WO2017028732A1 - 食欲素受体拮抗剂化合物的晶型及其制备方法和应用 - Google Patents

食欲素受体拮抗剂化合物的晶型及其制备方法和应用 Download PDF

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WO2017028732A1
WO2017028732A1 PCT/CN2016/094558 CN2016094558W WO2017028732A1 WO 2017028732 A1 WO2017028732 A1 WO 2017028732A1 CN 2016094558 W CN2016094558 W CN 2016094558W WO 2017028732 A1 WO2017028732 A1 WO 2017028732A1
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group
compound
water
organic solvent
solvent
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PCT/CN2016/094558
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English (en)
French (fr)
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吴松亮
罗志
陈远
王玉贺
秦大琨
李小林
王峥
李卫东
贺海鹰
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN202010948889.1A priority Critical patent/CN111848603B/zh
Priority to CN201680017909.5A priority patent/CN107709318B/zh
Priority to EP16836596.3A priority patent/EP3336088B1/en
Priority to CN202010591921.5A priority patent/CN111499625B/zh
Priority to US15/752,290 priority patent/US10668066B2/en
Priority to JP2018507552A priority patent/JP6772251B2/ja
Priority to DK16836596.3T priority patent/DK3336088T3/da
Publication of WO2017028732A1 publication Critical patent/WO2017028732A1/zh
Priority to US16/864,148 priority patent/US10912775B2/en
Priority to US16/864,153 priority patent/US10898486B2/en
Priority to US16/864,020 priority patent/US10874674B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the I crystal form, the II crystal form, the III crystal form and the IV crystal form of the orexin receptor antagonist compound 5-3, and a preparation method thereof, and relates to the preparation thereof for the treatment of a disease associated with orexin-related diseases. application.
  • Orexin includes two neuropeptides produced in the hypothalamus: orexin A (OX-A) (33 amino acid peptide) and orexin B (OX-B) (28 amino acid peptide) ( Sakurai T. et al., Cell, 1998, 92, 573-585). It has been found that orexin stimulates food consumption in rats, suggesting that these peptides have physiological roles as mediators in a central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573- 585). Orexin regulates the state of sleep and insomnia, potentially suggesting new ways to treat patients with narcolepsy or insomnia (Chemelli R. M.
  • Orexin also plays a role in arousal, motivation, learning, and memory (Harris, et al., Trends Neuroscl., 2006, 29(10), 571-577).
  • two orexin receptors have been cloned and characterized. They belong to the superfamily of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585):
  • the orexin-1 receptor (0X or 0X1R) is selective for OX-A, orexin
  • the -2 receptor (OX2 or OX2R) is capable of binding to OX-A and OX-B. It is believed that the physiological role involved in the hypothesis of orexin is expressed by one or both of the OXI receptor and OX 2 (as two subtypes of the orexin receptor).
  • Orexin receptors can be found in the brains of warm-blooded animals and have many implications in, for example, depression: anxiety; addiction; compulsive mandatory disorders; affective neurosis; depressive neurosis; anxiety Neurosis; depressive disorder; behavioral disorder; mood disorder; sexual dysfunction; sexual psychological dysfunction; gender disorder; schizophrenia; manic depression; mental disorder; dementia; severe mental retardation and dyskinesia, for example Huntington's disease and pruritus; eating disorders such as anorexia, bulimia, cachexia and obesity; addictive feeding behavior; feeding behavior of madness; cardiovascular disease; diabetes; appetite/taste Disorder; vomiting, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophilic adenoma; prolactinoma; hyperprolactinemia; pituitary tumor/adenomas; Thalamic disease; inflammatory bowel disease; gastric dysfunction; gastric ulcer; obesity genital degeneration; pituitary disease; pituitary disease; glandular hypofunction
  • the object of the present invention is to provide a process for the preparation of compound 5-3, which comprises the following steps:
  • the reaction pressure is normal pressure ⁇ 10Mpa;
  • reaction temperature is from 0 ° C to room temperature
  • the reaction solvent is selected from polar organic solvents.
  • the reaction pressure is from 1 MPa to 5 MPa.
  • the reaction temperature is optionally 5 to 10 °C.
  • the polar organic solvent is selected from the group consisting of ethyl acetate, tetrahydrofuran, methanol, ethanol, isopropanol, and dioxane.
  • the resolving agent is selected from the group consisting of D-tartaric acid;
  • the reaction solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, ethanol, methanol, tetrahydrofuran, dichloromethane, and water;
  • the recrystallization solvent is selected from water and ethanol.
  • the base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.
  • a method for preparing a compound 5-3 comprising the steps of:
  • the condensing agent is selected from the group consisting of T 3 P, CDI, EDCI, HOBt, and HATU.
  • the X crystal form of Compound 5-3 has an XRPD pattern as follows.
  • the present invention also provides a method for preparing Form I, which comprises adding Compound 5-3 to a polar organic solvent, heating to 40 ° C to reflux temperature, and then slowly adding weakly polar or non-polar The organic solvent is dropped, and the crystal is precipitated by cooling to 0 to 20 ° C in 1 to 10 hours.
  • the polar organic solvent is selected from the group consisting of a C 1-6 alkyl alcohol, a C 2-6 ester, an acetonitrile and/or a dichloromethane, a single solvent or a mixed solvent of several solvents. .
  • the C 1-6 alkyl alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and/or n-butanol.
  • the C 2-6 ester is selected from the group consisting of ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, and/or n-butyl acetate.
  • the weakly polar or non-polar organic solvent is selected from a C 5-10 alkane or a cycloalkane, a C 4-10 ether or a cyclic ether, a petroleum ether, and/or optionally 1 to 3 a benzene substituted with a methyl group or an ethyl group or a halogen atom.
  • the C 5-10 alkane or cycloalkane is selected from the group consisting of pentane, n-hexane, cyclohexane, n-heptane, and/or isooctane.
  • the C 4-10 ether or cyclic ether is selected from the group consisting of diethyl ether, methyl tert-butyl ether, n-propyl ether, n-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dimethyltetrahydrofuran, and / or dioxane.
  • the benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms is selected from the group consisting of toluene, xylene or chlorobenzene.
  • the ratio of the amount of the compound 5-3 to the polar machine solvent is from 1:1 to 10.
  • the ratio (weight/volume) of the compound 5-3 to the polar organic solvent is specifically 1:2 to 5.
  • the ratio (weight/volume) of the compound 5-3 to the weakly or non-polar organic solvent is from 1:1 to 15.
  • the ratio (weight/volume) of the compound 5-3 to the weakly or non-polar organic solvent is specifically 1:2 to 7
  • the present invention also provides Form II of Compound 5-3, the structure of which is shown in Figure 2.
  • the X crystal form of the II crystal form is resolved as follows.
  • the present invention also provides a method for preparing a crystal form of Form II, which is a crystalline form of Form I or Form III or Form IV of Compound 5-3 or a mixed crystal form or any other ratio formed by any of these three crystal forms. Any form is added to an organic solvent or a mixed solvent of an organic solvent and water, and stirred at 20 to 40 ° C for 5 to 120 hours.
  • the organic solvent is selected from a C 1-6 alkyl alcohols, C 5-10 alkane or cycloalkane, C 4-10 ether, or cyclic ethers, C 3-7 ketone, C 2- 6 ester, acetonitrile and/or benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms.
  • the C 1-6 alkyl alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and/or n-butanol.
  • C 5-10 alkane or cycloalkane is selected from pentane, n-hexane, n-heptane and / or cyclohexane.
  • the C 4-10 ether or cyclic ether is selected from the group consisting of methyl tert-butyl ether, tetrahydrofuran, dimethyltetrahydrofuran and/or 1,4-dioxane.
  • the ketone of C 3-7 is selected from the group consisting of acetone, methyl isobutyl ketone, and/or methyl ethyl ketone.
  • the C 2-6 ester is selected from the group consisting of ethyl acetate and/or isopropyl acetate;
  • the benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms is selected from the group consisting of toluene, xylene or chlorobenzene.
  • the mixed solvent of the organic solvent and water is selected from the group consisting of methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water, tetrahydrofuran/water or 1,4-dioxane. /water.
  • the volume ratio of the organic solvent to water is from 0.1 to 20:1.
  • the organic solvent is specifically selected from the group consisting of isopropanol, acetonitrile, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyltetrahydrofuran, toluene, and/or methanol;
  • the volume ratio of the organic solvent to water is specifically from 0.5 to 5:1.
  • the present invention also provides a crystalline form III of compound 5-3, the structure of which is shown in FIG.
  • the X crystal pattern of the III crystal form is resolved as follows.
  • the present invention also provides a method for preparing a crystal form of III, which is added to a polar organic solvent in any form other than the crystal form of compound 5-3 or in addition to the crystal form of II, and is heated to 40 ° C at room temperature.
  • the solution is dissolved at a reflux temperature, and then a weakly polar or non-polar organic solvent is slowly added dropwise, and the crystal is precipitated at room temperature or down to 20-30 ° C for 1 to 120 hours.
  • the organic solvent is selected from a C 1-6 alkyl alcohols, C 5-10 alkane or cycloalkane, C 4-10 ether, or cyclic ethers, C 3-7 ketone, C 2- 6 ester, acetonitrile and/or benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms.
  • the C 1-6 alkyl alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and/or n-butanol.
  • C 5-10 alkane or cycloalkane is selected from pentane, n-hexane, n-heptane and / or cyclohexane.
  • the C 4-10 ether or cyclic ether is selected from the group consisting of methyl tert-butyl ether, tetrahydrofuran, dimethyltetrahydrofuran and/or 1,4-dioxane.
  • the ketone of C 3-7 is selected from the group consisting of acetone, methyl isobutyl ketone, and/or methyl ethyl ketone.
  • the C 2-6 ester is selected from the group consisting of ethyl acetate and/or isopropyl acetate;
  • the benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms is selected from the group consisting of toluene, xylene or chlorobenzene.
  • the mixed solvent of the organic solvent and water is selected from the group consisting of methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water, tetrahydrofuran/water or 1,4-dioxane. /water.
  • the volume ratio of the organic solvent to water is from 0.1 to 20:1.
  • the organic solvent is specifically selected from the group consisting of isopropanol, acetonitrile, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyltetrahydrofuran, toluene, and/or methanol;
  • the volume ratio of the organic solvent to water is specifically from 0.5 to 5:1.
  • the present invention also provides an IV crystal form of the compound 5-3, the structure of which is shown in FIG.
  • the X crystal pattern of the IV crystal form is resolved as follows.
  • the present invention also provides a method for preparing Form IV, which is added to a polar organic solvent in any form other than Form I of Compound 5-3 or in addition to Form II, and is heated to 40 ° C at room temperature. The solution is dissolved at a reflux temperature, and then a weakly polar or non-polar organic solvent is slowly added dropwise, and the crystal is precipitated at room temperature or down to 20-30 ° C for 1 to 120 hours.
  • the organic solvent is selected from a C 1-6 alkyl alcohols, C 5-10 alkane or cycloalkane, C 4-10 ether, or cyclic ethers, C 3-7 ketone, C 2- 6 ester, acetonitrile and/or benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms.
  • the C 1-6 alkyl alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and/or n-butanol.
  • C 5-10 alkane or cycloalkane is selected from pentane, n-hexane, n-heptane and / or cyclohexane.
  • the C 4-10 ether or cyclic ether is selected from the group consisting of methyl tert-butyl ether, tetrahydrofuran, dimethyltetrahydrofuran and/or 1,4-dioxane.
  • the ketone of C 3-7 is selected from the group consisting of acetone, methyl isobutyl ketone, and/or methyl ethyl ketone.
  • the C 2-6 ester is selected from the group consisting of ethyl acetate and/or isopropyl acetate;
  • the benzene optionally substituted by 1 to 3 methyl or ethyl or halogen atoms is selected from the group consisting of toluene, xylene or chlorobenzene.
  • the mixed solvent of the organic solvent and water is selected from the group consisting of methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water, tetrahydrofuran/water or 1,4-dioxane. /water.
  • the volume ratio of the organic solvent to water is from 0.1 to 20:1.
  • the organic solvent is specifically selected from the group consisting of isopropanol, acetonitrile, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyltetrahydrofuran, toluene, and/or methanol;
  • the volume ratio of the organic solvent to water is specifically from 0.5 to 5:1.
  • Another object of the present invention is to provide a crystalline form or a crystalline form of the compound 5-3 or a crystalline form of the crystalline form or form IV as an orexin receptor antagonist for the preparation or treatment of a neurological or psychiatric condition or an orexin-related disease.
  • the application of the drug is to provide a crystalline form or a crystalline form of the compound 5-3 or a crystalline form of the crystalline form or form IV as an orexin receptor antagonist for the preparation or treatment of a neurological or psychiatric condition or an orexin-related disease.
  • the crystalline form I or the crystalline form of the above compound 5-3 or the crystalline form of the crystalline form or the crystalline form of the IV is used as an orexin receptor antagonist in the preparation of a medicament for treating or preventing a neurological or psychiatric disorder or an orexin-related disease.
  • the neurological and psychiatric condition or orexin-related diseases include insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, lethargy, anxiety, coercion, panic, nicotine dependence or eating disorders.
  • C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ;
  • C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C1-C4)alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or Multivalent (e.g., methine) may include divalent or multivalent radicals having a specified number of carbon atoms (e.g., C1-C10 represents from 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotonyl group, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, as well as higher homologs and isomers.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available and can be used without further purification.
  • the X-ray powder diffraction method is as follows:
  • Instrument Bruker D8 ADVANCE X-ray diffractometer; target: Cu: K-Alpha; wavelength Tube pressure: 40 kV; tube flow Current: 40 mA; scanning range: 4 to 40 °; sample rotation speed: 15 rpm; scanning speed: 10 ° / min.
  • SGF for simulated gastric fluid
  • Fassif for simulated intestinal fluid in the fasting state
  • LDA lithium diisopropylamide
  • MsCl for methylsulfonyl chloride
  • BOC for tert-butylcarbonyl
  • An amine protecting group THF stands for tetrahydrofuran; rt stands for room temperature
  • DCM stands for dichloromethane
  • TEA stands for triethylamine
  • DMF stands for N,N-dimethylformamide
  • DBU stands for 1,8-diazabicyclo ring Undec-7-ene
  • LAH stands for lithium tetrahydroaluminum
  • HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • CDI stands for carbonyldiimidazole
  • DMSO stands for dimethyl sulfoxide
  • Figure 1 is an XRPD spectrum of Form I Cu-K ⁇ radiation of Compound 5-3.
  • Figure 3 is an XRPD spectrum of III crystal form Cu-K ⁇ radiation of compound 5-3.
  • Figure 4 is an XRPD spectrum of Form IV Cu-K ⁇ radiation of Compound 5-3.
  • the reaction solution is cooled to about 60 ° C.
  • the viscous reaction solution is released while hot, and poured into 66 liters of ice water, 32.5 liters of ethyl acetate and 4.65 liters of hydrochloric acid.
  • the mixture was quenched during the mixing, and the stirring was continued during the period and the corresponding ice was added to control the temperature below 10 °C. After quenching, the mixture was allowed to stand for separation and liquid separation.
  • the aqueous phase was extracted with 10 liters of ethyl acetate.
  • the combined organic phases were washed with 11 liters of brine.
  • the temperature was controlled to be lower than 10 ° C, and hydrochloric acid (11.1 L, 2 M) was slowly dropped into the reaction vessel to adjust the pH to 6-7.
  • the quenched reaction mixture was directly concentrated under reduced pressure (-0.09 Mpa, ⁇ 55 ° C) to remove most of the ethanol.
  • the concentrated mixture was extracted twice with ethyl acetate (11 L x 2), and the organic phase was combined with brine. 5.5 L) Wash, dry anhydrous sodium sulfate (2.2 Kg), and filter.
  • the product solution was filtered and concentrated to dryness (-0.09M, ⁇ ⁇ RTIgt;
  • the reaction liquid was cooled to 25 ° C, and water (22 L) and ethyl acetate (33 L) were added thereto, and stirred for 10 minutes.
  • the mixture was separated and the aqueous was extracted with ethyl acetate (22L).
  • the organic phase was combined and washed with aq. EtOAc (EtOAc) (EtOAc (EtOAc).
  • EtOAc EtOAc
  • the temperature was controlled to 0 to 5 ° C, and a 15% aqueous sodium hydroxide solution (9 L) and water (4.5 L) were gradually added to the reaction mixture, and the mixture was heated to 15 ° C and stirred for 20 minutes.
  • the aqueous liquid phase of the system was extracted with toluene (10 L), and the organic phase was combined and washed with water (10 L), and then dried over anhydrous sodium sulfate (1Kg). 3.525 Kg, yield: 98.7%). This compound was used in the next reaction without purification.
  • the reaction solution was cooled to room temperature, and saturated brine (8.5 L) was added to the reaction mixture, and stirring was continued for 5 minutes.
  • the liquid phase was separated, and the organic phase was adjusted to pH 6-7 with 2.0 N hydrochloric acid.
  • the layers were separated, and the aqueous phases were combined, and the mixture was adjusted to pH 6-7 with EtOAc.
  • the organic phases were combined, dried over anhydrous sodium sulfate (1 Kg) and filtered.
  • reaction solution was cooled to 26 ° C (four-pot reaction combined treatment), and a 10 N sodium hydroxide solution (3.75 L) was slowly added to adjust the pH to 5-6.
  • the reaction solution was concentrated to about 35 L, and ethyl acetate (20 L), water (8 L) and 7% sodium hydrogen carbonate (10 L) were added to the mixture.
  • the mixture was stirred and the aqueous phase was combined with EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the product solution was concentrated to dryness (-0.09 MPa, ⁇ 55 ° C) to afford 2.5 Kg of product (yield: 95%) which was used in the next step without purification.
  • reaction solution was cooled to room temperature (25-34 ° C), then filtered over Celite and eluted with ethyl acetate (5L). Ethyl acetate (4L) and water (30L) were added to the filtrate, stirred, and left to stand. The organic phase was washed with sodium bicarbonate solution (5 L, 8%), saturated brine (5 L), and then anhydrous. Sodium sulfate (3 Kg) was dried. Filtration and concentration of the product solution ( ⁇ 55 ° C) afforded 8K g (yield: 80%).
  • reaction solution was cooled to room temperature (30 ° C), water (10 L) was added and stirred for 10 min.
  • the organic phases were combined, activated carbon powder (2.3 Kg) was added and stirred for 2 hours (two-pot reaction was combined here). Filtration through celite, the filtrate was concentrated ( ⁇ 50 ° C). The solid was dissolved in ethyl acetate (3 - 5 L), filtered and evaporated.
  • the mixture was cooled, partitioned, and the aqueous phase was washed with ethyl acetate (10L). Control the temperature of the aqueous phase to below 20 °C, slowly add 12N hydrochloric acid (3.3 L), adjust the pH to 1, and keep the temperature below 30 °C. During this process, the solid was precipitated, stirred for about 10 minutes, filtered, and the filter cake was rinsed with water (5 L*2). The filtered solid was dried in vacuo to give the product compound 14 (2600 g, purity: 99%, yield: 95.6%).
  • the ethyl acetate solution containing the product was used in the next step without further work.
  • Wet and water (15 L) were added to the kettle and heated to 80-90 ° C to dissolve, then continue to slowly cool to 15-25 ° C, and continue to stir for 16-20 hours.
  • the wet product (2.6 kg) was filtered and filtered, and the sample was tested to e.e.
  • the inhibitory effect of the compound on the OX1 and OX2 GPCR receptors was evaluated by measuring the intracellular calcium signal changes by FLIPR and using the IC50 values of the compounds as indicators.
  • Cell line HEK293-OX1 and OX2 stable cell lines
  • HEK293-OX1 cell culture medium (DMEM, Invitrogen #11960-044, 10% serum Gibco #10099141, L-Glutamine 1 ⁇ , Gibco #25030, sodium pyruvate 1 ⁇ , Gibco #11360, Geneticin 300 ⁇ g/mL, Gibco #10131 )
  • HEK293-OX2 cell culture medium (DMEM, Invitrogen #11960-044, 10% serum Gibco #10099141, L-Glutamine 1 ⁇ , Gibco #25030, sodium pyruvate 1 ⁇ , Gibco #11360, Geneticin 300 ⁇ g/mL, Gibco #10131 ,Blasticin 2 ⁇ g/mL, Invitrogen#R21001)
  • Each T150 was suspended with 10-15 mL of medium, centrifuged at 800 rpm for 5 minutes, resuspended in 10 mL of medium, and 1 mL of the cell suspension was aspirated and counted with Vi-cell;
  • OrexinA was manually diluted on ice, 3 fold dilution, 8 gradients, double duplicate wells.
  • a DMSO plate was prepared to give a DMSO concentration of 0.5%.
  • Cell plates, Orexin A plates, and DMSO plates were placed in FLIPR and the fluorescence values were read.
  • the compounds of the present invention have significant inhibitory effects on OX1 and OX2 GPCR receptors.
  • Solvent Exterior Solubility (mg/mL) Final pH Solubility Residual solid crystal form 0.1N HCl turbid 0.42 0.80 Slightly soluble II crystal form water turbid 0.14 7.95 Slightly soluble II crystal form Simulated gastric juice turbid 0.27 1.88 Slightly soluble II crystal form Simulated fasting intestinal fluid turbid 0.18 6.65 Slightly soluble II crystal form Simulated postprandial intestinal fluid turbid 0.29 5.04 Slightly soluble II crystal form

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Abstract

公开了食欲素受体拮抗剂化合物5-3的制备方法，该化合物的I-IV晶型及其制备方法，以及所述晶型在制备治疗与食欲素有关疾病的药物中的应用。

Description

[根据细则37.2由ISA制定的发明名称]　食欲素受体拮抗剂化合物的晶型及其制备方法和应用 技术领域
本发明涉及作为食欲素受体拮抗剂化合物5-3的I晶型、II晶型、III晶型和IV晶型及其制备方法，并涉及其在制备治疗与食欲素有关疾病的药物中的应用。
背景技术
食欲素(食欲肽)包括下丘脑中所产生的两种神经肽：食欲素A(OX-A)(33个氨基酸的肽)和食欲素B(OX-B)(28个氨基酸的肽)(SakuraiT.等人，Cell，1998，92，573-585)。人们发现，食欲素能够在大鼠中刺激食物消耗，这说明，在调节摄食行为的中心反馈机制中，这些肽具有作为介质的生理学作用(Sakurai T.等人，Cell，1998，92，573-585)。食欲素能够调节睡眠和失眠的状态，潜在地提出了治疗发作性睡眠或失眠症患者的新方法(Chemelli R.M.等人，Cell，1999，98，437-451)。食欲素还在觉醒、激励、学习和记忆中起一定作用(Harris，等人，Trends Neuroscl.，2006，29(10)，571-577)。在哺乳动物中，已经克隆和表征了两种食欲素受体。它们属于G蛋白偶联受体的超科(Sakurai T.等人，Cell，1998，92，573-585)：食欲素-1受体(0X或0X1R)对OX-A具有选择性，食欲素-2受体(OX2或OX2R)能够与OX-A以及OX-B结合。人们认为，假定食欲素所参与的生理作用是通过OXI受体和OX 2(作为食欲素受体的两个亚型)的其中一个或两个来表达的。
在温血动物脑中可以发现食欲素受体，并且在例如下列病变中具有许多牵连：忧郁症；焦虑症；成瘾；强迫性的强制病症；情感性神经症；抑郁性神经症；焦虑性神经症；精神抑郁病症；行为失常；心情病症；性功能紊乱；性心理的功能紊乱；性别病症；精神分裂症；躁狂性忧郁症；精神错乱；痴呆；严重的智力迟钝和运动障碍，例如亨丁顿舞蹈症和妥瑞症；进食障碍，例如厌食，贪食症，恶病体质和肥胖症；上瘾性摄食行为；狂吃狂泻的摄食行为；心血管性疾病；糖尿病；食欲/味觉失调；呕吐，呕，恶心；哮喘；癌症；帕金森氏症；库兴氏综合症/疾病；嗜碱细胞腺瘤；泌乳素瘤；高催乳素血症；脑下垂体肿瘤/腺瘤；下丘脑疾病；炎症性肠病；胃机能障碍；胃溃疡；肥胖性生殖器退化；腺垂体疾病；脑下垂体疾病；腺垂体机能减退；腺垂体机能亢进；下丘脑的性腺机能减退；卡尔曼氏综合症(嗅觉缺失，嗅觉减退)；功能性或心因性闭经；垂体机能减退；下丘脑的甲状腺机能减退；下丘脑-肾上腺功能紊乱；突发性的高催乳素血症；下丘脑病的生长激素缺乏；突发性的生长缺乏；侏儒症；巨人症；肢端肥大症；受到干扰的生物和昼夜节律；与疾病例如神经错乱、神经性疼痛和多动腿综合征相关的睡眠障碍；心脏和肺疾病，急性和充血性心力衰竭；低血压；高血压症；尿储留；骨质疏松症；心绞痛；急性心肌梗死；缺血性或出血性中风；蛛网膜出血；溃疡；变态反应；良性前列腺肥大；慢性肾衰竭；肾病；葡糖耐量削弱；偏头痛；痛觉过敏；疼痛；对疼痛敏感性增强或夸张，例如痛觉过敏、灼痛和触摸痛；急性疼痛；灼伤性疼痛；非典型性的面 部疼痛；神经性疼痛；背痛；复合区域疼痛综合症I和II；关节炎疼痛；运动创伤疼痛；与感染例如HIV相关的疼痛，化疗后疼痛；中风后的疼痛；手术后的疼痛；神经痛；呕吐，恶心，呕；与内脏疼痛相关的病症，例如过敏性肠综合症和心绞痛；偏头痛；膀胱失禁，例如急迫性尿失禁；对麻醉剂或戒除麻醉剂的耐受性；睡眠障碍；睡眠呼吸暂停；嗜眠病；失眠；深眠状态；时差综合症；和神经变性的病症，包括疾病分类实体，例如抑制解除-痴呆-震颤性麻痹-肌萎缩综合征；癫痫；癫痫发作病症及其它与普通食欲素系统功能紊乱相关的疾病。
氢化还原烯烃制备中间体酯基化合物在之前文献中均有报到，WO2009153178，WO2012036997，WO2012058127曾报道了使用钯碳和氢氧化钯氢化还原，不过这几篇文献均未考察氢化条件对于顺式、反式产物的影响。
发明内容
本发明的目的在于提供化合物5-3的制备方法，其包含如下步骤：
Figure PCTCN2016094558-appb-000001
其中，
a∶b＞1∶1；
反应压力为常压～10Mpa；
任选地，反应温度为0℃～室温；
反应溶剂选自极性有机溶剂。
本发明的一个方案中，a∶b＞3∶1。
本发明的一个方案中，反应压力为1Mpa～5Mpa。
本发明的一个方案中，任选地，反应温度为5～10℃。
本发明的一个方案中，上述极性有机溶剂选自乙酸乙酯、四氢呋喃、甲醇、乙醇、异丙醇、二氧六环。本发明的目的在于提供化合物5-3的制备方法，其包含如下步骤：
Figure PCTCN2016094558-appb-000002
其中，
拆分剂选自D-酒石酸；
反应溶剂选自乙酸乙酯、乙酸异丙酯、乙醇、甲醇、四氢呋喃、二氯甲烷、水；
重结晶溶剂选自水、乙醇
碱选自碳酸钠、碳酸钾、氢氧化钠、氢氧化钾。
本发明的一个方案中，化合物5-3的制备方法，其包括如下步骤：
Figure PCTCN2016094558-appb-000003
其中，缩合剂选自T3P、CDI、EDCI、HOBt、HATU。
本发明的目的在于提供化合物5-3的I晶型，其结构如图1所示。
Figure PCTCN2016094558-appb-000004
本发明的一个方案中，化合物5-3的I晶型，其XRPD图谱解析如下。
衍射角2θ 相对强度(％) 衍射角2θ 相对强度(％)
8.611 100.0 23.953 2.6
10.330 70.6 24.370 32.3
12.284 13.4 26.501 29.4
13.703 23.9 26.915 8.7
14.057 5.6 27.663 11.0
14.351 4.8 27.939 15.5
14.848 9.2 29.499 2.6
15.576 7.5 30.604 2.2
16.602 31.6 31.727 13.3
17.250 71.3 32.969 2.6
17.902 90.7 33.378 2.8
18.277 42.4 33.777 3.0
19.149 6.5 34.825 1.6
20.625 21.7 36.399 5.3
21.550 42.7 37.366 4.3
22.124 2.3 39.357 3.3
23.307 33.4    
本发明还提供了一种制备I晶型的方法，其为，将化合物5-3加入到极性有机溶剂中，加热至40℃～回流温度溶解，然后缓慢滴加弱极性或非极性有机溶剂，滴毕，1～10小时内降温至0～20℃析出晶体。
本发明的一个方案中，上述极性有机溶剂选自C1-6的烷基醇、C2-6的酯、乙腈和/或二氯甲烷其中的一种单一溶剂或几种溶剂的混合溶剂。
本发明的一个方案中，上述C1-6的烷基醇选自甲醇、乙醇、异丙醇、和/或正丁醇。
本发明的一个方案中，上述C2-6的酯选自甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸异丁酯、和/或乙酸正丁酯。
本发明的一个方案中，上述弱极性或非极性有机溶剂选自C5-10烷烃或环烷烃、C4-10醚或环醚、石油醚、和/或任选被1～3个甲基或乙基或卤原子取代的苯。
本发明的一些方案中，上述C5-10的烷烃或环烷烃选自戊烷、正己烷、环己烷、正庚烷和/或异辛烷。
本发明的一个方案中，上述C4-10醚或环醚选自乙醚、甲基叔丁基醚、正丙醚、正丁醚、乙二醇二甲醚、四氢呋喃、二甲基四氢呋喃、和/或二氧六环。
本发明的一个方案中，上述任选被1～3个甲基或乙基或卤原子取代的苯选自甲苯、二甲苯或氯苯。
本发明的一个方案中，化合物5-3与有极性机溶剂的用量(重量/体积)比为1∶1～10。
本发明的一个方案中，化合物5-3与极性有机溶剂的用量(重量/体积)比具体为1∶2～5。
本发明的一个方案中，化合物5-3与弱极性或非极性有机溶剂的用量(重量/体积)比为1∶1～15。
本发明的一个方案中，化合物5-3与弱极性或非极性有机溶剂的用量(重量/体积)比具体为1∶2～7
本发明还提供了化合物5-3的II晶型，其结构如图2所示。
本发明的一个方案中，所述的II晶型，其XRPD图谱解析如下。
衍射角2θ 相对强度(％) 衍射角2θ 相对强度(％)
10.428 60.0 25.533 8.2
11.968 100.0 26.083 11.0
13.542 17.8 27.133 3.1
14.238 3.4 27.506 17.7
14.767 12.1 28.316 3.0
15.851 73.9 29.557 2.2
16.818 72.0 30.740 4.2
18.003 9.2 31.846 5.1
19.087 2.1 32.550 2.0
19.755 47.6 33.775 3.1
20.900 25.7 34.682 2.2
22.652 2.9 36.422 3.4
23.858 49.2 36.953 3.4
24.844 23.2 38.569 3.0
本发明还提供了一种制备II晶型的方法，其为，将化合物5-3的I晶型或III晶型或IV晶型或由这三种晶型形成任何比例的混合晶型或其他任意形式加入到有机溶剂或有机溶剂与水的混合溶剂中，20～40℃下搅拌5～120小时。
本发明的一个方案中，上述有机溶剂选自C1-6的烷基醇、C5-10的烷烃或环烷烃、C4-10醚或环醚、C3-7的酮、C2-6的酯、乙腈和/或任选被1～3个甲基或乙基或卤原子取代的苯。
本发明的一个方案中，上述C1-6的烷基醇选自甲醇、乙醇、异丙醇、和/或正丁醇。
本发明的一个方案中，C5-10的烷烃或环烷烃选自戊烷、正己烷、正庚烷和/或环己烷。
本发明的一个方案中，上述C4-10醚或环醚选自甲基叔丁基醚、四氢呋喃、二甲基四氢呋喃和/或1，4-二氧六环。
本发明的一个方案中，上述C3-7的酮选自丙酮、甲基异丁酮、和/或甲基乙基酮。
本发明的一个方案中，上述C2-6的酯选自乙酸乙酯、和/或乙酸异丙酯；
本发明的一个方案中，任选被1～3个甲基或乙基或卤原子取代的苯选自甲苯、二甲苯或氯苯。
本发明的一个方案中，有机溶剂与水的混合溶剂选自甲醇/水、乙醇/水、异丙醇/水、乙腈/水、丙酮/水、四氢呋喃/水或1，4-二氧六环/水。
本发明的一个方案中，有机溶剂与水的体积比为0.1～20∶1。
本发明的一些方案中，有机溶剂具体选自异丙醇、乙腈、甲基异丁酮、乙酸乙酯、乙酸异丙酯、二甲基四氢呋喃、甲苯、和/或甲醇；
本发明的一个方案中，有机溶剂与水的体积比具体为0.5～5∶1。
本发明还提供了化合物5-3的III晶型，其结构如图3所示。
本发明的一个方案中，所述的III晶型，其XRPD图谱解析如下。
衍射角2θ 相对强度(％) 衍射角2θ 相对强度(％)
8.539 57.2 23.092 2.6
10.296 65.1 23.322 0.9
12.283 8.3 24.319 28.5
14.023 6.0 26.426 7.1
14.319 4.0 30.568 1.0
15.879 1.6 31.686 4.6
17.230 100.0 33.739 0.9
17.804 11.5 34.768 0.9
18.005 22.4 36.366 5.1
19.269 1.3 37.326 0.5
20.591 18.6 39.285 1.3
21.514 18.5    
本发明还提供了一种制备III晶型的方法，其为，将化合物5-3的I晶型或除了II晶型以外其他任意形式加入到极性有机溶剂中，室温或加热至40℃～回流温度溶解，然后缓慢滴加弱极性或非极性有机溶剂，滴毕，1～120小时内室温或降温至20-30℃析出晶体。
本发明的一个方案中，上述有机溶剂选自C1-6的烷基醇、C5-10的烷烃或环烷烃、C4-10醚或环醚、C3-7的酮、C2-6的酯、乙腈和/或任选被1～3个甲基或乙基或卤原子取代的苯。
本发明的一个方案中，上述C1-6的烷基醇选自甲醇、乙醇、异丙醇、和/或正丁醇。
本发明的一个方案中，C5-10的烷烃或环烷烃选自戊烷、正己烷、正庚烷和/或环己烷。
本发明的一个方案中，上述C4-10醚或环醚选自甲基叔丁基醚、四氢呋喃、二甲基四氢呋喃和/或1，4-二氧六环。
本发明的一个方案中，上述C3-7的酮选自丙酮、甲基异丁酮、和/或甲基乙基酮。
本发明的一个方案中，上述C2-6的酯选自乙酸乙酯、和/或乙酸异丙酯；
本发明的一个方案中，任选被1～3个甲基或乙基或卤原子取代的苯选自甲苯、二甲苯或氯苯。
本发明的一个方案中，有机溶剂与水的混合溶剂选自甲醇/水、乙醇/水、异丙醇/水、乙腈/水、丙酮/水、四氢呋喃/水或1，4-二氧六环/水。
本发明的一个方案中，有机溶剂与水的体积比为0.1～20∶1。
本发明的一些方案中，有机溶剂具体选自异丙醇、乙腈、甲基异丁酮、乙酸乙酯、乙酸异丙酯、二甲基四氢呋喃、甲苯、和/或甲醇；
本发明的一个方案中，有机溶剂与水的体积比具体为0.5～5∶1。
本发明还提供了化合物5-3的IV晶型，其结构如图3所示。
本发明的一个方案中，所述的IV晶型，其XRPD图谱解析如下。
衍射角2θ 相对强度(％) 衍射角2θ 相对强度(％)
8.653 100.0 23.385 22.1
10.408 94.7 23.997 44.0
12.106 45.5 24.430 30.5
12.362 15.5 24.965 15.2
13.723 14.5 26.225 9.3
14.152 6.1 26.562 23.9
14.414 7.3 26.977 6.8
14.925 10.6 27.647 16.3
15.988 18.9 27.983 10.9
16.682 20.1 29.659 3.1
16.937 33.6 30.842 3.0
17.311 79.1 31.788 12.4
17.982 61.7 33.031 2.7
18.338 29.2 33.426 2.2
19.245 5.9 33.858 2.8
19.856 29.2 34.884 2.3
20.721 24.1 36.499 4.8
21.020 8.2 37.427 2.9
21.611 34.8    
本发明还提供了一种制备IV晶型的方法，其为，将化合物5-3的I晶型或除了II晶型以外其他任意形式加入到极性有机溶剂中，室温或加热至40℃～回流温度溶解，然后缓慢滴加弱极性或非极性有机溶剂，滴毕，1～120小时内室温或降温至20-30℃析出晶体。
本发明的一个方案中，上述有机溶剂选自C1-6的烷基醇、C5-10的烷烃或环烷烃、C4-10醚或环醚、C3-7的酮、C2-6的酯、乙腈和/或任选被1～3个甲基或乙基或卤原子取代的苯。
本发明的一个方案中，上述C1-6的烷基醇选自甲醇、乙醇、异丙醇、和/或正丁醇。
本发明的一个方案中，C5-10的烷烃或环烷烃选自戊烷、正己烷、正庚烷和/或环己烷。
本发明的一个方案中，上述C4-10醚或环醚选自甲基叔丁基醚、四氢呋喃、二甲基四氢呋喃和/或1，4-二氧六环。
本发明的一个方案中，上述C3-7的酮选自丙酮、甲基异丁酮、和/或甲基乙基酮。
本发明的一个方案中，上述C2-6的酯选自乙酸乙酯、和/或乙酸异丙酯；
本发明的一个方案中，任选被1～3个甲基或乙基或卤原子取代的苯选自甲苯、二甲苯或氯苯。
本发明的一个方案中，有机溶剂与水的混合溶剂选自甲醇/水、乙醇/水、异丙醇/水、乙腈/水、丙酮/水、四氢呋喃/水或1，4-二氧六环/水。
本发明的一个方案中，有机溶剂与水的体积比为0.1～20∶1。
本发明的一些方案中，有机溶剂具体选自异丙醇、乙腈、甲基异丁酮、乙酸乙酯、乙酸异丙酯、二甲基四氢呋喃、甲苯、和/或甲醇；
本发明的一个方案中，有机溶剂与水的体积比具体为0.5～5∶1。
本发明的另一个目的在于提供化合物5-3的I晶型或II晶型或III晶型或IV晶型作为食欲素受体拮抗剂在制备治疗或预防神经和精神病症或与食欲素有关疾病的药物中的应用。
本发明的一个方案中，上述化合物5-3的I晶型或II晶型或III晶型或IV晶型作为食欲素受体拮抗剂在制备治疗或预防神经和精神病症或与食欲素有关疾病的药物中的应用，其中所述神经和精神病症或与食欲素有关疾病包括失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以是单取代、二取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C10表示1至10个碳)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烷基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、 2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烃基的任何内部位置(包括该烃基附着于分子其余部分的位置)。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1，2，5，6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得，无需进一步纯化即可使用。
化合物经手工或者
Figure PCTCN2016094558-appb-000005
软件命名，市售化合物采用供应商目录名称。
X-射线粉末衍射方法如下：
仪器：Bruker D8 ADVANCE X射线衍射仪；靶：Cu：K-Alpha；波长
Figure PCTCN2016094558-appb-000006
管压Voltage：40kV；管流Current：40mA；扫描范围：4～40°；样品旋转速度：15rpm；扫描速度：10°/分钟。
除非另有规定，本发明采用下述缩略词：SGF代表模拟胃液；Fassif代表空腹状态下模拟肠液；LDA代表二异丙基氨基锂；MsCl代表甲基磺酰氯；BOC代表叔丁基羰基是一种胺保护基团；THF代表四氢呋喃；r.t.代表室温；DCM代表二氯甲烷；TEA代表三乙胺；DMF代表N，N-二甲基甲酰胺；DBU代表1，8-二氮杂二环十一碳-7-烯；LAH代表四氢铝锂；HATU代表2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸 酯；CDI代表羰基二咪唑；DMSO代表二甲基亚砜；MeOH代表甲醇；EtOH代表乙醇；EtOAc代表乙酸乙酯；THF代表四氢呋喃；IPA代表异丙醇；ACN代表乙腈；MEK代表丁酮；MIBK代表甲基异丁酮；MTBE代表甲基叔丁基醚；DPBS代表杜氏磷酸缓冲溶液；T3P代表丙基磷酸酐；EDCI代表1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐；HOBt代表1-羟基苯并三唑。
附图说明
图1为化合物5-3的I晶型Cu-Kα辐射的XRPD谱图。
图2为化合物5-3的II晶型Cu-Kα辐射的XRPD谱图。
图3为化合物5-3的III晶型Cu-Kα辐射的XRPD谱图。
图4为化合物5-3的IV晶型Cu-Kα辐射的XRPD谱图。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1：化合物1的制备
流程1：
Figure PCTCN2016094558-appb-000007
步骤1：化合物3的制备
将22升无水甲苯加入到50升的反应釜中，在氮气保护下将钠氢(2.2Kg，55.5mol)慢慢分批加入甲苯溶液中，同时将化合物2(3.93Kg，33.3mol)滴入反应釜中。另取烧瓶将化合物1(5.0Kg，22.2mol)溶于甲苯(9L)中。将反应釜升温至85-95℃，将配制好的化合物1甲苯溶液慢慢加入反应釜中，耗时2小时左右，注意滴速控制温度在95℃左右。滴加完毕在该温度下继续搅拌0.5-1小时，取少许样品加水淬灭，上层有机相采用TLC检测显示反应完全。
反应液降温至60℃左右将粘稠反应液趁热放出，倒入66升冰水、32.5升乙酸乙酯和4.65升盐酸的混 合液中进行淬灭，期间不停搅拌并相应补加冰控制温度低于10℃。淬灭完全后静置分层、分液，水相再用10升乙酸乙酯萃取，合并有机相用11升饱和食盐水洗涤。洗涤后的有机相用2.8Kg无水硫酸钠干燥，在经过过滤，产物溶液减压(-0.09Mpa)在55℃下浓缩得到7.25Kg粗产物，产品无需纯化直接用于下一步。
步骤2：化合物4的制备
在50升反应釜中，将7.25Kg粗品化合物3溶于32升的乙醇中，降温至0-5℃，将硼氢化钠(843.6g，22.2mol)分批加入反应釜中，并注意控加入速度，使得温度低于10℃，耗时0.5-1.5小时。加料完毕后在0-10℃下继续搅拌2-3小时。取样监控，TLC(乙酸乙酯/石油醚＝1/3，茚三酮高温显色)检测显示反应完全。
控制温度低于10℃，将盐酸(11.1L，2M)慢慢滴入到反应釜中，调节pH至6-7。淬灭后的反应混合物直接减压浓缩(-0.09Mpa，＜55℃)去除大部分乙醇，浓缩后的混合物溶液用乙酸乙酯萃取两遍(11L x 2)，合并有机相用饱和食盐水(5.5L)洗涤，无水硫酸钠(2.2Kg)干燥，过滤。产物溶液减压浓缩干(-0.09Mpa，＜55℃)得到油状粗品，无需纯化直接用于下一步。
步骤3：化合物5的制备
在反应釜(50L)中将化合物4(6.82Kg，22.2mol，粗品)溶于二氯甲烷(30L)中，并加入三乙胺(5.80Kg，57.3mol)。将温度降至10℃以下，将甲烷磺酰氯(3.82Kg，33.3mol)慢慢滴入反应釜中，保持温度低于15℃，耗时1-2小时。将反应液升温至25℃搅拌16小时，取样，TLC(乙酸乙酯/石油醚＝1/3，茚三酮高温显色)检测显示化合物4消失，反应完全。
反应液用水(11L)洗涤两遍，再用稀盐酸(约7L，2M，)洗涤，控制水相pH＝6～8，再用饱和食盐水(11Kg)洗涤，最后用无水硫酸钠(1.57Kg)干燥。过滤得产品溶液，浓缩干(-0.09Mpa，＜55℃)得到粗品，无需纯化直接用于下一步。
步骤4：化合物6的制备
在50升反应釜中将化合物5(9.4Kg，粗品，22.2mol)溶于DMF(22L)，控制温度低于40℃，向反应釜中加入DBU(6.76Kg，44.4mol)。加料完毕，将温度升至100℃搅拌16-20小时，取样，TLC检测显示化合物5消失，反应完全。
将反应液冷却至25℃，向其中加入水(22L)和乙酸乙酯(33L)，搅拌10分钟。静置分液，水相用乙酸乙酯(22L)萃取。合并有机相并用0.5N盐酸水溶液(15L)洗涤(控制水相pH＝6～7)，有机相再用水(22L)洗涤，无水硫酸钠(2.2Kg)干燥。过滤后产物溶液拌硅胶浓缩干(-0.09Mpa，＜55℃)，得到粗品。粗品经过柱(洗脱剂：乙酸乙酯/正庚烷＝1/20)纯化得到到纯品化合物6(2.80Kg，四步总收率：44.9％)。1HNMR(CDCl3，400MHz)δ6.69(s，1H)，4.75(s，1H)，4.30(s，1H)，4.16(d，J＝6.4Hz，2H)，2.81(bs，1H)，2.12(m，1H)， 2.02(m，1H)，1.92(m，1H)，1.62(m，1H)，1.41(s，9H)，1.24(t，J＝7.2Hz，3H)。
流程2：
Figure PCTCN2016094558-appb-000008
步骤5：化合物7-a、7-b的制备
将乙醇(1L)加入到10L的高压釜中，在氩气保护下将湿Pd/C(170g)慢慢一次性加入釜中。将化合物6(563g，2.0mol)溶于乙醇(4.63L)加入釜中，加料完毕，将反应体系密封，抽真空，用氢气置换两次后通入氢气。控制反应体系氢气初始压力4.0Mpa，10～15℃下搅拌过夜。取样，TLC或HPLC监控反应。
反应混合物经硅藻土过滤，滤饼用乙醇(1L*2，0.79Kg*2)洗涤，滤液合并，减压浓缩干得到产物化合物7-a、7-b(552g，7-a/7-b＝3∶1，收率：97.5％)。该产品无需纯化直接用于下一步。
步骤6：化合物8-a、8-b的制备
在反应釜(50L)中将化合物7-a、7-b(4.2Kg，7-a/7-b＝3∶1，14.8mol)溶无水甲苯(20L)中，控制反应温度在0-5℃之间。搅拌下将红铝(5.1Kg，17.8mol)慢慢滴加到反应釜中，并保持温度在0-5℃之间，耗时约1小时。加料完毕后，0-5℃下继续搅拌1小时。取样，TLC(乙酸乙酯/石油醚＝1/3，高温显色)和GC监控反应显示反应结束。
控制温度0-5℃，向反应液中慢慢加入15％的氢氧化钠水溶液(9L)，水(4.5L)，升温至15℃搅拌20分钟。体系分液水相用甲苯(10L)萃取，合并有机相并用水(10L)洗涤，最后用无水硫酸钠(1Kg)干燥，过滤得到产物溶液减压浓缩得到化合物8-a、8-b(3.525Kg，收率：98.7％)。该化合物无需纯化直接用于下一步反应。1HNMR(CDCl3，400MHz)δ4.35(m，1H)，4.13(m，1H)，3.47(m，1H)，2.05(m，1H)，1.82(m， 1H)，1.73(m，2H)，1.67(m，3H)，1.45(s，9H)，1.28(m，2H)。
步骤7：化合物10-a、10-b的制备
在50L反应釜中将化合物8-a、8-b(3.425Kg)溶于四氢呋喃(17L)，向反应釜中加入氢氧化钠(1.136Kg)和化合物9(1.960Kg)。控制温度在75℃下搅拌24小时，取样，GC和TLC(乙酸乙酯/石油醚＝1/3，磷钼酸高温显色)检测，原料反应完全。
将反应液降至室温，向反应液中加入饱和食盐水(8.5L)，继续搅拌5分钟。分液，有机相用2.0N盐酸调节pH值至6-7。分液，合并水相，用2.0N盐酸调节pH值至6-7，水相用乙酸乙酯萃取(10L)。合并有机相，用无水硫酸钠(1Kg)干燥，过滤。产物溶液减压浓缩干(-0.09Mpa，＜55℃)，得到粗品。粗品经硅胶柱层析(正庚烷∶乙酸乙酯＝20∶1到5∶1)，得到淡黄色油状产品(4.5Kg，收率：92.9％)。1HNMR(CDCl3，400MHz)δ7.95(s，1H)，7.32(m，1H)，6.69(m，1H)，4.38(m，2.5H)，4.13(m，1.5H)，2.03(m，3H)，1.86(m，3H)，1.45(m，3H)，1.26(s，9H)。
流程3：
Figure PCTCN2016094558-appb-000009
步骤8：化合物16的制备
在反应釜中将化合物15(2.5Kg，9.54mol)溶于无水甲醇(10L)中，室温下将浓硫酸(360mL，7.16mol)慢慢滴入反应釜中。将反应釜升温至65-80℃，反应18小时。HPLC检测仍有5～7％原料剩余，补加浓硫酸(36mL，67.3g)并继续反应18小时。HPLC检测原料反应完全。
反应液冷却至26℃(四锅反应合并处理)，慢慢加入10N的氢氧化钠溶液(3.75L)，调节pH至5-6。反应液浓缩至35L左右，反应液中加入乙酸乙酯(20L)、水(8L)、7％碳酸氢钠(10L)。搅拌分液，水相用乙酸乙酯(20L)再萃取一遍，合并有机相，有机相用饱和食盐水(15L)洗涤、无水硫酸钠干燥。产物溶液浓缩干(-0.09MPa，＜55℃)得到2.5Kg产品(收率：95％)，无需纯化直接用于下一步。1HNMR(DMSO-d6，400MHz)δ7.76(d，J＝8.4Hz，1H)，7.45(s，1H)，6.98(d，J＝8.0，2.5H)，3.77(s，3H)，2.19(s，3H)。
步骤9：化合物18的制备
先将化合物16(5Kg，18.1mol)，化合物17(4.83Kg，19.0mol)，醋酸钾(4.44Kg，45.3mol)加入到反应 釜中，然后将无水DMF(20L)加入反应釜中室温下搅拌溶解。氮气保护下加入醋酸钯(122g，54.33mmol)，将反应釜升温至80～90℃，搅拌反应16小时。取样中控，TLC(乙酸乙酯/石油醚＝1/10，UV 254nm)&HPLC检测显示原料16反应完全。
反应液冷却至室温(25-34℃)，然后使用硅藻土过滤，并用乙酸乙酯(5L)淋洗(两锅反应后处理在此步合并)。滤液中继续加入乙酸乙酯(4L)和水(30L)，搅拌、静置分液，有机相分别用碳酸氢钠溶液(5L，8％)，饱和食盐水(5L)洗涤，最后采用无水硫酸钠(3Kg)干燥。过滤，产物溶液浓缩干(＜55℃)得到8Kg粗品(收率：80％)，无需纯化直接用于下一步。
步骤10：化合物20的制备
先将化合物18(4Kg，crude，14.485mol)，化合物19(1.74Kg，15.2mol)，和碳酸钠(3.5Kg，33mol)加入到50L反应釜中。然后将2-甲基四氢呋喃(25L，)和水(8L)加入到反应釜中，室温下搅拌溶解。氮气保护下加入Pd(dppf)Cl2·DCM(325g，0.398mol)，将反应釜升温至70～80℃，并搅拌反应16小时，取样中控：TLC(乙酸乙酯/石油醚＝1/2)显示原料反应完全。
反应液冷却至室温(30℃)，加入水(10L)并搅拌10分钟；分液，水相通过硅藻土过滤，并用乙酸乙酯(10L)萃取。合并有机相，加入活性炭粉(2.3Kg)，搅拌2小时(两锅反应在此合并)。通过硅藻土过滤，滤液浓缩(＜50℃)至固体析出，过滤，得到灰黑色固体。固体再用乙酸乙酯(3～5L)溶解，并用硅胶柱过滤，乙酸乙酯洗涤，浓缩得到化合物20(3.0Kg，收率：45.5％)。
除钯工艺：
将化合物20(3.0Kg)加入反应釜中，加入二氯甲烷(12L)，室温下(25-27℃)搅拌溶清。将氯化钠(210g)，硫氰尿酸(27g)，氨水(225mL)，水(2500mL)和乙醇(～2400mL)配制成TMT溶液(～5L)。将TMT溶液(～5L)加入到反应釜中，反应混合物在室温(20-25℃)下搅拌24小时。反应液通过硅藻土过滤，分掉水相，有机相浓缩干(-0.09Mpa，＜50℃)，得到化合物20(2.92Kg，收率：97.3％)。1HNMR(DMSO-d6，400MHz)δ8.87(d，J＝4.8Hz，2H)，7.96(d，J＝8.0Hz，1H)，7.46(m，3H)，3.62(s，3H)，2.41(s，3H)。
步骤11：化合物14的制备
在50L反应釜中，将化合物20(2900g，12.7mol)溶于2-甲基四氢呋喃(15L)中。制备氢氧化钠水溶液(氢氧化钠：1270g，31.8mol；水：20L，20Kg)，并将氢氧化钠溶液加入到反映釜中，反应液升温至70～75℃并搅拌16小时，中控TLC(乙酸乙酯/石油醚＝1/2，UV：254nm)检测反应完毕。
静置冷却，分液，水相用乙酸乙酯(10L)洗涤。控制水相温度至20℃以下，慢慢加入12N盐酸(3.3L)，调节pH至1，保持温度低于30℃。在这过程中析出固体，搅拌10分钟左右，过滤，滤饼用水(5L*2)淋洗。过滤固体真空干燥，得到产品化合物14(2600g，纯度：99％，收率：95.6％)。1HNMR(DMSO-d6，400MHz)δ12.67(br，s，1H)，8.85(d，J＝4.0Hz，2H)，7.81(d，J＝7.6Hz，1H)，7.48(s，1H)，7.43(m，2H)，2.40(s，3H)。
流程4：
Figure PCTCN2016094558-appb-000010
步骤12：化合物12-a、12-b的制备
在反应釜(30L)中将化合物10-a、10-b溶于乙酸乙酯(13.5L)。控制温度在10-20℃，将35％的浓盐酸(4.5L)滴加到反应釜中，控制温度低于15℃(注意控制滴速)。滴加完后控制温度在20-25℃反应16-20小时，取样中控，HPLC检测显示反应完全结束。
加入水(5L)并分层，收集水层，有机层再用水(5L)萃取一遍。合并水层，水层用乙酸乙酯(5L)洗涤一遍；分出水层，水层冷却到10℃以下。水层用氢氧化钠(3.0Kg)将pH调节到14(注意加碱速度，控制內温低于20℃)，水层用乙酸乙酯(10L+5L)萃取2遍。收集有机层(15.5Kg)，取样检测，纯度＝82.8％，含量＝16.4％，计算得出产品重量：2.54Kg。含产物的乙酸乙酯溶液无需其它处理，直接用于下一步。
步骤13：化合物13的制备
将化合物12-a、12-b的溶液(15.5Kg，含2.54Kg化合物10)加入到反应釜中，并升温到55-65℃。将D-酒石酸(1.62Kg)和水(3.5L)配成的溶液慢慢滴入到反应釜中，滴加完毕后在55-65℃继续反应2-3小时。缓慢降温到5-15℃，并搅拌过夜，过滤得湿品(5.78Kg)。将湿品和水(15L)加入到反应釜中加热到80-90℃溶清，然后继续缓慢降温到15-25℃，并持续搅拌16-20小时。过滤过滤得湿品(2.6kg)，取样检测e.e.＝90.8％。将湿品和水(6L)继续加入到反应釜中加热到80-90℃溶清，缓慢降温到15-25℃，时间16-20 小时。过滤得湿品(2.2kg)，取样检测ee＝99.6％。
将湿品(2.2Kg)和H2O(2L)加入反应釜中搅拌溶解，将配制的K2CO3水溶液(K2CO3：3.55Kg，水：10L)慢慢加入到反应釜中，并控制温度在15-25℃下搅拌0.5-1小时。用乙酸乙酯萃取反应液(10L*2)，合并有机相，用2.0Kg无水Na2SO4干燥，过滤。滤液旋干(-0.09MPa，＜50℃)得到无色油状物化合物13(1006g)，冷却之后变成白色固体。送样检测ee＝99.8％，HPLC纯度：99.7％。该产品无需进一步处理直接用于下一步反应。
步骤14：化合物5-3的制备
在反应釜中将化合物13(630g，2.67mol)溶于乙酸乙酯(7.9L)，将化合物14(685g，3.20mol)加入反应釜中，搅拌20分钟。控制温度15-25℃，慢慢加入T3P(1903mL，3.20mol)，20～30分钟加完后升温到40-60℃下搅拌2-3小时。取样中控HPLC显示原料/产物比小于2.5％。
降温至15-25℃并加H2O(7.9L)，搅拌0.5-1小时，分出有机相，水相用乙酸乙酯(7.9L)萃取。合并有机相，并用水(7.9L)洗涤一次。减压(-0.09MPa，＜50℃)旋干溶剂得到粗品化合物15(1.3kg)。将粗品加入3.0L乙酸乙酯室温打浆过滤得到目标化合物(1.1Kg，收率：95.4％)。HPLC纯度：99.9％，e.e值：100％。XRPD测试显示为I晶型。1H NMR(400MHz，DMSO-d6)＝8.83(br.s.，2H)，8.17-8.01(m，2H)，7.49-7.33(m，3H)，6.86(dd，J＝3.5，9.0Hz，1H)，6.86(dd，J＝3.5，9.0Hz，1H)，4.63(br.s.，1H)，4.43(m，1H)，4.11(br.s，1H)，3.79(m，1H)，2.52-2.48(m，2H)，2.35-1.95(m，8H)，1.29-1.20(m，2H)。
步骤15：II晶型的制备
将I晶型(1.1Kg)、乙酸乙酯(2750mL)和异丙醇(110mL)加入到5L反应瓶中，反应体系加热到65-80℃搅拌2-3小时，慢慢降低温度到50-60℃，耗时1-2小时，这一悬浊液在40-50℃下继续搅拌20-24小时，取少量样品XRPD检测完全转晶成功。缓慢将体系降温到10-20℃，保持在这一温度下搅拌20-24小时，XRPD检测显示转晶没有变。过滤得到固体，在40-50℃下真空干燥20-24小时，得到产品(660g，收率：60％)。HPLC纯度：99.13％，ee值：100％。XRPD测试显示为II晶型。
实施例2：III晶型的制备
将化合物5-3的I晶型0.30g加入到4.5毫升甲苯中，充分溶解并过滤，滤液在搅拌的条件下，逐渐滴加4毫升正庚烷至有沉淀析出，20～30℃持续搅拌16～22小时后，过滤得到固体，40℃下真空干燥，得III晶型0.22g(收率：73.3％)。
实施例3：IV晶型的制备
将化合物5-3的I晶型0.30g加入到4.5毫升乙醇中，充分溶解并过滤，滤液在搅拌的条件下，逐渐滴加9毫升纯水至有沉淀析出，20～30℃持续搅拌16～22小时后，过滤得到固体，40℃下真空干燥，得IV晶型0.23g(收率：76.7％)。
实验例1：OX1/2R体外测试
实验目的：
通过FLIPR检测细胞内钙信号变化，以化合物的IC50值为指标，来评价化合物对OX1和OX2 GPCR受体的抑制作用。
实验材料：
细胞系：HEK293-OX1和OX2稳转细胞株
HEK293-OX1细胞培养基(DMEM，Invitrogen#11960-044，10％血清Gibco#10099141，L-Glutamine 1×，Gibco#25030，丙酮酸钠1×，Gibco#11360，Geneticin 300μg/mL，Gibco#10131)
HEK293-OX2细胞培养基(DMEM，Invitrogen#11960-044，10％血清Gibco#10099141，L-Glutamine 1×，Gibco#25030，丙酮酸钠1×，Gibco#11360，Geneticin 300μg/mL，Gibco#10131，Blasticin 2μg/mL，Invitrogen#R21001)
胰酶(Invitrogen，#25200-072)
DPBS(Hyclone，#SH30028.01B)
Fluo-4AM，Invitrogen#F14202
F-127，Invitrogen#P3000MP
Probenecid，Sigma#P8761
384细胞板，Greiner#781946
384化合物板，Greiner#781280
CO2培养箱，Thermo#371
离心机，Eppendorf#5810R
Vi-cell细胞计数仪，Beckman Coulter
POD 810Plate Assembler全自动微孔板预处理系统
Labcyte FLIPR，Molecular Device。
实验步骤和方法：
a)细胞接种(HEK293-OX1和HEK293-OX2细胞)
1)37℃水浴预热培养基、胰酶、DPBS。吸掉细胞培养的培养基，用10mLD PBS清洗；
2)加入预热过的胰酶到培养瓶中，旋转培养瓶使胰酶均匀覆盖培养瓶，放到37℃、5％CO2培养箱中消化1-2分钟；
3)每个T150用10-15mL培养基垂悬细胞，800rpm离心5分钟，用10mL培养基重悬细胞，吸取1mL细胞重悬液，用Vi-cell计数；
4)用培养基稀释OX1细胞到5×105/mL，OX2细胞到4×105/mL，用排枪将稀释好的细胞加入到384板(Greiner.781946)(50μL/孔，OX1细胞25000cells/孔，OX2细胞20000cells/孔)。将细胞板放置于37℃、5％CO2培养箱过夜。
b)化合物加样：
1)用DMSO将化合物稀释成20mM，3倍稀释，8个梯度，双复孔，用Echo声波移液设备(Echo liquid handler)加到化合物板中。然后再加20μL缓冲液，保证DMSO终浓度为0.1％；
c)FLIPR实验：
1)用真空泵洗掉384板中的细胞培养基，加入30μL Fluo4AM荧光染料，37℃、5％CO2培养箱孵育1小时，室温再平衡10分钟。
2)EC50测试：在冰上手动稀释OrexinA，3倍稀释，8个梯度，双复孔。再准备DMSO板，使DMSO浓度为0.5％。分别把细胞板、OrexinA板，以及DMSO板放入FLIPR中，读取荧光值。
3)通过Orexin A的EC50值，计算出EC70值，准备5×EC70溶液，用排枪加到384化合物板中，放到冰上保存。
4)在FLIPR中，依次放入化合物板，5×EC70板，细胞板，FLIPR枪头，运行程序，读取荧光值。d)分析数据：用Prism5.0来分析数据，计算化合物的IC50值。
实验结果见表1：
表1 FLIPR检测IC50测试结果
供试样品 hOX1R hOX2R
化合物5-3 A A
注：A≤50nM。
结论：本发明化合物对OX1和OX2GPCR受体的抑制作用显著。
实验例2：溶解度测试
化合物5-3的I晶型溶解度研究：室温条件下，将1～1.5毫克化合物5-3的I晶型加入容量瓶中，少量多次加入单一有机溶剂或混合溶剂，直至目测溶液澄清或无固体颗粒存在，以此初略测定I晶型在不同溶剂中的溶解度，结果如表2所示。
表2 I晶型在不同溶剂中的溶解度
编号 溶剂 溶解度(mg/mL)
1 MeOH ＞53
2 EtOH 22-55
3 IPA 10-20
4 正丁醇 22-55
5 ACN 20-50
6 丙酮 ＞52
7 MEK ＞54
8 MIBK 24-60
9 EtOAc 19-48
10 MTBE ＜1
11 THF ＞53
12 甲苯 ＞54
13 1，4-二氧六环 ＞57
14 水 ＜1
15 MeOH-H2O(3∶1) 18-46
化合物5-3的II晶型溶解度研究：37℃下，将10mg II晶型加入到1.5mL容量瓶中，加入1mL溶剂，震动24小时，离心分离，上清液立即用HPLC分析，结果如表3所示。
表3 II晶型在不同含水溶媒中的溶解度
溶剂 外观 溶解度(mg/mL) 最终pH 溶解性 残留固体晶型
0.1N HCl 浑浊 0.42 0.80 微溶 II晶型
水 浑浊 0.14 7.95 微溶 II晶型
模拟胃液 浑浊 0.27 1.88 微溶 II晶型
模拟空腹肠液 浑浊 0.18 6.65 微溶 II晶型
模拟餐后肠液 浑浊 0.29 5.04 微溶 II晶型

Claims (10)

  1. 化合物5-3的制备方法，其包含如下步骤：
    Figure PCTCN2016094558-appb-100001
    其中，
    a∶b＞1∶1；
    优选地，a∶b＞3∶1；
    反应压力为常压～10Mpa；
    优选地，反应压力为1Mpa～5Mpa；
    任选地，反应温度为0℃～室温；
    任选地，反应温度为5～10℃；
    反应溶剂选自极性有机溶剂；
    优选地，所述极性有机溶剂选自乙酸乙酯、四氢呋喃、甲醇、乙醇、异丙醇、二氧六环。
  2. 化合物5-3的制备方法，其包含如下步骤：
    Figure PCTCN2016094558-appb-100002
    其中，
    拆分剂选自D-酒石酸；
    反应溶剂选自乙酸乙酯、乙酸异丙酯、乙醇、甲醇、四氢呋喃、二氯甲烷、水；
    重结晶溶剂选自水、乙醇；
    碱选自碳酸钠、碳酸钾、氢氧化钠、氢氧化钾。
  3. 根据权利要求2所述化合物5-3的制备方法，其包括如下步骤：
    Figure PCTCN2016094558-appb-100003
    其中，缩合剂选自T3P、CDI、EDCI、HOBt、HATU。
  4. 化合物5-3的I晶型，结构如图1所示。
  5. 化合物5-3的II晶型，其结构如图2所示。
  6. 化合物5-3的III晶型，其结构如图3所示。
  7. 化合物5-3的IV晶型，其结构如图4所示。
  8. 根据权利要求4所述的I晶型、II晶型、III晶型和IV晶型的制备方法，包括将化合物5-3加入到极性有机溶剂中，加热至40℃～回流温度溶解，然后缓慢滴加弱极性或非极性有机溶剂，滴毕，1～10小时内降温至0～20℃析出晶体；或
    将化合物5-3加入到单一有机溶剂、混合有机溶剂、单一有机溶剂与水的混合溶剂或混合有机溶剂与水的混合溶剂中，重结晶或打浆；
    优选地，
    有机溶剂选自C1-6的烷基醇、C5-10烷烃或环烷烃、C4-10醚或环醚、C3-7的酮、C2-6的酯、乙腈或任选被甲基或乙基或卤原子取代的苯，其中，取代基的数目选自1、2和/或3；
    极性有机溶剂选自C1-6的烷基醇、C2-6的酯、乙腈或二氯甲烷；
    弱极性或非极性有机溶剂选自C5-10的烷烃或环烷烃、C4-10醚或环醚、石油醚、或任选被甲基或乙基或卤原子取代的苯，其中，取代基的数目选自1、2或3；
    更优选地，
    有机溶剂选自甲醇、乙醇、异丙醇、正丁醇、戊烷、正己烷、正庚烷、环己烷、甲基叔丁基醚、四氢呋喃、二甲基四氢呋喃、1，4-二氧六环、丙酮、甲基异丁酮、甲基乙基酮、乙腈、乙酸乙酯、乙酸异丙酯、甲苯、二甲苯和/或氯苯；
    极性有机溶剂选自甲醇、乙醇、异丙醇、正丁醇、甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸异丁酯、乙酸正丁酯、乙腈和/或二氯甲烷中的一种单一溶剂或几种溶剂的混合溶剂；
    弱极性或非极性有机溶剂选自戊烷、正己烷、环己烷、正庚烷、异辛烷、乙醚、甲基叔丁基醚、正丙醚、正丁醚、乙二醇二甲醚、四氢呋喃、二甲基四氢呋喃、二氧六环、甲苯、二甲苯或氯苯；
    优选地，混合有机溶剂选自乙酸乙酯/异丙醇；
    优选地，有机溶剂与水的混合溶剂选自甲醇/水、乙醇/水、异丙醇/水、乙腈/水、丙酮/水、四氢呋喃/水或1，4-二氧六环/水；
    优选地，有机溶剂与水的体积比为0.1～20∶1；
    更优选地，有机溶剂与水的体积比为0.5～5∶1。
  9. 根据权利要求1～5任意一项所述化合物5-3的I晶型或II晶型或III晶型或IV晶型在制备治疗与食欲素有关疾病的药物中的应用。
  10. 根据权利要求5所述化合物5-3的I晶型、II晶型、III晶型或IV晶型的应用，其中所述与食欲素有关疾病包括失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍。
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