example 1 → Reference Example 2 in the specification. (2S) -2-propynyloctanoic acid can be produced by the method described in Reference Example 4 of JP-A-8-291106 using methyl 2- (2-propynyl) octanoate.
[Application to pharmaceutical products]
The crystals of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and amines of the present invention have strong activity in the central nervous system, and mammals (eg, humans, non-human animals, eg, , Monkeys, sheep, cows, horses, dogs, cats, rabbits, rats, mice, etc.), for example, useful for the prevention, treatment and / or suppression of symptom progression of neurodegenerative diseases, neuropathies, or diseases requiring nerve regeneration is there.

  Here, the neurodegenerative diseases include all diseases associated with neuronal degeneration and are not limited by the pathogenesis. The neurodegenerative disease in the present invention includes a neurological disorder and a disease requiring nerve regeneration. The nerve cell may be any nerve cell in the living body, for example, a central nerve (for example, cranial nerve, spinal nerve, etc.), a peripheral nerve (for example, autonomic nervous system (for example, sympathetic nerve, parasympathetic nerve, etc.), etc.) Or the like. Preferably, the neurodegenerative disease is, for example, a disease of the central nervous system, such as Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, progressive nucleus Supraparalysis, Huntington's disease, spinocerebellar ataxia, dentate nucleus red nucleus pallidal atrophy, olive bridge cerebellar atrophy, corticobasal degeneration, familial dementia, frontotemporal dementia, senile Dementia, diffuse Lewy body disease, striatum-substantia nigra degeneration, chorea-ataxia, dystonia, mage syndrome, late-onset cerebellar cortical atrophy, familial spastic paraplegia, motor neuropathy Nerve after Card Joseph disease, Pick disease, stroke (eg, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, etc.), cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, subarachnoid hemorrhage, etc. Dysfunction, after cerebrospinal trauma Neurological dysfunction, demyelinating disease (eg, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse myelitis, etc.), brain tumor (eg, astrocytoma, etc.), Cerebrospinal diseases associated with infections (eg meningitis, brain abscess, Creutzfeldt-Jakob disease, AIDS dementia, etc.), mental disorders (schizophrenia, manic depression, neurosis, psychosomatic disease, epilepsy, etc.) Can be mentioned. More preferable examples of the neurodegenerative disease include Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, and the like.

  Neuropathy encompasses all disorders of neurological function. That is, neurological disorders generally include those recognized as symptoms at the time of disease. For example, Parkinson's disease and Parkinson's syndrome include, for example, tremor, muscle stiffness (stiffness), slow movement, postural reflex disorder, autonomic disorder, lung phenomenon, gait disorder, psychiatric symptoms, etc. Diseases include, for example, dementia symptoms. For example, in amyotrophic lateral sclerosis and familial amyotrophic lateral sclerosis, muscle atrophy, muscle weakness, upper limb dysfunction, gait disorder, articulation disorder Also included are dysphagia, respiratory problems and the like.

  A disease that requires nerve regeneration means a disease in which the absolute number of nerve cells is reduced due to lack of nerve cells and normal nerve function is impaired, for example, the above-mentioned neurodegenerative diseases that have led to such a state Is mentioned. For such diseases, cells that can form normal nerves (for example, neural stem cells, neural progenitor cells, neural cells, other stem cells, glial cells, etc.) are surgically transplanted, or endogenous these Treatment is performed to activate cells and regenerate nerves. The crystal of the present invention can promote nerve regeneration by administering temporarily or continuously when transplanting the above-mentioned cells or activating endogenous cells.

  In addition, (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and amine crystals of the present invention and (2R) -2-propyloctanoic acid obtained using such crystals are used for nerve regeneration. It is also useful as a promoter or S100β production inhibitor. The crystal of the present invention is administered into a living body after formulation for the purpose of prevention, treatment and / or suppression of symptom progression of the above-mentioned diseases. In the present invention, “prevention” refers to preventing the establishment of the disease itself, “treatment” refers to guiding the disease state in the direction of healing, and “suppression of symptom progression” refers to suppressing progression of the disease state and progressing. Means to stay.

  (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and amine crystals of the present invention, and (2R) -2-propyloctanoic acid produced from these compounds as raw materials, or those In order to use a pharmaceutical composition containing a combination of a drug and another drug for the above purpose, it is usually administered systemically or locally in an oral or parenteral form.

  (2S) -2-propenyloctanoic acid or crystals composed of (2S) -2-propynyloctanoic acid and an amine, and (2R) -2-propyloctanoic acid obtained using these compounds, or other drugs When a pharmaceutical composition comprising a concomitant drug is administered, for example, a solid preparation for internal use for oral administration, a liquid preparation for internal use and an injection for parenteral administration, an external preparation, a suppository, eye drops Used as an agent, inhalant, etc.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Examples of capsules include hard capsules and soft capsules.

  In such solid preparations for internal use, for example, one or more active substances are left as they are, or excipients (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (for example, hydroxypropyl) Cellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (eg, calcium calcium glycolate), lubricant (eg, magnesium stearate), stabilizer, solubilizer (eg, glutamic acid, asparagine) Acid) and the like, and formulated into a conventional method. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  Examples of liquids for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  Examples of external dosage forms for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops, and spots. Includes nasal preparations. These contain one or more active substances and are prepared by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, it is prepared by mixing or melting one or more active substances in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recalls, macrogol, etc.), vegetable oils (castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (eg mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, anti-rash agents It is used alone or in combination of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), One selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption enhancers, and anti-rash agents, or a mixture of two or more types may be used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced by a known or commonly used formulation. For example, it is prepared by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.), emulsifiers (eg, polyoxy (Ethylene alkyl ethers, fatty acid esters, etc.), water, absorption accelerators, anti-rash agents, or a mixture of two or more thereof. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, a solubilizing agent, a tackifier, and a rash prevention agent may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support. The base for patch is selected from known or commonly used ones. For example, those selected from a polymer base, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is produced by a known or commonly used formulation. For example, one or more active substances are dissolved or suspended in one or more selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent and the like. Prepared by turbidity or emulsification. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays, inhalants, and sprays are commonly used diluents such as sodium bicarbonate, sodium citrate or citric acid to provide isotonicity with stabilizers such as sodium bisulfite. Such an isotonic agent may be contained. A method for producing a spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final process or manufactured by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

  Eye drops for parenteral administration include ophthalmic solutions, suspension type ophthalmic solutions, emulsion type ophthalmic solutions, pre-dissolving type ophthalmic solutions, and eye ointments.

  These eye drops are produced according to known methods. For example, one or more active substances are used by dissolving, suspending or emulsifying them in a solvent. As the solvent for the eye drops, for example, sterilized purified water, physiological saline, other aqueous solvents or non-aqueous preparations for injection (for example, vegetable oil) and the like, and combinations thereof are used. Eye drops include isotonic agents (eg, sodium chloride, concentrated glycerin, etc.), buffering agents (eg, sodium phosphate, sodium acetate, etc.), surfactants (eg, polysorbate 80 (trade name), stearic acid) Polyoxyl 40, polyoxyethylene hydrogenated castor oil, etc.), stabilizers (eg, sodium citrate, sodium edetate, etc.), preservatives (eg, benzalkonium chloride, parabens, etc.), etc. are selected as necessary. May be included. These are sterilized in the final step or prepared by aseptic manipulation. In addition, an aseptic solid preparation, for example, a freeze-dried product, can be produced and dissolved before use in a sterilized or aseptically sterilized purified water or other solvent.

  Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are used by dissolving or suspending them in water or other suitable media at the time of use. It may be.

  These inhalants are produced according to known methods.

  For example, in the case of inhalation solutions, preservatives (eg, benzalkonium chloride, parabens, etc.), colorants, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonic agents (eg, chloride) Sodium, concentrated glycerin, etc.), thickeners (for example, cariboxyvinyl polymer, etc.), absorption accelerators and the like are appropriately selected as necessary.

  In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary.

  When administering a liquid for inhalation, a nebulizer (for example, an atomizer, a nebulizer, etc.) is usually used, and when administering a powder for inhalation, an inhaler for powder medicine is usually used.

  Other compositions for parenteral administration include suppositories for rectal administration, pessaries for intravaginal administration, etc., which contain one or more active substances and are prescribed by conventional methods.

  The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually administered orally once to several times a day in the range of 1 mg to 5000 mg per adult. Or administered parenterally (preferably intravenously) once to several times daily, preferably in the range of 1 to 1200 mg per adult, or 1 to 24 hours per day It is continuously administered intravenously in the range.

  Of course, as described above, the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient or may be necessary beyond the range.

  The (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and amine crystals of the present invention, and (2R) -2-propyloctanoic acid obtained using such crystals are It has preventive, therapeutic and / or symptom progression-inhibiting effects on other diseases. Any of the above-mentioned preparations are preferable. However, since (2R) -2-propyloctanoic acid is oily, it should be formulated using the characteristics of being liquid, such as an injection or filling a soft capsule. Is more preferable. For example, the dose in the case of a soft capsule may be in the same range as described above. Particularly preferred is a daily dose of about 50 to about 5000 mg, especially about 100 to about 1200 mg. Further, the dose when it is used as an injection also varies depending on the degree of symptoms; age, sex, body weight of administration subject; timing of administration, interval, etc., and is not particularly limited. In addition, for example, when administered intravenously as a therapeutic agent for neurodegenerative diseases including cerebral infarction, the daily dose is preferably about 2 to about 12 mg per kg of the patient's body weight. More preferred doses include daily doses of about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, etc. per kg of patient body weight. Particularly preferably, the daily dose is about 4 mg, about 6 mg, about 8 mg, or about 10 mg per kg of the patient's body weight, and especially the daily dose is about 4 mg, or about 8 mg, per kg of the patient's body weight. Is preferred.

  A crystal of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine according to the present invention, and (2R) -2-propyloctanoic acid obtained by using such a crystal as an active ingredient Other drugs such as antiepileptic drugs (eg phenobarbital, mehobarbital, metalbital, primidone, phenytoin, ethotoin, trimetadione, ethosuximide, acetylphenetride, carbamazepine, acetazolamide, diazepam, sodium valproate) Acetylcholinesterase inhibitors (eg, donepezil hydrochloride, TAK-147, rivastigmine, galantamine, etc.), neurotrophic factors (eg, ABS-205, etc.), aldose reductase inhibitors, antithrombotic agents (eg, t-PA, heparin) ), Oral anticoagulants (eg, warfarin, etc.), synthetic antithrombin drugs (eg, gabexate mesylate, nafamostat mesylate, argatroban, etc.), antiplatelet agents (eg, aspirin, dipyridamole, ticlopine hydrochloride, beraprost sodium, cilostazol , Ozagrel sodium, etc.), thrombolytic agents (eg, urokinase, tisokinase, alteplase, etc.), factor Xa inhibitors, factor VIIa inhibitors, cerebral circulation metabolism improving agents (eg, idebenone, calcium hopantenate, amantadine hydrochloride, meclofenoxy hydrochloride) Sart, dihydroergotoxin mesylate, pyrithioxine hydrochloride, γ-aminobutyric acid, bifemelane hydrochloride, lisuride maleate, indeloxazine hydrochloride, nicergoline, propentophilin, etc.), antioxidants (For example, edaravone, etc.), glycerin preparation (for example, glycerol, etc.), β-secretase inhibitor (for example, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6 -(4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dipropylamino) methyltetralin, 2- (N, N -Dimethylamino) methyl-6- (4'-methoxybiphenyl-4-yl) methoxytetralin, 6- (4-biphenylyl) methoxy-2- [2- (N, N-diethylamino) ethyl] tetralin, 2- [ 2- (N, N-dimethylamino) ethyl] -6- (4′-methylbiphenyl-4-yl) methoxytetralin, 2- [2- (N, -Dimethylamino) ethyl] -6- (4'-methoxybiphenyl-4-yl) methoxytetralin, 6- (2 ', 4'-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N -Dimethylamino) ethyl] tetralin, 6- [4- (1,3-benzodioxol-5-yl) phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (3 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, its optically active substance, its salt and its hydrate, OM99-2 ( WO01 / 00663) etc.), β-amyloid protein aggregation inhibitor (for example, PTI-00703, ALZHEMED (NC-531), PPI-368 (Special Table 11-514333), PPI-558 (Special Table 2001-500852) SKF-74652 (Biochem. J., 340 (1), 283-289, 1999), etc.), brain machine Potency enhancer (for example, aniracetam, nicergoline, etc.), dopamine receptor agonist (for example, L-dopa, bromocriptene, pergolide, talipexol, prasipexol, cabergoline, amantadine, etc.), monoamine oxidase (MAO) inhibitor (for example, , Safrazine, deprenyl, sergiline (selegiline), remacemide, riluzole, etc.), anticholinergic agents (eg, trihexyphenidyl, biperidene, etc.), COMT inhibitors (eg, entacapone, etc.), muscle atrophy Lateral sclerosis drug (eg, riluzole, neurotrophic factor, etc.), Hyperlipidemia drug (eg, statin hyperlipidemia drug (eg, pravastatin sodium, atorvastatin calcium, simvastatin, lovastatin, rosuvastatin calcium) Pitavastatin, etc.), fibrate antihyperlipidemic drugs (eg, clofibrate, etc.), apoptosis inhibitors (eg, CPI-1189, IDN-6556, CEP-1347, etc.), neuronal differentiation / regeneration promoters (eg, , Leteprinim, xaliproden (SR-57746-A), SB-216763, etc.), non-steroidal anti-inflammatory drugs (eg meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (For example, dexamethasone, hexestrol, cortisone acetate, etc.), sex hormones or derivatives thereof (for example, progesterone, estradiol, estradiol benzoate, etc.) may be used in combination. In addition, nicotine receptor modulators, γ-secretase inhibitor, β-amyloid vaccine, β-amyloid-degrading enzyme, squalene synthase inhibitor, therapeutic agents for abnormal behavior and epilepsy associated with the progression of dementia, antihypertensives, anti-diabetics, Even when used together with antidepressants, anxiolytics, disease-modifying antirheumatic drugs, anti-cytokine drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.), parathyroid hormone (PTH), calcium receptor antagonists, etc. Good.

  The above concomitant drugs are illustrative and are not limited thereto.

Other drugs may be administered in combination of any two or more. In addition, the drugs used in combination include not only those found so far, but also those that will be found in the future based on the above-described mechanism.
[Pharmacological activity]
Although the crystal of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine of the present invention is useful as a synthetic intermediate for producing (2R) -2-propyloctanoic acid, The fact that these compounds themselves have pharmacological activity can also be confirmed by known methods, for example, the methods described in European Patent No. 0632008, European Patent Publication No. 1174131 and the like.
[toxicity]
The toxicity of the crystals of the present invention is very low and can be judged to be sufficiently safe for use as a medicine or pharmaceutical intermediate.

  According to the present invention, there is provided a crystal comprising (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine, which is a synthetic intermediate of (2R) -2-propyloctanoic acid. it can.

  Further, according to the present invention, (2R) -2-propyloctanoic acid having excellent handling and strong pharmacological activity can be provided with high optical purity and chemical yield. In addition, according to this invention, transfer of the double bond in (2S) -2-propenyloctanoic acid can be prevented.

  As a further effect of the present invention, for example, (2S) -2-propenyloctanoic acid and a crystal comprising an amine are used according to a known method (for example, the method described in Reference Example 1 of WO2000 / 48982) (2S ) -2-propenyloctanoic acid, and using the obtained (2S) -2-propenyloctanoic acid, for example, Example 4 of WO99 / 58513 specification, Implementation of WO2000 / 48982 specification (2R) -propyloctanoic acid can be prepared according to the method described in Example 1.

  Further, for example, (2S) -2-propynyl is obtained by using a crystal composed of (2S) -2-propynyloctanoic acid and an amine according to a known method (for example, the method described in Reference Example 1 of WO2000 / 48982). By using the obtained (2S) -2-propynyloctanoic acid, for example, Examples 8 (a) and 8 (b) of WO99 / 58513, WO2000 / 48982 (2R) -propyloctanoic acid can be prepared according to the method described in Example 2 of the description.

  According to the present invention, since the crystal of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine is stable, the optical purity can be increased, and as a result, the optical purity is higher. (2R) -propyloctanoic acid can be obtained.

  In addition, the crystals of (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and amine provided by the present invention have low toxicity and can be used as an active pharmaceutical ingredient for oral solid preparations. .

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. Moreover, you may change in the range which does not deviate from the range of this invention.
Example 1 Examination of Crystal Formation of (2S) -2-propenyloctanoic Acid and Various Amines Various amine salts of (2S) -2-propenyloctanoic acid were prepared and examined for crystallization. The results are shown below.

Experimental method: A mixture of (2S) -2-propenyloctanoic acid and various amines was dissolved in a solvent by heating, then cooled to room temperature and allowed to stand. When a solid was precipitated, the obtained solid was collected by filtration, and after drying, a powder X-ray diffraction spectrum, a ¹ H-NMR spectrum and an infrared absorption (IR) spectrum were measured, and their properties were evaluated.
[Crystal property data]
(2S)-2-molar ratio of propenyl salts of octanoic acid and an organic amine ((2S)-2-propenyl-octanoic acid: ratio of amine), properties, melting point, ¹ H-NMR spectral data, X-ray powder diffraction spectrum Data and infrared absorption (IR) spectrum data are shown below, and a powder X-ray diffraction spectrum chart and an infrared absorption (IR) spectrum chart are shown in the following drawings. Measurement conditions are as follows.
[1] Powder X-ray diffraction spectrum <Measurement conditions>
Equipment: BRUKER axs BRUKER D8 DISCOVER with GADD (C2),
Target: Cu, filter: none, voltage: 40 kV, current: 40 mA, exposure time: 5 minutes.
[2] Infrared absorption (IR) spectrum <measurement conditions>
Equipment: FTIR-660Plus from JASCO / DuraScope from SensIR TECHNOLOGIES,
Measurement method: measured by ATR method, resolution: 4 cm ⁻¹ , scan count: 16 times.
Example 1 (1): Dibenzylamine Molar ratio = 2: 1; Property: Crystal; Melting point: 73.2-74.8C;
¹ H-NMR (CDCl ₃ ): δ 7.36-7.26 (m, 10H), 7.15-6.70 (brs, 3H), 5.81-5.71 (m, 2H), 5.09-5.00 (m, 4H), 3.86 (s, 4H), 2.44-2.32 (m, 4H), 2.29-2.18 (m, 2H), 1.70-1.55 (m, 2H), 1.52-1.41 (m, 2H), 1.35-1.20 (m, 16H), 0.88 ( t, J = 6.2 Hz, 6H).
Powder X-ray diffraction spectrum data:

IR (TR): 2959, 2921, 2851, 1640, 1497, 1456, 1416, 1378, 1315, 1209, 1043, 990, 912, 760, 743, 725, 694, 587, 547, 498, 486, 445, 423 , 412, 402cm ^-1 ;
Solvent: acetonitrile, diethylene glycol dimethyl ether (diglyme) / water, isopropanol, acetone, dimethoxyethane.
Example 1 (2): (1R)-(+)-1-phenylethylamine Molar ratio = 1: 1; Property: Crystal; Melting point: 56.7-58.8 <0>C;
¹ H-NMR (CDCl ₃ ): δ 7.37-7.22 (m, 5H), 5.83-5.73 (m, 1H), 5.09-5.00 (m, 2H), 4.76-4.20 (brs, 3H), 4.16 (q, J = 6.8Hz, 1H), 2.47-2.31 (m, 2H), 2.28-2.17 (m, 1H), 1.67-1.54 (m, 1H), 1.50-1.40 (m, 4H), 1.35-1.18 (m, 8H), 0.87 (t, J = 6.6Hz, 3H).
Powder X-ray diffraction spectrum data:

IR (TR): 2925, 2855, 2204, 1698, 1636, 1523, 1456, 1397, 1315, 1291, 1233, 1117, 1091, 992, 907, 851, 762, 726, 697, 641, 591, 540, 488 , 443 cm ^-1 ;
Solvent: acetonitrile, n-hexane, isopropanol / water, acetone, dimethoxyethane, diglyme / water.
Example 1 (3): (R)-(+)-1- (p-tolyl) ethylamine molar ratio = 1: 1; properties: crystal; melting point: 70.9-72.9 <0> C.
¹ H-NMR (CDCl ₃ ): δ 7.23 (d, J = 8.0 Hz, 2H), 7.14 (q, J = 8.0 Hz, 2H), 5.82-5.72 (m, 1H), 5.38-4.90 (brs, 3H ), 5.07-4.98 (m, 2H), 4.16-4.12 (m, 1H), 2.40-2.30 (m, 1H), 2.33 (s, 3H), 2.24-2.10 (m, 1H), 1.65-1.50 (m , 1H), 1.47-1.19 (m, 13H), 0.87 (t, J = 7.0Hz, 3H).
Powder X-ray diffraction spectrum data:

IR (TR): 2925, 2856, 2696, 2216, 1623, 1520, 1456, 1439, 1402, 1383, 1316, 1262, 1232, 1090, 1021, 993, 911, 814, 763, 722, 697, 625, 560 , 536, 473, 444 cm ^-1 ;
Solvent: acetonitrile, diglyme.
Example 1 (4): (+) - cis-2-benzylamino cyclohexanemethanol <br/> molar ratio = 1: 1; Property: crystal; mp: 66.0-67.5 ° C.;
¹ H-NMR (CDCl ₃ ): δ 7.40-7.25 (m, 5H), 7.00-6.65 (brs, 3H), 5.80-5.72 (m, 1H), 5.17-4.93 (m, 2H), 4.04-3.90 ( m, 3H), 3.67 (dd, J = 2.8, 11.2 Hz, 1H), 3.08-3.00 (m, 1H), 2.38-2.27 (m, 2H), 2.23-2.10 (m, 2H), 1.92-1.81 ( m, 1H), 1.75-1.19 (m, 17H), 0.87 (t, J = 7.0 Hz, 3H);
Powder X-ray diffraction spectrum data:

IR (TR): 2924, 2853, 1624, 1525, 1496, 1456, 1389, 1340, 1059, 1037, 910, 748, 695, 630, 508, 492, 436 cm ^-1 ;
Solvent: acetonitrile.
Example 1 (5): (-) - cis-2-benzylamino cyclohexanemethanol <br/> molar ratio = 1: 1; Property: crystal; mp: 71.0-72.2 ° C.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.36-7.26 (m, 5H), 5.82-5.76 (m, 1H), 5.07-4.97 (m, 2H), 4.03-3.89 (m, 4H), 3.08 -3.00 (m, 1H), 2.40-2.28 (m, 2H), 2.25-2.15 (m, 1H), 2.15-2.08 (br.s, 1H), 1.92-1.80 (m, 1H), 1.66-1.32 ( m, 4H), 1.29-1.20 (m, 15H), 0.87 (t, J = 6.8 Hz, 3H).
Powder X-ray diffraction spectrum data:

IR (TR): 2925, 2853 , 1622, 1524, 1449, 1397, 1315, 1217, 1059, 1039, 912, 813, 751, 697, 620, 560, 509, 493, 436 cm -1;
Solvent: acetonitrile, diglyme.
Example 1 (6): (1S, 2R)-(+)-2-amino-1,2-diphenylethanol Molar ratio = 1: 1; Property: amorphous; Melting point: 117.8-118.5 <0>C;
IR (TR): 2924, 2854, 1749, 1558, 1508, 1455, 1396, 1318, 1201, 1050, 1033, 993, 906, 783, 767, 742, 696, 568, 503, 421, 411 cm ^-1 ;
¹ H-NMR (CDCl ₃ ): δ 7.30-7.18 (m, 10H), 5.82-5.72 (m, 1H), 5.08 (d, J = 17.2 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H ), 4.83 (d, J = 5.2 Hz, 1H), 4.19 (d, J = 6.0 Hz, 1H), 2.45-2.20 (m, 3H), 1.64-1.42 (m, 2H), 1.35-1.21 (m, 8H), 0.88 (t, J = 6.4 Hz, 3H).
Solvent: acetonitrile, isopropanol, diglyme, acetone.
Example 1 (7): (1R, 2S)-(-)-2-amino-1,2-diphenylethanol Molar ratio = 1: 1; Property: amorphous; Melting point: 119.8-120.6 [deg.] C.
IR (TR): 2924, 1749 , 1716, 1542, 1456, 1395, 1315, 1202, 1119, 1049, 1032, 995, 906, 783, 768, 695, 570, 502, 457, 445, 421, 411 cm - ¹ ;
¹ H-NMR (CDCl ₃ ): δ 7.29-7.20 (m, 10H), 5.83-5.73 (m, 1H), 5.11-5.02 (m, 2H), 4.82 (d, J = 5.6 Hz, 1H), 4.19 (d, J = 6.0 Hz, 1H), 2.46-2.20 (m, 3H), 1.66 -1.45 (m, 2H), 1.35-1.21 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H).
Solvent: acetonitrile, isopropanol, acetone.
Example 1 (8): (+)-dehydroabiethylamine Molar ratio = 3: 2; Property: Crystal; Melting point: 115.8-118.0 <0>C;
¹ H-NMR (CDCl ₃ ): δ 7.20-7.13 (d, J = 8.0Hz, 1H), 7.05-6.95 (d, J = 8.0Hz, 1H), 6.89 (s, 1H), 5.83-5.70 (m , 1.5H), 5.10-4.93 (m, 3H), 3.00-2.78 (m, 3H), 2.67-2.18 (m, 7.5H), 2.00-1.15 (m, 28H), 1.08-0.75 (m, 11.5H ).
Powder X-ray diffraction spectrum data:

IR (TR): 2925, 2850, 2194, 1749, 1636, 1542, 1457, 1436, 1393, 1318, 1208, 1144, 1057, 995, 906, 883, 850, 822, 726, 681, 630, 596, 520 , 434, 421, 411 cm ^-1 ;
Solvent: acetonitrile, diglyme.
Example 1 (9): (S)-(-)-1- (1-naphthyl) ethylamine Molar ratio: 1: 1; Property: crystal; Melting point: 63.0-64.2 <0>C;
¹ H-NMR (CDCl ₃ ): δ 8.13 (d, J = 8.0 Hz, 1H), 7.90-7.86 (m, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.56-7.46 (m, 3H), 5.84-5.72 (m, 1H), 5.12-5.08 (m, 3H), 3.90-3.50 (brs, 3H), 2.45-2.32 (m, 2H), 2.30-2.20 (m, 1H), 1.70-1.42 (m, 2H), 1.58 (d, J = 6.4 Hz, 3H), 1.40-1.20 (m, 8H), 0.88 (t, J = 6.8Hz, 3H) .
Powder X-ray diffraction spectrum data:

IR (TR): 2923, 2853, 2203, 1636, 1570, 1509, 1469, 1431, 1389, 1332, 1272, 1110, 995, 905, 860, 800, 774, 737, 684, 636, 613, 566, 532 , 499, 464, 438, 409 cm ^-1 ;
Solvent: acetonitrile.
Example 1 (10): benzhydrylamine molar ratio = 1: 1; properties: crystal; melting point: 81.5-83.0 [deg.] C.
¹ H-NMR (CDCl ₃ ): δ 7.36-7.20 (m, 10H), 5.83-5.71 (m, 1H), 5.23 (s, 1H), 5.11-5.01 (m, 2H), 3.80-3.20 (brs, 3H), 2.44-2.30 (m, 2H), 2.28-2.20 (m, 1H), 1.68-1.40 (m, 2H), 1.18-1.20 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H) .
Powder X-ray diffraction spectrum data:

IR (TR): 2921, 2851, 2617, 2181, 1618, 1573, 1508, 1497, 1457, 1445, 1396, 1319, 1031, 996, 906, 809, 756, 735, 693, 640, 542, 458, 431 , 409cm ^-1 ;
Solvent: acetonitrile.
Example 1 (11): 1,2-diphenyl-ethylamine <br/> molar ratio = 1: 1; Property: crystal; mp: 62.2-63.2 ° C.
¹ H-NMR (CDCl ₃ ): δ 7.36-7.14 (m, 10H), 5.83-5.73 (m, 1H), 5.10-5.02 (m, 2H), 4.21 (dd, J = 5.2, 8.8Hz, 1H) , 3.35-3.09 (brs, 3H), 3.02 (dd, J = 5.2, 13.6 Hz, 1H), 2.87 (dd, J = 8.8, 13.6Hz, 1H), 2.48-2.34 (m, 2H), 2.28-2.21 (m, 1H), 1.70-1.58 (m, 1H), 1.56-1.43 (m, 1H), 1.38-1.20 (m, 8H), 0.88 (t, J = 6.8Hz, 3H).
Powder X-ray diffraction spectrum data:

IR (TR): 2926, 2851, 2173, 1626, 1560, 1496, 1456, 1396, 1309, 1234, 1074, 1022, 993, 908, 851, 774, 758, 741, 725, 695, 615, 583, 548 , 499, 435cm ^-1 ;
Solvent: acetonitrile.

  On the other hand, amines that did not form crystals by combination with (2S) -2-propenyloctanoic acid are as follows.

(S)-(−)-1-phenylethylamine, (R)-(+)-1- (1-naphthyl) ethylamine, (S)-(−)-2-amino-3-phenyl-1-propanol, (R)-(+)-2-amino-3-phenyl-1-propanol, L-(+)-arginine, L-tyrosine amide, dicyclohexylamine, benzylamine, t-butylamine, 4-aminopyridine, imidazole, N-benzylethanolamine, 4-methoxybenzylamine, tetrahydrofurfurylamine, furfurylamine, trans-4-aminocyclohexanol.
Example 2 Examination of crystal formation of (2S) -2-propynyloctanoic acid and various amines In the same manner as in Example 1, (2S) -2-propynyloctanoic acid and various amines generate crystals. Was examined.

  As a result, the amine from which (2S) -2-propynyloctanoic acid forms crystals is as follows. The parenthesis represents the recrystallization solvent.

  (1S, 2R)-(+)-2-amino-1,2-diphenylethanol (ethyl acetate, toluene), (R) -1-phenylethylamine (hexane), L-arginine (isopropanol, n-hexane), (S) -1-phenylethylamine (hexane, isopropanol), (1R, 2S)-(−)-norephedrine (hexane).

  On the other hand, amines that did not form crystals by combination with (2S) -2-propynyloctanoic acid are as follows.

  (S)-(−)-1-methyl-2-pyrrolidinemethanol, (−)-threo-2-amino- (p-nitrophenyl) -1,3-propanediol, (1S, 2S)-(+) 2-Aminophenyl-1,3-propanediol, dehydroabiethylamine, (S)-(−)-nicotine, (−)-spartein, D-glucamine, (1S, 2S) -methyl pseudoephedrine.

  According to the present invention, (2R) -propyloctanoic acid having excellent handling and strong pharmacological activity is provided with high optical purity and chemical yield.

The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and dibenzylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and dibenzylamine is shown. The powder X-ray diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (R)-(+)-phenylethylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (R)-(+)-phenylethylamine is shown. The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (R)-(+)-1- (p-tolyl) ethylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (R)-(+)-1- (p-tolyl) ethylamine is shown. The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (+)-cis-2-benzylamino cyclohexane methanol is shown. An infrared absorption (IR) spectrum chart of a crystal composed of (2S) -2-propenyloctanoic acid and (+)-cis-2-benzylaminocyclohexanemethanol is shown. The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (-)-cis-2-benzylamino cyclohexane methanol is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (-)-cis-2-benzylamino cyclohexane methanol is shown. The powder X-ray diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (R)-(-)-phenylglycinol is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (R)-(-)-phenylglycinol is shown. 2 shows an amorphous powder X-ray diffraction spectrum chart of (2S) -2-propenyloctanoic acid and (1S, 2R)-(+)-2-amino-1,2-diphenylethanol. An amorphous infrared absorption (IR) spectrum chart composed of (2R) -2-propenyloctanoic acid and (1S, 2R)-(+)-2-amino-1,2-diphenylethanol is shown. 2 shows an amorphous powder X-ray diffraction spectrum chart of (2S) -2-propenyloctanoic acid and (1R, 2S)-(−)-2-amino-1,2-diphenylethanol. An amorphous infrared absorption (IR) spectrum chart composed of (2S) -2-propenyloctanoic acid and (1R, 2S)-(−)-2-amino-1,2-diphenylethanol is shown. The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (+)-dehydroabiethylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (+)-dehydroabiethylamine is shown. The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (S)-(+)-2-phenylglycinol is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (S)-(+)-2-phenylglycinol is shown. The powder X-ray diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (S)-(-)-1- (1-naphthyl) ethylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and (S)-(-)-1- (1-naphthyl) ethylamine is shown. The powder X-ray-diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and benzhydrylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and benzhydrylamine is shown. The powder X-ray diffraction spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and 1, 2- diphenylethylamine is shown. The infrared absorption (IR) spectrum chart of the crystal | crystallization which consists of (2S) -2-propenyl octanoic acid and 1, 2- diphenylethylamine is shown.

Claims (7)

Crystals comprising (2S) -2-propenyloctanoic acid or (2S) -2-propynyloctanoic acid and an amine (provided that crystals of (2S) -2-propenyloctanoic acid and cyclohexylamine and (2S) -2 -Excludes crystals of propynyloctanoic acid and (R)-(+)-1-phenylethylamine. The crystal according to claim 1, which is (2S) -2-propenyloctanoic acid. The crystal according to claim 1, which is (2S) -2-propynyloctanoic acid. The amine is (+)-dehydroabiethylamine, (R)-(+)-1- (p-tolyl) ethylamine, (S)-(−)-1- (1-naphthyl) ethylamine, (+)-cis- 2-benzylaminocyclohexanemethanol, (-)-cis-2-benzylaminocyclohexanemethanol, (R)-(+)-1-phenylethylamine, dibenzylamine, 1,2-diphenylethylamine or benzhydrylamine Item 3. The crystal according to Item 2. Amine is (S)-(−)-1-phenylethylamine, (1S, 2R)-(+)-2-amino-1,2-diphenylethanol, L-arginine, dibenzylamine, 1,2-diphenylethylamine The crystal according to claim 3, which is benzhydrylamine or cyclohexylamine. (2S) -2-propenyloctanoic acid and (R)-in which the diffraction angle 2θ in the powder X-ray diffraction spectrum is 11.99, 14.63, 17.48, 19.02, 22.89, 23.48, 24.13, 25.49, 26.66, 33.22 (degrees). Crystal with (+)-1-phenylethylamine. (2S) -2-propenyloctanoic acid with a diffraction angle 2θ in the powder X-ray diffraction spectrum of 15.87, 16.77, 17.87, 19.78, 20.36, 21.19, 23.41, 24.19, 25.05, 25.69, 32.01, 36.11 (degrees) Crystal with dibenzylamine.

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