WO2020034946A1 - 一种制备环己烷衍生物的方法 - Google Patents

一种制备环己烷衍生物的方法 Download PDF

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WO2020034946A1
WO2020034946A1 PCT/CN2019/100365 CN2019100365W WO2020034946A1 WO 2020034946 A1 WO2020034946 A1 WO 2020034946A1 CN 2019100365 W CN2019100365 W CN 2019100365W WO 2020034946 A1 WO2020034946 A1 WO 2020034946A1
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formula
compound
reaction
represented
cyclohexyl
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PCT/CN2019/100365
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English (en)
French (fr)
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黄悦
郑飞
徐辉
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浙江京新药业股份有限公司
上海京新生物医药有限公司
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Priority claimed from CN201810921042.7A external-priority patent/CN110818678B/zh
Priority claimed from CN201810920857.3A external-priority patent/CN110818677A/zh
Application filed by 浙江京新药业股份有限公司, 上海京新生物医药有限公司 filed Critical 浙江京新药业股份有限公司
Publication of WO2020034946A1 publication Critical patent/WO2020034946A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and particularly relates to a method for preparing a cyclohexane derivative.
  • CN106518841A discloses a class of cyclohexane derivatives or stereoisomers or salts thereof.
  • the structures of these cyclohexane derivatives are shown in the following formula IB:
  • R is:
  • cyclohexane derivatives have strong affinity for dopamine D 3 receptor and serotonin, but have weak affinity for D 2 receptor, showing high selectivity for D 3 / D 2 receptor and strong It has anti-schizophrenic symptoms and has only very low toxicity and good safety.
  • N, N-dimethylcarbamoyl chloride was docked in the last step.
  • the reaction in this step may be incomplete, and there are many impurities in the product, especially a large amount of methyl impurities. How to avoid the production of by-products and improve the product yield is an urgent problem.
  • the reaction of this step may be incomplete, especially the dimer impurity content of the nucleophilic substitution of urea And demethyl impurities are higher. How to avoid the production of by-products and improve the product yield is an urgent problem.
  • the final product often contains two types of unwanted impurities, namely dimer impurities imp6 and imp8, which are substituted by nucleophiles, and monomethyl impurities (or Remove methyl impurities, demethyl impurities, monomethyl impurities) imp1:
  • a method for preparing a cyclohexane derivative represented by Formula IB includes the following steps:
  • a compound represented by the formula SM01 is 2- (4- (3,3-dimethylureido) cyclohexyl) acetaldehyde and a compound represented by the formula SM02 or a salt thereof is subjected to a reductive amination reaction to obtain cyclohexane represented by the formula IB derivative:
  • R is:
  • the methods and conditions of the reductive amination reaction described above may be conventional methods and conditions in the art.
  • the reducing agent for the reductive amination reaction is preferably sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride plus acetic acid, or potassium borohydride plus acetic acid, and the equivalent of the reducing agent is preferably 1 to 10 eq. .
  • the solvent for the reductive amination reaction is preferably dichloromethane, tetrahydrofuran, toluene, acetic acid, or a mixture of two or more thereof.
  • the reaction temperature of the reductive amination is preferably -20 to 100 ° C, and the reaction time is preferably 1-48h.
  • the reaction raw material in the reductive amination reaction is SM02 free base. In the case of using a free base, no additional base needs to be added in the reductive amination reaction.
  • the reaction raw material in the reductive amination reaction is a salt of SM02, wherein the salt of the compound of formula SM02 is selected from the group consisting of hydrochloride, sulfate, acetate, sulfonate, and methanesulfonic acid.
  • the salt or p-toluenesulfonate is preferably the hydrochloride.
  • the salt of the compound represented by the above formula SM02 can be prepared by reacting the compound SM02 with an acid selected from hydrochloric acid, sulfuric acid, acetic acid, sulfonic acid, methanesulfonic acid or p-toluenesulfonic acid.
  • the reductive amination reaction is performed in the presence of a base, such as triethylamine, DIPEA, or DBU.
  • a base such as triethylamine, DIPEA, or DBU.
  • the SM01 compound can be prepared according to a conventional preparation method in the art.
  • the compound represented by the above formula SM01 is preferably prepared by a method including the following steps:
  • a compound represented by the formula III is subjected to an oxidation reaction to obtain a compound represented by the formula SM01, 2- (4- (3,3-dimethylureido) cyclohexyl) acetaldehyde.
  • the synthetic route is:
  • the acylation reaction in step 1) is performed in the presence of a base, and the base used is selected from the group consisting of triethylamine, DIPEA, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate
  • the alkali equivalent is 1 to 10 eq.
  • the solvent of the acylation reaction in step 1) is selected from the group consisting of dichloromethane, tetrahydrofuran, methyltetrahydrofuran, DMF, acetonitrile, toluene, or a mixture of two or more thereof.
  • the reaction temperature of the acylation reaction in the above step 1) is preferably -20 to 100 ° C, and the reaction time is preferably 1 to 48 hours.
  • the reducing agent in the reduction reaction in step 2) is selected from sodium borohydride and potassium borohydride, and the equivalent of the reducing agent is 1-10 eq.
  • the solvent for the reduction reaction in the above step 2) is preferably selected from methanol, tetrahydrofuran, ethanol, or a mixture of two or more thereof.
  • the reaction temperature of the reduction reaction in step 2) is preferably -20 to 100 ° C, and the reaction time is preferably 1-48 h.
  • the oxidation reaction described in step 3) may be a conventional oxidation reaction in the art, including but not limited to Swern oxidation, TEMPO oxidation, and the like.
  • the oxidation conditions of the oxidation reaction are preferably selected from: oxalyl chloride, DMSO; sulfur trioxide, pyridine, DMSO; TEMPO; sodium hypochlorite; PCC; PDC; or periodate.
  • the solvent for the oxidation reaction in the above step 3) is preferably selected from methylene chloride, tetrahydrofuran, methyltetrahydrofuran, or a mixture of two or more thereof.
  • the reaction temperature of the oxidation reaction in step 3) is preferably -80 to 100 ° C, and the reaction time is preferably 1-48h.
  • the SM02 compound can be prepared according to a conventional preparation method in the art.
  • the compound represented by the above formula SM02 is prepared by a coupling reaction between R-X and piperazine, and the synthetic route is:
  • X is Cl, Br or I, preferably X is Br.
  • R is as defined above.
  • the above coupling reaction is generally carried out under the catalysis of a palladium catalyst in the presence of a strongly basic substance.
  • the temperature of the coupling reaction is preferably 50-150 ° C, and the molar ratio of piperazine to R-X is preferably 1-5: 1.
  • the palladium catalyst is preferably selected from Pd 2 (dba) 3 , tetratriphenylphosphine palladium, or dppf palladium dichloride, and the phosphine ligand is BINAP.
  • the strongly basic substance is preferably potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
  • the compound represented by the above formula SM02 is prepared by a method including the following steps:
  • R-X is coupled with Pg-piperazine to form SM02-A;
  • the synthetic route is:
  • X is Cl, Br or I, preferably X is Br;
  • Pg is an amino protecting group selected from benzyl Bn, benzyl formate CBz or tert-butoxycarbonyl Boc; R is as defined above.
  • the coupling reaction in the above step 1 is generally carried out under the palladium catalyst.
  • the palladium catalyst is preferably selected from Pd 2 (dba) 3 , tetratriphenylphosphine palladium or dppf palladium dichloride, phosphine.
  • the ligand is BINAP.
  • the coupling reaction in step 1 is performed in the presence of a base, and the base used is preferably potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
  • the base used is preferably potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
  • the solvent of the coupling reaction in the above step 1 is preferably selected from toluene, xylene or a mixture thereof.
  • the reaction temperature of the coupling reaction in the above step 1 is preferably -20 to 180 ° C, and the reaction time is preferably 1 to 48 hours.
  • the deprotection reaction in step 2 is performed in the presence of an acid, and the acid used is preferably selected from hydrogen chloride (such as a hydrogen chloride ethanol solution), hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid.
  • hydrogen chloride such as a hydrogen chloride ethanol solution
  • hydrochloric acid such as a hydrogen chloride ethanol solution
  • sulfuric acid such as a hydrogen chloride ethanol solution
  • p-toluenesulfonic acid preferably selected from hydrogen chloride (such as a hydrogen chloride ethanol solution), hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid.
  • the solvent used in the deprotection reaction in the above step 2 is preferably selected from methylene chloride, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, ethyl acetate, or a mixture of two or more thereof.
  • the deprotection reaction temperature in the above step 2 is preferably -80 to 100 ° C, and the reaction time is preferably 1-48h.
  • step 2 when Pg is tert-butoxycarbonyl Boc, an acid is added to deaminate the protective group, and the acid is a hydrogen chloride organic solution (such as a hydrogen chloride ethanol solution) or trifluoroacetic acid;
  • Pg is benzyl Bn or benzyl formate CBz
  • palladium carbon hydrogenation is used to deaminate the protective group, and the hydrogenation pressure is 0.1-1Mpa.
  • compositions comprising the cyclohexane derivative represented by the formula IB and the compound imp1, wherein the mass ratio of the cyclohexane derivative represented by the formula IB to the compound imp1 is 99.5: 0.05 or more:
  • the mass ratio of the cyclohexane derivative represented by Formula IB to imp1 is 99.7: 0.02 or more.
  • Another aspect of the present invention provides a composition comprising the cyclohexane derivative represented by Formula IB, wherein the cyclohexane derivative represented by IB accounts for more than 99.5% of the mass of the composition; imp1, imp6, and The mass ratio of imp8 to cyclohexane derivatives shown by formula IB is all below 0.1%:
  • the mass ratios of imp6 and imp8 relative to the cyclohexane derivative represented by Formula IB are each independently 0.05% or less.
  • the mass ratio of imp6 and imp8 to the cyclohexane derivative represented by Formula IB is independently 0.02% or less.
  • the mass ratio of the compound imp1 to the cyclohexane derivative represented by Formula IB is 0.05% or less, and further, 0.02% or less.
  • imp6 and / or imp8 are not included in the composition.
  • the content of the cyclohexane derivative represented by Formula IB accounts for more than 99.6% of the mass of the composition, such as 99.6%, 99.7%, 99.8%, or 99.9% .
  • the present invention also provides another optional technical solution, including the following content.
  • a method for preparing a cyclohexane derivative represented by Formula IB includes the following steps:
  • compound SM01B is reacted to form compound SM01A; wherein L is a leaving group, preferably -OTs, -OMs, -Br, -Cl, or -I;
  • the synthetic route is:
  • R is:
  • the acylation reaction in step (i) is performed in the presence of a base
  • the base used is selected from organic bases such as triethylamine, DIPEA, DBU, etc .
  • the inorganic base is selected from sodium hydroxide , Potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and the equivalent of alkali is 1 to 10 eq.
  • the solvent of the acylation reaction in the step (i) is preferably selected from methylene chloride, tetrahydrofuran, methyltetrahydrofuran, DMF, acetonitrile, toluene, or a mixture of two or more thereof.
  • the reaction temperature of the acylation reaction in the step (i) is preferably -20 to 100 ° C, and the reaction time is preferably 1 to 48 hours.
  • the reducing agent in the reduction reaction in step (ii) is selected from sodium borohydride and / or potassium borohydride, and the equivalent of the reducing agent is 1 to 10 eq.
  • the solvent for the reduction reaction in the step (ii) is preferably selected from methanol, tetrahydrofuran, ethanol, or a mixture of two or more thereof.
  • the reaction temperature of the reduction reaction in the step (ii) is preferably -20 to 100 ° C, and the reaction time is preferably 1-48 h.
  • the reagent for the reaction in step (iii) is selected from p-toluenesulfonyl chloride, methanesulfonyl chloride, NBS, dichlorosulfoxide, phosphorus oxychloride, iodine, or phosphorus tribromide.
  • the reaction in the above step (iii) is generally performed in the presence of a base, which is preferably selected from one or more of triethylamine, diisopropylethylamine, and imidazole.
  • a base which is preferably selected from one or more of triethylamine, diisopropylethylamine, and imidazole.
  • the solvent used in the reaction in step (iii) is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, chloroform, or a mixture of two or more thereof.
  • the reaction temperature of the reaction in the step (iii) is preferably -20 to 180 ° C, and the reaction time is preferably 1 to 48 h.
  • step (iv) when SM01A is reacted with SM02 or a salt thereof, the nucleophilic substitution reaction is generally performed in the presence of a base, which is preferably selected from potassium carbonate, sodium carbonate, One or more of ethylamine and diisopropylethylamine.
  • a base which is preferably selected from potassium carbonate, sodium carbonate, One or more of ethylamine and diisopropylethylamine.
  • the solvent for the nucleophilic substitution reaction is preferably selected from acetonitrile, N, N-dimethylformamide, acetone, or a mixture of two or more thereof.
  • the reaction temperature of the nucleophilic substitution reaction is preferably -20 to 180 ° C, and the reaction time is preferably 1 to 48 hours.
  • the nucleophilic substitution reaction is generally performed under the catalysis of a ruthenium catalyst such as Ru 3 (CO) 12.
  • a ruthenium catalyst such as Ru 3 (CO) 12.
  • Phosphine The ligand is preferably selected from Xantphos, Ruphos or Xphos.
  • the solvent for the nucleophilic substitution reaction is preferably toluene, xylene, or a mixture thereof.
  • the reaction temperature of the nucleophilic substitution reaction is preferably -20 to 180 ° C, and the reaction time is preferably 1 to 48 hours.
  • step (iv) above in addition to the compound SM01A or the compound SM01B, another reaction raw material is the compound SM02 or a salt of the compound SM02.
  • the salt of the compound SM02 is preferably selected from the hydrochloride, sulfate, acetate, sulfonate, methanesulfonate or p-toluenesulfonate, and more preferably the hydrochloride.
  • Compound SM02 or a salt thereof can be prepared according to a conventional method in the art.
  • the salt of the SM02 compound can be prepared by reacting the SM02 compound with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, sulfonic acid, methanesulfonic acid, or p-toluenesulfonic acid; Reaction prepared.
  • the SM02 free base can be prepared by directly reacting SM02-A, or it can also be prepared by further freeing the salt of SM02-A.
  • the compound SM02 can be prepared by a coupling reaction between R-X and piperazine.
  • the synthetic route is:
  • X is Cl, Br or I, preferably X is Br.
  • the above coupling reaction is generally carried out under the catalysis of a palladium catalyst in the presence of a strongly basic substance.
  • the temperature of the coupling reaction is preferably 50-150 ° C, and the molar ratio of piperazine to R-X is preferably 1-5: 1.
  • the palladium catalyst is preferably selected from Pd 2 (dba) 3 , tetratriphenylphosphine palladium, or dppf palladium dichloride, and the phosphine ligand is BINAP.
  • the strongly basic substance is preferably selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
  • the compound SM02 can also be prepared by a method comprising the following steps:
  • R-X is coupled with Pg-piperazine to form SM02-A;
  • the synthetic route is:
  • X is Cl, Br or I, preferably X is Br;
  • Pg is an amino protecting group, preferably from benzyl Bn, benzyl formate CBz or tert-butoxycarbonyl Boc.
  • the coupling reaction in step A) is generally carried out under the catalysis of a palladium catalyst.
  • the palladium catalyst is preferably selected from Pd 2 (dba) 3 , tetratriphenylphosphine palladium or dppf palladium dichloride.
  • the phosphine ligand is BINAP.
  • the coupling reaction in step A) is performed in the presence of a base, and the base used is preferably selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
  • the solvent of the coupling reaction in the above step A) is preferably selected from toluene, xylene or a mixture thereof.
  • the reaction temperature of the coupling reaction in step A) is preferably -20 to 180 ° C, and the reaction time is preferably 1 to 48 h.
  • the deprotection reaction in step B) is generally performed in the presence of an acid, and the acid used is preferably selected from hydrogen chloride (such as a hydrogen chloride ethanol solution), hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid.
  • hydrogen chloride such as a hydrogen chloride ethanol solution
  • hydrochloric acid such as a hydrogen chloride ethanol solution
  • sulfuric acid such as a sulfuric acid
  • p-toluenesulfonic acid preferably selected from hydrogen chloride (such as a hydrogen chloride ethanol solution), hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid.
  • the solvent used in the deprotection reaction in the above step B) is preferably selected from methylene chloride, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, ethyl acetate, or a mixture of two or more thereof.
  • the deprotection reaction temperature in the above step B) is preferably -80 to 100 ° C, and the reaction time is preferably 1-48h.
  • step B when Pg is tert-butoxycarbonyl Boc, an acid is added to deaminate the protective group, and the acid is a hydrogen chloride organic solution (such as a hydrogen chloride ethanol solution) or trifluoroacetic acid;
  • the acid is a hydrogen chloride organic solution (such as a hydrogen chloride ethanol solution) or trifluoroacetic acid;
  • Pg is benzyl Bn or benzyl formate CBz
  • palladium carbon hydrogenation is used to deaminate the protective group, and the hydrogenation pressure is 0.1-1 Mpa.
  • the method of the invention has few side reactions, and the cyclohexane derivative IB product prepared by the method has high purity and high yield, which greatly reduces the impurity content, especially the dimer impurities imp6 and imp8, and the monomethyl impurity imp1 content. Low (less than 0.1% single impurity), so the product is high in purity, easy to meet drug quality standards, and mild reaction conditions, easy to control, simple and safe operation, so it is more suitable for industrial large-scale production.
  • compound X is sometimes expressed as “compound X”, which can be understood by those skilled in the art.
  • the compound represented by formula I and compound I refer to the same compound.
  • both the compound represented by formula SM01A and compound SM01A refer to the same compound; the compound represented by formula IB and compound IB refer to the same compound.
  • the compounds imp6 and imp8 belong to the dimer impurity, and the compound imp1 belongs to the monomethyl impurity (also called methyl impurity, demethyl impurity, mono impurity).
  • the preparation method of the present invention is generally divided into four steps:
  • the synthetic route is:
  • R is:
  • purification operations such as filtration, washing, and drying may be performed according to common knowledge in the art.
  • the product purification operation performed may not even include column chromatography purification, and can also obtain products without dimer impurities imp6 and imp8 and monomethyl impurity imp1 Or the content is extremely low and can hardly be detected.
  • the compound SM01 and its corresponding reaction raw material have corresponding stereo configurations.
  • the compound of Formula IB is N '-[trans-4- [2- [7- (benzo [b] thiophene) -7-piperazinyl] ethyl] cyclohexyl]-
  • N, N-dimethylurea the following formula IB-1
  • SM01 is 1,1-dimethyl-3- (trans-4- (2-oxoethyl) cyclohexyl) urea, but The SM01 was prepared using trans-2- (4-aminocyclohexyl) ethyl acetate.
  • the inventors also verified the prior art methods including CN106518841A. Experiments show that the last step of the prior art method is on the urea group, and the product has the monomethyl impurity imp1; and the alkyl group is used. Whether the first route is urea or the last urea step, dimer impurities imp6 and imp8 in which urea groups are substituted by nucleophiles are present in the product.
  • the positive progress effect of the present invention lies in that the preparation method of the present invention can prepare a cyclohexane derivative of Formula IB in a high yield, and the impurity content in the product is low, especially the dimer impurities imp6 and imp8, and monomethyl
  • the impurity imp1 content is low (less than 0.1 wt% of single impurity).
  • the reaction conditions are mild and easy to control, so the operation is simple and safe.
  • the temperature generally refers to room temperature (15-30 ° C).
  • Reagents The reactants and catalysts used in the examples of the present invention are chemically pure and can be used directly or simply purified as required; organic solvents and the like are all analytically pure and used directly. Reagents were purchased from China Pharmaceutical (Group) Shanghai Chemical Reagent Company.
  • Model of nuclear magnetic resonance instrument Bruker AV HD 600MHz, Bruker AV III III 400MHz;
  • Mass spectrometer liquid mass spectrometry (LCMS)
  • model Agilent 6120, B, and detector is DAD.
  • trans-2- (4-aminocyclohexyl) ethyl acetate hydrochloride (Compound I) (44.2 g, 0.2 mol), triethylamine (84 ml, 0.6 mol, 3 eq), two Methyl chloride (250ml), mixed and stirred, cooled to below 10 ° C in an ice bath, and added dropwise a dichloromethane solution of N, N-dimethylcarbamoyl chloride (32.2g of N, N-dimethylcarbamoyl chloride, 0.3mol, 1.5 eq was dissolved in 50 ml of dichloromethane), the temperature was raised, and the reaction was stirred for 2 h.
  • reaction solution was separated, and the aqueous phase was extracted with dichloromethane (30ml * 2).
  • the aqueous phase was extracted with dichloromethane (50 ml * 2).
  • the organic phases were combined, washed with saturated brine, and dried.
  • the sodium sulfate was dried, filtered, and spin-dried to obtain 3.4 g of crude product.
  • the activated carbon was decolorized to obtain 1.6 g of IB-1 as a white solid.
  • the HPLC detected a single impurity of less than 0.1% and a yield of 48%.
  • HPLC imp1 0.02%; target product 99.76%; imp6N / A, imp8N / A; no more than 0.1% single impurity.
  • trans-p-toluenesulfonic acid 2- (4- (3,3-dimethylurea) cyclohexyl) ethyl ester (Compound TM) (1.47 g, 0.004 mol), SM02 (0.96 g , 0.0044 mol, 1.1 eq), potassium carbonate (1.1 g, 0.008 mol, 2 eq), acetonitrile (40 ml), mixed and stirred, and the reaction was heated at 75 ° C. in an oil bath overnight. Sampling test, after the reaction of the raw materials is complete, stop heating. After the reaction solution was cooled to room temperature, the solvent was spin-dried.
  • Compound TM trans-p-toluenesulfonic acid 2- (4- (3,3-dimethylurea) cyclohexyl) ethyl ester
  • the product contains the dimer impurity imp8, the structural formula is:
  • intermediate B 62.28 g, 0.15 mol
  • aqueous sodium hydroxide solution sodium hydroxide 60 g, 1.5 mol, 10 eq, dissolved in 375 ml of water
  • dichloromethane 375 ml
  • Butylphosphonium bromide 6g was dissolved with stirring.
  • the ice bath was cooled to 5 ° C, and dimethylcarbamoyl chloride (64.2 g, 0.6 mol, 4 eq) was added dropwise, and the drop was completed in about 45 minutes. After the dropwise addition was completed, the reaction was stirred overnight (8 h) in an oil bath at 25 ° C.
  • HPLC imp1 32.25%; target product 61.35%; imp6 0.28%.
  • the crude IB-1 was purified by column chromatography.
  • the eluent: dichloromethane: methanol 50: 1 to 30: 1. 80 g of a pale yellow solid was obtained.
  • the solid was recrystallized from 800 ml of ethyl acetate to obtain IB-1 as a white solid. 35g.
  • HPLC imp1 0.06%; target product 99.64%; imp6 0.29%.
  • the product contains the dimer impurity imp6, the structural formula is:
  • Examples 1-8 show that the product IB-1 prepared by the method of the present invention has high purity, greatly reducing the content of impurities, especially the content of dimer impurities and monomethyl impurities (less than 0.1% of single impurities), and it is easy to reach the drug Quality Standard. Moreover, the post-processing is simple, which can significantly reduce the production cost, so it is more suitable for industrial large-scale production.
  • trans-2- (4-aminocyclohexyl) ethyl acetate hydrochloride (44.2 g, 0.2 mol), triethylamine (84 ml, 0.6 mol, 3 eq), and dichloromethane (250 ml).
  • ethyl acetate hydrochloride 44.2 g, 0.2 mol
  • triethylamine 84 ml, 0.6 mol, 3 eq
  • dichloromethane 250 ml.
  • a solution of N, N-dimethylcarbamoyl chloride in dichloromethane N, N-dimethylcarbamoyl chloride 32.2g, 0.3mol, 1.5eq in 50ml. In methyl chloride), the solution was heated naturally, and the reaction was stirred for 2 h.
  • the aqueous phase was extracted with dichloromethane (50 ml * 2).
  • the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and dried to give 2.5 g of a brown solid.
  • Purified by column chromatography, eluent: dichloromethane: methanol 50: 1 to 30: 1, 1.8 g of a pale yellow solid was obtained, and recrystallized from ethyl acetate to obtain 0.8 g of a white solid, which is compound IB-1 .
  • the methyl impurity imp1 and the disubstituted impurity imp6 were not detected in the product.
  • intermediate B 62.28 g, 0.15 mol
  • aqueous sodium hydroxide solution sodium hydroxide 60 g, 1.5 mol, 10 eq, dissolved in 375 ml of water
  • dichloromethane 375 ml
  • Butylphosphonium bromide 6g was dissolved with stirring.
  • the ice bath was cooled to 5 ° C, and dimethylcarbamoyl chloride (64.2 g, 0.6 mol, 4 eq) was added dropwise, and the drop was completed in about 45 minutes. After the dropwise addition was completed, the reaction was stirred overnight (8 h) in an oil bath at 25 ° C.
  • the crude IB-1 was purified by column chromatography.
  • the eluent: dichloromethane: methanol 50: 1 to 30: 1. 80 g of a pale yellow solid was obtained.
  • the solid was recrystallized from 800 ml of ethyl acetate to obtain IB-1 as a white solid. 35g.
  • HPLC imp1 0.06%; target product 99.64%; imp6 0.29%.
  • the reaction with dimethylcarbamoyl chloride showed that about 30% of the monomethyl impurity imp1 in the crude product was purified by column chromatography and ethyl acetate recrystallization, and the impurities could not be reduced to 0.05%. the following.

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Abstract

本发明提供了一种制备环己烷衍生物的方法，包括下述步骤：使式SM01所示化合物2-(4-(3,3-二甲基脲基)环己基)乙醛与式SM02所示化合物进行缩合亚胺还原反应，得到环己烷衍生物。本发明的方法副反应少、产品收率高、纯度高，有利于工业规模生产。

Description

一种制备环己烷衍生物的方法 技术领域
本发明属于药物合成领域，具体涉及一种制备环己烷衍生物的方法。
背景技术
CN106518841A中公开了一类环己烷衍生物或其立体异构体或盐，这些环己烷衍生物的结构如下式IB所示：
Figure PCTCN2019100365-appb-000001
其中X为N或C；R为：
Figure PCTCN2019100365-appb-000002
这些环己烷衍生物对多巴胺D 3受体、5-羟色胺具有较强亲和力，而对D 2受体亲和力较弱，表现出对D 3/D 2受体的高选择性，有较强的抗精神分裂症症状作用，并且仅有极低的毒性，安全性好，可用于制备神经精神类疾病药物。
在CN106518841A中，由哌嗪与R-Br对接形成式IV化合物，进而反应制得该些环己烷衍生物。然而，后续实验中发现，该反应会形成较多的双取代杂质。
Figure PCTCN2019100365-appb-000003
此外，在CN106518841A中，在最后一步对接N,N-二甲氨基甲酰氯，然而，该步反应存在反应不完全的情况，并且产物中杂质较多，尤其是存在大量的掉甲基杂质。如何避免副产物的产生、提高产品收率是个急需解决的问题。
由于许多候选药物因不需要的杂质对人体代谢产生无法预料的影响或毒性而在临 床试验中失败，因此在早期临床前研究中消除这些杂质很有必要。
发明内容
发明人经研究发现，采用CN106518841A中的合成路线，在最后一步对接N,N-二甲氨基甲酰氯，该步反应存在反应不完全的情况，尤其是脲被亲核取代的二聚体杂质含量和去甲基杂质较高。如何避免副产物的产生、提高产品收率是个急需解决的问题。在大规模制备式IB所示环己烷衍生物时，最终产物往往包含两类不需要的杂质，即脲分别被亲核取代的二聚体杂质imp6和imp8、以及单甲基杂质(或称掉甲基杂质、去甲基杂质、单甲基杂质)imp1：
Figure PCTCN2019100365-appb-000004
而且，通过目前工业上常用的纯化技术比如重结晶和柱层析方法无法实现该两类杂质的去除纯化。
针对现有技术中存在的产物收率低、杂质含量高、纯度低等缺陷，发明人另辟蹊径，改变了式IB所示环己烷衍生物的合成路线，提供了一种副反应少、产物纯度高的制备方法。具体而言，本发明采用以下技术方案。
一种制备式IB所示环己烷衍生物的方法，包括以下步骤：
使式SM01所示化合物2-(4-(3,3-二甲基脲基)环己基)乙醛与式SM02所示化合物或其盐进行还原胺化反应，得到式IB所示环己烷衍生物：
Figure PCTCN2019100365-appb-000005
其中R为：
Figure PCTCN2019100365-appb-000006
其中，上述还原胺化反应的方法和条件可为本领域常规的方法和条件。本发明中，所述还原胺化反应的还原剂优选自三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠加醋酸或者硼氢化钾加醋酸，还原剂的当量优选为1～10eq。
上述还原胺化反应的溶剂优选自二氯甲烷、四氢呋喃、甲苯、醋酸或者它们两种以上的混合物。
所述还原胺化的反应温度优选为-20～100℃，反应时间优选为1-48h。
在一种实施方式中，上述还原胺化反应中的反应原料为SM02游离碱，在采用游离碱的情况下，所述还原胺化反应中无需添加额外的碱。
在另一种实施方式中，上述还原胺化反应中的反应原料为SM02的盐，其中式SM02所示化合物的盐选自盐酸盐、硫酸盐、醋酸盐、磺酸盐、甲磺酸盐或对甲苯磺酸盐，较佳地为盐酸盐。
上述式SM02所示化合物的盐可以由化合物SM02与酸反应制得，所述酸选自盐酸、硫酸、醋酸、磺酸、甲磺酸或对甲苯磺酸。
优选地，上述还原胺化反应在碱存在条件下进行，所述碱比如是三乙胺、DIPEA、或DBU等。
本发明中，所述SM01化合物可按本领域常规的制备方法制得。
在一种实施方式中，上述式SM01所示化合物较佳地由包括以下步骤的方法制备：
1)使式I所示化合物2-(4-氨基环己基)乙酸乙酯与N,N-二甲氨基甲酰氯进行酰化反应，得到式II所示化合物2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯；
2)使式II所示化合物发生还原反应，生成式III所示化合物3-(4-(2-羟基乙基)环己基)-1,1-二甲基脲；
3)使式III所示化合物发生氧化反应，得到式SM01所示化合物2-(4-(3,3-二甲基脲基)环己基)乙醛。
合成路线为：
Figure PCTCN2019100365-appb-000007
优选地，步骤1)中所述酰化反应在碱存在的条件下进行，所用的碱选自三乙胺、DIPEA、DBU、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸氢钠，碱的当量为1～10eq。
优选地，上述步骤1)中所述酰化反应的溶剂选自二氯甲烷、四氢呋喃、甲基四氢呋喃、DMF、乙腈、甲苯或者它们两种以上的混合物。
上述步骤1)中所述酰化反应的反应温度优选为-20～100℃，反应时间优选为1-48h。
优选地，步骤2)中所述还原反应的还原剂选自硼氢化钠、硼氢化钾，还原剂的当量为1～10eq。
上述步骤2)中所述还原反应的溶剂优选自甲醇、四氢呋喃、乙醇或者它们两种以上的混合物。
上述步骤2)中所述还原反应的反应温度优选为-20～100℃，反应时间优选为1-48h。
按本领域常识，步骤3)中所述氧化反应可为本领域常规的氧化反应，包括但不限于Swern氧化、TEMPO氧化等。本发明中，所述氧化反应的氧化条件优选自：草酰氯，DMSO；三氧化硫吡啶，DMSO；TEMPO；次氯酸钠；PCC；PDC；或者，过碘酸酯。
上述步骤3)中所述氧化反应的溶剂优选自二氯甲烷、四氢呋喃、甲基四氢呋喃或者它们两种以上的混合物。
上述步骤3)中所述氧化反应的反应温度优选为-80～100℃，反应时间优选为1-48h。
本发明中，所述SM02化合物可按本领域常规的制备方法制得。
在一种实施方式中，上述式SM02所示化合物通过R-X与哌嗪进行偶联反应制得，合成路线为：
Figure PCTCN2019100365-appb-000008
其中X为Cl、Br或I，优选X为Br。R如上定义。
按本领域常识，上述偶联反应一般是在钯催化剂的催化下，在强碱性物质的存在下进行。所述偶联反应的温度优选为50-150℃，哌嗪与R-X的摩尔比优选为1-5:1。
上述钯催化剂优选自Pd 2(dba) 3、四三苯基膦钯或dppf二氯化钯，膦配体为BINAP。上述强碱性物质优选自叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯。
在另一种可选的实施方式中，上述式SM02所示化合物通过包含下述步骤的方法制得：
①R-X与Pg-哌嗪进行偶联反应，生成SM02-A；
②SM02-A脱保护，去除氨基保护基Pg，得到化合物SM02；
合成路线为：
Figure PCTCN2019100365-appb-000009
其中X为Cl、Br或I，优选X为Br；Pg是氨基保护基，选自苄基Bn、甲酸苄酯CBz或叔丁氧羰基Boc；R如上定义。
按本领域常识，上述步骤①中所述偶联反应一般是在钯催化剂催化下进行，所述钯催化剂优选自Pd 2(dba) 3、四三苯基膦钯或dppf二氯化钯，膦配体为BINAP。
优选地，步骤①中所述偶联反应在碱存在下进行，所用的碱优选自叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯。
上述步骤①中所述偶联反应的溶剂优选自甲苯、二甲苯或者它们的混合物。
上述步骤①中所述偶联反应的反应温度优选为-20～180℃，反应时间优选为1-48h。
优选地，步骤②中所述脱保护反应在酸存在下进行，所用的酸优选自氯化氢(比如氯化氢乙醇溶液)、盐酸、硫酸、对甲苯磺酸。
上述步骤②中所述脱保护反应所用的溶剂优选自二氯甲烷、四氢呋喃、甲基四氢呋喃、甲醇、乙醇、乙酸乙酯或者它们两种以上的混合物。
上述步骤②中所述脱保护反应温度优选为-80～100℃，反应时间优选为1-48h。
更具体地，步骤②中所述脱保护反应当Pg为叔丁氧羰基Boc时，加入酸来脱氨基保护基，所述酸为氯化氢有机溶液(比如氯化氢乙醇溶液)或三氟乙酸等；或者，当Pg为苄基Bn或甲酸苄酯CBz时，使用钯碳加氢来脱氨基保护基，加氢压力为0.1-1Mpa。
本发明的另一方面提供了一种包含上述式IB所示环己烷衍生物和化合物imp1的组 合物，其中式IB所示环己烷衍生物与化合物imp1的质量比在99.5:0.05以上：
Figure PCTCN2019100365-appb-000010
其中，基团R的定义如前所述。
较佳地，上述组合物中，式IB所示环己烷衍生物与imp1的质量比在99.7:0.02以上。
本发明的另一方面提供了一种包含所述式IB所示环己烷衍生物的组合物，其中IB所示环己烷衍生物占所述组合物质量的99.5％以上；imp1、imp6和imp8相对于式IB所示环己烷衍生物的质量比均在0.1％以下：
Figure PCTCN2019100365-appb-000011
其中，基团R的定义如前所述。
较佳地，imp6和imp8相对于式IB所示环己烷衍生物的质量比各自独立地在0.05％以下。
更佳地，imp6和imp8相对于式IB所示环己烷衍生物的质量比各自独立地在0.02％以下。
更佳地，化合物imp1相对于式IB所示环己烷衍生物的质量比在0.05％以下，进一步地在0.02％以下。
最佳地，所述组合物中不含imp6和/或imp8。
在本发明的一优选实施方式中，所述组合物中，式IB所示环己烷衍生物的含量占所述组合物质量的99.6％以上，例如99.6％、99.7％、99.8％或99.9％。
本发明还提供了另一种可选择的技术方案，包括如下内容。
一种制备式IB所示环己烷衍生物的方法，包括以下步骤：
(i)2-(4-氨基环己基)乙酸乙酯与N,N-二甲氨基甲酰氯进行酰化反应，生成 2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯；
(ii)2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯发生还原反应，生成式SM01B所示化合物3-(4-(2-羟基乙基)环己基)-1,1-二甲基脲(或称2-(4-(3,3-二甲基脲)环己基)乙醇)；
(iii)任选地，化合物SM01B经反应生成化合物SM01A；其中L为离去基团，较佳地为-OTs、-OMs、-Br、-Cl或-I；
(iv)化合物SM01A或者化合物SM01B，与化合物SM02或化合物SM02的盐进行亲核取代反应，即得化合物IB；
合成路线为：
Figure PCTCN2019100365-appb-000012
其中R为：
Figure PCTCN2019100365-appb-000013
在一种实施方式中，步骤(i)中所述酰化反应在碱存在的条件下进行，所用的碱选自有机碱比如：三乙胺、DIPEA、DBU等；无机碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠，碱的当量为1～10eq。
上述步骤(i)中所述酰化反应的溶剂优选自二氯甲烷、四氢呋喃、甲基四氢呋喃、DMF、乙腈、甲苯或者它们两种以上的混合物。
上述步骤(i)中所述酰化反应的反应温度优选为-20～100℃，反应时间优选为1-48h。
在一种实施方式中，上述步骤(ii)中所述还原反应的还原剂选自硼氢化钠和/或硼 氢化钾，还原剂的当量为1～10eq。
上述步骤(ii)中所述还原反应的溶剂优选自甲醇、四氢呋喃、乙醇或者它们两种以上的混合物。
上述步骤(ii)中所述还原反应的反应温度优选为-20～100℃，反应时间优选为1-48h。
在一种实施方式中，上述步骤(iii)中所述反应的试剂选自对甲苯磺酰氯、甲磺酰氯、NBS、二氯亚砜、三氯氧磷、碘或三溴化磷。
上述步骤(iii)中所述反应一般在碱存在下进行，所述碱优选自三乙胺、二异丙基乙基胺和咪唑中的一种或多种。
上述步骤(iii)中所述反应的溶剂选自二氯甲烷、四氢呋喃、甲苯、氯仿、或者它们两种以上的混合物。
上述步骤(iii)中所述反应的反应温度优选为-20～180℃，反应时间优选为1-48h。
在一种实施方式中，上述步骤(iv)中，当SM01A与SM02或其盐进行反应时，所述亲核取代反应一般在碱存在下进行，所述碱优选自碳酸钾、碳酸钠、三乙胺和二异丙基乙基胺中的一种或多种。
上述步骤(iv)中，当SM01A与SM02或其盐进行反应时，所述亲核取代反应的溶剂优选自乙腈、N,N-二甲基甲酰胺、丙酮、或者它们两种以上的混合物。
上述步骤(iv)中，当SM01A与SM02或其盐进行反应时，所述亲核取代反应的反应温度优选为-20～180℃，反应时间优选为1-48h。
在另一种实施方式中，上述步骤(iv)中，当SM01B与SM02或其盐进行反应时，所述亲核取代反应一般是在钌催化剂例如Ru 3(CO) 12的催化下进行，膦配体优选自Xantphos、Ruphos或Xphos等。
上述步骤(iv)中，当SM01B与SM02或其盐进行反应时，所述亲核取代反应的溶剂优选自甲苯、二甲苯、或者它们的混合物。
上述步骤(iv)中，当SM01B与SM02或其盐进行反应时，所述亲核取代反应的反应温度优选为-20～180℃，反应时间优选为1-48h。
在一种实施方式中，上述步骤(iv)中，除化合物SM01A或者化合物SM01B外，另一反应原料为化合物SM02或者化合物SM02的盐。其中化合物SM02的盐优选自盐酸盐、硫酸盐、醋酸盐、磺酸盐、甲磺酸盐或对甲苯磺酸盐，更佳地为盐酸盐。
化合物SM02或其盐可按本领域常规方法制得。例如，SM02化合物的盐可由SM02化合物与酸反应制得，所述酸选自盐酸、硫酸、醋酸、磺酸、甲磺酸或对甲苯磺酸；或 者，也可以由下式的SM02-A直接反应制得。相应地，SM02游离碱可以由SM02-A直接反应制得，或者，也可以由SM02-A的盐进一步游离制得。
在一种实施方式中，化合物SM02可以通过R-X与哌嗪进行偶联反应制得，合成路线为：
Figure PCTCN2019100365-appb-000014
其中X为Cl、Br或I，优选X为Br。
按本领域常识，上述偶联反应一般是在钯催化剂的催化下，在强碱性物质的存在下进行。所述偶联反应的温度优选为50-150℃，哌嗪与R-X的摩尔比优选为1-5:1。
上述钯催化剂优选自Pd 2(dba) 3、四三苯基膦钯或dppf二氯化钯，膦配体为BINAP。所述强碱性物质优选自叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯。
在另一种可选的实施方式中，化合物SM02还可以通过包含下述步骤的方法制得：
A)R-X与Pg-哌嗪进行偶联反应，生成SM02-A；
B)SM02-A脱保护，得到化合物SM02，
合成路线为：
Figure PCTCN2019100365-appb-000015
其中X为Cl、Br或I，优选X为Br；Pg是氨基保护基，优选自苄基Bn、甲酸苄酯CBz或叔丁氧羰基Boc。
按本领域常识，上述步骤A)中所述偶联反应一般是在钯催化剂催化下进行，所述钯催化剂优选自Pd 2(dba) 3、四三苯基膦钯或dppf二氯化钯，膦配体为BINAP。
优选地，步骤A)中所述偶联反应在碱存在下进行，所用的碱优选自叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯。
上述步骤A)中所述偶联反应的溶剂优选自甲苯、二甲苯或者它们的混合物。
上述步骤A)中所述偶联反应的反应温度优选为-20～180℃，反应时间优选为1-48h。
优选地，步骤B)中所述脱保护反应一般在酸存在下进行，所用的酸优选自氯化氢 (比如氯化氢乙醇溶液)、盐酸、硫酸或对甲苯磺酸。
上述步骤B)中所述脱保护反应所用的溶剂优选自二氯甲烷、四氢呋喃、甲基四氢呋喃、甲醇、乙醇、乙酸乙酯或者它们两种以上的混合物。
上述步骤B)中所述脱保护反应温度优选为-80～100℃，反应时间优选为1-48h。
更具体地，步骤B)中所述脱保护反应当Pg为叔丁氧羰基Boc时，加入酸来脱氨基保护基，所述酸为氯化氢有机溶液(比如氯化氢乙醇溶液)或三氟乙酸等；或者，当Pg为苄基Bn或甲酸苄酯CBz时，使用钯碳加氢来脱氨基保护基，加氢压力为0.1-1Mpa。
本发明的方法副反应少，通过该方法制备的环己烷衍生物IB产物纯度高、收率高，大大降低了杂质含量，特别是二聚体杂质imp6和imp8、以及单甲基杂质imp1含量低(单杂小于0.1％)，因而产品纯度高，容易达到药物质量标准，而且反应条件温和，易于控制，操作简单、安全，因而更适合工业化大规模生产。
具体实施方式
本文中，有时将术语“式X所示化合物”表述为“化合物X”，这是本领域技术人员能够理解的。比如式I所示化合物和化合物I都是指代相同的化合物。类似地，式SM01A所示化合物和化合物SM01A都是指代相同的化合物；式IB所示化合物和化合物IB都是指代相同的化合物。
本文中，化合物imp6和imp8属于二聚体杂质，化合物imp1属于单甲基杂质(或称掉甲基杂质、去甲基杂质、单杂)。
从商品原料式I所示化合物2-(4-氨基环己基)乙酸乙酯出发，直至最终产物环己烷衍生物IB的制备，本发明的制备方法总体上分为四个步骤：
1)使式I所示化合物2-(4-氨基环己基)乙酸乙酯与N,N-二甲氨基甲酰氯进行酰化反应，得到式II所示化合物2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯；
2)使式II所示化合物发生还原反应，生成式III所示化合物3-(4-(2-羟基乙基)环己基)-1,1-二甲基脲；
3)使式III所示化合物发生氧化反应，得到式SM01所示化合物2-(4-(3,3-二甲基脲基)环己基)乙醛；
4)使式SM01所示化合物与式SM02所示化合物进行还原胺化反应，得到式IB所示环己烷衍生物；
合成路线为：
Figure PCTCN2019100365-appb-000016
其中R为：
Figure PCTCN2019100365-appb-000017
在优选的实施方式中，在上述各步骤反应完成后，可按本领域常识进行过滤、洗涤、干燥等纯化操作。在最后一步即步骤4)的还原胺化反应之后，所进行的产物纯化操作甚至可以不包括柱层析纯化，也能得到不含二聚体杂质imp6和imp8、单甲基杂质imp1的产物，或者含量极低，几乎检测不出。通过省去柱层析纯化步骤，可以大大提高生产率，并且显著降低生产成本。
应理解，当式IB的环己烷衍生物具有特定的立体构型，则按照本领域常识，化合物SM01以及其相应的反应原料都具有相对应的立体构型。例如，在一具体实施方式中，式IB化合物为N’-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(下式IB-1)时，则SM01为1,1-二甲基-3-(反式-4-(2-氧代乙基)环己基)脲，可采用反式-2-(4-氨基环己基)乙酸乙酯制备该SM01。
Figure PCTCN2019100365-appb-000018
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
需说明的是，发明人还对包括CN106518841A在内的现有技术方法进行了验证，实验表明现有技术的方法中最后一步上脲基团，产物均存在单甲基杂质imp1；且采用烷基化路线无论是先上脲还是最后一步上脲，产物中均存在脲基团被亲核取代的二聚杂质imp6和imp8。
本发明的积极进步效果在于：本发明的制备方法能够以高收率制备得到式IB的环己烷衍生物，并且产物中杂质含量低，特别是二聚体杂质imp6和imp8、以及单甲基杂质imp1含量低(单杂小于0.1wt％)。而且，反应条件温和，易于控制，因而操作简单、安全。
以下通过实施例进一步阐述本发明。应理解，这些实施例仅用于举例说明目的，而不是对本发明的限制。本领域技术人员根据本发明构思对其作出的各种改变或调整，均应落入本发明的保护范围内。
本文中涉及到多种物质的添加量、含量及浓度，其中所述的百分含量，除特别说明 外，皆指质量百分含量。
本文的实施例中，如果对于反应温度或操作温度没有做出具体说明，则该温度通常指室温(15-30℃)。
实施例
试剂：本发明实施例中使用的反应物和催化剂均为化学纯，可直接使用或根据需要经过简单纯化；有机溶剂等均为分析纯，直接使用。试剂均购自中国医药(集团)上海化学试剂公司。
检测仪器：
核磁共振仪型号：Bruker avance HD 600MHz，Bruker avance III 400MHz；
质谱仪(液质联用(LCMS))，型号：Agilent 6120 B，检测器为DAD。
实施例1 反式-2-(4-(3,3-二甲基脲基)环己基)乙醛(化合物SM01-1)的制备
Figure PCTCN2019100365-appb-000019
反式-2-(4-(3,3-二甲基脲)环己基)乙酸乙酯(化合物II)的制备：
于500ml单口烧瓶中，加入反式-2-(4-氨基环己基)乙酸乙酯盐酸盐(化合物I)(44.2g，0.2mol)，三乙胺(84ml，0.6mol，3eq)，二氯甲烷(250ml)，混合搅拌，冰浴冷却至10℃以下，滴加N,N-二甲氨基甲酰氯的二氯甲烷溶液(N,N-二甲氨基甲酰氯32.2g，0.3mol，1.5eq溶于50ml二氯甲烷中)滴毕，自然升温，搅拌反应2h。取样检测原料反应完全，将反应液倒入100ml冰冷的1N稀盐酸中搅拌30min，分液，水相用二氯甲烷(100ml*2)萃取，合并有机相，依次用饱和碳酸氢钠水溶液，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得反式-2-(4-(3,3-二甲基脲)环己基)乙酸乙酯中间体(化合物II)，白色固体55g。
反式-2-(4-(3,3-二甲基脲)环己基)乙醇(化合物III)的制备：
于1L单口烧瓶中，加入中间体化合物II(55g，0.2mol)，四氢呋喃(500ml)，搅 拌溶清。分批加入硼氢化钠(38g，1mol，5eq)。加毕，搅拌15min后，滴加甲醇(250ml)。滴毕，升温回流反应过夜，取样检测原料反应完全，停止加热，待反应冷却至室温后，旋干反应液，残留物加水(300ml)和乙酸乙酯(250ml)搅拌溶清，分液，水相用乙酸乙酯(150ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得反式-2-(4-(3,3-二甲基脲)环己基)乙醇(化合物III)，白色固体31.2g。
反式-2-(4-(3,3-二甲基脲基)环己基)乙醛(SM01-1)的制备：
Swern氧化
于250ml三口烧瓶中，加入DMSO(4.37g，0.056mol，3eq)，溶于50ml二氯甲烷中，氮气置换，干冰浴冷却至-78℃。滴加草酰氯(4.74g，0.0373mol，2eq)，控温不超过-65℃。滴毕，保温-70～-78℃反应1小时。滴加化合物III的二氯甲烷溶液(反式-2-(4-(3,3-二甲基脲)环己基)乙醇4g，0.0187mol，溶于30ml二氯甲烷)，控温不超过-65℃。滴毕，保温-70～-78℃反应1小时。加入三乙胺(26ml，0.1867mol，10eq)，控温不超过-45℃。加毕，撤除干冰浴，自然升温至-20℃，将反应液倒入冰冷的1N盐酸(100ml)中，搅拌15min。分液，水相用二氯甲烷(50ml*2)萃取，合并有机相，依次用饱和碳酸氢钠水溶液，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得淡黄色固体3.8g。经柱层析纯化，洗脱剂：石油醚：乙酸乙酯＝1：1～0：1，得反式-2-(4-(3,3-二甲基脲基)环己基)乙醛(化合物SM01-1)，白色固体3g。
ESI:M+1＝213
TEMPO氧化
于250ml三口烧瓶中，加入化合物III(4.28g，0.02mol)，TEMPO(0.03g，0.0002mol，0.01eq)，碳酸氢钠(4.2g，0.05mol，2.5eq)，溴化钠(0.2g，0.002mol，0.1eq)，二氯甲烷(50ml)，水(50ml)，混合搅拌溶清后，冰盐浴冷却至0℃。滴加10％的次氯酸钠溶液，控温不超过5℃。滴毕，于0～10℃反应30min，取样检测原料基本反应完全。反应液分液，水相用二氯甲烷(30ml*2)萃取，合并有机相，依次用饱和硫代硫酸钠水溶液，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得到浅棕色油状物5g。经柱层析纯化，洗脱剂：石油醚：乙酸乙酯＝1：1～0：1，得反式-2-(4-(3,3-二甲基脲)环己基)乙醇(化合物III)，白色固体3.1g。
ESI:M+1＝213
实施例2 1-(苯并[b]噻吩-7-基)哌嗪(化合物SM02-1)的制备
Figure PCTCN2019100365-appb-000020
于500ml单口烧瓶中，加入7-溴苯并噻吩(21.2g，0.1mol)，Boc哌嗪(20.5g，0.11mol，1.1eq)，叔丁醇钾(16.8g，0.15mol，1.5eq)，甲苯(300ml)，混合搅拌，氮气置换3次。加入BINAP(3.74g)，Pd 2(dba) 3(2g)后，氮气置换3次。放入油浴中升温至100℃，搅拌反应过夜(8h)。取样点板(展开剂：石油醚：乙酸乙酯＝10：1)，原料基本反应完全。停止加热，待反应液冷却至室温后，硅藻土抽滤，滤饼用甲苯(300ml)淋洗，合并滤液，饱和食盐水洗涤，旋干(水浴45℃～60℃)得到棕红色油状物38g。经柱层析纯化，洗脱剂：石油醚：乙酸乙酯＝50：1～30：1，得到中间体SM02-A1，淡黄色油状物21.2g。
1H NMR(400MHz，CDCl 3)δ：7.55 1H d，7.42 1H d，7.33 2H m，6.93 1H d，3.67 4H m，3.17 4H m，1.51 9H s
于500L单口烧瓶中，加入上述中间体SM02-A1(21.2g)，氯化氢乙醇溶液(20ml)，无水乙醇(150ml)混合，油浴55℃加热反应2h，反应过程中有白色固体析出。取样点板(展开剂：石油醚：乙酸乙酯＝10：1)，原料基本反应完全。停止加热，待反应液冷却至室温后，抽滤，滤饼用乙醇淋洗，烘干后得到SM02-1盐酸盐，类白色固体15g。
上述15g盐酸盐经氢氧化钠溶液游离后，DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，抽滤旋干后，得到黄色油状物12g，即为1-(苯并[b]噻吩-7-基)哌嗪(SM02-1)。
ESI:M+1＝219
实施例3 N’-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物IB-1)的制备
Figure PCTCN2019100365-appb-000021
用SM02-1盐酸盐制备IB-1
于100ml单口烧瓶中，加入SM01-1(1.7g，0.008mol)，SM02-1盐酸盐(2.03g，0.008mol，1eq)，三乙胺(1.3ml，0.0096mol，1.2eq)，二氯甲烷50ml，混合搅拌溶清，分批加入三乙酰氧基硼氢化钠(2.6g，0.0241mol，1.5eq)。加毕，搅拌反应4h。取样检测，原料基本反应完全，反应液倒入50ml饱和碳酸氢钠水溶液中，搅拌15min，分液，水相用二氯甲烷(50ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得粗品3.4g，经乙酸乙酯重结晶，活性炭脱色得到IB-1白色固体1.6g，HPLC检测到单杂小于0.1％，收率48％。
1H NMR(400MHz,CDCl 3)δ:7.52 1H d，7.41 1H d，7.32 2H m，6.94 1H d，4.12 1H d，3.59 1H m，3.29 4H s，2.88 6H s，2.72 4H m，2.50 2H m，2.03 2H m，1.79 2H m，1.50 2H m，1.26 1H m，1.11 4H m；
MS(EI)m/z:M+1＝415
HPLC:imp1 0.02％；目的产物99.76％；imp6N/A，imp8N/A；无大于0.1％单杂。
Figure PCTCN2019100365-appb-000022
用SM02-1游离碱制备IB-1：
于100ml单口烧瓶中，加入SM01-1(1.7g，0.008mol)，SM02-1游离碱(1.75g，0.008mol，1eq)，二氯甲烷50ml，混合搅拌溶清，分批加入三乙酰氧基硼氢化钠(2.6g，0.0241mol，1.5eq)。加毕，搅拌反应4h。取样检测，原料基本反应完全，反应液倒入50ml饱和碳酸氢钠水溶液中，搅拌15min，分液，水相用二氯甲烷(50ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得粗品3.2g。经乙酸乙酯重结晶，活性炭脱色得到IB-1白色固体1.7g，HPLC检测到单杂小于0.1％，51％收率。
实施例4-8 合成不同R取代基的IB化合物
参照实施例1-3中的合成方法，按下述合成路线合成不同R取代基的IB化合物。相应的结构和收率见下表1。
Figure PCTCN2019100365-appb-000023
表1、多种IB化合物的收率
Figure PCTCN2019100365-appb-000024
Figure PCTCN2019100365-appb-000025
经HPLC检测，实施例4-8所制得的产物中无大于0.1％的单杂，IB化合物占99.5％以上。
对比例1用SM02与反式-对甲苯磺酸2-(4-(3,3-二甲基脲)环己基)乙酯(式TM)制备IB-1
Figure PCTCN2019100365-appb-000026
于100ml单口烧瓶中，加入反式-对甲苯磺酸2-(4-(3,3-二甲基脲)环己基)乙酯(化合物TM)(1.47g，0.004mol)，SM02(0.96g，0.0044mol，1.1eq)，碳酸钾(1.1g，0.008mol，2eq)，乙腈(40ml)，混合搅拌，油浴75℃加热反应过夜。取样检测，原料反应完全后，停止加热。待反应液冷却至室温后，旋干溶剂，残留物加水(50ml)和二氯甲烷(30ml) 搅拌溶清，分液。水相用二氯甲烷(50ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干，得到棕色固体2.5g。经柱层析纯化，洗脱剂：二氯甲烷：甲醇＝50：1～30：1，得淡黄色固体1.8g，经乙酸乙酯重结晶得到IB-1白色固体0.8g。
HPLC：IB-1，86.35％；二聚物杂质imp8，13.22％。
产物中包含二聚物杂质imp8，结构式为：
Figure PCTCN2019100365-appb-000027
对比例2用其他合成路线制备IB-1
Figure PCTCN2019100365-appb-000028
于2L单口烧瓶中，加入化合物A(100g)，无水甲醇700ml，混合搅拌，加入氯化氢乙醇溶液(100ml)后，油浴升温55℃搅拌反应，随着反应有白色固体析出，反应2h后，取样检测中间体A反应完全，停止加热，待反应液冷却至室温后，抽滤，滤饼用乙醇淋洗，烘干后得到中间体B，类白色固体85g。
于2L单口烧瓶中，加入中间体B(62.28g，0.15mol)，氢氧化钠水溶液(氢氧化钠60g，1.5mol，10eq，溶于375ml水中)，二氯甲烷(375ml)，混合，加入四丁基溴化磷(6g)，搅拌溶清。冰浴冷却至5℃，滴加二甲氨基甲酰氯(64.2g，0.6mol，4eq)，约45min滴完。滴毕，于25℃油浴升温搅拌反应过夜(8h)。取样检测，原料基本反应完 全，反应液分液，水相用二氯甲烷(200ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得到IB-1粗品100g，淡黄色粘稠固体。
HPLC：imp1 32.25％；目的产物61.35％；imp6 0.28％。
IB-1粗品经柱层析纯化，洗脱剂：二氯甲烷：甲醇＝50：1～30：1，得到淡黄色固体80g，上述固体用800ml乙酸乙酯重结晶，得到IB-1白色固体35g。
HPLC：imp1 0.06％；目的产物99.64％；imp6 0.29％。
该路线最后一步中，与二甲氨基甲酰氯的反应，粗品中有约30％的单甲基杂质imp1，乙酸乙酯重结晶无法去除该杂质，而采用多次柱层析无法将该杂质降到0.05％以下。
产物中包含二聚物杂质imp6，结构式为：
Figure PCTCN2019100365-appb-000029
专利CN106518841A中最后一步上脲结果同对比例2，存在大量单甲基杂质和二聚杂质，无法除去。
上述实施例1-8表明，本发明的方法制备的产物IB-1纯度高，大大降低了杂质含量、特别是二聚体杂质和单甲基杂质含量(单杂小于0.1％)，容易达到药物质量标准。而且后处理简单，能够显著降低生产成本，因而更适合工业化大规模生产。
实施例9 化合物SM01B-1和SM01A-1的制备
Figure PCTCN2019100365-appb-000030
反式-2-(4-(3,3-二甲基脲)环己基)乙酸乙酯的制备：
于500ml单口烧瓶中，加入反式-2-(4-氨基环己基)乙酸乙酯盐酸盐(44.2g，0.2mol)，三乙胺(84ml，0.6mol，3eq)，二氯甲烷(250ml)混合搅拌，冰浴冷却至10℃以下， 滴加N,N-二甲氨基甲酰氯的二氯甲烷溶液(N,N-二甲氨基甲酰氯32.2g，0.3mol，1.5eq溶于50ml二氯甲烷中)滴毕，自然升温，搅拌反应2h。取样检测原料反应完全，将反应液倒入100ml冰冷的1N稀盐酸中搅拌30min，分液，水相用二氯甲烷(100ml*2)萃取，合并有机相，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得白色固体55g，即为反式-2-(4-(3,3-二甲基脲)环己基)乙酸乙酯。
反式-2-(4-(3,3-二甲基脲)环己基)乙醇(化合物SM01B-1)的制备：
于1L单口烧瓶中，加入上述反式-2-(4-(3,3-二甲基脲)环己基)乙酸乙酯(55g，0.2mol)，四氢呋喃(500ml)，搅拌溶清。分批加入硼氢化钠(38g，1mol，5eq)。加毕，搅拌15min后，滴加甲醇(250ml)。滴毕，升温回流反应过夜，取样检测原料反应完全，停止加热，待反应冷却至室温后，旋干反应液，残留物加水(300ml)和乙酸乙酯(250ml)搅拌溶清，分液，水相乙酸乙酯(150ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得白色固体31.2g，即为化合物SM01B-1。
反式-2-(4-(3,3-二甲基脲)环己基)乙基-4甲基苯磺酸酯(化合物SM01A-1)的制备：
于100ml单口烧瓶中，加入化合物SM01B(3.3g，0.0154mol)，三乙胺(4.7g，0.0463mol，3eq)，二氯甲烷(40ml)混合搅拌，分批加入对甲苯磺酰氯(3.5g，0.0185mol，1.2eq)。加毕，搅拌反应过夜。取样检测原料反应完全后，将反应液倒入冰的1N稀盐酸(50ml)中，搅拌15min，分液，水相用二氯甲烷(40ml*2)萃取，合并有机相，一次用饱和碳酸氢钠水溶液，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干，得粗品，经柱层析纯化，洗脱剂：石油醚：乙酸乙酯＝1：1～0：1，得到白色固体2.6g，即为化合物SM01A-1。
实施例10 化合物SM02-1的制备
Figure PCTCN2019100365-appb-000031
于500ml单口烧瓶中，加入7-溴苯并噻吩(21.2g，0.1mol)，Boc哌嗪(20.5g，0.11mol，1.1eq)，叔丁醇钾(16.8g，0.15mol，1.5eq)，甲苯(300ml)，混合搅拌，氮气置换3次。加入BINAP(3.74g)，Pd 2(dba) 3(2g)后，氮气置换3次。放入油浴中升温至100℃， 搅拌反应过夜(8h)。取样点板(展开剂：石油醚：乙酸乙酯＝10：1)，原料基本反应完全。停止加热，待反应液冷却至室温后，硅藻土抽滤，滤饼用甲苯(300ml)淋洗，合并滤液，饱和食盐水洗涤，旋干(水浴45℃～60℃)得到棕红色油状物38g。经柱层析纯化，洗脱剂：石油醚：乙酸乙酯＝50：1～30：1，得到淡黄色油状物21.2g，即为化合物SM02-A1。
1H NMR(400MHz，CDCl 3)δ：7.55 1H d，7.42 1H d，7.33 2H m，6.93 1H d，3.67 4H m，3.17 4H m，1.51 9H s
于500L单口烧瓶中，加入上述中间体SM02-A(21.2g)，氯化氢乙醇溶液(20ml)，无水乙醇(150ml)混合，油浴55℃加热反应2h，反应过程中有白色固体析出。取样点板(展开剂：石油醚：乙酸乙酯＝10：1)，原料基本反应完全。停止加热，待反应液冷却至室温后，抽滤，滤饼用乙醇淋洗，烘干后得到类白色固体15g，即为化合物SM02-1盐酸盐。
上述15g盐酸盐经氢氧化钠溶液游离后，DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，抽滤旋干后，得到黄色油状物12g，即为1-(苯并[b]噻吩-7-基)哌嗪(SM02-1)。
实施例11 化合物IB-1的制备
Figure PCTCN2019100365-appb-000032
于100ml单口烧瓶中，加入化合物SM01A-1(1.47g，0.004mol)，化合物SM02-1(0.96g，0.0044mol，1.1eq)，碳酸钾(1.1g，0.008mol，2eq)，乙腈(40ml)，混合搅拌，油浴75℃加热反应过夜。取样检测，原料反应完全后，停止加热。待反应液冷却至室温后，旋干溶剂，残留物加水(50ml)和二氯甲烷(30ml)搅拌溶清，分液。水相用二氯甲烷(50ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干，得到棕色固体2.5g。经柱层析纯化，洗脱剂：二氯甲烷：甲醇＝50：1～30：1，得淡黄色固体1.8g，经乙酸乙酯重结晶，得到白色固体0.8g，即为化合物IB-1。
1H NMR(400MHz,CDCl 3)δ:7.52 1H d，7.41 1H d，7.32 2H m，6.94 1H d，4.12 1H d，3.59 1H m，3.29 4H s，2.88 6H s，2.72 4H m，2.50 2H m，2.03 2H m，1.79 2H m， 1.50 2H m，1.26 1H m，1.11 4H m；
MS(EI)m/z:M+1＝415
HPLC:IB-1，86.35％；二聚物杂质imp8，13.22％。
产物中未检出掉甲基杂质imp1和双取代杂质imp6。
Figure PCTCN2019100365-appb-000033
另一种方法制备化合物IB-1：
Figure PCTCN2019100365-appb-000034
于100ml单口烧瓶中，加入化合物SM01B(2.14g，0.01mol)，化合物SM02游离碱(2.4g，0.011mol，1.1eq)，Ru 3(CO) 12(0.25g，0.0004mol，0.04eq)，Xantphos(0.35g，0.0006mol，0.06eq)，甲苯(20ml)混合搅拌。氮气置换后，加热回流反应过夜。旋干溶剂，柱层析纯化，洗脱剂：二氯甲烷：甲醇＝50：1～30：1，得到淡黄色固体2g，上述固体用乙酸乙酯重结晶，得到白色固体0.8g，即为化合物IB-1。
实施例12-16 合成不同R取代基的IB化合物
参照实施例9-11中的合成方法，按下述合成路线合成不同R取代基的IB化合物。相应的结构和收率见下表2。
Figure PCTCN2019100365-appb-000035
表2、多种IB化合物的收率
Figure PCTCN2019100365-appb-000036
Figure PCTCN2019100365-appb-000037
经HPLC检测，实施例12-16所制得的产物中无单杂imp1和二聚体杂质imp6，IB化合物占85％以上。
对比例3用其他合成路线制备化合物IB-1
Figure PCTCN2019100365-appb-000038
于2L单口烧瓶中，加入化合物A(100g)，无水甲醇700ml，混合搅拌，加入氯化氢乙醇溶液(100ml)后，油浴升温55℃搅拌反应，随着反应有白色固体析出，反应2h后，取样检测中间体A反应完全，停止加热，待反应液冷却至室温后，抽滤，滤饼用乙醇淋洗，烘干后得到中间体B，类白色固体85g。
于2L单口烧瓶中，加入中间体B(62.28g，0.15mol)，氢氧化钠水溶液(氢氧化钠60g，1.5mol，10eq，溶于375ml水中)，二氯甲烷(375ml)，混合，加入四丁基溴化磷 (6g)，搅拌溶清。冰浴冷却至5℃，滴加二甲氨基甲酰氯(64.2g，0.6mol，4eq)，约45min滴完。滴毕，于25℃油浴升温搅拌反应过夜(8h)。取样检测，原料基本反应完全，反应液分液，水相用二氯甲烷(200ml*2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干得到IB-1粗品100g，淡黄色粘稠固体。
HPLC:10.62min(imp1)32.25％；12.63min(IB-1)61.35％；29.52min(imp6)0.28％。
IB-1粗品经柱层析纯化，洗脱剂：二氯甲烷：甲醇＝50：1～30：1，得到淡黄色固体80g，上述固体用800ml乙酸乙酯重结晶，得到IB-1白色固体35g。
HPLC：imp1 0.06％；目的产物99.64％；imp6 0.29％。
该路线最后一步中，与二甲氨基甲酰氯的反应，粗品中有约30％的单甲基杂质imp1，采用柱层析和乙酸乙酯重结晶进行纯化，均无法将该杂质降到0.05％以下。
上述实施例9-19表明，本发明的方法制备的产物中未检出imp6和单甲基杂质imp1，而且后处理简单，能够显著降低生产成本，因而更适合工业化大规模生产。

Claims (20)

  1. 一种制备式IB所示环己烷衍生物的方法，包括以下步骤：
    使式SM01所示化合物2-(4-(3,3-二甲基脲基)环己基)乙醛与式SM02所示化合物或其盐进行还原胺化反应，得到式IB所示环己烷衍生物：
    Figure PCTCN2019100365-appb-100001
    其中R为：
    Figure PCTCN2019100365-appb-100002
  2. 根据权利要求1所述的方法，其特征在于，所述还原胺化反应的还原剂选自三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠加醋酸或者硼氢化钾加醋酸，还原剂的当量为1～10eq。
  3. 根据权利要求1所述的方法，其特征在于，还原胺化反应中的反应原料为SM02的盐，其中式SM02所示化合物的盐选自盐酸盐、硫酸盐、醋酸盐、磺酸盐、甲磺酸盐或对甲苯磺酸盐。
  4. 根据权利要求1所述的方法，其特征在于，式SM01所示化合物的制备方法包括以下步骤：
    1)使式I所示化合物2-(4-氨基环己基)乙酸乙酯与N,N-二甲氨基甲酰氯进行酰化反应，得到式II所示化合物2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯；
    2)使式II所示化合物发生还原反应，生成式III所示化合物3-(4-(2-羟基乙基)环己基)-1,1-二甲基脲；
    3)使式III所示化合物发生氧化反应，得到式SM01所示化合物2-(4-(3,3-二甲基脲基)环己基)乙醛；
    合成路线为：
    Figure PCTCN2019100365-appb-100003
  5. 根据权利要求1所述的方法，其特征在于，式SM02所示化合物通过R-X与哌嗪进行偶联反应制得，合成路线为：
    Figure PCTCN2019100365-appb-100004
    其中X为Cl、Br或I。
  6. 根据权利要求1所述的方法，其特征在于，式SM02所示化合物通过包含下述步骤的方法制得：
    ①R-X与Pg-哌嗪进行偶联反应，生成SM02-A；
    ②SM02-A脱保护，去除氨基保护基Pg，得到化合物SM02，
    合成路线为：
    Figure PCTCN2019100365-appb-100005
    其中X为Cl、Br或I；Pg是氨基保护基，选自苄基Bn、甲酸苄酯CBz或叔丁氧羰基Boc。
  7. 根据权利要求6所述的方法，其特征在于，步骤②中所述脱保护反应在酸存在下进行，所用的酸选自氯化氢、盐酸、硫酸或对甲苯磺酸。
  8. 一种包含权利要求1中所述式IB所示环己烷衍生物和化合物imp1的组合物，其中式IB所示环己烷衍生物与化合物imp1的质量比在99.5:0.05以上：
    Figure PCTCN2019100365-appb-100006
    其中，R为：
    Figure PCTCN2019100365-appb-100007
    较佳地，式IB所示环己烷衍生物与imp1的质量比在99.7:0.02以上。
  9. 一种包含权利要求1中所述式IB所示环己烷衍生物的组合物，其中IB所示环己烷衍生物占所述组合物质量的99.5％以上；imp1、imp6和imp8相对于式IB所示环己烷衍生物的质量比均在0.1％以下：
    Figure PCTCN2019100365-appb-100008
    其中，R为：
    Figure PCTCN2019100365-appb-100009
  10. 根据权利要求9所述的组合物，其特征在于，imp6和imp8相对于式IB所示环己烷衍生物的质量比各自独立地在0.05％以下；
    较佳地，imp6和imp8相对于式IB所示环己烷衍生物的质量比各自独立地在0.02％以下；
    更佳地，组合物imp1相对于式IB所示环己烷衍生物的质量比在0.05％以下，进一步地在0.02％以下；
    最佳地，所述组合物中不含式imp6所示化合物和/或式imp8所示化合物。
  11. 一种制备式IB所示环己烷衍生物的方法，包括以下步骤：
    (i)2-(4-氨基环己基)乙酸乙酯与N,N-二甲氨基甲酰氯进行酰化反应，生成2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯；
    (ii)2-(4-(3,3-二甲基脲基)环己基)乙酸乙酯发生还原反应，生成式SM01B所示化合物3-(4-(2-羟基乙基)环己基)-1,1-二甲基脲；
    (iii)化合物SM01B经反应生成化合物SM01A；其中L为离去基团；
    (iv)化合物SM01A或者化合物SM01B，与化合物SM02或化合物SM02的盐进行亲核取代反应，即得化合物IB，合成路线为：
    Figure PCTCN2019100365-appb-100010
    其中R为：
    Figure PCTCN2019100365-appb-100011
  12. 根据权利要求11所述的方法，其特征在于，L选自-OTs、-OMs、-Br、-Cl或-I。
  13. 根据权利要求11所述的方法，其特征在于，步骤(i)中所述酰化反应在碱存在的条件下进行，所用的碱选自：三乙胺、DIPEA、DBU、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾和碳酸氢钠中的一种或多种，碱的当量为1～10eq。
  14. 根据权利要求11所述的方法，其特征在于，步骤(ii)中所述还原反应的还原剂选自硼氢化钠和/或硼氢化钾，还原剂的当量为1～10eq。
  15. 根据权利要求11所述的方法，其特征在于，步骤(iii)中所述反应的试剂选自对甲苯磺酰氯、甲磺酰氯、NBS、二氯亚砜、三氯氧磷、碘或三溴化磷；和/或，
    步骤(iii)在碱存在下进行，所述碱选自三乙胺、二异丙基乙基胺和咪唑中的一种或多种。
  16. 根据权利要求11所述的方法，其特征在于，步骤(iv)中，当SM01A与SM02或其盐进行反应时，所述亲核取代反应在碱存在下进行，所述碱选自碳酸钾、碳酸钠、三乙胺和二异丙基乙基胺中的一种或多种。
  17. 根据权利要求11所述的方法，其特征在于，步骤(iv)中，当SM01B与SM02或其盐进行反应时，所述亲核取代反应是在钌催化剂Ru 3(CO) 12的催化下进行，膦配体选自Xantphos、Ruphos或Xphos。
  18. 根据权利要求11所述的方法，其特征在于，化合物SM02通过R-X与哌嗪进行偶联反应制得，合成路线为：
    Figure PCTCN2019100365-appb-100012
    其中X为Cl、Br或I。
  19. 根据权利要求18所述的方法，其特征在于，所述偶联反应是在钯催化剂的催化下，在强碱性物质的存在下进行，所述强碱性物质优选自叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯。
  20. 根据权利要求11所述的方法，其特征在于，化合物SM02通过包含下述步骤的方法制得：
    A)R-X与Pg-哌嗪进行偶联反应，生成SM02-A；
    B)SM02-A脱保护，得到化合物SM02，
    合成路线为：
    Figure PCTCN2019100365-appb-100013
    其中X为Cl、Br或I；Pg是氨基保护基，优选自苄基Bn、甲酸苄酯CBz或叔丁氧羰基Boc。
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