WO2018133533A1 - 孟鲁司特钠中间体及其制备方法和应用 - Google Patents

孟鲁司特钠中间体及其制备方法和应用 Download PDF

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WO2018133533A1
WO2018133533A1 PCT/CN2017/112847 CN2017112847W WO2018133533A1 WO 2018133533 A1 WO2018133533 A1 WO 2018133533A1 CN 2017112847 W CN2017112847 W CN 2017112847W WO 2018133533 A1 WO2018133533 A1 WO 2018133533A1
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compound
formula
acid
reaction
salt
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PCT/CN2017/112847
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French (fr)
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张志强
甄宜战
陈敬金
赵显栋
邱欣
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山东百诺医药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems
    • 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
    • C07B2200/07—Optical isomers

Definitions

  • This application belongs to the field of pharmaceutical and chemical technology.
  • Montelukast sodium is an anti-asthma drug developed by Merck in the United States. It was approved by the US Food and Drug Administration (FDA) on February 20, 1998. . It was listed in Finland and Mexico in February 1998, sold in the United States in October 1998, and subsequently listed in the United Kingdom, Canada, Italy, France, Germany and other countries.
  • FDA US Food and Drug Administration
  • montelukast sodium can selectively bind to leukotriene receptors in the respiratory tract, competitively block the action of allergic mediators, and thereby block organs to leukotrienes.
  • the reaction which improves the inflammation of the respiratory tract and makes the respiratory tract unobstructed, is an effective, low-toxic and safe anti-allergic and anti-allergic drug. Clinically used in children with asthma and exercise-induced asthma, has broad prospects.
  • the chemical name of montelukast sodium is 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinoline)vinyl]phenyl]-3- [2-(1-Hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate, the chemical structural formula is as follows:
  • the prior art patent documents for the synthesis of montelukast sodium are mainly CN1046711C, CN1139429A, CN1171873C, CN101321732A, CN105294556A, US20050107612A1, US20080275243A1, US7417149B2, WO20070572271A1, US20080097104A1, WO2009016191A1, US7189853B2, WO2005105751A1, WO2005105749A2, WO2008072872A1, WO2007116240A1. WO2008035086A2 and so on.
  • the first intermediate 1 2-(2-(3-(2-(7-chloro-2-quinolyl)-vinylphenyl)-3-hydroxypropyl)phenyl)- Conversion of a chiral alcohol hydroxyl group to a leaving group in 2-propanol to give intermediate 2, followed by nucleophilic passage of intermediate 2 and the nucleophilic reagent 1-indolylmethylcyclopropylacetic acid (or an analog thereof) under basic conditions Substitution reaction gives Intermediate 3, and then the target product of montelukast sodium is obtained by hydrolysis, salt formation, etc., as shown in Scheme 1:
  • Such a synthesis method mainly involves reacting an alcoholic hydroxyl group and a methylsulfonyl chloride linked to a chiral carbon to form a mesylate intermediate 2, but the intermediate is extremely unstable, and side reactions such as elimination and intramolecular cyclization are liable to occur.
  • a reaction must be carried out at a low temperature of about -30 ° C, and the product is required to be stored at about -15 ° C, which is harsh in conditions, which is disadvantageous for industrial large-scale production.
  • the patent US20080275243A1 mentions that the alcoholic hydroxyl group is converted into a chlorinated product by the reaction of the intermediate 1 and the thionyl chloride.
  • the ee value of the intermediate 2 obtained by the method is only 64%, and it is necessary to split and crystallize to obtain the desired target product, and the overall product is collected. The rate is significantly reduced, the cost is significantly increased, and a large amount of useless enantiomeric by-products are produced.
  • the tertiary alcohol acts as a nucleophilic reaction site and easily attacks the chiral carbon linked to diphenyl phosphate. It is prone to intramolecular cyclization and side reactions, which is not conducive to product purification and reduction.
  • the reaction yield increases the economic cost.
  • intermediate 2 is obtained by the reaction of intermediate 1, it is reacted with thioacetic acid or its potassium salt to obtain intermediate 4, intermediate 4 is deprotected by acetyl group and 2-(1-(bromomethyl) ring is removed.
  • the propyl)methyl acetate (or its analog) is condensed to give the intermediate 3, and the target product of montelukast sodium is obtained by the steps of hydrolysis, salt formation, etc., as shown in the synthetic route 2:
  • the preparation method of montelukast sodium generally has problems such as unstable chemical properties, easy elimination, intramolecular cyclization and the like, and the reaction conditions are harsh, which is not conducive to industrial production. Therefore, in the field of preparation technology of the anti-asthma drug montelukast sodium, it is necessary to develop a more mature and excellent process route.
  • LG means a leaving group such as OMs, OTs, Cl, Br, I, phosphate, etc.;
  • the term "compound” includes not only the compound itself but also a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Alkyl means an acyclic straight or branched, unsaturated or saturated hydrocarbon, for example those containing from 1 to 10 carbon atoms, typically from 1 to 6 carbon atoms.
  • an alkyl group herein may mean an alkyl group ( C1-6 alkyl group) having 1 to 6 carbons.
  • Representative saturated linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, and the like; Propyl, sec-butyl, isobutyl, tert-butyl, isopentyl and the like.
  • the unsaturated alkyl group contains at least one double bond or triple bond between adjacent carbon atoms (referred to as "alkenyl” or “alkynyl”, respectively).
  • Representative straight chain and branched alkenyl groups include ethenyl, propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1- Butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, etc.; and representative straight-chain and branched alkynyl groups include ethynyl, propynyl, 1- Butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl and the like.
  • Aryl means an aromatic carbocyclic monocyclic or polycyclic ring, such as a C6-20 aryl group.
  • the aryl group may be a phenyl group or a naphthyl group.
  • Polycyclic systems may, but do not necessarily, contain one or more non-aromatic rings, as long as one ring is aromatic.
  • Alkoxy means an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and sec-pentyl Oxygen.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy.
  • Aryloxy means an aryl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. Examples of aryloxy groups include, but are not limited to, phenoxy or naphthyloxy.
  • Arylalkylene refers to a group after substituting an alkyl group as defined above with an aryl group as defined above, examples of which include, but are not limited to, benzyl.
  • Arylalkyleneoxy refers to an arylalkylene group as defined above attached through an oxygen bridge, examples of which include, but are not limited to, benzyloxy.
  • the application provides a compound of formula (III): and a pharmaceutically acceptable salt or solvate thereof:
  • X represents a methyl group, an alkoxy group, an aryloxy group or an arylalkyleneoxy group
  • R 1 represents an alkyl group, an aryl group or an arylalkylene group
  • R 2 represents an alkyl group, an aryl group or an arylalkylene group.
  • X may represent methyl, C 1-6 alkoxy, phenoxy or benzyloxy;
  • R 1 may represent C 1-6 alkyl, phenyl or benzyl, and
  • R 2 may Represents a C 1-6 alkyl group, a phenyl group or a benzyl group.
  • X may be represented by a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • X may represent a methyl group, a methoxy group or an ethoxy group; and R 1 and R 2 may represent a phenyl group.
  • X may represent a methoxy group
  • R 1 and R 2 may represent a phenyl group
  • the compound of the formula (III) of the present application may be selected from the following:
  • the present application provides a method of preparing a compound of the above formula (III), and a pharmaceutically acceptable salt or solvate thereof, the method comprising: formulating a compound of formula (IV) (IV A ) compound dissolved in an aprotic organic solvent, reacted under the action of a base to obtain a compound of formula (III);
  • the base may be an organic base or an inorganic base.
  • the base may be selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-di Azabicycloundec-7-ene, 4-dimethylaminopyridine, pyridine, imidazole, NaH, NaOH, KOH, Ca(OH) 2 , NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , CsCO 3 One or more of CsOH, KHCO 3 , Ca(HCO 3 ) 2 and CaO.
  • the molar ratio of the compound of the formula (IV) to the base may range from 1:1 to 1:5.
  • the molar ratio of the compound of formula (IV) to the base may range from 1:2 to 1:3.
  • the molar ratio of the compound of the formula (IV) to the compound of the formula (IV A ) may range from 1:1 to 1:5.
  • the molar ratio of the compound of the formula (IV) to the compound of the formula (IV A ) may range from 1:1 to 1:2.
  • the compound of the formula (IV) and the compound of the formula (IV A ) may be dissolved in an aprotic organic solvent and reacted under the action of a base at a reaction temperature of from 0 ° C to 100 ° C.
  • the compound of the formula (IV) and the compound of the formula (IV A ) may be dissolved in an aprotic organic solvent and reacted under the action of a base at a reaction temperature of from 20 ° C to 50 ° C.
  • the compound of the formula (IV) and the compound of the formula (IV A ) may be dissolved in an aprotic organic solvent and reacted at the reaction temperature for 1 to 5 hours under the action of a base.
  • the compound of the formula (IV) and the compound of the formula (IV A ) may be dissolved in an aprotic organic solvent and reacted at the reaction temperature for 2 to 3 hours under the action of a base.
  • the present application provides the use of a compound of formula (III), as defined above, and a pharmaceutically acceptable salt or solvate thereof, as an intermediate, for the preparation of montelukast sodium.
  • the present application provides a method for synthesizing montelukast sodium, the method comprising:
  • the compound of the formula (II) or a salt thereof is reacted with a methyl Grignard reagent, and the mixture obtained by the reaction is treated with cold dilute acid to obtain a montelic acid;
  • Montelust acid or its organic amine salt is reacted with a base having a counter cation of sodium to prepare montelukast sodium;
  • the compound of the formula (II) or a salt thereof can be reacted with a methyl Grignard reagent in the presence of a Lewis acid activator, and the mixture obtained by treating the reaction with cold dilute acid can be used to obtain Monrust. acid.
  • the synthesizing method may include:
  • a Lewis acid activator-methyl Grignard reagent reaction solution the mixture is reacted for 1.5 to 5 hours, and the resulting mixture is treated with cold dilute acid to prepare montelukast acid.
  • salting a compound of formula (II) can comprise reacting a compound of formula (II) with an organic amine compound to form a salt.
  • the organic amine compound may include, but is not limited to, n-propylamine, isopropylamine, t-butylamine, benzylamine, alpha-methylbenzylamine, dicyclohexylamine, or a combination thereof.
  • the base in which the counter cation is sodium may be selected from one or more of sodium hydroxide, sodium hydride, sodium t-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, and sodium hydrogencarbonate.
  • the base used in the reaction for preparing the compound of the formula (II) may be an organic base or an inorganic base.
  • the salt of the compound of formula (II) may be such that a compound of formula (II) is reacted with dicyclohexylamine to form a dicyclohexylamine salt.
  • the base may be selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8- Diazabicycloundec-7-ene, 4-dimethylaminopyridine, pyridine, imidazole, NaH, NaOH, KOH, Ca(OH) 2 , NaHCO 3 , Ca(HCO 3 ) 2 , KHCO 3 , Na One or more of 2 CO 3 , K 2 CO 3 , CsCO 3 , CsOH, and CaO.
  • the molar ratio of the compound of the formula (III) to the base may be in the range of 1:2 to 1:4.
  • the molar ratio of the compound of formula (III) to 1-indolylmethylcyclopropylacetic acid or salt may range from 1:1 to 1:5.
  • the molar ratio of the compound of formula (III) to 1-indolylmethylcyclopropylacetic acid or salt may range from 1:2 to 1:3.
  • the step of preparing the compound of the formula (II) may be: dissolving 1-indole methylcyclopropylacetic acid in dimethyl sulfoxide, adding a sodium methoxide methanol solution under a nitrogen atmosphere, and stirring 0.5. h, then the compound of the formula (III) is dissolved in dimethyl sulfoxide and added to the above reaction system, and the reaction is stirred at 20 ° C to 60 ° C for 2 h to 4 h, and after quenching with 1 mol / L of dilute hydrochloric acid. The reaction, extraction, and collection of the organic phase are concentrated under reduced pressure and dried to give a compound of formula (II).
  • the Lewis acid activator in the presence of a Lewis acid activator, may be selected from the group consisting of antimony trichloride, zinc chloride, lithium chloride, cobalt chloride, barium chloride, and chlorination.
  • the Lewis acid activator may be selected from the group consisting of antimony trichloride, zinc chloride, lithium chloride, cobalt chloride, barium chloride, and chlorination.
  • One or more of chromium may be selected from the group consisting of antimony trichloride, zinc chloride, lithium chloride, cobalt chloride, barium chloride, and chlorination.
  • chromium one or more of chromium.
  • the Lewis acid activator may be antimony trichloride in the presence of a Lewis acid activator.
  • the number of moles of the Lewis acid activator is within 2 moles relative to 1 mole of the compound of the formula (II) or a salt thereof.
  • the molar ratio of the compound of the formula (II) to the Lewis acid activator may be in the range of 1:1 to 1:1.5.
  • the methyl Grignard reagent in the reaction for preparing montelukast acid, may be methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
  • the molar ratio of the compound of the formula (II) or a salt thereof to the methyl Grignard reagent may range from 1:3 to 1:10.
  • the molar ratio of the compound of the formula (II) or a salt thereof to the methyl Grignard reagent may range from 1:4 to 1:6.
  • the step of preparing the montelukine acid may be: ruthenium trichloride Adding to tetrahydrofuran, heating to 50 ° C to 80 ° C, stirring for 1 h, cooling to -10 ° C to 5 ° C, at -10 ° C to 5 ° C conditions, adding methyl magnesium chloride tetrahydrofuran solution, stirring 0.5h to 1h, and then A solution of the compound of the formula (II) or a salt thereof in tetrahydrofuran is added to the reaction system, and montelukast acid is prepared by an addition reaction.
  • the Montelust acid is first reacted with an organic amine to form an organic amine salt of the montelic acid, and then the organic amine salt is reacted with a base having a counter cation of sodium to thereby produce a Meng Rust sodium.
  • the reagents and starting materials used in the examples of the present application are all commercially available, or the materials used can be prepared by conventional techniques in the art; the instruments used are all conventional commercially available instruments. In different embodiments, the same reagent source is the same.
  • the compound of formula IV a (purchased from Zhongshan Antai Pharmaceutical Technology Co., Ltd., batch number: MTNOTR 160801) (50 g, 109.2 mmol) was dissolved in 500 mL of dichloromethane, and triethylamine (purchased from Tianjin Fuyu Fine Chemical Co., Ltd., Conventional reagent) (22.1g, 218.4mmol), diphenyl chlorophosphate (purchased from Heze Dijie Chemical Co., Ltd., batch number: 201705004) (44g, 163.8mmol) was added at a temperature below 10 °C.
  • the reaction solution was poured into 500 mL of 1 mol/L of dilute hydrochloric acid, and the organic phase was separated and the organic phase was washed successively with saturated sodium hydrogen carbonate solution and brine, and the organic phase was collected, dried over anhydrous magnesium sulfate Concentration gave 72.3 g of an oil. After testing, the oil is a compound of formula III b, in 97% yield.
  • the compounds of formula IV B prepared in Example 2 (30g, 63.6mmol) was dissolved in 300mL of toluene, cooled to 0 deg.] C, was added N, N- diisopropylethylamine (41.1g, 317.8mmol), was added dropwise Diethyl phosphate (54.8 g, 317.8 mmol), after completion of the dropwise addition, was stirred at 100 ° C for 1 h, and the reaction of the compound of formula IV b was completed by TLC. The reaction solution was poured into 300 mL of 1 mol/L of dilute hydrochloric acid, and extracted with 300 mL of ethyl acetate.
  • the reaction solution was poured into 400 mL of 1 mol/L of dilute hydrochloric acid, 400 mL of ethyl acetate was added, and the organic phase was washed successively with saturated sodium hydrogen carbonate solution and brine, and the organic phase was collected, dried over anhydrous magnesium sulfate Concentration gave 50 g of oil.
  • the oil was found to be a compound of formula IIId in a yield of 93.5%.
  • the thus prepared compound of the formula IV f (10 g, 19.2 mmol) was dissolved in 100 mL of 2-butanone, potassium hydroxide (2.2 g, 38.4 mmol) was added thereto, and the temperature was controlled below 10 ° C, and diphenyl chlorophosphate was added dropwise. 10.3g, 38.4mmol), after the completion of the dropwise addition, the mixture was stirred at 30 ° C for 3 h, and the reaction of the starting compound IV f was detected by TLC to terminate the reaction. The reaction solution was poured into 100 mL of 1 mol/L of dilute hydrochloric acid, and extracted with 100 mL of ethyl acetate.
  • reaction solution was added to 300 mL of 1 mol/L cold dilute hydrochloric acid, and the temperature was controlled at 0 ° C to precipitate a solid.
  • the mixture was filtered, and the filter cake was washed with water.
  • the filter cake was dissolved in ethyl acetate and washed twice with saturated brine. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, 35.8 g of a brownish brown oil was obtained as compound IIa.
  • the sodium 1-indolemethylcyclopropylacetate (12.5 g, 74.4 mmol) thus prepared was dissolved in 125 mL of dimethylformamide, and potassium t-butoxide (12.7 g, 113.6 mmol) was added at around 20 ° C under nitrogen atmosphere.
  • the compound of the formula IIIb (20 g, 28.4 mmol) prepared according to Example 2 was dissolved in 200 ml of dimethylformamide and added to the reaction system, and the mixture was heated to 60 ° C for 2 h, and the TLC was used to detect the starting material. The reaction is terminated after completion of the reaction of the III b compound.
  • the reaction solution was added to 200 mL of 1 mol/L of cold dilute hydrochloric acid, and the temperature was controlled at 0 ° C to precipitate a solid.
  • the mixture was filtered, and the filter cake was washed with water.
  • the filter cake was dissolved in ethyl acetate and washed twice with saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to give 22 g of brownish brown oil.
  • reaction solution was added to 200 mL of 1 mol/L of cold dilute hydrochloric acid, and the temperature was controlled at 0 ° C to precipitate a solid.
  • the mixture was filtered, and the filter cake was washed with water.
  • the filter cake was dissolved in ethyl acetate and washed twice with saturated brine. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, 23 g of a brownish brown oil was obtained as compound IIb.
  • the oil was obtained as a dicyclohexylamine salt of the compound of the formula IIb (23.6 g).
  • Lithium 1-indolemethylcyclopropylacetate (2.4 g, 15.4 mmol) was dissolved in 25 mL of ethyl acetate and protected with nitrogen. At about 20 ° C, 1,8-diazabicyclo[5,4,0 was added. 11-carbon-7-ene (purchased from Angie Chemical, conventional reagent) (2.3 g, 15.4 mmol), added, and reacted at room temperature for 0.5 h, the compound of formula III d prepared according to Example 4 (10 g, 15.4) Methyl) was dissolved in 100 mL of ethyl acetate and added dropwise to the reaction mixture. After the addition, the temperature was raised to 40 ° C for 4 h.
  • the TLC was used to detect the reaction of the compound of formula IIId.
  • the reaction solution was added to 100 mL of 1 mol/L cold dilute hydrochloric acid, and the temperature was controlled at 0 ° C to precipitate a solid.
  • the mixture was filtered, and the filter cake was washed with water.
  • the cake was dissolved in ethyl acetate and washed twice with saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to give 10 g of brown oil, Compound IId.
  • the oil was obtained as a dicyclohexylamine salt of the compound of the formula IId in a yield of 90%.
  • 1- ⁇ methylcyclopropylacetic acid (9.8 g, 66.9 mmol) was dissolved in 100 mL of acetonitrile and protected with nitrogen. At about 20 ° C, potassium hydroxide (3.8 g, 66.9 mmol) was added, and the reaction was carried out at room temperature for 0.5 h.
  • the compound of the formula IIIe (15 g, 22.3 mmol) prepared according to Example 5 was dissolved in 150 mL of acetonitrile and added dropwise to the reaction solution. After the addition, the temperature was raised to 30 ° C for 3 h, and the reaction of the compound of the formula IIIe was terminated by TLC. reaction.
  • the reaction solution was added to 150 mL of 1 mol/L cold dilute hydrochloric acid, and the temperature was controlled at 0 ° C to precipitate a solid.
  • the mixture was filtered, and the filter cake was washed with water.
  • the filter cake was dissolved in ethyl acetate and washed twice with saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to give 16.6 g of a brown oil.
  • the oil was obtained as a dicyclohexylamine salt of the compound of the formula IIe (15.4 g, yield: 92%).
  • 1- ⁇ methylcyclopropylacetic acid (3.9 g, 26.6 mmol) was dissolved in 100 mL of acetonitrile and protected with nitrogen. At about 20 ° C, 60 wt% of sodium hydride (purchased from Angie Chemical, conventional reagent) was added. g, 26.6 mmol), added, and reacted at room temperature for 0.5 h, the compound of formula IIIf (10 g, prepared according to Example 6 13.3 mmol) was dissolved in 150 mL of acetonitrile and added dropwise to the reaction solution. After the addition, the temperature was raised to 50 ° C for 2 h, and the reaction of the starting compound of formula IIIf was completed by TLC to terminate the reaction.
  • sodium hydride purchased from Angie Chemical, conventional reagent
  • reaction solution was added to 100 mL of 1 mol/L cold dilute hydrochloric acid, and the temperature was controlled at 0 ° C to precipitate a solid.
  • the mixture was filtered, and the filter cake was washed with water.
  • the filter cake was dissolved in ethyl acetate and washed twice with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 12 g,yel.
  • the antimony trichloride (Nanjing Yannuo Chemical Technology Co., Ltd., batch number: XN17031201) (4.2g, 17.1mmol) was suspended in 100mL of tetrahydrofuran, protected by nitrogen, heated to 65 ° C for 1 h, cooled to -5 ° C, added 22.8 mL methylmagnesium chloride tetrahydrofuran solution (Shaoxing Shangyu Chemical Co., Ltd.) (68.4 mmol, 3 mol/L), added, and stirred for 1 h, the dicyclohexylamine salt of the compound of formula IIa prepared according to Example 8 (12.9 g, 17.1 mmol) Dissolved in 13 mL of tetrahydrofuran and added dropwise to the reaction solution, added, and kept at 0 ° C for 1.5 h.
  • the reaction of the dicyclohexylamine salt of the compound of the formula IIa is detected by TLC, and the reaction is terminated.
  • the reaction solution was added to 100 mL of 1 mol/L cold dilute hydrochloric acid, extracted with dichloromethane, and the organic phase was washed once with saturated sodium bicarbonate solution, 0.5 mol/L tartaric acid solution and water, and the organic phase was collected and dried over anhydrous magnesium sulfate. After drying, it was concentrated under reduced pressure to give 9.8 g of a yellow oil of montelic acid.
  • the reaction of the dicyclohexylamine salt of the compound of the formula IIb is detected by TLC, and the reaction is terminated.
  • the reaction solution was added to 100 mL of 1 mol/L of cold dilute hydrochloric acid, extracted with dichloromethane, and washed twice with saturated brine. The organic phase was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 9.2 g of yellow oil.
  • the montelukast isopropylamine salt prepared in the step 2 was prepared according to the sodium salt formation method of Example 14 to obtain 4.5 g of montelukast sodium in a yield of 96%.
  • Zinc chloride (Anne Chemical) (4.4 g, 32.6 mmol) was suspended in 100 mL of tetrahydrofuran, and 16.3 mL of methylmagnesium chloride tetrahydrofuran solution (Shaoxing Shangyu Chemical Co., Ltd.) was added dropwise under a nitrogen atmosphere at a temperature of 5 °C. (48.9 mmol, 3 mol/L), stirring was continued for 40 min, and the dicyclohexylamine salt of the compound of the formula IId prepared in Example 11 (13.0 g, 16.3 mmol) was dissolved in 130 mL of tetrahydrofuran and added dropwise to the upper reaction system, and added dropwise.
  • reaction solution was added to 100 mL of 1 mol/L of cold dilute hydrochloric acid, extracted with dichloromethane, and the organic phase was washed once with saturated sodium bicarbonate solution, 0.5 mol/L tartaric acid solution and water, and the organic phase was collected and dried over anhydrous magnesium sulfate. After drying, it was concentrated under reduced pressure to give 8.8 g of a yellow oily montelic acid.
  • the montelukast isopropylamine salt prepared in the step 2 was prepared according to the method of the sodium salt formation in Example 14 to obtain 7.8 g of montelukast sodium in a yield of 95%.
  • Lithium chloride (Anne Chemical) (1.1 g, 26.3 mmol) was suspended in 100 mL of tetrahydrofuran, and 35 mL of methylmagnesium bromide tetrahydrofuran solution (105 mmol, 3 mol/L) was added dropwise at -10 ° C and stirred.
  • the dicyclohexylamine salt (13.1 g, 17.5 mmol) of the compound of the formula IIe prepared in Example 12 was dissolved in 130 mL of tetrahydrofuran and added dropwise to the reaction system for 5 h. The reaction was terminated after completion of the reaction of the dicyclohexylamine salt of the starting material IIe compound by TLC.
  • the reaction solution was added to 100 mL of 1 mol/L of cold dilute hydrochloric acid, and extracted with dichloromethane.
  • the organic phase was washed once with saturated sodium bicarbonate solution, 0.5 mol/L tartaric acid solution and water, and the organic phase was collected and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 9.2 g of a yellow oil of montelukide acid was obtained.
  • the montelukast isopropylamine salt prepared in the step 1 was prepared according to the sodium salt formation method in Example 14 to obtain 8.9 g of montelukast sodium in a yield of 96%. MS: 586 [M+H]
  • TLC is used to detect the dicyclohexylamine salt of the compound of formula IIf, and the reaction is terminated.
  • the reaction solution was added to 100 mL of 1 mol/L of cold dilute hydrochloric acid, and extracted with dichloromethane.
  • the organic phase was washed once with saturated sodium bicarbonate solution, 0.5 mol/L tartaric acid solution and water, and the organic phase was collected and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 8.5 g of a yellow oil montelukast acid was obtained.
  • the montelukast isopropylamine salt prepared in the step 2 was prepared according to the method of the sodium salt formation in Example 14 to obtain 7.4 g of montelukast sodium in a yield of 95%.
  • the montelukast sodium was prepared according to the method of Example 18, except that in the step 1, the compound of the formula IIf was substituted for its dicyclohexylamine salt and the amount of methyl magnesium iodide was accordingly doubled.
  • the montelukast sodium was prepared according to the method of Example 18, except that without the step 2, the montelukast isopropylamine salt was formed.
  • the present application provides, in one aspect, a compound represented by formula (III) as described above and a process for the preparation thereof.
  • This compound can be used as a key intermediate for the preparation of montelukast sodium.
  • the present application provides a new process route for synthesizing montelukast sodium using a compound represented by formula (III) as a key intermediate.
  • the compound represented by the formula (III) which is a key intermediate, is chemically stable, and can be used for preparing montelukast sodium to overcome the use of a tertiary alcohol as a nucleophilic reaction site in the existing preparation route, and is easy to attack and deviate.
  • the chiral carbon connected to the group is prone to intramolecular cyclization and has many disadvantages, and the whole reaction process is mild.
  • the chiral carbon configuration does not change during the reaction, and the optical purity is high, and it is easy to be purified. In industrialized production.

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Abstract

本申请提供一种以下通式(Ⅲ)所表示的化合物及其制备方法和其作为关键中间体用于制备孟鲁司特钠的用途：

Description

孟鲁司特钠中间体及其制备方法和应用 技术领域
本申请属于医药化工技术领域。
背景技术
孟鲁司特钠是由美国默克公司开发的抗哮喘药物，于1998年2月20日获得美国食品药品监督管理局(FDA)的上市批准，商品名为
Figure PCTCN2017112847-appb-000001
。1998年2月在芬兰和墨西哥上市，1998年10月在美国上市销售，随后在英国、加拿大、意大利、法国、德国等国家相继上市。孟鲁司特钠作为选择性的白三烯受体拮抗剂，可与呼吸道中的白三烯受体选择性的结合，竞争性地阻断过敏介质的作用，进而阻断器官对白三烯的反应，改善呼吸道炎症，使呼吸道通畅，是一种高效、低毒、安全的平喘消炎和抗过敏药物。临床用于儿童哮喘和运动引起哮喘的治疗，具有广阔的前景。
孟鲁司特钠的化学名为：1-[[[(1R)-1-[3-[(1E)-2-(7-氯-2-喹啉)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫代]甲基]环丙烷乙酸钠，其化学结构式如下：
Figure PCTCN2017112847-appb-000002
现有技术中关于孟鲁司特钠的合成方法的专利文献主要有CN1046711C、CN1139429A、CN1171873C、CN101321732A、CN105294556A、US20050107612A1、US20080275243A1、US7417149B2、WO20070572271A1、US20080097104A1、WO2009016191A1、US7189853B2、WO2005105751A1、WO2005105749A2、WO2008072872A1、WO2007116240A1、WO2008035086A2等。
目前关于孟鲁司特钠的合成方法很多，这些方法主要是围绕手性碳与侧 链构建C-S键的策略，可大体归纳为以下几类：
第一类，首先将中间体1，即2-(2-(3-(2-(7-氯-2-喹啉基)-乙烯基苯基)-3-羟基丙基)苯基)-2-丙醇中手性醇羟基转化为离去基团得到中间体2，然后在碱性条件下中间体2和亲核试剂1-巯甲基环丙基乙酸(或者其类似物)通过亲核取代反应得到中间体3，再通过水解、成盐等步骤得到孟鲁司特钠目标产物，如合成路线1所示：
Figure PCTCN2017112847-appb-000003
此类合成方法主要是将与手性碳相连的醇羟基和甲基磺酰氯反应生成甲磺酸酯中间体2，但是该中间体极不稳定，容易发生消除、分子内环化等副反应。另一方面该类反应必须在约-30℃的低温下进行，并且要求产物保存在约-15℃，条件苛刻，不利于工业大生产。专利US20080275243A1中提到通过中间体1和二氯亚砜反应将醇羟基转为氯代物，该方法所得中间体2的ee值仅64％，需要拆分结晶才能得到符合要求的目标产物，整体收率显著降低，成本明显提高，同时产生大量无用的对映体副产物。
韩美科学株式会社专利文件CN101558042B、CN101808998B及上海迪赛诺化学制药有限公司专利申请文件CN105294556A中公开了使用氯磷酸酯二苯酯作为亲电试剂与手性醇羟基反应制备孟鲁司特中间体的方法，具体如下：
Figure PCTCN2017112847-appb-000004
此反应路线中，在碱性条件下，叔醇作为亲核反应位点很容易进攻和磷酸二苯酯相连的手性碳，容易发生分子内环化、副反应多，不利于产品纯化，降低了反应产率，增加了经济成本。
第二类，通过中间体1反应得到中间体2后，和硫代乙酸或其钾盐反应得到中间体4，中间体4脱掉乙酰基保护后和2-(1-(溴甲基)环丙基)乙酸甲酯(或其类似物)缩合得到中间体3，再通过水解、成盐等步骤得到孟鲁司特钠目标产物，如合成路线2所示：
Figure PCTCN2017112847-appb-000005
也有采用(E)-2-[3-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-氧代丙基]苯甲酸甲酯为起始原料，先得到中间体4的类似物4’，然后与甲基溴化镁格氏试剂加成得到中间体4，再和2-(1-(溴甲基)环丙基)乙酸甲酯得到中间体3。
Figure PCTCN2017112847-appb-000006
对于上述第二类合成策略，同样存在甲磺酸酯中间体2不稳定的问题；另一方面，引入硫代乙酰基，增加了反应步骤进而降低了经济性；同时关键起始原料2-(1-(溴甲基)环丙基)乙酸甲酯市场上基本上没有厂家提供，该合成 策略不适宜工业化大生产。
综上所述，现有技术中孟鲁司特钠的制备方法普遍存在着中间体化学性质不稳定、容易发生消除、分子内环化等副反应，反应条件苛刻，不利于工业化生产等问题，因此在抗哮喘药物孟鲁司特钠的制备技术领域，需要开发一种更加成熟的且稳定性优异的工艺路线。
发明概述
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
除非另有说明，下列用在权利要求书和说明书中的术语具有如下含义：
在本申请中
Figure PCTCN2017112847-appb-000007
表示发生化学反应的位点；
在本申请中，“LG”表示离去基团，如OMs、OTs、Cl、Br、I、磷酸酯等；
在本申请中，术语“化合物”不仅包括所述化合物本身，还包括其药学上可接受的盐或其溶剂化物。
“烷基”意指一种非环状直链或支链、不饱和或饱和烃，例如包含从1至10个碳原子、典型地是1至6个碳原子的那些。在任何实施例内，在此的烷基可以是指具有1至6个碳的烷基(C1-6烷基)。代表性饱和直链烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基等；同时饱和支链烷基包括异丙基、仲丁基、异丁基、叔丁基、异戊基等。不饱和烷基包含在相邻碳原子之间的至少一个双键或者三键(分别称为“烯基”或“炔基”)。代表性直链和支链烯基包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基等；同时代表性直链和支链炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基等。
“芳基”意指芳香族碳环单环或多环，例如C6-20的芳基。该芳基可以为苯基或萘基。多环系统可以，但不必需包含一个或多个非芳香族环，只要一个环是芳香族即可。
“烷氧基”是指通过一个氧桥附接的具有指定数目的碳原子的如上所定义的烷基。烷氧基的实例包括但不限于，甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基以及仲戊氧基。优选的烷氧基是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、或叔丁氧基。
“芳氧基”是指通过一个氧桥附接的具有指定数目的碳原子的如上所定义的芳基。芳氧基的实例包括但不限于，苯氧基或萘氧基。
“芳基亚烷基”是指用如上所定义的芳基取代如上所定义的烷基后的基团，其实例包括但不限于苄基。
“芳基亚烷氧基”是指通过一个氧桥附接的被如上所定义的芳基亚烷基，其实例包括但不限于苄氧基。
一方面，本申请提供了一种通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物：
Figure PCTCN2017112847-appb-000008
其中：
X表示甲基、烷氧基、芳氧基或芳基亚烷氧基；
R1表示烷基、芳基或芳基亚烷基；
R2表示烷基、芳基或芳基亚烷基。
在以上或其他实施方式中，X可以表示甲基、C1-6烷氧基、苯氧基或苄氧基；R1可以表示C1-6烷基、苯基或苄基，R2可以表示C1-6烷基、苯基或苄基。
在以上或其他实施方式中，X可以表示为具有1～4个碳原子的直链或支链烷氧基。
在以上或其他实施方式中，X可以表示甲基、甲氧基或乙氧基；R1、R2可以表示苯基。
在以上或其他实施方式中，X可以表示甲氧基；R1、R2可以表示苯基。
本申请的通式(Ⅲ)所示的化合物可以选自如下：
Figure PCTCN2017112847-appb-000009
在另一方面，本申请提供一种制备如上所述的通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物的方法，该方法包括：将式(Ⅳ)化合物和式(ⅣA)化合物溶解于非质子有机溶剂中，在碱的作用下反应得到式(Ⅲ)化合物；
Figure PCTCN2017112847-appb-000010
其中，X、R1和R2如上所定义的。
在以上或其他实施方式中，所述碱可以为有机碱或无机碱。
在以上或其他实施方式中，所述碱可以选自甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、吡啶、咪唑、NaH、NaOH、KOH、Ca(OH)2、NaHCO3、Na2CO3、K2CO3、CsCO3、CsOH、KHCO3、Ca(HCO3)2和CaO中的一种或更多种。
在以上或其他实施方式中，其中所述式(Ⅳ)化合物与所述碱的摩尔比可以为1：1至1：5范围内。
在以上或其他实施方式中，其中所述式(Ⅳ)化合物与所述碱的摩尔比可以为1：2至1：3范围内。
在以上或其他实施方式中，所述式(Ⅳ)化合物和式(ⅣA)化合物的摩尔比可以为1：1至1：5范围内。
在以上或其他实施方式中，所述式(Ⅳ)化合物和式(ⅣA)化合物的摩尔比可以为1：1至1：2范围内。
在以上或其他实施方式中，可以将式(Ⅳ)化合物和式(ⅣA)化合物溶解于非质子有机溶剂中，在碱的作用下在0℃至100℃的反应温度下反应。
在以上或其他实施方式中，可以将式(Ⅳ)化合物和式(ⅣA)化合物溶解于非质子有机溶剂中，在碱的作用下在20℃至50℃的反应温度下反应。
在以上或其他实施方式中，可以将式(Ⅳ)化合物和式(ⅣA)化合物溶解于非质子有机溶剂中，在碱的作用下在反应温度下反应1h至5h。
在以上或其他实施方式中，可以将式(Ⅳ)化合物和式(ⅣA)化合物溶解于非质子有机溶剂中，在碱的作用下在反应温度下反应2h至3h。
在又一方面，本申请提供了如上所定义的通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物作为中间体用于制备孟鲁司特钠的用途。
在又一方面，本申请提供了一种孟鲁司特钠的合成方法，所述合成方法包括：
在碱的存在下，使1-巯甲基环丙基乙酸或其盐与上述的通式(Ⅲ)所示的化合物反应，用冷稀酸处理反应得到的混合物，以制备式(Ⅱ)化合物；
任选地使式(II)化合物成盐；
使式(Ⅱ)化合物或其盐与甲基格氏试剂反应，用冷稀酸处理反应得到的混合物，制得孟鲁斯特酸；
任选地使孟鲁斯特酸与有机胺反应，形成孟鲁斯特酸的有机胺盐；
使孟鲁斯特酸或其有机胺盐与抗衡阳离子为钠的碱反应，以制得孟鲁斯特钠；
Figure PCTCN2017112847-appb-000011
在以上或其他实施方式中，可以在路易斯酸活化剂的存在下使式(Ⅱ)化合物或其盐与甲基格氏试剂反应，用冷稀酸处理反应得到的混合物，制得孟鲁斯特酸。
在以上或其他实施方式中，所述合成方法可以包括：
将1-巯甲基环丙基乙酸或其盐和碱依次加入有机溶剂中，然后加入式(Ⅲ)化合物，在20℃至60℃搅拌反应，使反应进行2h至4h，用冷稀酸处理反应得到的混合物，得到式(Ⅱ)化合物；
任选地使式(II)化合物成盐；
将路易斯酸活化剂加入到有机溶剂中，然后在-10℃至5℃的温度条件下，加入甲基格氏试剂，搅拌0h至1h，再将式(Ⅱ)化合物或其盐的溶液加至路易斯酸活化剂-甲基格氏试剂反应液中，反应1.5h至5h，用冷稀酸处理反应得到的混合物，以制备孟鲁斯特酸。
在以上或其他实施方式中，使式(II)化合物成盐可以包括使式(II)化合物与有机胺化合物反应，以形成盐。
在以上或其他实施方式中，所述有机胺化合物可以包括，但不限于，正丙胺、异丙胺、叔丁胺、苄胺、α-甲基苄胺、二环己胺或其组合。
在以上或其他实施方式中，所述抗衡阳离子为钠的碱可以选自氢氧化钠、氢化钠、叔丁醇钠、甲醇钠、乙醇钠、碳酸钠和碳酸氢钠中的一种或更多种。
在以上或其他实施方式中，其中制备式(Ⅱ)化合物的反应中所使用的碱可以为有机碱或无机碱。
在以上或其他实施方式中，使式(Ⅱ)化合物成盐可以为使式(Ⅱ)化合物与二环己胺反应，形成二环己胺盐。
在以上或其他实施方式中，其中所述碱可以选自甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、吡啶、咪唑、NaH、NaOH、KOH、Ca(OH)2、NaHCO3、Ca(HCO3)2、KHCO3、Na2CO3、K2CO3、CsCO3、CsOH和CaO中的一种或更多种。
在以上或其他实施方式中，在制备式(Ⅱ)化合物的反应中，式(Ⅲ) 化合物与所述碱的摩尔比可以为1：1至1：5范围内。
在以上或其他实施方式中，在制备式(Ⅱ)化合物的反应中，式(Ⅲ)化合物与所述碱的摩尔比可以为1：2至1：4范围内。
在以上或其他实施方式中，式(Ⅲ)化合物与1-巯甲基环丙基乙酸或盐的摩尔比可以为1：1至1：5范围内。
在以上或其他实施方式中，式(Ⅲ)化合物与1-巯甲基环丙基乙酸或盐的摩尔比可以为1：2至1：3范围内。
在以上或其他实施方式中，制备式(Ⅱ)化合物的步骤可以为：将1-巯甲基环丙基乙酸溶解在二甲基亚砜中，氮气氛围下，加入甲醇钠甲醇溶液，搅拌0.5h，然后将式(Ⅲ)化合物溶解于二甲亚砜中，并加入至上述反应体系中，在20℃至60℃搅拌反应2h至4h，待反应完毕后用1mol/L的稀盐酸淬灭反应，萃取，收集有机相，进行减压浓缩、干燥，得到式(Ⅱ)化合物。
在以上或其他实施方式中，在存在路易斯酸活化剂的情况下，所述路易斯酸活化剂可以选自三氯化铈、氯化锌、氯化锂、氯化钴、氯化镧以及氯化铬中的一种或更多种。
在以上或其他实施方式中，在存在路易斯酸活化剂的情况下，所述路易斯酸活化剂可以为三氯化铈。
在以上或其他实施方式中，在制备孟鲁斯特酸的反应中，相对于1摩尔的所述式(II)化合物或其盐，路易斯酸活化剂的摩尔数在2摩尔以内。
在以上或其他实施方式中，在制备孟鲁斯特酸的反应中，所述式(Ⅱ)化合物和路易斯酸活化剂的摩尔比可以为1：1至1：1.5范围内。
在以上或其他实施方式中，在制备孟鲁斯特酸的反应中，所述甲基格氏试剂可以为甲基氯化镁、甲基溴化镁或甲基碘化镁。
在以上或其他实施方式中，所述式(Ⅱ)化合物或其盐与甲基格氏试剂的摩尔比可以为1：3至1：10范围内。
在以上或其他实施方式中，所述式(Ⅱ)化合物或其盐与甲基格氏试剂的摩尔比可以为1：4至1：6范围内。
在以上或其他实施方式中，制备孟鲁斯特酸的步骤可以为：将三氯化铈 加入到四氢呋喃中，升温至50℃至80℃，搅拌1h，降温至-10℃至5℃，在-10℃至5℃温度条件下，加入甲基氯化镁四氢呋喃溶液，搅拌0.5h至1h，再将式(Ⅱ)化合物或其盐的四氢呋喃溶液加至反应体系中，通过加成反应制备孟鲁斯特酸。
在以上或其他实施方式中，先使孟鲁斯特酸与有机胺反应，形成孟鲁斯特酸的有机胺盐，然后使该有机胺盐与抗衡阳离子为钠的碱反应，从而制得孟鲁斯特钠。
详述
以下对本申请的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅是说明性的和示例性的，并不由此以任何方式限制本申请权利要求的保护范围。
除非另有说明，本申请实施例所用到的试剂、原料均为市售商品，或者所用到的原料能够通过本领域的常规技术手段进行制备；所用到的仪器均为常规市售仪器。在不同的实施例中，相同的试剂来源相同。
实施例1：中间体Ⅲa的合成
Figure PCTCN2017112847-appb-000012
将式Ⅳa化合物(购自中山奕安泰医药科技有限公司，批号：MTNOTR160801)(50g，109.2mmol)溶于500mL二氯甲烷中，加入三乙胺(购自天津市富宇精细化工有限公司，常规试剂)(22.1g，218.4mmol)，控温10℃以下滴加氯磷酸二苯酯(购自菏泽帝捷化工股份有限公司，批号：201705004)(44g,163.8mmol)，滴加完毕后，升至30℃下搅拌3h，薄层色谱(TLC)检测原料式Ⅳa化合物反应完全。将反应液倒入500mL 1mol/L的稀盐酸中，分离且收集有机相，依次用饱和碳酸氢钠溶液和饱和食盐水洗涤并收集有机相，经无水硫酸镁干燥，后进行减压浓缩，即得74.5g油状物。经检测，该油状物为式Ⅲa化合物，收率为99％。
Figure PCTCN2017112847-appb-000013
(C＝1.0,甲醇)。
MS:690[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz,1H),7.82(s,1H),7.80-7.78(d,1H),7.75-7.73(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4 Hz,1H),7.47-7.10(m,15H),5.75-5.70(m,1H),3.76(s,3H),3.03-2.96(td,1H),2.86-2.78(td,1H),2.37-2.36(m,1H),2.34-2.33(m,1H)。
根据核磁双键处氢的耦合常数J＝16.4，即可推测出此处双键的立体构型为E式(其中，Z式一般为8-12Hz，E式为12-16Hz)。
实施例2：中间体Ⅲb的合成
Figure PCTCN2017112847-appb-000014
将式Ⅳa化合物(51g，111.5mmol)溶于510mL乙醇中，加入硝酸铈铵(购自安耐吉化学，型号E060147)(122.2g，223mmol)，室温下反应50h，减压浓缩除去反应溶剂，加入200mL水，产品用二氯甲烷萃取(300mL×2)，有机相用无水硫酸镁干燥后进行减压浓缩，制得式50g IVb化合物。
将由此制得的式Ⅳb化合物(50g，105.9mmol)溶于500mL乙酸乙酯中，加入三乙胺(32.1g，317.7mmol)，控温10℃以下，滴加氯磷酸二苯酯(56.9g,211.8mmol)，滴加完毕后，升至50℃下搅拌2h，TLC检测原料式Ⅳb化合物反应完全。将反应液倒入至500mL 1mol/L的稀盐酸中，分离且收集有机相，有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤并收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得72.3g油状物。经检测，该油状物为式Ⅲb化合物，收率为97％。
MS:704[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz 1H),7.82(s,1H),7.80-7.78(d,1H),7.75-7.73(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz1H),7.47-7.10(m,15H),5.75-5.70(m,1H),4.20(m,2H),3.03-2.96(td,1H), 2.86-2.78(td,1H),2.37-2.36(m,1H),2.34-2.33(m,1H),1.36-1.32(t,2H)。
实施例3：中间体Ⅲc的合成
Figure PCTCN2017112847-appb-000015
将实施例2中制备的式Ⅳb化合物(30g，63.6mmol)溶于300mL甲苯中，降温至0℃，加入N,N-二异丙基乙胺(41.1g，317.8mmol)，滴加氯磷酸二乙酯(54.8g，317.8mmol)，滴加完毕后，升至100℃下搅拌1h，TLC检测原料式Ⅳb化合物反应完全。将反应液倒入至300mL 1mol/L的稀盐酸中，加入300mL乙酸乙酯萃取，有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤并收集有机相，后经无水硫酸镁干燥后进行减压浓缩，即得38g油状物。经检测，该油状物为式Ⅲc化合物，收率为98％。
MS:608[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz 1H),7.82(s,1H),7.80-7.78(d,1H),7.75-7.73(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz1H),7.47-7.10(m,5H),5.75-5.70(m,1H),4.20(m,6H),3.03-2.96(m,2H),2.86-2.78((m,2H),,1.32-1.29(m,9H)。
实施例4：中间体Ⅲd的合成
Figure PCTCN2017112847-appb-000016
将式Ⅳa化合物(50g，109.2mmol)溶于500mL异丙醇中，加入硝酸铈铵(119.7g，218.4mmol)，室温下反应50h，减压浓缩除去反应溶剂，加入200mL水，产品用二氯甲烷萃取(300mL×2)，有机相用无水硫酸镁干燥后进行减压浓缩，制得式40g IVd化合物。
将由此制得的式Ⅳd化合物(40g，82.3mmol)溶于400mL四氢呋喃中，降 温至0℃，加入4-二甲氨基吡啶(10.1g，82.3mmol)，滴加氯磷酸二异丙酯(16.5g，82.3mmol)，滴加完毕后，保持0℃下搅拌5h，TLC检测原料式Ⅳd化合物基本反应完毕后终止反应。将反应液倒入至400mL 1mol/L的稀盐酸中，加入400mL乙酸乙酯，有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，收集有机相，经无水硫酸镁干燥并进行减压浓缩，即得50g油状物。经检测，该油状物为式Ⅲd化合物，收率为93.5％。
MS:650[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz 1H),7.82(s,1H),7.80-7.78(d,1H),7.75-7.73(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz1H),7.47-7.10(m,5H),5.75-5.70(m,1H),4.65(m,2H)4.20(m,2H),3.03-2.96(m,2H),2.86-2.78((m,2H),1.32-1.28(m,15H)。
实施例5：中间体Ⅲe的合成
Figure PCTCN2017112847-appb-000017
将式Ⅳa化合物化合物(15g，32.8mmol)，二甲羟胺盐酸盐(3.9g，39.4mmol)加至150ml四氢呋喃中，氮气保护下，控温0℃滴加109ml甲基氯化镁四氢呋喃溶液(3mol/L)，加毕，搅拌反应10h。将反应液倒入1N盐酸中，搅拌2h，抽滤，滤饼水洗，60℃烘干，得黄色固体式Ⅳe化合物10.0g。
将由此制得的式Ⅳe化合物(10g，22.6mmol)溶于100mL乙腈中，加入氢氧化钠(2.712g，67.8mmol)，控温10℃以下，滴加氯磷酸二苯酯(18.2g，67.8mmol)，滴加完毕后，升至40℃下搅拌2.5h，TLC检测原料式Ⅳe化合物反应完毕，终止反应。将反应液倒入至100mL 1mol/L的稀盐酸中，加入100mL乙酸乙酯萃取分离有机相，依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得15g油状物。经检测，该油状物为式Ⅲe化合物，收率为98.7％。
MS:674[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz,1H),7.82(s,1H),7.80-7.78(d,1H),7.75-7.73(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz,1H),7.47-7.10(m,15H),5.75-5.70(m,1H),2.91-2.84(m,1H),2.76-2.69(m,1H),2.53(s,3H),2.34-2.31(m,1H),2.36-2.28(m,1H)
实施例6：中间体Ⅲf的合成
Figure PCTCN2017112847-appb-000018
将式Ⅳa化合物(15g，32.8mmol)溶于150ml甲苯中，加入钛酸四异丙酯(9.3g，32.8mmol)，回流反应15h，减压浓缩除去反应溶剂，加入50mL水，产品用二氯甲烷萃取(150mL×2)，有机相用无水硫酸镁干燥后进行减压浓缩，制得式10g IVf化合物。
将由此制得的式Ⅳf化合物(10g，19.2mmol)溶于100mL 2-丁酮中，加入氢氧化钾(2.2g，38.4mmol)，控温10℃以下，滴加氯磷酸二苯酯(10.3g，38.4mmol)，滴加完毕后，升至30℃下搅拌3h，TLC检测原料式Ⅳf化合物反应完毕，终止反应。将反应液倒入至100mL 1mol/L的稀盐酸中，加入100mL乙酸乙酯萃取，有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得15g油状物。经检测，该油状物为式Ⅲf化合物，收率为98.7％。
MS:752[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz,1H),7.82(s,1H),7.80-7.78(d,1H),7.75-7.73(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz,1H),7.47-7.10(m,20H),5.75-5.70(m,1H),3.03-2.53(m,2H),2.86-2.78(m,2H)。
实施例7：中间体Ⅱa的合成
Figure PCTCN2017112847-appb-000019
将1-巯甲基环丙基乙酸(牡丹江恒远药业股份有限公司，批号：BP26-20160901H)(16g，109.5mmol)溶于160mL二甲亚砜中，氮气保护条件下，在20℃左右，滴加30wt％甲醇钠的甲醇溶液(37.5g，208.1mmol)，加毕，室温反应0.5h，将根据实施例1制备的Ⅲa化合物(37.8g，54.8mmol)溶于380ml二甲亚砜中并加至反应体系中，后升温至30℃搅拌反应3h，TLC检测原料式Ⅲa化合物反应完毕后终止反应。将反应液加入至300mL1mol/L的冷稀盐酸中，控温0℃，析出固体，抽滤，滤饼水洗，将滤饼溶于乙酸乙酯中，饱和食盐水洗涤2次，收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得35.8g黄褐色油状式物，即为化合物Ⅱa。
实施例8：中间体Ⅱa的二环己胺盐合成
将实施例7制备得到的35.8g黄褐色油状的化合物Ⅱa溶于215mL乙酸乙酯中，氮气保护下，滴加二环己胺(27.7g，152.7mmol)，加毕，室温搅拌5h，析出少量固体，缓慢滴加430mL正己烷，加毕，室温搅拌12h，抽滤，滤饼用1:1的乙酸乙酯/正己烷混合溶剂洗涤，50℃干燥，得式Ⅱa化合物的二环己胺盐41.2g。
Figure PCTCN2017112847-appb-000020
(C＝1.0,甲醇)
MS:586[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz,1H),7.82(s,1H),7.80-7.78(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz,1H),7.47-7.10(m,8H),3.91(m,1H),3.32(t,4H),2.84(m,1H),2.68(m,1H),2.34(s,2H),2.11(m,2H),2.05(s,2H),2.02(m,4H),1.60(t,2H),0.36(m,4H)。
实施例9：中间体Ⅱb及其二环己胺盐的合成
Figure PCTCN2017112847-appb-000021
将1-巯甲基环丙基乙酸(10.9g，74.4mmol)溶于甲醇中，加入氢氧化钠(3.0g，75.1mmol)后，室温反应1h，旋蒸出去溶剂，得12.5g固体粉末状产物1-巯甲基环丙基乙酸钠。
将由此制备的1-巯甲基环丙基乙酸钠(12.5g，74.4mmol)溶于125mL二甲基甲酰胺中，氮气保护条件下在20℃左右加入叔丁醇钾(12.7g，113.6mmol)，之后室温反应0.5h，将根据实施例2制备的式Ⅲb化合物(20g，28.4mmol)溶于200ml二甲基甲酰胺并加入至反应体系中，升温至60℃反应2h，TLC检测原料式Ⅲb化合物反应完毕后终止反应。将反应液加入至200mL1mol/L的冷稀盐酸中，控温0℃，析出固体，抽滤，滤饼水洗，将滤饼溶于乙酸乙酯中，饱和食盐水洗涤两次，收集有机相，无水硫酸镁干燥后进行减压浓缩，即得22g黄褐色油状物，即为化合物Ⅱb。
将该油状物按实施例8中的成二环己胺盐的方法得到式Ⅱb化合物的二环己胺盐21.1g，收率为95％。MS:600[M+H]
实施例10：中间体Ⅱb及其二环己胺盐的合成
Figure PCTCN2017112847-appb-000022
将1-巯甲基环丙基乙酸(24.0g，164.5mmol)溶于甲醇中，加入氢氧化钾(9.3g，166.1mmol)后，室温反应1h，旋蒸出去溶剂，得30.3g固体粉末状产物1-巯甲基环丙基乙酸钾。
将由此制得的1-巯甲基环丙基乙酸钾(30.3g，164.5mmol)溶于300mL二甲基甲酰胺中，氮气保护，在20℃左右，加入叔丁醇钾(18.4g，164.5mmol)，加毕，室温反应0.5h，将根据实施例3制备的Ⅲc化合物(20g，32.9mmol)溶于200ml二甲基甲酰胺并加至反应体系中，在20℃反应2h，TLC检测原料 式Ⅲc化合物反应完毕后终止反应。将反应液加入至200mL1mol/L的冷稀盐酸中，控温0℃，析出固体，抽滤，滤饼水洗，将滤饼溶于乙酸乙酯中，饱和食盐水洗涤两次，收集有机相，经过无水硫酸镁干燥后进行减压浓缩，即得23g黄褐色油状物，即为化合物Ⅱb。
将该油状物按实施例8中的成二环己胺盐的方法得到式Ⅱb化合物的二环己胺盐23.6g，收率为92％。
实施例11：中间体Ⅱd及其二环己胺盐的合成
Figure PCTCN2017112847-appb-000023
将1-巯甲基环丙基乙酸(2.3g，15.4mmol)溶于甲醇中，加入氢氧化锂(0.37g，15.6mmol)后，室温反应1h，旋蒸出去溶剂，得2.4g固体粉末状产物1-巯甲基环丙基乙酸锂。
将1-巯甲基环丙基乙酸锂(2.4g，15.4mmol)溶于25mL乙酸乙酯中，氮气保护，在20℃左右，加入1,8-二氮杂二环[5,4,0]十一碳-7-烯(购自安耐吉化学，常规试剂)(2.3g，15.4mmol)，加毕，室温反应0.5h，将根据实施例4制备的式Ⅲd化合物(10g，15.4mmol)溶于100mL乙酸乙酯中并滴加至反应液中，加毕，升温至40℃反应4h，TLC检测原料式Ⅲd化合物基本反应完毕后终止反应。将反应液加入至100mL 1mol/L的冷稀盐酸中，控温0℃，析出固体，抽滤，滤饼水洗，将滤饼溶于乙酸乙酯中，饱和食盐水洗涤2次，收集有机相，经无水硫酸镁干燥后进行减压浓缩，得10g黄褐色油状物，即为化合物Ⅱd。
将该油状物按实施例8中的成二环己胺盐的方法得到式Ⅱd化合物的二环己胺盐10.9g，收率为90％。
MS:614[M+H]
实施例12：中间体Ⅱe及其二环己胺盐的合成
Figure PCTCN2017112847-appb-000024
将1-巯甲基环丙基乙酸(9.8g，66.9mmol)溶于100mL乙腈中，氮气保护，在20℃左右，加入氢氧化钾(3.8g，66.9mmol)，加毕，室温反应0.5h，将根据实施例5制备的式Ⅲe化合物(15g，22.3mmol)溶于150mL乙腈中并滴加至反应液中，加毕，升温至30℃反应3h，TLC检测原料式Ⅲe化合物反应完毕，终止反应。将反应液加入150mL 1mol/L的冷稀盐酸中，控温0℃，析出固体，抽滤，滤饼水洗，将滤饼溶于乙酸乙酯中，饱和食盐水洗涤2次，收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得16.6g黄褐色油状物，即为化合物Ⅱe。
将该油状物按实施例8中的成二环己胺盐的方法得到式Ⅱe化合物的二环己胺盐15.4g，收率为92％。
MS:570[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz,1H),7.82(s,1H),7.80-7.78(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz,1H),7.47-7.10(m,8H),3.91(m,1H),3.32(t,4H),2.84(m,1H),2.68(m,1H),2.34(s,2H),2.11(m,2H),2.05(s,4H),2.02(m,4H),1.60(t,2H),0.36(m,4H)。
实施例13：中间体Ⅱf及其二环己胺盐的合成
Figure PCTCN2017112847-appb-000025
将1-巯甲基环丙基乙酸(3.9g，26.6mmol)溶于100mL乙腈中，氮气保护，在20℃左右，加入60wt％的氢化钠(购自安耐吉化学，常规试剂)(1.1g，26.6mmol)，加毕，室温反应0.5h，将根据实施例6制备的式Ⅲf化合物(10g， 13.3mmol)溶于150mL乙腈中并滴加至反应液中，加毕，升温至50℃反应2h，TLC检测原料式Ⅲf化合物反应完毕，终止反应。将反应液加入至100mL1mol/L的冷稀盐酸中，控温0℃，析出固体，抽滤，滤饼水洗，将滤饼溶于乙酸乙酯中，饱和食盐水洗涤2次，收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得12g黄褐色油状物，即为化合物Ⅱf。
将该油状物按实施例8中的成二环己胺盐的方法得到式Ⅱf化合物的二环己胺盐9.9g，收率为90％。MS:648[M+H]
实施例14：孟鲁司特钠的制备
步骤1：孟鲁司特酸的制备
Figure PCTCN2017112847-appb-000026
将三氯化铈(南京细诺化工科技有限公司，批号：XN17031201)(4.2g，17.1mmol)悬浮于100mL四氢呋喃中，氮气保护，升温至65℃搅拌1h，降温至-5℃，滴加22.8mL甲基氯化镁四氢呋喃溶液(绍兴上虞化工有限公司)(68.4mmol，3mol/L)，加毕，搅拌1h,将根据实施例8制备的式Ⅱa化合物的二环己胺盐(12.9g，17.1mmol)溶于13mL四氢呋喃中并滴加至反应液中，加毕，保持0℃反应1.5h。TLC检测原料式Ⅱa化合物的二环己胺盐反应完毕，终止反应。将反应液加入100mL 1mol/L的冷稀盐酸中，二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液、0.5mol/L酒石酸溶液、水洗涤1次，收集有机相，经过无水硫酸镁干燥后进行减压浓缩，即得9.8g黄色油状物孟鲁司特酸。
步骤2：孟鲁司特异丙胺盐的制备
将步骤1制备的9.8g黄色油状物孟鲁司特酸溶于60ml甲苯中，滴加1.3g异丙胺，氮气保护，搅拌过夜析晶。翌日，抽滤，滤饼分别用5ml甲苯、10ml正己烷洗涤，45℃真空干燥，得9.8g白色固体孟鲁司特异丙胺盐。收率：89％。MS:586[M+H]
步骤3：孟鲁司特钠的制备
Figure PCTCN2017112847-appb-000027
将步骤2制备的孟鲁司特异丙胺盐(9.8g,16.7mmol)加至100ml甲苯中，加甲醇钠0.9g，氮气保护下升温至78℃保温反应1h，热滤，滤液滴加至剧烈搅拌的正己烷中，搅拌0.5h，抽滤，滤饼用50ml正己烷洗涤，45℃真空干燥，得白色固体9.0g，收率：97.5％。ee 100.0％，
Figure PCTCN2017112847-appb-000028
(C＝1.0,甲醇)
MS:586[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40(d,1H),8.04(d,1H),8.02-7.99(d,1H),7.93-7.91(d,1H),7.90-7.86(d,J＝16.4Hz,1H),7.82(s,1H),7.80-7.78(d,1H),7.61-7.59(dd,1H),7.51-7.50(d,J＝16.4Hz,1H),7.47-7.10(m,6H),3.91(m,1H),2.84(m,1H),2.68(m,1H),2.34(s,2H),2.11(m,2H),2.05(s,2H),1.44(s,6H)。
实施例15：孟鲁司特钠的制备
步骤1：孟鲁司特酸的制备
Figure PCTCN2017112847-appb-000029
将55.7mL甲基溴化镁甲苯溶液(绍兴上虞化工有限公司)(167mmol，3mol/L)加入到100mL甲苯，降温至-10℃，然后将根据实施例9制备的式Ⅱb化合物的二环己胺盐(13g，16.7mmol)溶于100mL甲苯中，氮气保护下，滴加至反应液中，加毕，保持-5℃反应5h。TLC检测原料式Ⅱb化合物的二环己胺盐反应完毕，终止反应。将反应液加入100mL 1mol/L的冷稀盐酸中，二氯甲烷萃取，饱和食盐水洗涤2次，收集有机相，经无水硫酸镁干燥后进行减压浓缩，即得9.2g黄色油状物，该油状物通过柱层析(二氯甲烷：甲醇 ＝50:1-10:1)分离得到5g孟鲁司特酸。
步骤2：孟鲁司特异丙胺盐的制备
将5g孟鲁司特酸溶于30ml甲苯中，滴加0.6g异丙胺，氮气保护，搅拌过夜析晶。翌日，抽滤，滤饼分别用5ml甲苯、10ml正己烷洗涤，45℃真空干燥，得5g白色固体，收率：90％。
步骤3：孟鲁司特钠的制备
将步骤2制备的孟鲁司特异丙胺盐按实施例14中的成钠盐的方法制备得到4.5g孟鲁司特钠，收率为96％。
经检测，其氢谱、质谱及光学测定的结果与实施例15相同。
实施例16：孟鲁司特钠的制备
步骤1：孟鲁司特酸的制备
Figure PCTCN2017112847-appb-000030
将氯化锌(安耐吉化学)(4.4g，32.6mmol)悬浮于100mL四氢呋喃中，在氮气氛围下和5℃温度条件下，滴加16.3mL甲基氯化镁四氢呋喃溶液(绍兴上虞化工有限公司)(48.9mmol，3mol/L)后继续搅拌40min，将实施例11制备的式Ⅱd化合物的二环己胺盐(13.0g，16.3mmol)溶于130mL四氢呋喃中并滴加至上反应体系中，滴加完毕后继续反应4h。经TLC检测原料式Ⅱd化合物的二环己胺盐基本反应完毕后终止反应。将反应液加入至100mL1mol/L的冷稀盐酸中，二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液、0.5mol/L酒石酸溶液、水洗涤1次，收集有机相，经过无水硫酸镁干燥后进行减压浓缩即得8.8g黄色油状物孟鲁司特酸。
步骤2：孟鲁司特异丙胺盐的制备
将油状物溶于55ml甲苯中，滴加0.9g异丙胺，氮气保护，搅拌过夜析晶。翌日，抽滤，滤饼分别用5ml甲苯、10ml正己烷洗涤，45℃真空干燥， 得8.7g白色固体孟鲁司特异丙胺盐，收率：83％。
步骤3：孟鲁司特钠的制备
将步骤2制备的孟鲁司特异丙胺盐按照实施例14中的成钠盐的方法制备得到7.8g孟鲁司特钠，收率为95％。
经检测，其氢谱、质谱和光学测定的结果与实施例15相同。
实施例17：孟鲁司特钠的制备
步骤1：孟鲁司特酸的制备
Figure PCTCN2017112847-appb-000031
将氯化锂(安耐吉化学)(1.1g，26.3mmol)悬浮于100mL四氢呋喃中，在-10℃条件下，滴加35mL甲基溴化镁四氢呋喃溶液(105mmol，3mol/L)并搅拌0.5h，将实施例12制备的式Ⅱe化合物的二环己胺盐(13.1g，17.5mmol)溶于130mL四氢呋喃中并滴加至反应体系中，反应5h。经TLC检测原料Ⅱe化合物的二环己胺盐反应完毕后终止反应。将反应液加入100mL1mol/L的冷稀盐酸中，二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液、0.5mol/L酒石酸溶液、水洗涤1次，收集有机相，经过无水硫酸镁干燥后进行减压浓缩，即得9.2g黄色油状物孟鲁司特酸。
步骤2：孟鲁司特异丙胺盐的制备
将9.2g黄色油状物孟鲁司特酸溶于60ml甲苯中，滴加1.0g异丙胺，氮气保护，搅拌过夜析晶。翌日，抽滤，滤饼分别用5ml甲苯、10ml正己烷洗涤，45℃真空干燥，得9.9g白色固体孟鲁司特异丙胺盐，收率：88％。
步骤3：孟鲁司特钠的制备
将步骤1制备的孟鲁司特异丙胺盐按实施例14中的成钠盐的方法制备得到8.9g孟鲁司特钠，收率为96％。MS:586[M+H]
经检测，其氢谱、质谱和光学测定的结果与实施例15相同。
实施例18：孟鲁司特钠的制备
步骤1：孟鲁司特酸的制备
Figure PCTCN2017112847-appb-000032
将氯化镧(安耐吉化学)(3.6g，15.4mmol)和氯化锂(0.65g，15.4mmol)悬浮于100mL甲苯中，室温搅拌1h，降温至0℃，氮气保护，滴加20.5mL甲基碘化镁四氢呋喃溶液(绍兴上虞化工有限公司)(61.6mmol，3mol/L)，加毕，搅拌1h,将实施例13制备的式Ⅱf化合物的二环己胺盐(12.8g，15.4mmol)溶于130mL四氢呋喃中并滴加至反应液中，加毕，保持0℃反应3h。TLC检测式Ⅱf化合物的二环己胺盐反应完毕，终止反应。将反应液加入100mL1mol/L的冷稀盐酸中，二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液、0.5mol/L酒石酸溶液、水洗涤1次，收集有机相，经过无水硫酸镁干燥后进行减压浓缩即得，即得8.5g黄色油状物孟鲁司特酸。
步骤2：孟鲁司特异丙胺盐的制备
将8.5g黄色油状物孟鲁司特酸溶于50ml甲苯中，滴加0.8g异丙胺，氮气保护，搅拌过夜析晶。翌日，抽滤，滤饼分别用5ml甲苯、10ml正己烷洗涤，45℃真空干燥，得8.2g白色固体孟鲁司特异丙胺盐，收率：83％。
步骤3：孟鲁司特钠的制备
将步骤2制备的孟鲁司特异丙胺盐按照实施例14中的成钠盐的方法制备得到7.4g孟鲁司特钠，收率为95％。
经检测，其氢谱、质谱和光学测定的结果与实施例15相同。
实施例19孟鲁司特钠的制备
依照实施例18的方法制备孟鲁司特钠，其中除了在步骤1中式Ⅱf化合物代替其其二环己胺盐且相应地使甲基碘化镁的用量增加一倍以外。
经检测，目标产物的氢谱、质谱和光学测定的结果与实施例15相同。
实施例20孟鲁司特钠的制备
依照实施例18的方法制备孟鲁司特钠，其中除了没有步骤2形成孟鲁司特异丙胺盐以外。
经检测，目标产物的氢谱、质谱和光学测定的结果与实施例15相同。
在此处所述的本申请实施例的物料、操作和配置上可以进行变动，而不背离如本申请权利要求中所限定的本申请的精神和范围。虽然可以以许多不同形式来使本申请具体化，但是此处详细描述本申请的一些实施方案。本公开内容是本申请的精神的示例，且并不规定为使本申请限于所示的具体实施方案。此外，本申请包括此处所述的各种实施方案的一些或全部的任意可能的组合。在本申请中或在任一个引用的专利、引用的专利申请或其它引用的资料中任何地方所提及的所有专利、专利申请和其它引用资料据此通过引用以其整体并入。
以上公开内容规定为说明性的而不是穷尽性的。对于本领域技术人员来说，本说明书将暗示许多变化和可选择方案。所有这些可选择方案和变化规定为被包括在本权利要求的范围内，其中术语“包括”以及“包含”意思均是“包括，但不限于”。本领域技术人员应认识到此处所述的实施方案的其它等效变换，这些等效变换也规定为由本权利要求所包括。
在此完成了对本申请可选择的实施方案的描述。本领域技术人员可认识到此处所述的实施方案的其它等效变换，这些等效变换规定为由附于本文的权利要求所包括。
工业实用性
本申请在一个方面提供了一种如上所述的式(Ⅲ)所表示的化合物及其制备方法。该化合物能够作为关键中间体用于制备孟鲁斯特钠。同时，本申请提供了一条使用式(Ⅲ)所表示的化合物作为关键中间体来合成孟鲁斯特钠的新工艺路线。其中，作为关键中间体的式(Ⅲ)所表示的化合物的化学性质稳定，用于制备孟鲁司特钠时可克服现有制备路线中以叔醇作为亲核反应位点，很容易进攻与离去基团相连的手性碳，易发生分子内环化，副反应多的缺点，且整个反应过程条件温和，反应过程中手性碳构型不会发生变化，光学纯度高，易于纯化，适于工业化大生产。

Claims (15)

  1. 一种通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物：
    Figure PCTCN2017112847-appb-100001
    其中：
    X表示甲基、烷氧基、芳氧基或芳基亚烷氧基；
    R1表示烷基、芳基或芳基亚烷基；
    R2表示烷基、芳基或芳基亚烷基。
  2. 根据权利要求1所述的通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物，其中X表示甲基、C1-6烷氧基、苯氧基或苄氧基，R1表示C1-6烷基、苯基或苄基，R2表示C1-6烷基、苯基或苄基；任选地，X表示甲基、甲氧基或乙氧基，R1和R2表示苯基。
  3. 一种制备如权利要求1或2所述的通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物的方法，所述方法包括：将式(Ⅳ)化合物和式(ⅣA)化合物溶解于非质子有机溶剂中，在碱的作用下反应得到式(Ⅲ)化合物；
    Figure PCTCN2017112847-appb-100002
    其中，X、R1和R2如权利要求1或2中所定义的。
  4. 根据权利要求3所述的方法，其中所述碱为有机碱或无机碱；任选地，所述碱选自甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、吡啶、咪唑、NaH、NaOH、KOH、Ca(OH)2、NaHCO3、Na2CO3、K2CO3、CsCO3、CsOH、KHCO3、Ca(HCO3)2和CaO中的一种或更多种。
  5. 根据权利要求4所述的方法，其中所述式(Ⅳ)化合物与所述碱的摩 尔比为1：1至1：5范围内，可选地1：2至1：3范围内；所述式(Ⅳ)化合物和式(ⅣA)化合物的摩尔比为1：1至1：5范围内，可选地1：1至1：2范围内。
  6. 根据权利要求3所述的方法，其中反应温度为0℃至100℃，可选地反应温度为20℃至50℃；任选地反应时间为1h至5h，可选地2h至3h。
  7. 根据权利要求1或2所述的通式(Ⅲ)所示的化合物及其药学上可接受的盐或溶剂化物作为中间体用于制备孟鲁司特钠的用途。
  8. 一种孟鲁司特钠的合成方法，所述合成方法包括：
    在碱的存在下，使1-巯甲基环丙基乙酸或其盐与如权利要求1或2所述的通式(Ⅲ)所示的化合物反应，用冷稀酸处理反应得到的混合物，以制备式(Ⅱ)化合物；
    任选地使式(Ⅱ)化合物成盐；
    使式(Ⅱ)化合物或其盐与甲基格氏试剂反应，用冷稀酸处理反应得到的混合物，制得孟鲁斯特酸，任选地在路易斯酸活化剂的存在下使式(Ⅱ)化合物或其盐与甲基格氏试剂反应；
    任选地使孟鲁斯特酸与有机胺反应，形成孟鲁斯特酸的有机胺盐；
    使孟鲁斯特酸或其有机胺盐与抗衡阳离子为钠的碱反应，以制得孟鲁斯特钠；
    Figure PCTCN2017112847-appb-100003
  9. 根据权利要求8所述的合成方法，其中所述合成方法包括：将1-巯甲基环丙基乙酸或其盐和碱依次加入有机溶剂中，然后加入式(Ⅲ)化合物，在20℃至60℃搅拌反应，使反应进行2h至4h，用冷稀酸处理反应得到的混合物，得到式(Ⅱ)化合物；
    任选地，使式(Ⅱ)化合物成盐；
    将路易斯酸活化剂加入到有机溶剂中，然后在-10℃至5℃的温度条件下，加入甲基格氏试剂，搅拌0h至1h，再将式(Ⅱ)化合物或其盐的溶液加至路易斯酸活化剂-甲基格氏试剂反应液中，反应1.5h至5h，用冷稀酸处理反应得到的混合物，以制备孟鲁斯特酸；
    将路易斯酸活化剂加入到有机溶剂中，然后在-10℃至5℃的温度条件下，加入甲基格氏试剂，搅拌0h至1h，再将式(Ⅱ)化合物的盐的溶液加至路易斯酸活化剂-甲基格氏试剂反应液中，反应1.5h至5h，用冷稀酸处理反应 得到的混合物，以制备孟鲁斯特酸；
    任选地使孟鲁斯特酸与有机胺反应，形成孟鲁斯特酸的有机胺盐；
    使孟鲁斯特酸或其有机胺盐与抗衡阳离子为钠的碱反应，以制得孟鲁斯特钠。
  10. 根据权利要求8或9所述的合成方法，其中制备式(Ⅱ)化合物的反应中所使用的碱为有机碱或无机碱，任选地选自甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、吡啶、咪唑、NaH、NaOH、KOH、Ca(OH)2、NaHCO3、Na2CO3、K2CO3、CsCO3、CsOH、Ca(HCO3)2、KHCO3和CaO中的一种或更多种；任选地，式(Ⅲ)化合物与所述碱的摩尔比为1：1至1：5范围内，可选地1：2至1：4范围内。
  11. 根据权利要求8或9所述的合成方法，其中在存在路易斯酸活化剂的情况下，所述路易斯酸活化剂选自三氯化铈、氯化锌、氯化锂、氯化钴、氯化镧以及氯化铬中的一种或更多种，可选地三氯化铈。
  12. 根据权利要求8或9所述的合成方法，其中在制备孟鲁斯特酸的反应中，相对于1摩尔的所述式(II)化合物或其盐，路易斯酸活化剂的摩尔数在2摩尔以内。
  13. 根据权利要求8或9所述的合成方法，其中在制备孟鲁斯特酸的反应中，所述甲基格氏试剂为甲基氯化镁、甲基溴化镁或甲基碘化镁；任选地，所述式(Ⅱ)化合物与甲基格氏试剂的摩尔比为1：3至1：10范围内，可选1：4至1：6范围内。
  14. 根据权利要求8或9所述的合成方法，其中式(Ⅲ)化合物与1-巯甲基环丙基乙酸或盐的摩尔比为1：1至1：5范围内，可选地1：2至1：3范围内。
  15. 根据权利要求8或9所述的合成方法，其中使式(II)化合物成盐包括使式(II)化合物与有机胺化合物反应，以形成式(II)化合物的盐；任选地，在所述合成方法中用到的有机胺选自正丙胺、异丙胺、叔丁胺、苄胺、α-甲基苄胺和二环己胺中的一种或更多种。
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