WO2021218833A1 - 一种m受体拮抗剂的晶体、制备方法及其应用 - Google Patents

一种m受体拮抗剂的晶体、制备方法及其应用 Download PDF

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WO2021218833A1
WO2021218833A1 PCT/CN2021/089464 CN2021089464W WO2021218833A1 WO 2021218833 A1 WO2021218833 A1 WO 2021218833A1 CN 2021089464 W CN2021089464 W CN 2021089464W WO 2021218833 A1 WO2021218833 A1 WO 2021218833A1
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degrees
crystal
cyclopentyl
hydroxy
solvent
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PCT/CN2021/089464
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English (en)
French (fr)
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陈小平
高泽军
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北京硕佰医药科技有限责任公司
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Priority to KR1020227039948A priority Critical patent/KR20230004640A/ko
Priority to JP2022565863A priority patent/JP2023523453A/ja
Priority to CN202180027015.5A priority patent/CN115397823A/zh
Priority to AU2021264829A priority patent/AU2021264829B2/en
Priority to US17/921,610 priority patent/US20230167107A1/en
Priority to CA3181333A priority patent/CA3181333A1/en
Priority to EP21795961.8A priority patent/EP4144733A4/en
Publication of WO2021218833A1 publication Critical patent/WO2021218833A1/zh
Priority to ZA2022/12305A priority patent/ZA202212305B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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 invention belongs to the technical field of medicine, and specifically relates to bromination (2R, 3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3 -Phenoxypropyl)-1-azabicyclo[2,2,2]octium salt (hereinafter referred to as compound I) novel crystals and preparation method thereof; the present invention also relates to the application of the novel crystals of compound I in the field of medicine .
  • bronchodilators are the drugs of choice for the treatment of asthma and COPD.
  • M receptor antagonists such as ipratropium bromide and tiotropium bromide.
  • WO2015007073 discloses a long-acting compound with selective antagonism to M receptor subtypes, which is comparable to the prior art in the treatment of asthma, COPD, allergic rhinitis, post-cold rhinitis, gastric and duodenal ulcers It has a selective effect on M receptor subtypes, so it has low toxic and side effects, and has the characteristics of fast onset and long-acting.
  • Brominated (2R,3R)-3-[(2-cyclopentyl-2-hydroxyl -2-Phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octium salt (compound I) is one of the preferred compounds, its structural formula as follows:
  • Compound I can be used to treat rhinitis, post-cold rhinitis, chronic bronchitis, high airway, asthma, COPD, cough, urinary incontinence, frequent urination, unstable bladder syndrome, bladder spasm, cystitis, and stomach Intestinal diseases such as irritable bowel syndrome, spastic colitis, and duodenal and gastric ulcers.
  • it has the characteristics of long drug effect, quick onset, and low toxic and side effects.
  • Compound I can also be used in combination with ⁇ 2 receptor agonists, steroid hormones, anti-allergic drugs, anti-inflammatory drugs, anti-infectives, phospholipase 4 inhibitors, etc. to treat the above-mentioned respiratory diseases such as allergic rhinitis, post-cold rhinitis, Asthma and COPD, etc.
  • WO2015007073 uses cyclopentyl benzophenone and dimethyl sulfate to react in the presence of sodium hydride (NaH) to prepare 1-phenyl-1-cyclopentyl ring Oxyethane (intermediate); in the presence of NaH, the intermediate reacts with (R)-3-quinitol to form the diastereoisomer (2S,3R)-3-[(2-cyclopentyl-2 -Hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base and (2R,3R)-3-[(2-cyclopentyl-2-hydroxy- 2-Phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base; (2R,3R)-3-[(2-cyclopentyl-2- Hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,
  • One of the objectives of the present invention is to provide a new preparation method of compound I.
  • Another object of the present invention is to provide a novel crystal of Compound I, a method for preparing the novel crystal, and a pharmaceutical composition containing the crystal as an effective ingredient, specifically the following (1) to (4).
  • a type A crystal of compound I (hereinafter referred to as type A crystal of the present invention or crystal A), in its powder X-ray diffraction pattern, at least the following diffraction angles 2 ⁇ : 5.7 ⁇ 0.2 degrees, 12.9 ⁇ 0.2 degrees, 16.7 ⁇ 0.2 degrees, 18.0 ⁇ 0.2 degrees, 19.5 ⁇ 0.2 degrees, 21.1 ⁇ 0.2 degrees, 22.3 ⁇ 0.2 degrees and 23.3 ⁇ 0.2 degrees show diffraction peaks.
  • the powder X-ray diffraction pattern is a pattern obtained by Cu K ⁇ rays .
  • a type B crystal of compound I (hereinafter referred to as the type B crystal of the present invention or crystal B), which is a hydrate of compound I and 1.5 molecules of H 2 O, in its powder X-ray diffraction pattern, At least the following diffraction angles 2 ⁇ : 5.2 ⁇ 0.2 degrees, 15.8 ⁇ 0.2 degrees, 16.9 ⁇ 0.2 degrees, 17.7 ⁇ 0.2 degrees, 19.5 ⁇ 0.2 degrees, 20.2 ⁇ 0.2 degrees, and 22.1 ⁇ 0.2 degrees, showing diffraction peaks, the powder
  • the X-ray diffraction pattern is a pattern obtained by Cu K ⁇ rays.
  • a pharmaceutical composition containing the crystal described in any one of (2) to (3) as an active ingredient (hereinafter referred to as the pharmaceutical composition of the present invention).
  • the obtained value should be understood to be within the range of ⁇ 0.2 degrees of the value, preferably within the range of ⁇ 0.1 degrees of the value.
  • Step 1 Using cyclopentyl mandelic acid or cyclopentyl mandelic acid ester as starting materials, reduction with sodium borohydride to obtain racemic 2-hydroxy-2-cyclopentyl-2-phenylethanol (Z02); reaction solvent It is selected from ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, etc., preferably ethylene glycol dimethyl ether, tetrahydrofuran, etc.; the molar ratio of sodium borohydride to the starting material is 2-5:1, preferably 2 ⁇ 3.5:1; Lewis acid should be added to catalyze the reduction of cyclopentylmandelic acid (ester), the Lewis acid is selected from aluminum trichloride, boron trifluoride, zinc chloride, tin tetrachloride and titanium tetrachloride Etc., the molar ratio of Lewis acid to cyclopentylmandelic acid is 2-5:1, preferably 2.5
  • Step 2 After the esterification reaction between Z02 and chiral acid chloride, the chiral carboxylic acid 2-hydroxy-2-cyclopentyl-2-phenylethanol ester (Z03) is crystallized.
  • Chiral acid chlorides include but are not limited to L-camphorsulfonyl chloride, D-camphorsulfonyl chloride, mandelic acid derivative acid chloride, etc.
  • the molar ratio of Z02 to chiral acid chloride is 1:1 to 3, preferably 1:1.5 to 2;
  • the solvent is selected from dichloromethane, chloroform, tetrahydrofuran, dioxane, etc., preferably dichloromethane, tetrahydrofuran;
  • the base is selected from organic bases such as triethylamine, pyridine, N-methylmorpholine, alkali and chiral acid chloride
  • the molar ratio of is 1 ⁇ 4:1, preferably 1 ⁇ 2:1.
  • Step 3 Treat Z03 with alkali to obtain R-1-phenyl-1-cyclopentyl oxirane (Z04).
  • the base includes, but is not limited to, NaH, potassium tert-butoxide, butyl lithium, sodium amide, etc., preferably NaH, potassium tert-butoxide.
  • the molar ratio of base to Z03 is 1 to 3:1, preferably 1 to 1.5:1; the reaction solvent is selected from dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc., preferably dimethyl sulfoxide, tetrahydrofuran .
  • Step 4 Z04 reacts with R-(-)3-quinitol to obtain (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-nitrogen Heterobicyclo[2,2,2]octane free base (Z05).
  • the base includes, but is not limited to, NaH, potassium tert-butoxide, butyl lithium, sodium amide, etc., preferably NaH, potassium tert-butoxide.
  • the molar ratio of R-(-)3-quinitol to base is 1 to 3:1, preferably 1 to 1.5:1;
  • the reaction solvent is selected from dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc. , Preferably dimethyl sulfoxide and tetrahydrofuran.
  • Step 5 After the quaternization reaction between Z05 and 3-phenoxy-1-bromopropane (Z06), bromide (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2- Phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octium salt (Compound I).
  • each compound used as a raw material can be commercially available or can be prepared according to a published method.
  • Step 1 Dissolution process
  • This process is a process of heating to dissolve the compound I in a solvent.
  • good solvents include, for example, alcohol solvents, acetonitrile, dichloromethane, and chloroform.
  • alcohol solvents that can be used in this process are C1-C5 small-molecule alcohols, preferably, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or 3-methyl- 1-butanol, preferably ethanol.
  • the amount used is preferably in the range of 1 time (mL/g) to 10 times (mL/g), and more preferably 1 time (mL/g) relative to compound I. g) to 5 times (mL/g), more preferably 2 times (mL/g) to 3 times (mL/g).
  • the dissolution temperature varies according to the type of solvent and its amount. Usually, it is stirred below the boiling point of the solvent or refluxed at the boiling point of the solvent, and is preferably in the range of 20°C to 100°C, more preferably in the range of 60°C to 90°C. .
  • the solution of compound I can be adsorbed and filtered on activated carbon as needed to remove insoluble matter.
  • the filtration is preferably carried out with a funnel with a heating device under pressure.
  • the filtered solution maintains a certain temperature, and is preferably in the range of 20°C to 100°C, more preferably in the range of 60°C to 90°C.
  • the saturated hydrocarbon anti-solvent of compound I such as linear or branched C6-C8 alkanes or C5-C8 cycloalkanes, specifically but not limited to cyclopentane, pentahexane, heptane, octane Alkanes, cyclohexane, cycloheptane, cyclooctane.
  • the ketone anti-solvent of compound I such as linear or branched C3-C8 ketones, specifically but not limited to acetone, 2-butanone, and methyl isobutyl ketone.
  • the ester anti-solvent of compound I is specifically but not limited to ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate and the like.
  • the ether anti-solvent of compound I is specifically but not limited to isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran.
  • the other anti-solvent of compound I is specifically but not limited to toluene and the like.
  • the anti-solvent that can be used in this process is preferably ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, acetone, butanone, etc., preferably ethyl acetate.
  • the anti-solvent is preferably in the range of 1 times (mL/mL) to 20 times (mL/mL) relative to the compound I solution, more preferably It is in the range of 5 times (mL/mL) to 15 times (mL/mL), and more preferably in the range of 8 times (mL/mL) to 10 times (mL/mL).
  • Step 3 Cooling and crystallization process
  • This process is a process of cooling the solution prepared in step 2 above to precipitate the A-type crystal of the present invention.
  • the process preferably uses a crystallization device with a heating function and a stirring function.
  • the cooling temperature (temperature at which precipitated crystals are collected) is preferably in the range of -10°C to 50°C, preferably in the range of -5°C to 20°C, and more preferably in the range of 0°C to 10°C. In this process, it is preferable to slowly cool it over a period of 0.5 h to 10 h until the cooling temperature is reached. It is also possible to distill off part of the solvent in the solution prepared in the above step 1 under heating and stirring, which can promote the precipitation of crystal A.
  • the seed crystal of the type A crystal of the present invention may be added in this process; in the case of adding the seed crystal of the type A crystal of the present invention, it is preferably added when the solution is cooled to a range of 40°C to 80°C.
  • the addition amount of the seed crystal of the type A crystal of the present invention is not particularly limited, and is preferably in the range of 1% (g/g) to 5% (g/g) relative to compound I.
  • Step 4 Crystal collection and drying process
  • This process is a process in which the precipitated crystals obtained in step 3 are collected and dried by methods such as filtration and centrifugal separation.
  • the drying process can be carried out by conventional methods such as drying under reduced pressure and drying with a desiccant, preferably under reduced pressure, and more preferably under the conditions of 20°C to 70°C and 10 mmHg or less for 1 h to 48 h to obtain type A crystals.
  • Method 1 Dissolving process by adding a certain amount of purified water in a good solvent
  • Step 1 Dissolution process
  • This process is a process of heating to dissolve the compound I in a solvent.
  • the good solvent that can be used in this process is specifically but not limited to C1-C5 small molecular alcohols or acetonitrile, preferably methanol, ethanol, n-propanol, isopropanol, preferably ethanol. These solvents are mixed with a certain amount of water as the solvent of compound I.
  • the ratio of water to the above-mentioned solvent is preferably 2% (ml/ml) to 10% (ml/ml), most preferably 4% (ml/ml) ⁇ 6% (ml/ml).
  • the amount used is preferably in the range of 1 time (mL/g) to 10 times (mL/g), and more preferably 2 times (mL/g) relative to compound I. g) ⁇ 5 times (mL/g) range.
  • the dissolution temperature differs depending on the type of solvent and its amount, and it is usually stirred or refluxed below the boiling point of the solvent, and is preferably in the range of 20°C to 100°C, more preferably in the range of 60°C to 90°C.
  • the solution of compound I can be adsorbed and filtered on activated carbon as needed to remove insoluble matter.
  • the filtration is preferably carried out with a funnel with a heating device under pressure.
  • the filtered solution maintains a certain temperature, and is preferably in the range of 20°C to 100°C, more preferably in the range of 60°C to 90°C.
  • Good anti-solvents that can be used in this process include esters, water, ethers, ketones, liquid cycloalkanes or aromatic hydrocarbons, preferably ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, 2-butanone, methyl Isobutyl ketone, water, isopropyl ether, methyl tert-butyl ether, and ethyl acetate is most preferred.
  • the good solvent in step 1 may not be added with water.
  • the good solvent can also be dichloromethane or chloroform and other solvents that are immiscible with water.
  • the anti-solvent is preferably in the range of 3 times (mL/mL) to 20 times (mL/mL) relative to the compound I solution, more preferably It is in the range of 5 times (mL/mL) to 15 times (mL/mL), and more preferably in the range of 8 times (mL/mL) to 10 times (mL/mL).
  • Step 3 Cooling and crystallization process
  • This process is a process of cooling the solution prepared in step 2 above to precipitate the type B crystal of the present invention.
  • the process preferably uses a crystallization device with a heating function and a stirring function.
  • the cooling temperature (temperature at which precipitated crystals are collected) is preferably in the range of -10°C to 50°C, preferably in the range of -5°C to 20°C, and more preferably in the range of 0°C to 10°C. In this process, it is preferable to cool slowly in a period of 0.5 h to 10 h until the cooling temperature is reached.
  • the seed crystal of the type B crystal of the present invention may be added in this process; in the case of adding the seed crystal of the type B crystal of the present invention, it is preferably added when the solution is cooled to a range of 40°C to 80°C.
  • the addition amount of the seed crystal of the type B crystal of the present invention is not particularly limited, and is preferably in the range of 1% (g/g) to 5% (g/g) relative to compound I.
  • Step 4 Crystal collection and drying process
  • This process is a process in which the precipitated crystals obtained in step 3 are collected and dried by methods such as filtration and centrifugal separation.
  • the drying process can be carried out by conventional methods such as reduced-pressure drying and drying with a desiccant, preferably under reduced pressure, more preferably at 20°C to 70°C and well-ventilated conditions for 1h to 48h to obtain type B crystals.
  • Method 2 The type B crystal of the present invention can also be obtained by the method of converting the type A crystal
  • Add type A crystals of the present invention to a reaction vessel add purified water, and the weight ratio of water to type A crystals is 3 to 30 times (g/g), preferably 5 to 20 times (g/g), It is preferably 8 to 12 times (g/g).
  • the temperature is preferably controlled between 10°C and 50°C, and most preferably between 20°C and 30°C.
  • the beating time is preferably 0.3h to 10h, preferably 0.5h to 5h, suction filtration, the solid is air-dried at 40°C to 80°C, and after reaching a constant weight, type B crystals are obtained.
  • the drying time is 2-24h.
  • any pharmaceutical composition containing compound I crystal A or crystal B is within the scope of the patent of the present invention.
  • the compound I of the present invention has an excellent M receptor antagonistic effect and has a selective effect on M receptor subtypes.
  • the M3 receptor has a strong effect and has a weak effect on the M2 receptor, so it shows gland secretion inhibition, tracheal dilatation, bronchiectasis, etc. Therefore, the crystal of the present invention and its pharmaceutical composition can be used for the treatment of allergic rhinitis and colds.
  • Various diseases such as posterior rhinitis, asthma, COPD, gastric and duodenal ulcers (refer to patent document WO2015007073).
  • another object of the present invention is to provide a pharmaceutical composition containing crystal A of compound I and crystal B (hydrate of compound I), including an acceptable pharmaceutical carrier.
  • the above-mentioned pharmaceutical composition of crystal A and crystal B may optionally contain other therapeutic ingredients, such as but not limited to steroidal anti-inflammatory drugs, phosphodiesterase 4 inhibitors (PDE-4), ⁇ 2 receptor agonists, and Amine receptor antagonists and so on.
  • the crystal of the present invention When administering the crystal of the present invention as a medicine, the crystal of the present invention is directly administered or, for example, 0.001 to 99.9% is contained in a pharmaceutically acceptable non-toxic inert carrier for administration.
  • the carrier of the above composition may be a solid, semi-solid or liquid diluent, filler, or other prescription auxiliary.
  • One or two or more of these carriers can be used.
  • the pharmaceutical composition of the present invention can take a solid, semi-solid or liquid dosage form: for example, a powder mist (DPI), an inhalation solution, a metered dose inhalation spray (or soft mist: SMI), a metered dose aerosol (MDI) treatment Asthma and COPD; use nose drops and nasal spray to treat post-cold rhinitis, seasonal allergic rhinitis and perennial allergic rhinitis; use capsules, tablets, granules, powders, suspensions, solutions, syrups Oral preparations such as elixirs and elixirs treat gastric and duodenal ulcers; injections are used for anti-muscle relaxation or tracheal hypersecretion during surgery. Among them, particularly important preparations are used to treat diseases such as asthma, COPD, post-cold rhinitis, allergic rhinitis, stomach and duodenal ulcers.
  • DPI powder mist
  • SMI soft mist
  • MDI metered dose aerosol
  • crushing equipment can be used to make the crystals of the present invention reach a suitable particle size requirement.
  • the powder can make the crystals of the present invention reach an appropriate degree of pulverization, and then mix with edible carbohydrates such as starch, mannitol and other medicinal carriers to be granulated.
  • edible carbohydrates such as starch, mannitol and other medicinal carriers.
  • Flavoring agents, preservatives, dispersing agents, coloring agents, fragrances, etc. can be added arbitrarily.
  • Tablets can be prepared as follows: Add excipients to the powdered crystals of the present invention to make a powder mixture, granulate or pulverize, or press into large tablets and then pulverize, and then add disintegrants or lubricants and then press piece.
  • the powder mixture can be prepared by mixing appropriate pulverized crystals of the present invention with a diluent or a base. If necessary, binders (such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retarders (such as paraffin), adsorption Agent (for example, bentonite, kaolin) and the like.
  • binders such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
  • dissolution retarders such as paraffin
  • adsorption Agent for example, bentonite, kaolin
  • the powder mixture can be prepared as follows: first, wet with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stir and mix, dry and pulverize it to form granules. By adding stearic acid, stearate, talc, mineral oil, etc. as lubricants to the particles prepared in this way, mutual adhesion can be prevented.
  • a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution.
  • tablets can be manufactured by mixing the crystals of the present invention and an inert carrier with good fluidity without going through the above-mentioned granulation or pulverization process, and then directly compressing the tablets.
  • the prepared tablets may be film-coated or sugar-coated.
  • Capsules can be prepared by filling crystals or pulverized crystal powder formed as described above into a capsule skin such as a gelatin capsule according to a powder or a material obtained by granulating as described in the item of tablets.
  • the micropowder of the crystals of the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and surfactant, and wrapped with a gelatinous material to make a soft capsule.
  • oral preparations such as liquid preparations, syrups, lozenges, elixirs, etc.
  • liquid preparations such as syrups, lozenges, elixirs, etc.
  • elixirs can also be prepared in a form that contains a certain amount of crystals of the present invention.
  • the syrup can be produced by dissolving the crystals of the present invention in an appropriate flavor aqueous solution.
  • the elixirs can be manufactured by using a non-toxic alcoholic carrier.
  • Suspensions can be produced by dispersing the crystals of the present invention in a non-toxic carrier. If necessary, solubilizers or emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin), etc. may be added.
  • solubilizers or emulsifiers for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives for example, peppermint oil, saccharin, etc.
  • the dosage unit for oral administration can be microencapsulated.
  • the pharmaceutical composition of the present invention may also be in the form of suppositories for rectal administration.
  • suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature to release the drug in the rectum.
  • suitable non-irritating excipient include cocoa butter, beeswax, polyethylene glycol, hard fat and/or hydrogenated coconut glycerides.
  • Non-oral preparations may be in the form of liquid preparations for subcutaneous, intramuscular or intravenous injection, such as solutions or suspensions.
  • the parenteral preparation can be prepared as follows: suspend or dissolve a certain amount of the crystals of the present invention in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and then sterilize the suspension or solution .
  • a non-toxic liquid carrier suitable for injection such as an aqueous or oily medium
  • stabilizers, preservatives, emulsifiers, etc. can also be added.
  • the injection solution is prepared at pH 4.5 to 7.5.
  • the crystals of compound I of the present invention can be administered locally rather than systemically, and the composition of the crystals of the present invention can be formulated as a drug for administration to mammals, preferably humans.
  • the composition composed of crystals of the compound of the present invention and suitable excipients can be administered repeatedly, or the composition can be administered continuously.
  • Suitable sites for administration include, but are not limited to, the nasal cavity, lungs, trachea, and bronchi.
  • composition of the pharmaceutical crystals of the present invention can be in the form of nasal drops, nasal sprays, inhalation solutions, DPI, solution type quantitative inhalation aerosols, suspension type quantitative inhalation aerosols, SMI and the like.
  • the composition of the present invention containing the crystals of the present invention is administered through a nebulizer inhaler.
  • the nebulization device usually generates a high-speed airflow, which nebulizes the pharmaceutical composition containing the active ingredient and is inhaled into the respiratory tract of the patient. Therefore, the active ingredient is usually dissolved in a suitable solvent to make a solution and placed in a nebulizer inhaler. Or the active ingredient is micronized and combined with a suitable carrier to form a suspension of micronized particles suitable for inhalation. Micronization is generally defined as making more than 90% of the solid particles less than 10 ⁇ m in diameter. Suitable atomization devices are commercially available.
  • the representative vehicle of the composition is physiological saline or ethanol solution.
  • composition of the present invention containing the crystals of the invention is administered by inhalation using a metered-dose inhaler.
  • the metered-dose inhalation device uses mechanical force to atomize the drug solution is called metered-dose inhalation spray (SMI).
  • SMI uses isotonic aqueous solution as the solvent; the use of propellant to quantitatively release the therapeutic drug is called MDI, using metered-dose inhaler
  • MDI metered-dose inhalation spray
  • the administered composition is contained in a solution or suspension, and the above two metered-dose inhalation devices are commercially available.
  • its latent solvents include but are not limited to one or more mixtures of absolute ethanol, glycerol, and glycols.
  • the glycols include, but are not limited to, ethylene glycol, propylene glycol, and poly(ethylene glycol). Ethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, etc.
  • the propellant includes but is not limited to one of tetrafluoroethane (HFA-134a), heptafluoropropane (HFA-227ea) or a mixture thereof.
  • the surfactants include but are not limited to oleic acid; oligomeric lactic acid (OLA); sorbitans, such as span20, span65, span80, and span85; polyoxyethylene sorbitols, such as Tween 20 and Tween 80; Oxyethylene fatty alcohols, such as Brij30, Brij35, Cremophor; polyoxyethylene polyoxypropylene copolymers, such as Pluronic F-68; polyethylene glycol stearates, such as Solutol HS15; phospholipids, such as soybean phospholipids, eggs One or more of phospholipids.
  • OVA oligomeric lactic acid
  • sorbitans such as span20, span65, span80, and span85
  • polyoxyethylene sorbitols such as Tween 20 and Tween 80
  • Oxyethylene fatty alcohols such as Brij30, Brij35, Cremophor
  • polyoxyethylene polyoxypropylene copolymers such as Pluronic F-
  • DPI can be prepared by mixing active ingredients and excipients, or without excipients, and then filling the drug or composition into a powder mist dispenser, or into an inhalation cartridge or capsule used with the DPI administration device, DPI drug delivery devices are commercially available.
  • DPI containing compound I crystals the inert carrier contains a diluent and a lubricant, and the diluent is dextran, arabinose, lactose, mannitol, mannitol, xylitol, sucrose, fructose, sorbitol, A mixture of one or more of maltose, amino acids and glucose, and the lubricant is magnesium stearate or sodium benzoate.
  • Nasal sprays and nasal drops are devices containing compound I crystals in nasal sprays and nasal drops, and these devices are commercially available.
  • a nose drop or a quantitative nasal spray containing compound I crystals, the inert carrier is selected from benzalkonium chloride, benzalkonium bromide, benzyl alcohol, benzoic acid, chlorobutanol, parabens, One or a combination of sorbic acid, phenol, thymol and volatile oil.
  • the present invention also provides the application of the pharmaceutical composition, which can be used to prepare and treat various acute and chronic airway obstructive diseases in mammals and humans, such as COPD, bronchial asthma, gastric ulcer, duodenal ulcer , Acute and chronic rhinitis and rhinitis after a cold.
  • various acute and chronic airway obstructive diseases in mammals and humans such as COPD, bronchial asthma, gastric ulcer, duodenal ulcer , Acute and chronic rhinitis and rhinitis after a cold.
  • Method 1 Add 124.0g (0.500mol) of ethyl cyclopentylmandelic acid and 1000mL of anhydrous ethanol into a 2L three-necked reaction flask, then ice-salt bath until the internal temperature is below 5°C, and add sodium borohydride 37.83g in batches. 1.00mol), keep the internal temperature not exceeding 5°C, and then increase the internal temperature to about 45°C to react for 2h. After the reaction was completed, the solvent was removed under reduced pressure, the residue was neutralized with 0.5M hydrochloric acid, and extracted with dichloromethane three times (3 ⁇ 500 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to dryness to obtain 98.6 g of a yellow oily substance with a yield of 95.60%. Used directly in the next reaction.
  • Method 2 Add 200.00g (0.908mol) of cyclopentylmandelic acid and 3000ml of ethylene glycol dimethyl ether into a 5L three-necked reaction flask, then ice-salt bath until the internal temperature is below 0°C, and add 363.20g of aluminum trichloride ( 2.724mol), when adding aluminum trichloride, keep the internal temperature not exceeding 5°C, after the addition, stir and react at this temperature for half an hour, then add 137.40g (3.632mol) of sodium borohydride in batches, keeping the internal temperature not exceeding 5°C, then rise to an internal temperature of 55°C and react for 2h. Thin layer detection, the reaction is complete.
  • Elemental analysis C 29 H 40 BrNO 3 calculated value C65.65, H7.60, Br15.06, N2.64; measured value C65.60, H7.58, Br15.0, N2.62. Elemental analysis results show that this product does not contain crystal water or other crystal solvents, which is consistent with the molecular formula of compound I.
  • Elemental analysis C 29 H 40 BrNO 3 , calculated value C65.65, H7.60, Br15.06, N2.64; measured value C65.45, H7.42, Br15.11, N2.50. Elemental analysis results show that this product does not contain crystal water or other crystal solvents, which is consistent with the molecular formula of compound I.
  • the crystal A of the present invention is micronized so that the average particle size D 50 is less than 5 ⁇ m, and it is thoroughly mixed with lactose with a particle size of 1-100 ⁇ m, and the mixture is filled into capsules.
  • the amount of the drug/lactose mixture per capsule is 25.1 mg.
  • the powder is used Inhaler administration.
  • the type A crystal of the present invention is prepared by using the method of Example 2 or the same mechanism as that of Example 2; the type B crystal of the present invention is prepared by using the method of Examples 4 and 6 or the method of the same mechanism as that of Examples 4 and 6. preparation.
  • the solid samples obtained in the experiment were analyzed with a powder X-ray diffraction analyzer (Bruker D8 advance), which was equipped with a LynxEye detector.
  • the 2 ⁇ scanning angle of the sample is from 3° to 40°, the scanning step is 0.02°, and the tube voltage and tube current are 40KV and 40mA, respectively.
  • the sample pan used for sample measurement is the zero background sample pan.
  • Type A crystals are shown in Figure 1. Considering factors such as D value, low angle data, intensity characteristic line and peak shape integrity, the characteristic peak is selected from the following 2 ⁇ values: 5.7 ⁇ 0.2 degrees, 12.9 ⁇ 0.2 degrees, 16.7 ⁇ 0.2 degrees, 18.0 ⁇ 0.2 degrees, 19.5 ⁇ 0.2 degrees, 21.1 ⁇ 0.2 degrees, 22.3 ⁇ 0.2 degrees and 23.3 ⁇ 0.2 degrees.
  • the X powder diffraction data of crystal A of the present invention are shown in Table 1:
  • Type B crystals are shown in Figure 2. Considering factors such as D value, low angle data, intensity characteristic line and peak shape integrity, the characteristic peak is selected from the following 2 ⁇ values: 5.2 ⁇ 0.2 degrees, 15.8 ⁇ 0.2 degrees, 16.9 ⁇ 0.2 degrees, 17.7 ⁇ 0.2 degrees, 19.5 ⁇ 0.2 degrees, 20.2 ⁇ 0.2 degrees and 22.1 ⁇ 0.2 degrees.
  • the X powder diffraction data of crystal B of the present invention is shown in Table 2:
  • Test example 1 shows that the B-type crystal is more stable than the A-type crystal in a high-humidity environment.
  • TGA Use TA TGA Q500 for thermogravimetric analysis of solid samples.
  • the 2 ⁇ 3mg sample is placed in a balanced aluminum sample pan, and the mass of the sample is automatically weighed in the TGA heating furnace.
  • the sample is heated to 200-300°C at a rate of 10°C/min.
  • the nitrogen flow rate of nitrogen to the balance chamber and the sample chamber were 40 mL/min and 60 mL/min, respectively.
  • TA DSC Q200 is used for solid samples for differential scanning calorimetry analysis, and the standard sample used for calibration is indium. After accurately weighing 2 ⁇ 3mg samples, place them in the TA DSC sample pan, and record the accurate mass of the samples. The sample was heated to 200-250°C at a temperature increase rate of 10°C/min in a nitrogen flow of 50 mL/min.
  • results The results of TGA are shown in Figures 3 and 4.
  • Figure 3 shows that crystal A has no significant weight loss before decomposition, indicating that crystal A does not contain crystal water in its molecules.
  • Figure 4 shows that the crystal B sample has two weight loss before decomposition, respectively 3.163% and 1.131%, which is consistent with the characteristic that crystal B is a 1.5 molecular hydrate of compound I.
  • DSC results are shown in Figure 3 and Figure 5.
  • Figure 3 shows that crystal A has only one endothermic peak, and the starting temperature and peak temperature are 157.44°C and 161.03°C, respectively, which are the melting point peaks.
  • Figure 5 shows that the crystal form B has three endothermic peaks, the peaks are respectively 90.52°C, 113.26°C and 160.65°C.
  • the hydrate becomes a mixed crystal of hydrate and type A crystal by XRPD detection, indicating that the first two endothermic peaks are caused by the departure of crystal water, and the third endothermic peak is loss The melting peak of anhydrous after crystallization water.
  • the dynamic moisture adsorption and desorption analysis is performed on the IGA SORP (HidenIsochema) instrument.
  • the samples are tested in gradient mode.
  • the humidity range of the test is 0% to 90%.
  • the incremental humidity of each gradient is 10%, and the shortest test of each gradient
  • the time is 30min, the longest test time is 120min, and the time interval for the system to collect data is 3min.
  • the concentration of the residual solvent contained in the crystal of the present invention was measured using the following measurement conditions. The results are shown in Table 3.
  • Headspace parameters headspace balance temperature 80°C, headspace balance time 30min
  • Each of the recrystallization processes of the present invention removes the residual solvent.
  • the type A crystal of the present invention and the type B crystal of the present invention have very little residual solvent. In Example 6, no residual solvent was detected in the crystal.
  • Phase A 0.01mol/L potassium dihydrogen phosphate solution (add 0.04mol/L ammonium chloride, adjust the pH to 3.0 with phosphoric acid)-methanol (38:62); Phase B: acetonitrile
  • Phase A Phase B (%) 0 100 0 30 75 25 60 40 60 65 40 60 68 100 0 80 100 0
  • the good solvents for this phenomenon in the preparation of type B crystals are alcohol/water solution and acetonitrile at 2°C-4°C, and the anti-solvents are tetrahydrofuran and methyl tert-butyl ether.
  • Ratio 2 Anti-solvent/good solvent ratio (ml/ml)

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Abstract

本发明的主要目的在于提供一种季铵盐结构化合物溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐(以下称为化合物I)的新型晶体。化合物I的A型晶体在其粉末X射线衍射图中在下述衍射角2θ：5.7±0.2度、12.9±0.2度、16.7±0.2度、18.0±0.2度、19.5±0.2度、21.1±0.2度、22.3±0.2度及23.3±0.2度处显示出衍射峰。化合物I的B型晶体在其粉末X射线衍射图中在下述衍射角2θ：5.2±0.2度、15.8±0.2度、16.9±0.2度、17.7±0.2度、19.5±0.2度、20.2±0.2度及22.1±0.2度处显示出衍射峰。本发明还涉及化合物Ⅰ的新的制备方法和上述两种新型晶体在医药领域中的应用。

Description

一种M受体拮抗剂的晶体、制备方法及其应用 技术领域
本发明属于医药技术领域，具体涉及季铵盐结构化合物溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐(以下简称化合物Ⅰ)新型晶体及其制备方法；本发明还涉及化合物Ⅰ的新型晶体在医药领域中的应用。
背景技术
哮喘和慢性阻塞性肺部疾病(COPD，简称：慢阻肺)是最常见的流行病。支气管扩张剂是哮喘和COPD治疗的首选药物。常用的支气管扩张剂包括M受体拮抗剂，如异丙托溴铵、噻托溴铵等。
WO2015007073公开了一类长效且对M受体亚型具有选择性拮抗作用的化合物，其在治疗哮喘、COPD、过敏性鼻炎、感冒后鼻炎、胃及十二指肠溃疡时与现有技术相比具有对M受体亚型有选择性作用，因而毒副作用低，并且有起效快和长效的特点，溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐(化合物I)是其中的一个优选化合物，其结构式如下：
Figure PCTCN2021089464-appb-000001
具体而言，化合物I可以用于治疗鼻炎、感冒后鼻炎、慢性气管炎、气道高、哮喘、COPD、咳嗽、尿失禁、尿频、不稳定性膀胱综合症、膀胱痉挛、膀胱炎、和胃肠道疾病如应激性大肠综合症、痉挛性结肠炎以及十二指肠和胃溃疡等疾病。尤其与现有技术比较具有药效长、起效快、毒副作用低的特点。
化合物I也可以与β 2受体激动剂、甾类激素、抗过敏药、抗炎药、抗感染药、磷脂酶4抑制剂等联合用于治疗上述呼吸道疾病如过敏性鼻炎、感冒后鼻炎、哮喘和慢阻肺等。
如上所述，已知化合物Ⅰ可用作针对多种疾病的治疗药等，但对于其晶体的存在与否等信息既无记载也无启示。
发明人研究发现，关于化合物Ⅰ的合成工艺，WO2015007073中采用环戊基苯甲酮与硫酸二甲酯在氢化钠(NaH)存在的条件下反应制得1-苯基-1-环戊基环氧乙烷(中间体)；在NaH存在下，中间体与(R)-3-奎宁醇反应生成非对映异构体(2S,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷游离碱和(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷游离碱；通过柱层析得到(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷游离碱，再与3-溴丙氧基苯反应并真空抽除溶剂得到黄色油状物，加入乙醚沉淀得到类白色固体(化合物Ⅰ)。上述工艺虽合成路线较短，但存在诸多弊端：(1)在制备中间体1-苯基-1-环戊基环氧乙烷时需使用硫酸二甲酯、二甲硫醚等剧毒甚至基因毒试剂，且此反应中大量使用NaH时容易产生爆炸；(2)制备(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷游离碱时需要进行柱层析分离，使(R)-3-奎宁醇这种昂贵的原料的利用率只有50％，增加生产成本，且生产规模受到限制；(3)最后一步使用乙醚获得固体原料药，由于乙醚为高危溶剂，不适合于现代工业化生产。
发明人经过大量创造性研究，成功解决化合物Ⅰ的晶型问题，同时研究并确定了化合物Ⅰ的新生产工艺。
发明内容
发明的目的
本发明的目的之一是提供化合物I的新的制备方法。
本发明的另一目的是在于提供化合物I的新型晶体、新型晶体的制备方法和含有该晶体作为有效成分的医药组合物，具体为下述(1)～(4)。
(1)一种化合物I的新的制备方法。
(2)一种化合物Ⅰ的A型晶体(以下称为本发明A型晶体或晶体A)，其粉末X射线衍射图中，至少在下述衍射角2θ：5.7±0.2度、12.9±0.2度、16.7±0.2度、18.0±0.2度、19.5±0.2度、21.1±0.2度、22.3±0.2度及23.3±0.2度处显示出衍射峰，所述粉末X射线衍射图是用Cu Kα射线得到的图谱。
(3)一种化合物Ⅰ的B型晶体(以下称为本发明B型晶体或晶体B)，该B型晶体为化合物Ⅰ与1.5分子H 2O的水合物，其粉末X射线衍射图中，至少在下述衍射角2θ：5.2±0.2 度、15.8±0.2度、16.9±0.2度、17.7±0.2度、19.5±0.2度、20.2±0.2度及22.1±0.2度处显示出衍射峰，所述粉末X射线衍射图是用Cu Kα射线得到的图谱。
Figure PCTCN2021089464-appb-000002
(4)含有(2)～(3)中任一项所述的晶体作为有效成分的医药组合物(以下称为本发明医药组合物)。
确定本发明的实施例及权利要求书中的衍射峰的衍射角2θ时，所得的值应理解为在该值的±0.2度的范围内，优选在该值的±0.1度的范围内。
解决问题的手段
人们希望医药品原料药是具有治疗作用的高纯度、性质稳定的产品，并且在工业生产过程中具有环保、安全和廉价的特点。因此，发明人进行了反复认真的研究从而发明了化合物Ⅰ的新合成方法和化合物Ⅰ的2种新型晶体，分别命名为晶体A和晶体B。经过试验意外发现：(1)与化合物Ⅰ相比，晶体A和晶体B残留溶剂大大降低甚至可以完全除去；(2)晶体A和晶体B的结晶工艺能除去化合物Ⅰ的绝大部分杂质；(3)晶体A在各种湿度条件下都有很强的吸湿性，晶体B即使在高湿条件下吸湿性也很弱，比晶体A更稳定，利于工业化操作和储存。
实现发明的最佳方法
1、化合物Ⅰ的制备：
步骤1：以环戊基扁桃酸或环戊基扁桃酸酯为起始物料，经硼氢化钠还原得到消旋的2-羟基-2-环戊基-2-苯乙醇(Z02)；反应溶剂选自乙二醇二甲醚、四氢呋喃、二氧六环、甲醇、乙醇等，优选乙二醇二甲醚、四氢呋喃等；硼氢化钠与起始物料的摩尔比为2～5:1，优选2～3.5:1；还原环戊基扁桃酸(酯)时要加入路易斯酸进行催化，路易斯酸选自三氯化铝、三氟 化硼、氯化锌、四氯化锡和四氯化钛等，路易斯酸与环戊基扁桃酸的摩尔比为2～5:1，优选2.5～3:1。
步骤2：Z02与手性酰氯进行酯化反应后，结晶得手性羧酸2-羟基-2-环戊基-2-苯乙醇酯(Z03)。手性酰氯包括但不限于L-樟脑磺酰氯、D-樟脑磺酰氯、扁桃酸衍生物酰氯等，Z02与手性酰氯的摩尔比为1:1～3，优选为1:1.5～2；反应溶剂选自二氯甲烷、三氯甲烷、四氢呋喃、二氧六环等，优选二氯甲烷、四氢呋喃；碱选自三乙胺、吡啶、N-甲基吗啡啉等有机碱，碱与手性酰氯的摩尔比为1～4:1，优选1～2:1。
步骤3：Z03用碱处理即可得到R-1-苯基-1-环戊基环氧乙烷(Z04)。碱包括但不限于NaH、叔丁醇钾、丁基锂、氨基钠等，优选NaH、叔丁醇钾。碱与Z03摩尔比为1～3:1，优选为1～1.5:1；反应溶剂选自二氯甲烷、四氢呋喃、二氧六环、二甲基亚砜等，优选二甲基亚砜、四氢呋喃。
步骤4：Z04与R-(-)3-奎宁醇反应得到(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷游离碱(Z05)。碱包括但不限于NaH、叔丁醇钾、丁基锂、氨基钠等，优选NaH、叔丁醇钾。R-(-)3-奎宁醇与碱摩尔比为1～3:1，优选为1～1.5:1；反应溶剂选自二氯甲烷、四氢呋喃、二氧六环、二甲基亚砜等，优选二甲基亚砜、四氢呋喃。
步骤5：Z05与3-苯氧基-1-溴丙烷(Z06)进行季铵化反应后，得到溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐(化合物Ⅰ)。
Figure PCTCN2021089464-appb-000003
上述化合物Ⅰ的制备过程中，作为原料使用的各化合物可以通过市售或者可以根据公开的方法制备。
2、本发明A型晶体、B型晶体(以下统称为本发明晶体)的制备
(1)本发明A型晶体的制备：
步骤1：溶解工艺
该工艺是进行加热以使化合物Ⅰ溶解于溶剂的工艺。作为可在该工艺中使用的溶剂，良溶剂有例如醇类溶剂、乙腈、二氯甲烷、三氯甲烷。作为可在该工艺中使用的醇类溶剂为C1～C5的小分子醇类，较好是例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇或3-甲基-1-丁醇，优选乙醇。
作为可在该工艺中溶解化合物Ⅰ的良溶剂，使用的量，相对于化合物Ⅰ优选在1倍(mL/g)～10倍(mL/g)的范围内，更优选在1倍(mL/g)～5倍(mL/g)的范围内，更优选在2倍(mL/g)～3倍(mL/g)的范围内。溶解温度根据溶剂的种类及其用量而不同，通常在溶剂的沸点以下搅拌或在溶剂的沸点进行回流，且优选在20℃～100℃的范围内，更优选在60℃～90℃的范围内。
该工艺中可以根据需要对化合物Ⅰ的溶液进行活性炭吸附和过滤以除去不溶物。为了防止过滤过程中的晶体析出，过滤优选在加压下用带加热装置的漏斗进行。过滤后的溶液保持一定的温度，且优选在20℃～100℃的范围内，更优选在60℃～90℃的范围内。
步骤2：加入反溶剂析晶工艺
经过溶解度测定试验，化合物Ⅰ的饱和烃类反溶剂，例如直链或支链的C6～C8的烷烃或C5～C8的环烷烃，具体但不限于环戊烷、戊己烷、庚烷、辛烷、环己烷、环庚烷、环辛烷。化合物Ⅰ的酮类反溶剂，例如直链或支链的C3～C8的酮，具体但不限于丙酮、2-丁酮、甲基异丁基酮。化合物Ⅰ的酯类反溶剂具体但不限于甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯等。化合物Ⅰ的醚类反溶剂具体但不限于如异丙醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃。化合物Ⅰ的其它反溶剂具体但不限于如甲苯等。可以用于本工艺的反溶剂较好的是甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、丙酮、丁酮等，优选乙酸乙酯。
在搅拌条件下将选择的上述反溶剂缓慢加入步骤1过滤好的溶液中，反溶剂相对于化合物Ⅰ溶液优选在1倍(mL/mL)～20倍(mL/mL)的范围内，更优选在5倍(mL/mL)～15倍(mL/mL)的范围内，更优选在8倍(mL/mL)～10倍(mL/mL)的范围内。
在制备A型晶体的过程中，所有步骤都要严格防止接触水分。所使用的溶剂需要保证无水，容器必须干燥。
步骤3：冷却析晶工艺
该工艺是将上述步骤2中制备的溶液冷却、使本发明A型晶体析出的工艺。该工艺优选使用带加温功能和搅拌功能的析晶装置。
冷却温度(收集析出晶体时的温度)较好是在-10℃～50℃的范围内，优选在-5℃～20℃的范围内，更优选在0℃～10℃的范围内。该工艺中，较好是用0.5h～10h的时间缓慢冷却， 直至到达该冷却温度。也可以将上述步骤1中制备的溶液在加热搅拌下蒸除部分溶剂，可促进晶体A的析出。
此外，该工艺中可以添加本发明A型晶体的晶种；添加本发明A型晶体的晶种的情况下，优选在溶液被冷却至40℃～80℃的范围内时添加。本发明A型晶体的晶种的添加量没有特别限制，相对于化合物Ⅰ优选在1％(g/g)～5％(g/g)的范围内。
步骤4：晶体收集、干燥工艺
该工艺是通过过滤、离心分离等方法收集上述步骤3中得到的析出晶体并使其干燥的工艺。
干燥工艺可通过减压干燥、采用干燥剂的干燥等常规方法进行，优选在减压下进行，更优选在20℃～70℃、10mmHg以下的条件下进行1h～48h，得到A型晶体。
(2)本发明B型晶体的制备：
方法1：溶解工艺在良溶剂中加入一定的纯化水
步骤1：溶解工艺
该工艺是进行加热以使化合物Ⅰ溶解于溶剂的工艺。作为可在该工艺中使用的良溶剂具体为但不限于C1～C5的小分子醇类或乙腈，较好是例如甲醇、乙醇、正丙醇、异丙醇，优选乙醇。这些溶剂与一定量的水混合后作为化合物Ⅰ的溶剂，水与上述溶剂的比例较好为2％(ml/ml)～10％(ml/ml),最好为4％(ml/ml)～6％(ml/ml)。
作为可在该工艺中溶解化合物Ⅰ的混合溶剂，使用的量，相对于化合物Ⅰ优选在1倍(mL/g)～10倍(mL/g)的范围内，更优选在2倍(mL/g)～5倍(mL/g)的范围内。溶解温度根据溶剂的种类及其用量而不同，通常在溶剂的沸点以下搅拌或沸点进行回流，且优选在20℃～100℃的范围内，更优选在60℃～90℃的范围内。
该工艺中可以根据需要对化合物Ⅰ的溶液进行活性炭吸附和过滤以除去不溶物。为了防止过滤过程中的晶体析出，过滤优选在加压下用带加热装置的漏斗进行。过滤后的溶液保持一定的温度，且优选在20℃～100℃的范围内，更优选在60℃～90℃的范围内。
步骤2：加入反溶剂析晶工艺
可用于本工艺的较好的反溶剂包括酯、水、醚、酮、液态环烷烃或芳烃，优选甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、2-丁酮、甲基异丁基酮、水、异丙醚、甲基叔丁基醚，最优选乙酸乙酯。
用水作为反溶剂时，步骤1的良溶剂可以不加水，良溶剂除步骤1的醇和乙腈外还可以选择二氯甲烷或三氯甲烷等与水不互溶的溶剂。
在搅拌条件下将选择的上述反溶剂缓慢加入步骤1过滤好的溶液中，反溶剂相对于化合物Ⅰ溶液优选在3倍(mL/mL)～20倍(mL/mL)的范围内，更优选在5倍(mL/mL)～15倍(mL/mL)的范围内，更优选在8倍(mL/mL)～10倍(mL/mL)的范围内。
步骤3：冷却析晶工艺
该工艺是将上述步骤2中制备的溶液冷却、使本发明B型晶体析出的工艺。该工艺优选使用带加温功能和搅拌功能的晶析装置。
冷却温度(收集析出晶体时的温度)较好是在-10℃～50℃的范围内，优选在-5℃～20℃的范围内，更优选在0℃～10℃的范围内。该工艺中，较好是用0.5h～10h的时间缓慢冷却，直至到达该冷却温度。
此外，该工艺中可以添加本发明B型晶体的晶种；添加本发明B型晶体的晶种的情况下，优选在溶液被冷却至40℃～80℃的范围内时添加。本发明B型晶体的晶种的添加量没有特别限制，相对于化合物Ⅰ优选在1％(g/g)～5％(g/g)的范围内。
步骤4：晶体收集、干燥工艺
该工艺是通过过滤、离心分离等方法收集上述步骤3中得到的析出晶体并使其干燥的工艺。
干燥工艺可通过减压干燥、采用干燥剂的干燥等常规方法进行，优选在减压下进行，更优选在20℃～70℃、通风良好的条件下进行1h～48h干燥，得到B型晶体。
方法2：本发明B型晶体也可通过A型晶体转晶的方法获得
将本发明A型晶体加入到反应容器中，加入纯化水，水与A型晶体的重量比为3倍～30倍(g/g)，较好为5倍～20倍(g/g)，最好为8倍～12倍(g/g)。搅拌打浆，温度控制较好为10℃～50℃，最好为20℃～30℃。打浆时间较好为0.3h～10h，最好为0.5h～5h，抽滤，将固体在40℃～80℃鼓风干燥，达到恒重后，得到B型晶体。干燥时间为2～24h。
3、医药用途、本发明医药组合物
任何含有化合物Ⅰ晶体A或晶体B的药用组合物均在本发明专利的要求范围内，本发明的化合物Ⅰ具有优良的M受体拮抗作用，对M受体亚型有选择性作用，对M3受体作用强，对M2受体作用很弱，因此显示出腺体分泌抑制作用、气管扩张作用、支气管扩张作用等，因此，本发明晶体及其医药组合物可用于治疗过敏性鼻炎、感冒后鼻炎、哮喘、COPD、胃与十二指肠溃疡等各种疾病(参照专利文献WO2015007073)。所以本发明的又一目的是提供含有化合物Ⅰ的晶体A、晶体B(化合物Ⅰ的水合物)的药物组合物，包括可接受的药学载体。上述晶体A、晶体B的药物组合物可以选择性地含有其他治疗成分，诸如但不限于甾体类抗炎药、磷酸二酯酶4抑制剂(PDE-4)、β2受体激动剂、组胺受体拮抗剂等。
将本发明晶体作为药品给药时，直接给予本发明晶体，或者在例如0.001～99.9％的范围内含于医药学上允许的无毒性惰性载体中给药。
作为上述组合物的载体，可以是固体、半固体或液状的稀释剂、填充剂或其他处方用的助剂。这些载体可以使用一种或两种以上。
本发明医药组合物可采取固体、半固体或液状剂型：例如采用粉雾剂(DPI)、吸入溶液、定量吸入喷雾剂(或称软雾剂：SMI)、定量吸入气雾剂(MDI)治疗哮喘和COPD；采用滴鼻剂和鼻喷雾剂治疗感冒后鼻炎、季节性过敏性炎鼻和常年性过敏性鼻炎；采用胶囊剂、片剂、颗粒剂、散剂、混悬剂、溶液剂、糖浆剂、酏剂等口服制剂治疗胃和十二指溃疡；采用注射剂用于手术中抗肌松或气管分泌过度等。其中，特别重要的用于治疗哮喘、COPD、感冒后鼻炎、过敏性鼻炎、胃和十二指溃疡等疾病的制剂。
在制备固体制剂时可以通过粉碎设备使本发明晶体达到合适的粒径要求。
散剂可以使本发明晶体达到适当的粉碎程度，再与同样粉碎的例如淀粉、甘露醇这样的可食用性碳水化合物等医药用载体混合并颗粒化。可以任意地添加矫味剂、防腐剂、分散剂、着色剂、香料等。
片剂可以按如下方法制备：在经粉末化的本发明晶体中加入赋形剂制成粉末混合物，制粒或粉碎，也可压成大片后再粉碎，再加入崩解剂或润滑剂后压片。
粉末混合物可以通过将经粉碎适当的本发明晶体与稀释剂或基质混合后制备。根据需要，可以添加粘合剂(例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、明胶、聚乙烯吡咯烷酮、聚乙烯醇)、溶解延迟剂(例如石蜡)、吸附剂(例如膨润土、高岭土)等。
粉末混合物可以按如下方法制备：首先，用例如糖浆、淀粉糊、阿拉伯胶、纤维素溶液或高分子物质溶液等粘合剂湿润，搅拌混合，将其干燥、粉碎而制成颗粒。通过在这样制成的颗粒中添加作为润滑剂的硬脂酸、硬脂酸盐、滑石粉、矿物油等，可以防止相互附着。
此外，片剂可以不经过上述的颗粒化或粉碎工艺，通过将本发明晶体与流动性好的惰性载体混合后直接压片来制造。
对于制成的片剂，可以实施薄膜包衣或包糖衣。
胶囊剂可以通过将晶体或如上所述形成的粉碎后的晶体粉末按照散剂或者如片剂项中所述颗粒化而得的材料，填充至明胶胶囊等胶囊外皮中而制备。此外，还可以将本发明晶体的微粉悬浮分散于植物油、聚乙二醇、甘油、表面活性剂中，将其用明胶片材包裹而制成软胶囊剂。
例如液体制剂、糖浆剂、含片、酏剂等其他口服制剂也能够以含有一定量的本发明晶体的方式制成制剂形态。
糖浆剂可以通过使本发明晶体溶解于适当的香味水溶液来制造。酏剂可以通过使用无毒性的醇性载体来制造。
混悬剂可以通过使本发明晶体分散于无毒性载体中来制造。根据需要，可以添加助溶剂或乳化剂(例如乙氧基化的异硬脂醇类、聚氧乙烯山梨糖醇酯类)、防腐剂、调味剂(例如薄荷油、糖精)等。
如果需要，可以将用于口服的用量单位处方微胶囊化。
本发明药用组合物还可以为用于直肠给药的栓剂形式。可通过使药物与合适的在室温下为固体但在直肠温度下为液体而在直肠中释放药物的合适的非刺激性赋形剂混合，制备这些栓剂。此类材料包括可可豆脂、蜂蜡、聚乙二醇、硬脂肪和/或氢化椰油甘油酯。
非口服制剂可以采用皮下、肌肉或静脉内注射用的液体制剂，例如溶液或混悬液的形态。该非口服制剂可以按照如下方法制备：将一定量的本发明晶体悬浮或溶解于适合用于注射的无毒性的液体载体，例如水性或油性的介质，再对该混悬液或溶液进行灭菌。此外，还可以添加稳定剂、防腐剂、乳化剂等。优选，在pH4.5～7.5中配制注射液。
另外，可通过局部而非全身方式给予本发明化合物Ⅰ的晶体，本发明晶体的组合物可配制为给予哺乳动物，优选用于人的药物。可重复给予本发明化合物晶体和合适的赋形剂组成的组合物，或可通过连续给予组合物。给药的合适部位包括但不限于鼻腔、肺部、气管、支气管。
本发明药物晶体的组合物可为滴鼻剂、喷鼻剂、吸入溶液、DPI、溶液型定量吸入剂气雾剂、混悬型定量吸入气雾剂、SMI等形式。
本发明包含发明晶体的组合物通过雾化吸入器雾化给药。雾化装置通常能产生高速气流，使含有活性成分的药物组合物雾化而被患者吸入呼吸道。因此活性成分通常被溶解于合适的溶剂中制成溶液而置于雾化吸入器中。或者活性成分微粉化与适宜的载体组合形成适于吸入的微粉化颗粒混悬液。微粉化通常定义为使90％以上的固体颗粒直径小于10μm。适宜的雾化装置商业上可以提供。组合物的代表性溶媒为生理盐水或乙醇溶液。
本发明包含发明晶体的组合物利用定量吸入器通过吸入方式给药。定量吸入装置利用机械力使药物溶液雾化的称为定量吸入喷雾剂(SMI)，SMI选用等渗的水溶液为溶媒；利用抛射剂的推动力定量释放出治疗药物称为MDI，利用定量吸入器给药的组合物包含在溶液或混悬液中，上述2种定量吸入装置商业上可以提供。含有化合物Ⅰ晶体的MDI，其潜溶剂包括但不限于无水乙醇、甘油、二醇类中的一种或一种以上的混合物，其中的二醇类包括但不限于乙二醇、丙二醇、聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇800等。其抛射剂包括但不限于四氟乙烷(HFA-134a)、七氟丙烷(HFA-227ea)中的一种或它们 的混合物。其表面活性剂包括但不限于油酸；寡聚乳酸(OLA)；脱水山梨醇类，如span20、span65、span80、span85；聚氧乙烯脱水山梨醇类，如吐温20、吐温80；聚氧乙烯脂肪醇类，如Brij30、Brij35、Cremophor；聚氧乙烯聚氧丙烯共聚物，如Pluronic F-68；聚乙二醇硬脂酸酯类，如Solutol HS15；磷脂类，如大豆磷脂、卵磷脂中的一种或几种。
DPI可以通过混合活性成分与赋形剂制备，也可不加赋形剂，然后将药物或组合物装入粉雾分配器中，或装入与DPI给药装置一起使用的吸入药筒或胶囊，DPI给药装置商业上可获得。含有化合物Ⅰ晶体的DPI，所述惰性载体包含稀释剂和润滑剂，所述稀释剂为葡聚糖、阿拉伯糖、乳糖、甘露糖醇、甘露醇、木糖醇、蔗糖、果糖、山梨醇、麦芽糖、氨基酸和葡萄糖中的一种或几种的混合，所述润滑剂为硬脂酸镁或苯甲酸钠。
鼻喷雾剂和滴鼻剂是将含有化合物Ⅰ晶体的组合物分装于鼻喷雾剂和滴鼻剂的装置中，这些装置商业上均可获得。含有化合物Ⅰ晶体的滴鼻剂或定量鼻喷雾剂，所述惰性载体为选自苯扎氯铵、苯扎溴铵、苯甲醇、苯甲酸、三氯叔丁醇、对羟基苯甲酸酯类、山梨酸、苯酚、麝香草酚和挥发油中的一种或几种的混合。
本发明同时提供所述药物组合物的应用，可将其用于制备预防和治疗哺乳动物和人的各种急慢性气道阻塞性疾病，如COPD、支气管哮喘、胃溃疡、十二指肠溃疡、急慢性鼻炎和感冒后鼻炎的药物。
除上述那些代表性剂型外，本领域技术人员通常还已知其他的药学上可接受的赋形剂、载体和剂型，均包括在本发明中。应理解，任何具体患者的特定剂量和治疗方案要取决于多种因素，它们包括患者的年龄、体重、一般健康状况、性别、饮食状况、给药时间、排泄速度、联合药物、治疗医师的判断和所治疗的具体疾病的严重性。活性成分的量还取决于组合物中的其它治疗药物的种类和量(如果存在的话)。
附图说明
图1、A型晶体的XRPD谱图
图2、B型晶体的XRPD谱图
图3、A型晶体的TGA和DSC谱图(下线为晶体A，上线为晶体B)
图4、B型晶体的TGA谱图
图5、A型晶体和B型晶体的DSC对比谱图(下实线为晶体A，上虚线为晶体B)
图6、A型晶体的DVS吸附曲线
图7、B型晶体的DVS吸附曲线
具体实施方式
以下所举实施例和试验例对本发明进行更详细的说明，但本领域的技术人员都知晓本发明并不限于这些实施例和试验例。
[实施例1]本发明化合物Ⅰ(原料药)的制备
步骤1：2-羟基-2-环戊基-2-苯乙醇的制备
方法一：将环戊基扁桃酸乙酯124.0g(0.500mol)和无水乙醇1000mL加入到2L三口反应瓶中，然后冰盐浴至内温5℃以下，分批加入硼氢化钠37.83g(1.00mol),保持内温不超5℃，再升至内温45℃左右反应2h。反应完毕，减压除去溶剂，残留物用0.5M盐酸中和至中性，二氯甲烷萃取三次(3×500mL)，合并有机相，用无水硫酸镁干燥。滤除干燥剂，滤液减压除去溶剂至干，得黄色油状物98.6克，收率95.60％。直接用于下步反应。
方法二：将环戊基扁桃酸200.00g(0.908mol)和乙二醇二甲醚3000ml加入到5L三口反应瓶中，然后冰盐浴至内温0℃以下，加入三氯化铝363.20g(2.724mol),加入三氯化铝时，保持内温不超5℃，加毕，在此温度下搅拌反应半小时，然后分批加入硼氢化钠137.40g(3.632mol),保持内温不超5℃，再升至内温55℃左右反应2h。薄层检测，反应完毕。将反应混合物缓缓倒入冰冷的1600mL的1mol/L盐酸中，同时不断搅拌，控制溶液温度不超25℃，加毕，乙酸乙酯萃取三次(3×1000mL)，合并有机相，用5％的碳酸钠水溶液洗涤有机相三次(3×500mL)，分离有机相，再用5％的氯化钠水溶液洗涤三次(3×500mL)，有机相用无水硫酸镁干燥。滤除干燥剂，在50℃下减压除去溶剂，残留物用异丙醚(1000mL)溶解，再加入2mol/L氢氧化钠水溶液(450mL)机械搅拌洗涤10min，然后置于分液漏斗中，分离出有机层加入无水硫酸镁干燥。滤除干燥剂，水泵减压旋蒸除去溶剂，最后得到浅黄色油状物145.80g。收率：77.84％％，直接用于下步反应。
步骤2：(R)-2-羟基-2-环戊基-2-苯乙醇基L-(-)-樟脑磺酰的制备
将2-羟基-2-环戊基-2-苯乙醇112.50g(545.38mmol)用二氯甲烷700mL溶解后，倒入5L反应三口瓶中，反应液澄清透明，室温下加三乙胺入165.55g(1636.03mmol),然后冰水浴至内温10℃以下，再滴加500ml含L-(-)-樟脑磺酰氯164.10g(654.46mmol)二氯甲烷溶液，加毕，升至内温10℃左右反应1h。反应完成后，加入1L水，然后置于分液漏斗中，分离出水相和有机相，有机相再用水洗涤三次(3×1000mL)，每次用量1L，最后收集有机相，加入无水硫酸镁干燥。滤除干燥剂，在40℃下减压旋蒸除去溶剂，残留物用200mL乙酸乙酯溶解，冷冻结晶，滤集固体，干燥，得到白色固体70.03g，收率61.0％。
步骤3：(R)-2-环戊基-2-苯基环氧乙烷的制备
将二甲基亚砜(350mL)、2-羟基-2-环戊基-2-苯乙醇基L-(-)-樟脑磺酰(69.23g，164.6mmol)倒入1L反应三口瓶中，溶液澄清后，在室温下加入叔丁醇钾(17.54g，156.31mmol),然后油浴加热至内温50℃反应1h。TLC检测：(展开剂：石油醚：乙酸乙酯＝3mL：1mL)冰水浴至内温10℃以下，滴加450mL水，然后置于分液漏斗中，用异丙醚提取三次(3×200mL)，合并有机相，再用5％的氯化钠溶液洗涤三次(3×200mL)，有机相中加入无水硫酸镁干燥，过滤，滤液在水浴45℃减压旋蒸，除去溶剂，最后得到淡黄色液体28.02g，收率：90.42％。
步骤4：(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷的制备
将R-(-)-3-奎宁醇(16.46g，129.45mmol)、干燥四氢呋喃250ml加入1L反应三口瓶中，固体溶解后，室温下加入Z04(24.38g,129.45mmol用四氢呋喃50ml溶解)油浴加热至内温85℃，然后加入NaH(60％，3.45g，86.3mmol)，保持在85℃反应2h。TLC检测(展开剂：石油醚：乙酸乙酯＝5l：0.1)，反应完毕，减压除去溶剂，残留物中滴加冰水500ml水，然后用乙酸乙酯萃取3次(3×500mL)，合并有机相，无水硫酸镁干燥。滤除去干燥剂，减压除去溶剂，得到浅黄棕色固体，固体用异丙醚加热回流溶解，冷冻结晶，滤集固体，干燥至恒重，最后得到类白色固体36.28g，即为目标化合物，收率：88.85％。
步骤5：(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-溴化-1-氮杂双环[2，2，2]辛鎓盐
将(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷98.46g(0.312mol)和无水乙醇490mL置于5L反应釜中，在室温下搅拌溶解，溶解完全后，加入约100mL含3-苯氧基溴丙烷82.93g(0.386mol)的无水乙醇溶液，加热回流反应2h。反应完毕，减压除去溶剂，得类白色固体。得化合物Ⅰ的类白色固体149.28g，收率90.2％。
[实施例2]本发明A型晶体的制备
称量化合物Ⅰ(按实施例1制备，下同，也称原料药)43.3g和86.7ml无水乙醇，置于200mL茄形瓶中，回流搅拌溶解。加入活性炭0.87g，回流搅拌脱色0.5h。趁热抽滤除去活性炭，得到浅黄色透明滤液，将滤液移入1.0L茄形瓶中，在回流条件下，加入1.0L乙酸乙酯，冷却至25±5℃搅拌析晶2h。抽滤，将固体在80℃鼓风干燥4h，得到本发明A型晶体(39.2g，收率90.5％)。本发明A型晶体的粉末X射线衍射图示于图1。
元素分析C 29H 40BrNO 3，计算值C65.65，H7.60,Br15.06,N2.64；实测值C65.60,H7.58,Br15.0,N2.62。元素分析结果显示本品不含结晶水或其它结晶溶剂，与化合物Ⅰ分子式一致。
[实施例3]本发明A型晶体的制备
称量原料药35.1g和300ml二氯甲烷，置于500mL茄形瓶中，回流搅拌溶解。加入活性炭0.7g，回流搅拌脱色2h。趁热抽滤除去活性炭，得到浅黄色透明滤液，将滤液移入2.0L茄形瓶中，在回流条件下，先加入3g晶体A，再加入900L异丙醚，冷却至5±5℃搅拌析晶48h。抽滤，将固体在40℃、10mmHg以下的条件下干燥24h，得到本发明A型晶体(27.6g，收率72.3％)。
元素分析C 29H 40BrNO 3，计算值C65.65，H7.60,Br15.06,N2.64；实测值C65.45,H7.42,Br15.11,N2.50。元素分析结果显示本品不含晶体水或其它晶体溶剂，与化合物Ⅰ分子式一致。
[实施例4]本发明B型晶体的制备
称量化合物Ⅰ(按实施例1制备，下同，也称原料药)30.3g和100ml95％乙醇，置于200mL茄形瓶中，回流搅拌溶解。加入活性炭0.6g，回流搅拌脱色2h。趁热抽滤除去活性炭，得到浅黄色透明滤液，将滤液移入2.0L茄形瓶中，在回流条件下，加入1000mL四氢呋喃，冷却至20±5℃搅拌析晶2h。抽滤，将固体在60℃鼓风干燥8h至恒重，得到本发明B型晶体(26.5g，收率83.3％)。本发明B型晶体的粉末X射线衍射图示于图2。
元素分析证明化合物Ⅰ的B型晶体含1.5个晶体水，其分子式为C 29H 40BrNO 3.1.5H 2O，计算值C62.47，H7.77,Br14.33,N2.51，实测值C62.60,H7.82,Br14.25,N2.48。
[实施例5]本发明B型晶体的制备
称量原料药32.8g和200ml98％乙醇，置于500mL茄形瓶中，回流搅拌溶解。加入活性炭0.7g，回流搅拌脱色4h。趁热抽滤除去活性炭，得到浅黄色透明滤液，将滤液移入5.0L反应釜中，在回流条件下，加入1000mL丙酮，冷却至10±5℃搅拌析晶24h。抽滤，将固体在80℃鼓风干燥4h至恒重，得到本发明B型晶体(25.5g，收率74.9％)。
元素分析证明化合物Ⅰ的B型晶体含1.5个晶体水，其分子式为C 29H 40BrNO 3.1.5H 2O，计算值C62.47，H7.77,Br14.33,N2.51，实测值C62.36,H7.79,Br14.21,N2.68。
[实施例6]转晶法制备B型晶体
称量化合物Ⅰ晶体A40.3g，加入到1L反应釜中，加入纯化水400mL，转速250-270r/min，25±5℃搅拌打浆5h，抽滤，将固体在60℃鼓风干燥12h，经检测水分恒重后，得到本发明B型晶体(35.7g，收率84.3％)。本发明B型晶体的粉末X射线衍射图示于图2。
元素分析证明化合物Ⅰ的B型晶体含1.5个晶体水，其分子式为C 29H 40BrNO 3.1.5H 2O，计算值C62.47，H7.77,Br14.33,N2.51，实测值C62.41,H7.84,Br14.16,N2.63。
[制剂例7]干粉吸入剂组合物的制备，用于哮喘和COPD的维持治疗
组合物中各组分及其用量
晶体A 100mg
乳糖25000mg
将本发明晶体A微粉化，使平均粒径D 50小于5μm，与粒径为1～100μm的乳糖充分混合，将该混合物装入胶囊，每胶囊药物/乳糖混合物的量为25.1mg，利用粉末吸入器给药。
试验例
本发明A型晶体是通过采用实施例2的方法或与实施例2机理相同的方法制备；本发明B型晶体是通过采用实施例4、6的方法或与实施例4、6机理相同的方法制备。
[试验例1]本发明晶体的X射线粉末衍射(XRPD)试验
实验所得固体样品均用粉末X射线衍射分析仪(Bruker D8 advance)进行分析，该仪器配备了LynxEye检测器。样品的2θ扫描角度是从3°到40°，扫描步长是0.02°，管电压和管电流分别为40KV和40mA。样品测量采用的样品盘为零背景样品盘。
结果：
(1)A型晶体见附图1。综合考虑D值、低角度数据、强度大小特征线和峰形完整等因素，其特征峰选自下面的2θ值：5.7±0.2度、12.9±0.2度、16.7±0.2度，18.0±0.2度、19.5±0.2度、21.1±0.2度、22.3±0.2度及23.3±0.2度。本发明晶体A的X粉末衍射数据见表1：
表1、实施例2晶体A的X粉末衍射数据
Figure PCTCN2021089464-appb-000004
Figure PCTCN2021089464-appb-000005
称取约10mg晶体A于8ml样品瓶中，用滤纸封口后放入40℃/75％RH稳定性试验箱中，3天后取样进行XRPD检测，结果显示晶体A已部分转变为晶体B。说明A型晶体在高湿度条件下不稳定。
(2)B型晶体见附图2。综合考虑D值、低角度数据、强度大小特征线和峰形完整等因素，其特征峰选自下面的2θ值：5.2±0.2度、15.8±0.2度、16.9±0.2度、17.7±0.2度、19.5±0.2度、20.2±0.2度及22.1±0.2度。本发明晶体B的X粉末衍射数据见表2：
表2、实施例6晶体B的特征X粉末衍射数据
Figure PCTCN2021089464-appb-000006
称取约10mg晶体B于8ml样品瓶中，用滤纸封口后放入40℃/75％RH稳定性试验箱中，3天后取样进行XRPD检测，结果显示晶体B没有发生变化。
试验例1说明对高湿环境，B型晶体比A型晶体稳定。
[试验例2]热重分析(TGA)和差示扫描量热分析(DSC)试验
TGA:固体样品使用TA TGA Q500进行热重分析。2～3mg样品置于已平衡的铝制样品盘中，样品质量在TGA加热炉内自动称量。样品以10℃/min的速率加热至200～300℃。测试过程中，氮气对天平室和样品室的氮气流量分别是40mL/min和60mL/min。
DSC:固体样品使用TA DSC Q200进行差示扫描量热分析，其校正使用的标准样品是铟。2～3mg样品精确称重后置于TA DSC样品盘中，并记录下样品的准确质量。样品在50mL/min的氮气流中以10℃/min的升温速率加热至200～250℃。
结果：TGA结果见附图3、4，图3显示晶体A在分解前没有明显失重，说明晶体A分子中不含结晶水。图4显示晶体B样品分解前有两段失重，分别为3.163％和1.131％，符合晶体B为化合物Ⅰ的1.5分子水合物的特征。DSC结果见附图3、图5。图3显示晶体A只有一个吸热峰，起始温度和峰温度分别为157.44℃和161.03℃，为熔点峰。图5显示晶型B共有三个吸热峰，峰值分别为90.52℃、113.26℃和160.65℃。DSC加热至105℃后，经XRPD检测，水合物变为水合物和A型晶体的混晶，说明前面两个吸热峰是因为结晶水的离去引起的，第三个吸热峰为失去结晶水后转变成的无水物的熔融峰。
[试验例3]动态水分吸附(DVS)
动态水分吸附脱附分析在IGA SORP(HidenIsochema)仪器上进行，样品采用梯度模式进行测试，测试的湿度范围是0％～90％，每个梯度的增量湿度是10％，每梯度的最短测试时间是30min，最长测试时间是120min，系统收集数据的时间间隔是3min。
结果：DVS结果见图6和图7，显示晶体A吸湿性较强，在RH80％湿度时，吸湿增重达到52.4％。晶体B的吸湿性远小于晶体A，在80％RH湿度时，吸湿增重仅2.58％。
[试验例4]本发明晶体中所含的残留溶剂浓度的测定
采用以下测定条件测定本发明晶体中所含的残留溶剂浓度。其结果示于表3。
测定条件:
气相色谱法配备FID检测器
色谱柱：OPTIMA-624(30m×0.32mm×1.8μm)
柱温：60℃(3min)20℃/min 200℃(5min)
进样口温度：200℃
检测器温度：250℃
载气：氮气
柱流量：2ml/min
顶空参数：顶空平衡温度80℃，顶空平衡时间30min
分流比：10：1
表3:原料药与发明晶体的残留溶剂
Figure PCTCN2021089464-appb-000007
各本发明重结晶工艺除去了残留溶剂，本发明A型晶体与本发明B型晶体残留溶剂都很少，实施例6中晶体没有检出残留溶剂。
[试验例5]重结晶的杂质除去效果
采用以下高效相色谱条件测定本发明晶体的重结晶工艺的杂质除去效果。
仪器：高效液相色谱仪配备紫外检测器
色谱柱：AgelaPromosil C18 4.6×250mm，5μm
流动相：A相：0.01mol/L磷酸二氢钾溶液(加0.04mol/L的氯化铵，用磷酸调pH至3.0)-甲醇(38：62)；B相：乙腈
梯度洗脱表：
时间(min) A相(％) B相(％)
0 100 0
30 75 25
60 40 60
65 40 60
68 100 0
80 100 0
检测波长：210nm
流速：1.0ml/min
进样量：20μl
柱温：30℃
溶剂：流动相A
首先，根据HPLC色谱通过下式算出各晶体中的化合物Ⅰ的纯度(％)：各晶体中的化合物Ⅰ的纯度(％)＝(各晶体中的化合物Ⅰ的峰面积)/(所有峰面积的总和)×100；接着，通过下式算出各晶体中的杂质除去率(％)：各晶体中的杂质除去率(％)＝[{(各晶体中的化合物Ⅰ的纯度)-(原料中的化合物Ⅰ的纯度)}/{100-(原料中的化合物Ⅰ的纯度)}]×100
其结果示于表4。
[表4]重结晶除去原料药中的杂质结果
序号 晶型 各晶型中化合物Ⅰ的纯度(％) 各晶型中杂质除去率(％)
1 原料药 98.15 -
2 本发明A型晶体 99.78 88.1
3 本发明B型晶体 99.82 90.3
结果显示：本发明A型晶体与本发明B型晶体其重结晶工艺都能除去原料药中大多数杂质。
[试验例6]结晶化溶剂的研究
按照“实现发明的最佳方法”中“2、本发明A型晶体、本发明B型晶体(以下统称为本发明晶体)的制备”，本发明的A型晶体、B型晶体的重结晶法中有时在一定条件下析不出结晶，即使除去溶剂，最后原料药会变成油状物。在制备A型晶体时发生该现象的良溶剂为2℃～4℃的醇和乙腈，反溶剂为四氢呋喃、甲基叔丁基醚。在制备B型晶体时发生该现象的良溶剂为2℃-4℃的醇/水溶液和乙腈，反溶剂为四氢呋喃、甲基叔丁基醚。使用了12种良溶剂(包括含一定量水的良溶剂)和8中反溶剂，共进行了192个结晶组合，发现下表中9种情况没有获得结晶，并且挥发溶剂后原料药变成了油状物。
[表5]重结晶不能获得晶体的情况
Figure PCTCN2021089464-appb-000008
*比值1：良溶剂/原料药比值(ml/g)
Figure PCTCN2021089464-appb-000009
比值2：反溶剂/良溶剂比值(ml/ml)
研究发现，可以提高反溶剂/良溶剂的比值到≥8的水平，可以有效避免不能重结晶的结果。

Claims (9)

  1. 溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐的A型晶体，该晶体的粉末X射线衍射图中，在下述衍射角2θ：5.7±0.2度、12.9±0.2度、16.7±0.2度、18.0±0.2度、19.5±0.2度、21.1±0.2度、22.3±0.2度及23.3±0.2度处显示出衍射峰，所述粉末X射线衍射图是用Cu Kα射线得到的图谱。
  2. 溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐的B型晶体，该晶体的粉末X射线衍射图中，在下述衍射角2θ：5.2±0.2度、15.8±0.2度、16.9±0.2度、17.7±0.2度、19.5±0.2度、20.2±0.2度及22.1±0.2度处显示出衍射峰，所述粉末X射线衍射图是用Cu Kα射线得到的图谱。
  3. 溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐的制备方法，其步骤如下：
    (1)以环戊基扁桃酸或环戊基扁桃酸酯为起始物料，经硼氢化钠还原得到消旋的2-羟基-2-环戊基-2-苯乙醇(Z02)；反应溶剂选自乙二醇二甲醚、四氢呋喃、二氧六环、甲醇、乙醇；硼氢化钠与起始物料的摩尔比为2～5:1；还原环戊基扁桃酸时加入路易斯酸进行催化，路易斯酸选自三氯化铝、三氟化硼、氯化锌、四氯化锡和四氯化钛，路易斯酸与环戊基扁桃酸的摩尔比为2～5:1，优选2.5～3:1；
    (2)Z02与手性酰氯进行酯化反应后，晶体得手性羧酸2-羟基-2-环戊基-2-苯乙醇酯(Z03)；手性酰氯选自L-樟脑磺酰氯、D-樟脑磺酰氯、扁桃酸衍羟基生物酰氯；Z02与手性酰氯的摩尔比为1:1～3，优选为1:1.5～2；反应溶剂选自二氯甲烷、三氯甲烷、四氢呋喃、二氧六环，优选二氯甲烷、四氢呋喃；碱选自三乙胺、吡啶、N-甲基吗啡啉，碱与手性酰氯的摩尔比为1～4:1，优选1～2:1；
    (3)Z03用碱处理即可得到R-1-苯基-1-环戊基环氧乙烷(Z04)；碱选自氢化钠、叔丁醇钾、丁基锂、氨基钠，优选氢化钠、叔丁醇钾；碱与Z03摩尔比为1～3:1，优选为1～1.5:1；反应溶剂选自二氯甲烷、四氢呋喃、二氧六环、二甲基亚砜，优选二甲基亚砜、四氢呋喃；
    (4)Z04与R-(-)3-奎宁醇反应得到(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-氮杂双环[2，2，2]辛烷游离碱(Z05)；碱包括但不限于氢化钠、叔丁醇钾、丁基锂、氨基钠，优选氢化钠、叔丁醇钾；R-(-)3-奎宁醇与碱摩尔比为1～3:1，优选为1～1.5:1；反应溶剂选自二氯甲烷、四氢呋喃、二氧六环、二甲基亚砜，优选二甲基亚砜、四氢呋喃；
    (5)Z05与3-苯氧基-1-溴丙烷进行季铵化反应后，得到溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐。
  4. 溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮 杂双环[2，2，2]辛鎓盐的A型晶体的制造方法，其特征在于，进行加热以使溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐溶解于良溶剂，所述良溶剂选自醇类、乙腈、二氯甲烷或三氯甲烷，将反溶剂加入上述溶液，所述反溶剂选自酯、醚、酮、液态环烷烃或芳烃，所得溶液缓慢冷却以使其结晶化，得到A型晶体，整个过程必须避免接触水。
  5. 溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐的B型晶体的制造方法，其特征在于，进行加热以使溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐溶解于醇类或乙腈与水的混合溶剂，最优为乙醇；将反溶剂加入上述溶液，所述反溶液选自酯、水、醚、酮、液态环烷烃或芳烃，最优为乙酸乙酯；所得溶液缓慢冷却以使其结晶化；也可将溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐在加热条件下溶于醇、乙腈、二氯甲烷或三氯甲烷等溶剂，将水加入上述溶液，所得溶液缓慢冷却以使其结晶化，得到B型晶体。
  6. 溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐的B型晶体的制造方法，其特征在于，将溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐的A型晶体加入到反应容器中，加入纯化水，搅拌打浆，抽滤，将固体在40℃～80℃鼓风干燥，达到恒重后，得到B型晶体。
  7. 一种医药组合物，其含有权利要求1～2中任一项所述的晶体作为有效成分。
  8. 权利要求1～2所述的任一项晶体在制备M受体亚型选择性拮抗剂中的应用。
  9. 权利要求1～2中所述的任一项晶体在制备鼻炎、感冒后鼻炎、慢性气管炎、气道高、哮喘、COPD、咳嗽、尿失禁、尿频、不稳定性膀胱综合症、膀胱痉挛、膀胱炎、和胃肠道疾病如应激性大肠综合症、痉挛性结肠炎以及十二指肠和胃溃疡等疾病的预防剂或治疗剂中的应用。
PCT/CN2021/089464 2020-04-26 2021-04-24 一种m受体拮抗剂的晶体、制备方法及其应用 WO2021218833A1 (zh)

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