WO2024048714A1 - METHOD FOR PRODUCING 6-(4,4-DIMETHYLCYCLOHEXYL)-4-[(1,1-DIOXO-1λ6-THIOMORPHOLIN-4-YL)METHYL]-2-METHYLTHIENO[2,3-D]PYRIMIDINE OR SALT THEREOF - Google Patents

METHOD FOR PRODUCING 6-(4,4-DIMETHYLCYCLOHEXYL)-4-[(1,1-DIOXO-1λ6-THIOMORPHOLIN-4-YL)METHYL]-2-METHYLTHIENO[2,3-D]PYRIMIDINE OR SALT THEREOF Download PDF

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WO2024048714A1
WO2024048714A1 PCT/JP2023/031795 JP2023031795W WO2024048714A1 WO 2024048714 A1 WO2024048714 A1 WO 2024048714A1 JP 2023031795 W JP2023031795 W JP 2023031795W WO 2024048714 A1 WO2024048714 A1 WO 2024048714A1
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compound
compound represented
reaction
stirred
methylthieno
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PCT/JP2023/031795
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French (fr)
Japanese (ja)
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絵理子 大▲高▼
和義 小櫃
義徳 ▲高▼村
陽平 山下
悠正 ▲高▼松
俊 平澤
透 福山
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アステラス製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or
  • the present invention relates to a method for producing the salt.
  • Patent Document 1 International Publication 2015/056771A1 discloses 6-(4,4-dimethylcyclohexyl)-4-[(1,1 - dioxo -1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is described. Furthermore, as a method for synthesizing the compound represented by Formula I, a synthetic method including a method of forming a thienopyrimidine skeleton from a cyclohexane derivative through thiophene cyclization is described. This synthetic method requires a large number of steps and also involves the use and production of toxic compounds.
  • the problem of the present invention is to solve the problem of 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]
  • the purpose of the present invention is to develop a synthetic method for pyrimidine or its salt that is efficient and more preferable from the viewpoint of green chemistry.
  • 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d] Pyrimidine or a salt thereof can be synthesized efficiently and more preferably from the viewpoint of green chemistry.
  • 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine has the following formula: This is a compound represented by I.
  • the compound represented by Formula I may be in a free form that does not form an ester or salt, or may form a salt with an acid or the like.
  • Such salts are preferably pharmaceutically acceptable salts, but are not limited thereto, and include, for example, acid addition salts with inorganic acids, organic acids, etc.
  • inorganic acids include examples of organic acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, and lactic acid. , malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, carbonic acid, etc. Yes, but not limited to this.
  • a compound may be described using a structural formula, such as "a compound represented by formula X,” but it may also be simply described as compound X. Therefore, the compound represented by Formula I may be simply referred to as "Compound I".
  • the present invention provides, in one embodiment, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3 -d] A method for producing pyrimidine or its salt. When producing various hydrates, solvates, crystal polymorphs, etc. of the compound represented by Formula I, the hydrates may be obtained by appropriately known methods.
  • the labeling may be carried out appropriately by a known method.
  • the functional group can be replaced with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from raw materials to intermediates.
  • protecting groups include the protecting groups described in "Greene's Protective Groups in Organic Synthesis” (4th edition, 2006), which can be selected and used as appropriate depending on the reaction conditions. Good, but not limited to this.
  • a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
  • lower alkyl typically refers to a straight chain or branched chain having 1 to 6 carbon atoms (hereinafter also referred to as C 1-6 , hereinafter the number of carbon atoms is expressed in the same manner).
  • alkyl such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.
  • Examples of the "lower alkyl group” include a methyl group, an ethyl group, a propyl group, and the like, with an ethyl group being preferred.
  • Cycloalkane is typically a C 3-8 saturated hydrocarbon ring, including, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclo Examples include octane.
  • the "cycloalkane” is preferably a C 5-6 cycloalkane, such as cyclohexane or cyclopropane, preferably cyclopropane.
  • Halogen means F, Cl, Br, or I.
  • a 1M NaOH aqueous solution means a 1 mol/L NaOH aqueous solution.
  • 4-chloro-2-methylthieno[2,3-d]pyrimidine or a derivative thereof is used as a starting material. That is, in the present invention, the following formula: For 4-chloro-2-methylthieno[2,3-d]pyrimidine or its derivatives represented by the following formula: By selectively adding the compound represented by the 6-position, the following formula: A compound represented by is obtained.
  • International Publication No. 2015/056771A1 describes a method for synthesizing the compound represented by Formula I, but it involves cyclizing thiophene from a cyclohexane derivative and finally forming a thienopyrimidine skeleton, which requires a large number of steps. The yield of the target compound is also low.
  • the basic skeleton of the target compound is formed at an early stage by adding 4,4-dimethylcyclohexanone to the 6-position of 4-chloro-2-methylthieno[2,3-d]pyrimidine.
  • the number of steps can be reduced and the yield can be significantly improved.
  • 1-(4-chloro-2-methylthieno[2,3 -d]pyrimidin-6-yl)-4,4-dimethylcyclohexan-1-ol (A-200) the solvent is not particularly limited as long as it does not interfere with the reaction, but for example, THF is typically used.
  • the base include, but are not limited to, typically organic lithium compounds such as n-BuLi, sec-BuLi, lithium diisopropylamide, and lithium hexamethyldisilazide. , preferably n-BuLi can be used.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically ethers such as THF, diethyl ether, and cyclopentyl methyl ether, or aromatic hydrocarbons such as toluene and xylene can be used.
  • ethers such as THF, diethyl ether, and cyclopentyl methyl ether, or aromatic hydrocarbons such as toluene and xylene can be used.
  • THF can be used.
  • the base is not particularly limited as long as the reaction proceeds, but typically organic lithium compounds such as n-BuLi, sec-BuLi, lithium diisopropylamide, and lithium hexamethyldisilazide can be used. , preferably n-BuLi can be used.
  • Organic amines such as, but not limited to, DIPEA, triethylamine, DBU, pyridine may additionally be used to convert cycloalkanes to cycloalkenes in one pot.
  • DIPEA triethylamine
  • DBU triethylamine
  • pyridine may additionally be used to convert cycloalkanes to cycloalkenes in one pot.
  • the halogen in A-101 is not particularly limited as long as the reaction proceeds, but Br is preferably used.
  • the manufacturing method according to the present invention is performed using the following formula:
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically an aprotic polar solvent such as MeCN, DMF, or DMSO can be used, and MeCN can be preferably used.
  • the present invention provides the following formula: From the compound represented by the following formula:
  • R is an alkyl group
  • the method may further include a step of obtaining a compound represented by:
  • This reaction is not particularly limited as long as the reaction progresses, but for example, 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A- 300), for example, is typically carried out in the presence of an alkyl alcohol and an acid or acid halide (optionally in a suitable solvent).
  • an acid or acid halide HCl, acyl chloride, etc. can be used, and as a solvent, EtOH or any mixed solvent containing EtOH can be used.
  • This reaction is not particularly limited as long as the reaction progresses, but for example, typically, after adding the alkyl alcohol and acid under cooling, the reaction is carried out at around room temperature, and the mixture is stirred at 40°C to 60°C for several hours to overnight. It can be done by
  • the present invention provides the following formula:
  • the method may include a step of obtaining a compound represented by: Ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400) was reduced to [6-( The process of obtaining 4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500) is particularly Although not limited, the reaction may be carried out using a solvent inert to the reaction and in the presence of a reducing agent.
  • the reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at -20°C to 80°C, for 0.1 hour to 3 days.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically ethers, aromatic hydrocarbons, alcohols, halogenated hydrocarbons, or mixed solvents thereof can be used.
  • the reducing agent is not limited to these, typically sodium borohydride (NaBH 4 ), lithium aluminum hydride (LiAlH 4 ), borane (BH 3 ), reducing agents described in the following literature, etc. are used. NaBH4 may be used with CaCl2 .
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as EtOH and MeOH, ethers such as THF, etc. can be used.
  • Metal catalysts include, but are not limited to, typically palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , rhodium catalysts such as Wilkinson catalysts, etc., and are suitable. Pd(OH) 2 can be used for.
  • As the hydrogen source formic acid, ammonium formate, etc. can also be used in an equivalent to excess amount of compound A-500, instead of hydrogen gas. [Literature] M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996; “Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 19 (2005) (Maruzen)
  • the present invention provides the following formula:
  • the method may further include a step of obtaining a target compound represented by:
  • This amination step may be carried out by any suitable method known in the art, for example by direct amination, typically with a catalyst, or by converting the hydroxyl group into a leaving group. be able to.
  • the hydroxyl group of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600) is substituted with a halogen, an alkylsulfonate, a fluoroalkylsulfonate, etc.
  • thiomorpholine-1,1-dioxide A-20
  • A-20 thiomorpholine-1,1-dioxide
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes aromatic hydrocarbons such as toluene and xylene, ethers such as Et 2 O, THF, DME, and dioxane, DCM, DCE, Halogenated hydrocarbons such as chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof can be used.
  • an organic base such as TEA, DIPEA or NMO
  • an inorganic base such as K 2 CO 3 , Na 2 CO 3 or KOH
  • the present invention provides the following formula: From the compound represented by the following formula: After obtaining the compound represented by, the compound is reduced to form the following formula:
  • the method may include a step of obtaining a compound represented by: Hydrolysis of ethyl ester of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400)
  • A-400 The process for obtaining 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) is well known in the art.
  • reaction may be carried out by any known appropriate method, and is not particularly limited as long as the reaction proceeds, but for example, it may be carried out typically in the presence of an aqueous alkaline solution using a solvent inert to the reaction.
  • the reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at 0° C. to 50° C., for 0.1 hour to 3 days.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, or mixed solvents thereof can be used.
  • the alkaline aqueous solution is not particularly limited as long as the reaction proceeds, but typically, for example, a NaOH aqueous solution, a KOH aqueous solution, a LiOH aqueous solution, etc. can be used.
  • 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) is reduced to The step of obtaining 4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) may be performed by hydrogenation reaction of compound (B-100).
  • This reaction is not particularly limited as long as the reaction proceeds, but for example, compound B-100 is preferably mixed with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, and typically by cooling to heating. The mixture may be stirred at room temperature, usually for 1 hour to 5 days.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, etc. can be used.
  • the metal catalyst include, but are not limited to, palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst.
  • As the hydrogen source formic acid, ammonium formate, etc.
  • the present invention provides the following formula:
  • the compound is reduced to form the following formula:
  • the method may include a step of obtaining a target compound represented by 4-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonyl]-1 ⁇ 6 -thiomorpholine-1,1-dione (B-300) is 6 -(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) and thiomorpholine-1-dioxide (A-20).
  • Compound B-200 and Compound A-20 are used in equal amounts or in excess of one of them, in the presence of a condensing agent, in a solvent inert to the reaction, typically by cooling to heating, and preferably Stir at -20°C to 60°C, usually for 0.1 hour to 5 days.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes aromatic hydrocarbons, halogenated hydrocarbons such as DCM, ethers, DMF, DMSO, EtOAc, CH 3 CN, or water, Mixed solvents of these can be used.
  • the condensing agent is not limited thereto, for example, typically WSC, CDI, HATU, DCC, DMTMM, etc. can be used.
  • Additives such as HOBt may facilitate the reaction.
  • Organic bases such as pyridine, TEA, DIPEA or NMO, inorganic bases such as K 2 CO 3 , Na 2 CO 3 or KOH may facilitate the reaction.
  • Compound B-300 can also be produced from a reactive derivative of carboxylic acid and compound A-20.
  • Reactive derivatives include, but are not limited to, acid halides obtained by reacting the carboxylic acid of compound B-200 with a halogenating agent, typically phosphorus oxychloride, thionyl chloride; chloroformic acid; Examples include mixed acid anhydrides obtained by reacting with isobutyl, ethyl chlorocarbonate, etc.; active esters obtained by condensation with HOBt, etc.; preferred is ethyl chlorocarbonate.
  • the reaction of the reactive derivative with compound A-20 is carried out with an organic base such as pyridine, TEA, DIPEA or NMO in a solvent inert to the reaction, typically by cooling to heating, preferably from -20°C to 60°C.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, CH 3 CN, water, or a mixed solvent thereof. Can be used. Moreover, the above organic base can also serve as a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, and for example, THF, aromatic hydrocarbons, etc. can be used.
  • the reducing agent is not limited to this, but typically a combination of LiAlH 4 and aluminum chloride (AlCl 3 ), Red-Al, DIBAL, BH 3 , Et 3 SiH, etc. can be used, and are suitable.
  • a combination of LiAlH 4 and aluminum chloride (AlCl 3 ) can be used.
  • the present invention provides the following formula: From the compound represented by the following formula: The method may include a step of obtaining a compound represented by or a salt such as its hydrochloride (C-300).
  • the invention provides the following formula: From the compound represented by the following formula: After obtaining a compound represented by or a salt such as its hydrochloride (C-200), the compound is reduced to form the following formula:
  • the method may include a step of obtaining a compound represented by or a salt such as its hydrochloride (C-300).
  • 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300) to 1-[6-(4,4-dimethylcyclohexyl) Reactions to obtain salts such as -1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its hydrochloride (C-200) include, but are not limited to, The cyano group is reduced using a nickel catalyst such as Raney nickel or a palladium catalyst such as Pd, Pd(OH) 2 in a reaction-inert solvent under a hydrogen atmosphere, followed by MeOH hydrochloric acid solution, hydrochloric acid, sulfuric acid, etc.
  • the cycloalkene can be obtained by dehydration using .
  • the reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at 0° C. to 50° C., for 0.1 hour to 3 days.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, or mixed solvents thereof can be used.
  • cyano group reduction and Boc protection of the primary amine are performed at once using Raney nickel in the presence of (Boc) 2 O, and then dehydration and Boc removal are simultaneously performed with MeOH hydrochloric acid solution, thereby converting the primary amine into The reaction can proceed while suppressing side reactions derived from the nucleophilicity of .
  • the step of obtaining it may be a hydrogenation reaction.
  • This reaction can be carried out, for example, by stirring the compound (C-200) with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, by cooling to heating, preferably at room temperature, usually for 1 hour to 5 days. , but not limited to.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF and CPME, etc.
  • EtOH can be preferably used.
  • metal catalyst include, but are not limited to, palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst.
  • hydrogen source formic acid, ammonium formate, etc. can also be used instead of hydrogen gas.
  • the present invention provides the following formula: By reducing the compound represented by the following formula: You may obtain a compound represented by 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-200) is reduced to 1-[6- The process of obtaining (4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its salt such as hydrochloride (C-300) may be carried out by hydrogenation reaction. .
  • This reaction is carried out, for example, by combining compound D-200 with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, typically between cooling and heating, preferably between 0°C and 80°C, usually for 1 hour to 80°C. It may be stirred for 5 days, but is not limited thereto.
  • the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF and CPME, etc. can be used, and MeOH or EtOH is preferably used. can.
  • metal catalysts include, but are not limited to, typically palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst.
  • a hydrogen source formic acid, ammonium formate, etc. can also be used instead of hydrogen gas.
  • catalytic reduction using a palladium catalyst such as Pd(OH) 2 is carried out under heating conditions of 70°C, for example, but not limited thereto, to simultaneously convert the alkene into the cyano group of compound D-200. Since the reduction can be performed in one pot, the synthesis process can be shortened.
  • the invention provides the following formula:
  • the compound represented by is reacted with divinyl sulfone to form the following formula:
  • the method may include a step of obtaining a compound represented by:
  • the target compound is obtained by reacting 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine-hydrogen chloride (C-300) with divinyl sulfone.
  • the solvent is not particularly limited as long as the reaction proceeds, but typically includes alcohols such as MeOH and EtOH, aromatic hydrocarbons such as toluene and xylene, Et 2 O, Ethers such as THF, DME, and dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof can be used, and MeOH is preferably used. be able to.
  • a base for example, typically an organic amine such as TEA, DIPEA, DBU, NMI, etc. can be used, preferably DIPEA.
  • the reaction can proceed favorably by slowly dropping a MeOH solution of C-300 and DIPEA into a reaction solution in which divinyl sulfone is dissolved in MeOH.
  • the compounds described in this specification may exist as tautomers or geometric isomers depending on the type of substituent. Although only one isomer form of a compound may be described herein, it is understood that the present invention includes other isomers as well as separated isomers or mixtures thereof. Should. Similarly, the compounds described in this specification may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on this may exist. In such cases, the present invention also includes separated optical isomers of the compound or mixtures thereof.
  • concentrations and the like are based on weight, and numerical ranges include the end points.
  • Reference example International Publication 2015/056771A1 contains 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]- based on the scheme below.
  • the synthesis of 2-methylthieno[2,3-d]pyrimidine has been described.
  • Process 1 DMSO (50 mL) and TEA (100 mL) were added to a mixture of 2-(4,4-dimethylcyclohexyl)EtOH (25.3 g) and DCM (200 mL) under an argon atmosphere, and the mixture was further cooled on ice.
  • reaction mixture was allowed to cool to room temperature, and then concentrated under reduced pressure. Chloroform and saturated aqueous sodium bicarbonate were added to the residue and stirred. The organic layer was washed successively with water and brine. MgSO 4 , activated carbon (10 g), and silica gel (100 mL) were added to the organic layer, stirred, filtered through Celite, concentrated under reduced pressure, and 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[ 2,3-d]pyrimidine (31.3 g) was obtained.
  • Process 8 Calcium chloride was added to a mixture of ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (13.0 g), THF (150 mL) and EtOH (150 mL). (6.6 g) was added thereto, and after stirring at room temperature for 30 minutes, NaBH 4 (1.8 g) was added in small portions over 15 minutes under ice cooling. After stirring at room temperature for 4.5 h, water (100 mL) and EtOAc (100 mL) were added to the reaction mixture under ice-cooling, and 1M HCl (100 mL) was added until the suspension became a solution, followed by vacuum reduction.
  • Step 10 Methanesulfonic acid [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4 was added to a mixture of thiomorpholine-1,1-dioxide (70 mg) and DMF (4 mL). -yl]methyl (120 mg) and TEA (150 ⁇ L) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and concentrated under reduced pressure.
  • the yield is about 68%, and many raw materials are required to synthesize the target substance (Bioorganic & Medicinal Chemistry Letters (2011), 21(15), pp. 4409- 4415).
  • step 1 the oxidation reaction using SO 3 pyridine/DMSO generates toxic and foul-smelling dimethyl sulfide, and in step 5, In this process, phosphoryl chloride (POCl 3 ), which is a poisonous substance under the Poisonous and Deleterious Substances Control Law, will be used for chlorination. From the perspective of green chemistry, it is desirable to establish a method for synthesizing target substances without using as many harmful substances as possible.
  • Organic layers 1 to 3 were mixed, activated carbon (purified Shirasagi W50, manufactured by Osaka Gas Chemical Co., Ltd., 63.0 kg) and THF (82.0 kg) were charged into reaction tank 3, and the mixture was stirred at an internal temperature of 23°C to 26°C for 3 hours.
  • the suspension was filtered and the solution was transferred to reaction tank 2.
  • Reaction tank 3 was washed with THF (112.5 kg) and transferred to reaction tank 2 via a filter.
  • the solution was concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 252 L.
  • THF 224.4 kg was charged and concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 252 L.
  • the suspension containing the crystals was filtered, and the crystals were washed with an aqueous MeCN solution (25 v/v%, 238.5 kg).
  • the crystals were dried under reduced pressure at an external temperature of 50° C. or less for 43 hours to obtain 92.17 kg of Compound A-200.
  • the yield of compound A-200 based on compound A-100 charged as a raw material was 86.6%.
  • the suspension was filtered, and the crystals were washed with an aqueous MeCN solution (50 v/v%, 408.8 kg), and then with ordinary water (457.9 kg).
  • the washed crystals (total amount) and an aqueous MeCN solution (33 v/v%, 510.4 kg) were charged into a reaction tank 1 purged with nitrogen, and stirred at an internal temperature of 40°C to 45°C for 2 hours.
  • the suspension was cooled and stirred for 30 minutes at an internal temperature of 27°C to 30°C.
  • the suspension was filtered and the crystals were washed with an aqueous MeCN solution (33 v/v%, 256.7 kg).
  • the suspension was filtered and the crystals were washed with aqueous EtOH (67 v/v%, 282.9 kg).
  • the crystals were washed three times with ordinary water (244.8 kg) and dried under reduced pressure at an external temperature of 50° C. or lower for 27 hours to obtain 80.81 kg of Compound A-400.
  • the yield of compound A-400 based on the charged compound A-300 was 90.5%.
  • reaction tank 3 Isopropyl acetate (353.8 kg) was charged into reaction tank 3 at an internal temperature of 6°C, and the reaction solution in reaction tank 2 was dropped into reaction tank 3 at an internal temperature of 4°C to 5°C.
  • Reaction tank 2 was washed with isopropyl acetate (353.1 kg) and transferred to reaction tank 3. After stirring the reaction solution in reaction tank 3 for 30 minutes, it was allowed to stand still, and the aqueous layer was separated.
  • An aqueous potassium carbonate solution (10 v/v%, 440.2 kg) was added to the organic layer, and after stirring for 10 minutes, the mixture was allowed to stand, and the aqueous layer was separated. The organic layer was concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 310 L.
  • EtOH (317.8 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 310 L.
  • EtOH (316.8 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 280 L.
  • EtOH (95.7 kg) was charged, and then ordinary water (480.0 kg) was charged at 24°C to 30°C. The suspension was stirred at an internal temperature of 24°C to 25°C for 12 hours.
  • the suspension was filtered and the crystals were washed with an aqueous EtOH solution (40 v/v%, 221.0 kg).
  • the crystals were dried under reduced pressure at an external temperature of 50°C or less for 15 hours to obtain 63.1 kg of Compound A-500.
  • the yield of compound A-500 based on the charged compound A-400 was 90.4%.
  • reaction solution After increasing the hydrogen pressure to 0.7 MPa, the reaction solution was heated and stirred at an internal temperature of 65°C to 70°C for 5 hours. After the reaction solution was cooled and the pressure was released, the atmosphere was replaced with nitrogen four times.
  • Pd(OH) 2 /C (palladium content 20 w/w%, water wet product, 6.6 kg) was suspended in purified water (19.1 kg) and charged into reaction tank 1 at an internal temperature of 28°C. Reaction tank 1 was purged with nitrogen three times and further with hydrogen three times, and the reaction solution was heated and stirred at an internal temperature of 65°C to 70°C for 6 hours. After confirming the completion of the reaction, the reaction solution was cooled, the pressure was released, and the atmosphere was replaced with nitrogen three times.
  • reaction tank 2 was purged with nitrogen.
  • Reaction tank 1 was washed with EtOH (151.1 kg) and transferred to reaction tank 2 via a filter.
  • the solution was stirred and ordinary water (283.2 kg) was charged at an internal temperature of 24°C to 25°C. Seed crystals (63 g) of compound A-600 were charged at an internal temperature of 25°C, and stirred for 1 hour at an internal temperature of 23°C to 25°C. Further, ordinary water (628.8 kg) was charged at an internal temperature of 22°C to 27°C, and the mixture was stirred for 1 hour at an internal temperature of 25°C to 27°C. The suspension was filtered and the crystals were washed with aqueous EtOH (33 v/v%, 177.8 kg).
  • reaction tank 3 purged with nitrogen and stirred to prepare an EtOH/AcOH aqueous solution.
  • Reaction tank 2 was purged with nitrogen, the washed crystals (total amount) and the prepared EtOH/AcOH aqueous solution (531.1 kg) were charged, and the mixture was stirred at an internal temperature of 35°C to 41°C for 2 hours and an internal temperature of 26°C to 30°C for 2 hours. did.
  • the suspension was filtered and the crystals were washed with aqueous EtOH (33 v/v%, 175.8 kg).
  • MeCN 297.5 kg
  • ordinary water 853.8 kg
  • the suspension was stirred for 1 hour at an internal temperature of 25°C to 26°C.
  • the suspension was filtered and the crystals were washed with an aqueous MeCN solution (40 v/v%, 215.1 kg).
  • Reaction tank 1 was purged with nitrogen, washed crystals (total amount) and MeCN aqueous solution (30 v/v%, 1330 kg) were charged, and the mixture was stirred at an internal temperature of 22°C to 23°C for 1 hour.
  • the suspension was filtered and the crystals were washed with an aqueous MeCN solution (30 v/v%, 221.7 kg).
  • the crystals were dried under reduced pressure for 30 hours at an external temperature of 50°C or less.
  • the vacuum-dried crystals (total amount) and a mixed solution of MEK (114.7 kg) and n-heptane (548.5 kg) were charged into reaction tank 2, which was purged with nitrogen, and stirred.
  • the suspension was heated to 40°C to 45°C and stirred for 1 hour. It was then cooled and stirred at -3°C to 5°C for 15 hours.
  • the suspension was filtered and the crystals were washed with MEK/n-heptane solution (15 v/v%, 63.5 kg).
  • the crystals were dried under reduced pressure at an external temperature of 50° C. or lower for 15 hours to obtain 54.9 kg of unpurified compound A-800.
  • the yield of unpurified compound A-800 relative to the charged compound A-600 was 82.6%.
  • reaction tank 1 unpurified compound A-800 (54.6 kg) and MEK (265.9 kg) were charged into reaction tank 1 which was purged with nitrogen and stirred. The temperature of the suspension was raised, dissolution was confirmed at an internal temperature of 71°C, and the suspension was transferred to reaction tank 2 which was purged with nitrogen via a cartridge filter.
  • MEK (22.4 kg) and n-heptane (18.9 kg) were charged into reaction tank 1 and stirred. The solution was heated to an internal temperature of 73° C. and transferred to reaction tank 2, which was purged with nitrogen via a cartridge filter.
  • N-heptane (632.9 kg) was charged into reaction tank 2 at an internal temperature of 68°C to 71°C, and stirred for 1 hour at an internal temperature of 69°C to 70°C. The suspension was cooled and stirred at an internal temperature of -1°C to 5°C for 1 hour. N-heptane (633.1 kg) was charged at an internal temperature of -3°C to 1°C, and stirred for 1 hour at an internal temperature of 0°C to 1°C. MEK (22.1 kg) and n-heptane (93.4 kg) were placed in another container purged with nitrogen and stirred to prepare a MEK/n-heptane solution.
  • the suspension was filtered, and the crystals were washed with the entire amount of the prepared MEK/n-heptane solution.
  • the crystals were dried under reduced pressure at an external temperature of 50°C or lower for 12 hours to obtain 49.3 kg of Compound A-800.
  • the yield in this purification step that is, the yield of compound A-800 based on the charged unpurified compound A-800, was 90.3%.
  • the total yield (total yield) in Example 1 that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 36.8%.
  • the suspension was filtered, the crystals were washed with ordinary water (50 mL), ordinary water (150 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the suspension was filtered and the crystals were washed with ordinary water (50 mL).
  • the crystals were dried under reduced pressure at an external temperature of 50°C to obtain 3.93 g of Compound B-100.
  • the yield of compound B-100 based on the charged compound A-400 was 85.5%.
  • the suspension was filtered and the crystals were washed with an appropriate amount of MEK/n-heptane solution (1:2 v/v).
  • the crystals were dried under reduced pressure at an external temperature of 50°C to obtain 800.7 mg of Compound B-300.
  • the yield of compound B-300 based on the charged compound B-100 was 54.2%.
  • LiAlH 4 (90 mg) and THF (5 mL) were mixed in a container purged with nitrogen, and AlCl 3 (474 mg) was added at an internal temperature of 0°C. 500 ⁇ L of this solution was added dropwise to a solution of compound B-300 (50 mg) in THF (1 mL), and the mixture was stirred at room temperature for 2 hours.
  • An aqueous ammonium chloride solution (15 w/w%) and t-butyl methyl ether were added to the reaction mixture, and the organic layer was washed with water and concentrated.
  • MEK (234 ⁇ L) and n-heptane (630 ⁇ L, 612 ⁇ L) were added, and the mixture was stirred at 0° C. for 3 hours.
  • Example 2 The suspension was filtered and the crystals were washed with MEK/n-heptane solution (15 v/v%). The crystals were dried under reduced pressure to obtain 36.64 mg of Compound A-800.
  • the yield of compound A-800 relative to compound B-300 was 75.8%.
  • the total yield (total yield) in Example 2 that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 25.4%.
  • the inside of the reactor was purged with nitrogen, and Pd(OH) 2 /C was filtered through Celite and washed twice with MeOH (50 mL).
  • the solution was concentrated, purified water (20 mL) was added, and the mixture was stirred at 25°C for 30 minutes.
  • the suspension was filtered, and the crystals were dried under reduced pressure at room temperature for 1 hour and at an external temperature of 40°C for 4 hours to obtain 3.4 g of compound C-300.
  • the yield of compound C-300 based on the charged compound C-100 was 68.0%.
  • Divinylsulfone (0.15 mL) and MeOH (3.5 mL) were charged into Container 1 and stirred.
  • Compound C-300 (0.5 g), DIPEA (0.32 mL), and MeOH (3 mL) were placed in another container, and added dropwise to Container 1 over 1 hour at an internal temperature of 0°C to 5°C. After the dropwise addition was completed, the sample was washed with MeOH (0.5 mL). The mixture was stirred for 1.5 hours at an internal temperature of 5°C or less, and ordinary water (7 mL) was slowly added dropwise at the same temperature, followed by stirring for 1.5 hours.
  • the suspension was filtered and the crystals were washed with an aqueous MeOH solution (50 v/v%, 2 mL). Subsequently, the crystals were dried under reduced pressure. In a separate container, the crystals (total amount) dried under reduced pressure, MEK (1.5 mL), and n-heptane (8.5 mL) were charged, and the mixture was stirred at an internal temperature of 45°C for 1 hour. The mixture was cooled to an internal temperature of 5°C and further stirred at the same temperature for 1 hour. The suspension was filtered and the crystals were washed with MEK/n-heptane solution (25 v/v%, 1 mL).
  • Example 3 the total yield (total yield) in Example 3, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 38.2%.
  • the washed crystals (total amount) and MeCN aqueous solution (33 v/v%, approximately 60 mL) were charged, and after stirring at an internal temperature of 45°C for 2 hours, it was cooled and stirred for 30 minutes at an internal temperature of 25°C. .
  • the suspension was filtered and the crystals were washed with an aqueous MeCN solution (33 v/v%, 30 mL).
  • the crystals were dried under reduced pressure to obtain 7.84 g of Compound D-200.
  • the yield of compound D-200 based on the charged compound D-100 was 81.0%.
  • EtOAc Further EtOAc (10 mL) was added, and the mixture was again concentrated under reduced pressure to 5 mL. EtOAc (5 mL) was added to the concentrated solution, stirred, and cooled to 3°C. A 4 M hydrogen chloride ethyl acetate solution (1.3 mL) was added dropwise to this over 1 hour, and the mixture was stirred at the same temperature for 3 hours. The suspension was filtered and the crystals were washed with an EtOH/THF solution (1:2 v/v, 6 mL) prepared by mixing EtOH (2 mL) and THF (4 mL) in a separate container.
  • the mixture was stirred for 1.5 hours at an internal temperature of 5°C or less, and ordinary water (7 mL) was slowly added dropwise at the same temperature, followed by stirring for 1.5 hours.
  • the suspension was filtered and the crystals were washed with an aqueous MeOH solution (50 v/v%, 2 mL). Subsequently, the crystals were dried under reduced pressure. In a separate container, the crystals (total amount) dried under reduced pressure, MEK (1.5 mL), and n-heptane (8.5 mL) were charged, and the mixture was stirred at an internal temperature of 45°C for 1 hour. The mixture was cooled to an internal temperature of 5°C and further stirred at the same temperature for 1 hour.
  • Example 4 the yield of Compound A-800 based on the charged compound C-300 was 85.4%. Further, the total yield (total yield) in Example 4, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 23.9%. Discussion Regarding the reference example (method described in WO2015/056771A1) and the methods described in Examples 1 to 4, the yield (total yield) of the compound of formula I, which is the target compound, is shown below.
  • the present invention provides 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine and its A more preferable synthesis method from the viewpoint of efficient and green chemistry regarding salts is provided.

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Abstract

The present invention addresses the problem of providing a novel synthesis method for 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine and a salt thereof, which is efficient and is preferred from the viewpoint of green chemistry.　6-(4,4-Dimethylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is synthesized safely and efficiently by a method including a step for adding 4,4-dimethyl-cyclohexanone to position-6 in a compound represented by the formula shown below [in the formula, Hal represents a halogen atom].

Description

６－（４，４－ジメチルシクロヘキシル）－４－［（１，１－ジオキソ－１λ６－チオモルホリン－４－イル）メチル］－２－メチルチエノ［２，３－ｄ］ピリミジンまたはその塩の製造方法Method for producing 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or its salt
　本発明は、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩を製造する方法に関する。 The present invention relates to 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or The present invention relates to a method for producing the salt.
　特許文献１（国際公開２０１５／０５６７７１Ａ１）は、GABAB受容体のポジティブアロステリックモジュレーターとして、下記の式Ｉで表される6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンが記載されている。
　また、式Ｉに表される化合物を合成する方法として、シクロヘキサン誘導体からチオフェン環化を経て、最後にチエノピリミジン骨格を形成させる方法を含む合成方法が記載されている。この合成方法は必要な工程数が多く、また、毒性のある化合物の使用や生成が含まれる。
　したがって、当技術分野では、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩について、効率的でグリーンケミストリーの観点でより好ましい合成方法の確立が依然として求められている。 Patent Document 1 (International Publication 2015/056771A1) discloses 6-(4,4-dimethylcyclohexyl)-4-[(1,1 - dioxo -1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is described.
Furthermore, as a method for synthesizing the compound represented by Formula I, a synthetic method including a method of forming a thienopyrimidine skeleton from a cyclohexane derivative through thiophene cyclization is described. This synthetic method requires a large number of steps and also involves the use and production of toxic compounds.
Therefore, in the art, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d ] There is still a need to establish a synthetic method for pyrimidine or its salts that is efficient and more preferable from the viewpoint of green chemistry.
国際公開２０１５／０５６７７１Ａ１International publication 2015/056771A1
　本発明の課題は、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩について、効率的でグリーンケミストリーの観点でより好ましい合成方法を開発することである。 The problem of the present invention is to solve the problem of 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d] The purpose of the present invention is to develop a synthetic method for pyrimidine or its salt that is efficient and more preferable from the viewpoint of green chemistry.
　上記課題について鋭意検討したところ、本発明者らは、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩について、効率的でグリーンケミストリーの観点でより好ましい合成方法を確立することができた。
　これに限定されるものではないが、本発明は、下記の態様を包含するものである。
［１］
　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩を合成する方法であって、
　下式：
で表される化合物［式中、Halはハロゲンである］の６位に、下式：
で表される化合物を付加させて、下式：
で表される化合物を得る工程を含む、上記方法。
［２］
　下式：
で表される化合物をシアノ化して、下式：
で表される化合物を得る工程をさらに含む、［１］に記載の方法。
［３］
　下式：
で表される化合物から、下式：
で表される化合物［式中、Rはアルキル基である］を得る工程をさらに含む、［２］に記載の方法。
［４］
（１）下式：
で表される化合物［式中、Rはアルキル基である］から、下式：
で表される化合物を得た後、その化合物を還元して、下式：
で表される化合物を得る工程；次いで、
（２）下式：
で表される化合物に、下式：
で表される化合物を付加して、下式：
で表される化合物を得る工程；
をさらに含む、［３］に記載の方法。
［５］
（１）下式：
で表される化合物［式中、Rはアルキル基である］から、下式：
で表される化合物を得た後、その化合物を還元して、下式：
で表される化合物を得る工程；次いで、
（２）下式：
で表される化合物に、下式：
で表される化合物を付加して、下式：
で表される化合物を得た後、その化合物を還元して、下式：
で表される化合物を得る工程；
をさらに含む、［３］に記載の方法。
［６］
（１）下式：
で表される化合物から、下式：
で表される化合物を得る工程；及び、
（２）下式：
で表される化合物をジビニルスルホンと反応させて、下式：
で表される化合物を得る工程；
をさらに含む、［２］に記載の方法。
［７］
　下式：
で表される化合物から、下式：
 で表される化合物を得た後、その化合物を還元して、下式：
で表される化合物を得る工程；
を含む、［６］に記載の方法。
［８］
　下式：
で表される化合物を還元して、下式：
で表される化合物を得る工程；
を含む、［６］に記載の方法。 After intensive study on the above problem, the present inventors found that 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2- We have successfully established a synthetic method for methylthieno[2,3-d]pyrimidine or its salts that is efficient and more preferable from the viewpoint of green chemistry.
Although not limited thereto, the present invention includes the following embodiments.
[1]
Synthesis of 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or its salt A method of
Below formula:
At the 6th position of the compound represented by [in the formula, Hal is a halogen], the following formula:
By adding the compound represented by the following formula:
The above method, comprising the step of obtaining a compound represented by:
[2]
Below formula:
By cyanating the compound represented by the following formula:
The method according to [1], further comprising the step of obtaining a compound represented by.
[3]
Below formula:
From the compound represented by the following formula:
The method according to [2], further comprising the step of obtaining a compound represented by [wherein R is an alkyl group].
[4]
(1) Below formula:
From the compound represented by [wherein R is an alkyl group], the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
A step of obtaining a compound represented by;
(2) Below formula:
For the compound represented by the following formula:
By adding the compound represented by the following formula:
A step of obtaining a compound represented by;
The method according to [3], further comprising:
[5]
(1) Below formula:
From the compound represented by [wherein R is an alkyl group], the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
A step of obtaining a compound represented by;
(2) Below formula:
For the compound represented by the following formula:
By adding the compound represented by the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
A step of obtaining a compound represented by;
The method according to [3], further comprising:
[6]
(1) Below formula:
From the compound represented by the following formula:
A step of obtaining a compound represented by; and
(2) Below formula:
The compound represented by is reacted with divinyl sulfone to form the following formula:
A step of obtaining a compound represented by;
The method according to [2], further comprising:
[7]
Below formula:
From the compound represented by the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
A step of obtaining a compound represented by;
The method according to [6], comprising:
[8]
Below formula:
By reducing the compound represented by the following formula:
A step of obtaining a compound represented by;
The method according to [6], comprising:
　本発明によれば、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩を効率的でグリーンケミストリーの観点でより好ましく合成することができる。 According to the invention, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d] Pyrimidine or a salt thereof can be synthesized efficiently and more preferably from the viewpoint of green chemistry.
　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンは、下記の式Ｉで表される化合物である。
　式Ｉで表される化合物は、エステルや塩などを形成していない遊離の形態であってよいことはもちろん、酸などと塩を形成してもよい。そのような塩としては薬学的に許容可能な塩が好ましく、これに制限されるものではないが、例えば、無機酸や有機酸などとの酸付加塩を挙げることができ、無機酸の例として、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸など、有機酸の例として、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、ピクリン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸、炭酸などを挙げることができるがこれに制限されない。
　なお、本明細書において、「式Ｘで表される化合物」などと構造式を用いて化合物を記述することがあるが、単に化合物Ｘと記載する場合もある。したがって、式Ｉで表される化合物を、単に「化合物Ｉ」と記載する場合もある。
　本発明は、一つの態様において、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩の製造方法である。
　式Ｉで表される化合物について、各種の水和物や溶媒和物、結晶多形などを製造する場合は、適宜、公知の方法によって水和物などを得ればよい。また、式Ｉで表される化合物について、種々の放射性または非放射性同位体でラベルされた化合物を製造する場合も、適宜、公知の方法でラベルすればよい。
　また、本発明においては、官能基の種類に応じて、当該官能基を原料から中間体へ至る段階で適当な保護基（容易に当該官能基に転化可能な基）に置き換えておくことができる。このような保護基としては、例えば、「Greene's Protective Groups in Organic Synthesis」（第４版、2006年）に記載の保護基などを挙げることができ、これらの反応条件に応じて適宜選択して用いればよいがこれに制限されない。このような方法では、当該保護基を導入して反応を行なったあと、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine has the following formula: This is a compound represented by I.
The compound represented by Formula I may be in a free form that does not form an ester or salt, or may form a salt with an acid or the like. Such salts are preferably pharmaceutically acceptable salts, but are not limited thereto, and include, for example, acid addition salts with inorganic acids, organic acids, etc. Examples of inorganic acids include Examples of organic acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, and lactic acid. , malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, carbonic acid, etc. Yes, but not limited to this.
In addition, in this specification, a compound may be described using a structural formula, such as "a compound represented by formula X," but it may also be simply described as compound X. Therefore, the compound represented by Formula I may be simply referred to as "Compound I".
The present invention provides, in one embodiment, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3 -d] A method for producing pyrimidine or its salt.
When producing various hydrates, solvates, crystal polymorphs, etc. of the compound represented by Formula I, the hydrates may be obtained by appropriately known methods. Furthermore, when producing a compound represented by formula I labeled with various radioactive or non-radioactive isotopes, the labeling may be carried out appropriately by a known method.
Furthermore, in the present invention, depending on the type of functional group, the functional group can be replaced with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from raw materials to intermediates. . Examples of such protecting groups include the protecting groups described in "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006), which can be selected and used as appropriate depending on the reaction conditions. Good, but not limited to this. In such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
　本明細書において「低級アルキル」とは、典型的には、直鎖または分枝状の炭素数が１から６（以下、C1-6ともいう。以下炭素数を同様に表記する。）であるアルキルであり、これに制限されるものではないが、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、n-ヘキシルなどが挙げられる。「低級アルキル基」としては、例えば、メチル基、エチル基、プロピル基などが挙げられ、好適にはエチル基である。 In this specification, "lower alkyl" typically refers to a straight chain or branched chain having 1 to 6 carbon atoms (hereinafter also referred to as C 1-6 , hereinafter the number of carbon atoms is expressed in the same manner). alkyl, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Can be mentioned. Examples of the "lower alkyl group" include a methyl group, an ethyl group, a propyl group, and the like, with an ethyl group being preferred.
　「シクロアルカン」とは、典型的には、C3-8の飽和炭化水素環であり、これに制限されるものではないが、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタンなどが挙げられる。「シクロアルカン」としては、C5-6シクロアルカンが好ましく、例えば、シクロヘキサンまたはシクロプロパンであり、好適にはシクロプロパンである。
　「ハロゲン」は、F、Cl、Br、または、Iを意味する。 "Cycloalkane" is typically a C 3-8 saturated hydrocarbon ring, including, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclo Examples include octane. The "cycloalkane" is preferably a C 5-6 cycloalkane, such as cyclohexane or cyclopropane, preferably cyclopropane.
"Halogen" means F, Cl, Br, or I.
　本明細書において、濃度の単位であるmol/LをMとして表すことがある。例えば、1M NaOH水溶液は、1mol/LのNaOH水溶液であることを意味する。 In this specification, the unit of concentration, mol/L, may be expressed as M. For example, a 1M NaOH aqueous solution means a 1 mol/L NaOH aqueous solution.
　また、本明細書においては、以下の略号を用いることがある：
AcCl＝塩化アセチル、AcOH＝酢酸、AlCl3＝塩化アルミニウム、brine＝飽和食塩水、CDI＝1,1'-カルボニルジイミダゾール、DBU＝ジアザビシクロウンデセン、DCE＝1,2-ジクロロエタン、DCM＝ジクロロメタン、Boc2O＝二炭酸ジ－tert－ブチル、DIPEA＝N,N-ジイソプロピルエチルアミン、DME＝ジメトキシエタン、DMF＝N,N-ジメチルホルムアミド、DMSO＝ジメチルスルホキシド、DPPA＝ジフェニルリン酸アジド、Et2O＝ジエチルエーテル、EtOAc＝酢酸エチル、EtOH＝エタノール、HATU＝1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジン-1-イウム3-オキシド・ヘキサフルオロホスファート、HCl/EtOAc＝塩化水素/EtOAc溶液、HCl/ジオキサン＝塩化水素/ジオキサン溶液、HPLC＝高速液体クロマトグラフィー、HOBt＝1-ヒドロキシベンゾトリアゾール、IPA＝2-プロパノール、IPE＝ジイソプロピルエチルエーテル、KCN＝シアン化カリウム、MeCN＝アセトニトリル、MEK＝メチルエチルケトン、MeOH＝メタノール、MgSO4＝無水硫酸マグネシウム、MsCl＝メタンスルホニルクロリド、Na2SO4＝無水硫酸ナトリウム、NaBH(OAc)3＝トリアセトキシ水素化ホウ素ナトリウム、n-BuLi＝n-ブチルリチウム、p-TolSO2Na＝p-トルエンスルフィン酸ナトリウム、Pd(OAc)2＝酢酸パラジウム(II)、Pd(OH)2/C ＝水酸化パラジウム担持炭素、Pd/C＝パラジウム担持炭素、TEA＝トリエチルアミン、THF＝テトラヒドロフラン、WSC＝1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、シリカゲルカラム＝シリカゲルカラムクロマトグラフィー、塩基性シリカゲルカラム＝塩基性シリカゲルカラムクロマトグラフィー、飽和重曹水＝飽和NaHCO3水溶液、Ac＝アセチル、Bn＝ベンジル、Boc＝tert-ブトキシカルボニル、Et＝エチル、Me＝メチル、Ms＝メタンスルホニル(SO2CH3)、Ph＝フェニル、tBuまたはBut＝tert-ブチル。 Additionally, in this specification, the following abbreviations may be used:
AcCl = acetyl chloride, AcOH = acetic acid, AlCl 3 = aluminum chloride, brine = saturated saline, CDI = 1,1'-carbonyldiimidazole, DBU = diazabicycloundecene, DCE = 1,2-dichloroethane, DCM = Dichloromethane, Boc 2 O = di-tert-butyl dicarbonate, DIPEA = N,N-diisopropylethylamine, DME = dimethoxyethane, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, DPPA = diphenyl phosphate azide, Et 2 O = diethyl ether, EtOAc = ethyl acetate, EtOH = ethanol, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium3 -Oxide hexafluorophosphate, HCl/EtOAc = hydrogen chloride/EtOAc solution, HCl/dioxane = hydrogen chloride/dioxane solution, HPLC = high performance liquid chromatography, HOBt = 1-hydroxybenzotriazole, IPA = 2-propanol, IPE = diisopropylethyl ether, KCN = potassium cyanide, MeCN = acetonitrile, MEK = methyl ethyl ketone, MeOH = methanol, MgSO 4 = anhydrous magnesium sulfate, MsCl = methanesulfonyl chloride, Na 2 SO 4 = anhydrous sodium sulfate, NaBH(OAc) 3 = tri Sodium acetoxyborohydride, n-BuLi = n-butyllithium, p-TolSO 2 Na = sodium p-toluenesulfinate, Pd(OAc) 2 = palladium(II) acetate, Pd(OH) 2 /C = hydroxide Palladium-supported carbon, Pd/C = palladium-supported carbon, TEA = triethylamine, THF = tetrahydrofuran, WSC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, silica gel column = silica gel column chromatography, basic silica gel column = Basic silica gel column chromatography, saturated aqueous sodium bicarbonate solution = saturated aqueous NaHCO 3 solution, Ac = acetyl, Bn = benzyl, Boc = tert-butoxycarbonyl, Et = ethyl, Me = methyl, Ms = methanesulfonyl (SO 2 CH 3 ), Ph = phenyl, tBu or But = tert-butyl.
　本発明に係る製造方法について、その態様を以下に詳述するが、本発明の製造法は以下に示した具体的な態様には限定されず、適宜、変更や修正を行うことができるものと理解すべきである。 The aspects of the manufacturing method according to the present invention will be described in detail below, but the manufacturing method of the present invention is not limited to the specific aspects shown below, and changes and modifications can be made as appropriate. should be understood.
　本発明においては、4-クロロ-2-メチルチエノ[2,3-d]ピリミジンまたはその誘導体を出発物質として使用する。すなわち、本発明においては、下式：
で表される4-クロロ-2-メチルチエノ[2,3-d]ピリミジンまたはその誘導体に対して、下式：
で表される化合物を６位選択的に付加させて、下式：
で表される化合物を得る。
　国際公開２０１５／０５６７７１Ａ１には、式Ｉに表される化合物を合成する方法が記載されているものの、シクロヘキサン誘導体からチオフェン環化を経て、最後にチエノピリミジン骨格を形成させており、必要な工程数が多く、目的化合物の収率も低い。本発明においては、4-クロロ-2-メチルチエノ[2,3-d]ピリミジンの６位に4,4-ジメチルシクロヘキサノンを付加させることによって早い段階で目的化合物の基本骨格を形成させるため、従来公知の方法と比較して、工程数を削減し、収率を大幅に向上させることができる。
　4-クロロ-2-メチルチエノ[2,3-d]ピリミジン（A-100）と4,4-ジメチルシクロヘキサノン（A-10）を反応させて1-(4-クロロ-2-メチルチエノ[2,3-d]ピリミジン-6-イル)-4,4-ジメチルシクロヘキサン-1-オール（A-200）を得る場合、溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはTHF、ジエチルエーテル、シクロペンチルメチルエーテルなどのエーテル類、またはトルエン、キシレンなどの芳香族炭化水素類を使用することができ、好適には、THFを使用することができる。塩基としては、これに制限されるものではないが、例えば、典型的には、n-BuLi、sec-BuLi、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジドなどの有機リチウム化合物などを挙げることができ、好適にはn-BuLiを使用することができる。
　また、4-クロロ-2-メチルチエノ[2,3-d]ピリミジン（A-100）と4,4-ジメチルシクロヘキサノン（A-10）を反応させて6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル）-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル（D-100）を得る場合、化合物A-100と化合物A-10によって得られるアルコキシドに、これに限定されるものではないが、例えば、Ms2OまたはAcClなどを加えることによって、ワンポットでシクロアルカンをシクロアルケンに変換することができる。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはTHF、ジエチルエーテル、シクロペンチルメチルエーテルなどのエーテル類、またはトルエン、キシレンなどの芳香族炭化水素類などを使用することができ、好適にはTHFを使用することができる。塩基としては、反応が進行すれば特に限定されないが、例えば、典型的にはn-BuLi、sec-BuLi、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジドなどの有機リチウム化合物などを使用することができ、好適にはn-BuLiを使用することができる。ワンポットでシクロアルカンをシクロアルケンに変換するために、これに限定されないが、例えば、DIPEA、トリエチルアミン、DBU、ピリジンなどの有機アミンを追加で使用してもよい。
　また本発明においては、4-クロロ-2-メチルチエノ[2,3-d]ピリミジンの誘導体として、下式：
［式中、Halはハロゲンである］
で表される化合物を使用してもよい。なお、A-101のハロゲンは、反応が進行すれば特に制限されないが、好適にはBrである。4-クロロ-2-メチルチエノ[2,3-d]ピリミジン（A-100）を出発物質として使用する場合、極低温での反応が必要になることがあるが、６位をハロゲン化した誘導体を用いることによって、これに制限されないが、例えば、金属マグネシウムによるグリニャール反応やいわゆるiPrMgCl2などのターボグリニャー試薬、TMP-MgCl2などの使用によって極低温を回避して反応を進めることができる。好適な様態として、iPrMgCl2を０℃付近で使用することができる。また、4-クロロ-2-メチルチエノ[2,3-d]ピリミジン由来の臭気を抑制することができる。 In the present invention, 4-chloro-2-methylthieno[2,3-d]pyrimidine or a derivative thereof is used as a starting material. That is, in the present invention, the following formula:
For 4-chloro-2-methylthieno[2,3-d]pyrimidine or its derivatives represented by the following formula:
By selectively adding the compound represented by the 6-position, the following formula:
A compound represented by is obtained.
International Publication No. 2015/056771A1 describes a method for synthesizing the compound represented by Formula I, but it involves cyclizing thiophene from a cyclohexane derivative and finally forming a thienopyrimidine skeleton, which requires a large number of steps. The yield of the target compound is also low. In the present invention, the basic skeleton of the target compound is formed at an early stage by adding 4,4-dimethylcyclohexanone to the 6-position of 4-chloro-2-methylthieno[2,3-d]pyrimidine. Compared to the previous method, the number of steps can be reduced and the yield can be significantly improved.
1-(4-chloro-2-methylthieno[2,3 -d]pyrimidin-6-yl)-4,4-dimethylcyclohexan-1-ol (A-200), the solvent is not particularly limited as long as it does not interfere with the reaction, but for example, THF is typically used. , diethyl ether, cyclopentyl methyl ether, or aromatic hydrocarbons such as toluene and xylene, preferably THF. Examples of the base include, but are not limited to, typically organic lithium compounds such as n-BuLi, sec-BuLi, lithium diisopropylamide, and lithium hexamethyldisilazide. , preferably n-BuLi can be used.
In addition, by reacting 4-chloro-2-methylthieno[2,3-d]pyrimidine (A-100) with 4,4-dimethylcyclohexanone (A-10), -en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-100), add this to the alkoxide obtained by compound A-100 and compound A-10. Cycloalkanes can be converted to cycloalkenes in one pot by adding, for example, but not limited to, Ms 2 O or AcCl. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically ethers such as THF, diethyl ether, and cyclopentyl methyl ether, or aromatic hydrocarbons such as toluene and xylene can be used. Preferably, THF can be used. The base is not particularly limited as long as the reaction proceeds, but typically organic lithium compounds such as n-BuLi, sec-BuLi, lithium diisopropylamide, and lithium hexamethyldisilazide can be used. , preferably n-BuLi can be used. Organic amines such as, but not limited to, DIPEA, triethylamine, DBU, pyridine may additionally be used to convert cycloalkanes to cycloalkenes in one pot.
Further, in the present invention, as a derivative of 4-chloro-2-methylthieno[2,3-d]pyrimidine, the following formula:
[In the formula, Hal is halogen]
You may use the compound represented by. The halogen in A-101 is not particularly limited as long as the reaction proceeds, but Br is preferably used. When using 4-chloro-2-methylthieno[2,3-d]pyrimidine (A-100) as a starting material, it may be necessary to react at extremely low temperatures; By using, for example, but not limited to, a Grignard reaction using metallic magnesium, a turbo Grignard reagent such as so-called iPrMgCl 2 , TMP-MgCl 2 , etc., the reaction can be proceeded while avoiding extremely low temperatures. In a preferred embodiment, iPrMgCl 2 can be used at around 0°C. Further, odor derived from 4-chloro-2-methylthieno[2,3-d]pyrimidine can be suppressed.
　また、一つの態様において本発明に係る製造方法は、下式：
で表される化合物をシアノ化して、下式：
で表される化合物を得る工程をさらに含んでいてよい。
　化合物A-200や化合物D-100のシアノ化は、反応が進行すれば特に制限されないが、例えば、典型的にはNaCN、KCN、Zn(CN)2などのCN源を、p-TolSO2NaやCH3SO2Na、ジメチルアミノピリジン、DABCOなどの触媒とともに使用すればよく、好適にはKCNとp-TolSO2Naを使用することができる。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはMeCN、DMF、DMSOなどの非プロトン性極性溶媒を使用することができ、好適にはMeCNを使用することができる。 Further, in one embodiment, the manufacturing method according to the present invention is performed using the following formula:
By cyanating the compound represented by the following formula:
The method may further include a step of obtaining a compound represented by:
Cyanation of Compound A-200 and Compound D-100 is not particularly limited as long as the reaction proceeds, but for example, typically a CN source such as NaCN, KCN, Zn(CN) 2 is converted into p-TolSO 2 Na It may be used together with a catalyst such as, CH 3 SO 2 Na, dimethylaminopyridine, or DABCO, and KCN and p-TolSO 2 Na can be preferably used. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically an aprotic polar solvent such as MeCN, DMF, or DMSO can be used, and MeCN can be preferably used.
　一つの態様において本発明は、下式：
で表される化合物から、下式：
 In one embodiment, the present invention provides the following formula:
From the compound represented by the following formula:
［式中、Rはアルキル基である］
で表される化合物を得る工程をさらに含んでいてよい。 [In the formula, R is an alkyl group]
The method may further include a step of obtaining a compound represented by:
　この反応は、反応が進行すれば特に制限されないが、例えば、6-(1-ヒドロキシ-4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル（A-300）を、例えば、典型的には、アルキルアルコール及び酸又は酸ハロゲン化物の存在下で（任意に適切な溶媒中で）実施される。適切な酸又は酸ハロゲン化物としては、HCl、塩化アシルなどを使用することができ、溶媒としてはEtOH、またはEtOHを含む任意の混合溶媒などを使用することができる。この反応は、反応が進行すれば特に制限されないが、例えば、典型的にはアルキルアルコール及び酸を冷却下で添加した後、室温付近で反応させ、40℃～60℃で数時間～終夜撹拌して行うことができる。 This reaction is not particularly limited as long as the reaction progresses, but for example, 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A- 300), for example, is typically carried out in the presence of an alkyl alcohol and an acid or acid halide (optionally in a suitable solvent). As a suitable acid or acid halide, HCl, acyl chloride, etc. can be used, and as a solvent, EtOH or any mixed solvent containing EtOH can be used. This reaction is not particularly limited as long as the reaction progresses, but for example, typically, after adding the alkyl alcohol and acid under cooling, the reaction is carried out at around room temperature, and the mixture is stirred at 40°C to 60°C for several hours to overnight. It can be done by
　一つの態様において本発明は、下式：
で表される化合物を還元して、下式：
で表される化合物を得た後、その化合物を還元して、下式：
で表される化合物を得る工程を含んでいてよい。
　6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸エチル（A-400）を還元して[6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタノール（A-500）を得る工程は、反応が進行すれば特に制限されないが、反応に不活性な溶媒を用いて、還元剤の存在下で行えばよい。反応条件は特に制限されないが、例えば、典型的には冷却～加熱、好適には-20℃～80℃で、0.1時間～3日間とすることができる。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはエーテル類、芳香族炭化水素類、アルコール、ハロゲン化炭化水素あるいは、これらの混合溶媒などを使用することができる。還元剤は、これに限定されないが、例えば、典型的には水素化ホウ素ナトリウム（NaBH4）、水素化アルミニウムリチウム（LiAlH4）、ボラン(BH3)、下記文献に記載の還元剤などが用いられ、NaBH4をCaCl2とともに使用してもよい。また、特に好ましい態様において、0℃～5℃でKBH4をMgCl2とともに使用することで核還元などの副反応を抑制することができる。
〔文献〕
M. Hudlicky著, 「Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)」, ACS, 1996年
R. C. Larock著、「Comprehensive Organic Transformations」, 第2版, VCH Publishers, Inc., 1999年;
T. J. Donohoe著, 「Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)」, Oxford Science Publications, 2000年;
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) In one embodiment, the present invention provides the following formula:
By reducing the compound represented by the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
The method may include a step of obtaining a compound represented by:
Ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400) was reduced to [6-( The process of obtaining 4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500) is particularly Although not limited, the reaction may be carried out using a solvent inert to the reaction and in the presence of a reducing agent. The reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at -20°C to 80°C, for 0.1 hour to 3 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically ethers, aromatic hydrocarbons, alcohols, halogenated hydrocarbons, or mixed solvents thereof can be used. Although the reducing agent is not limited to these, typically sodium borohydride (NaBH 4 ), lithium aluminum hydride (LiAlH 4 ), borane (BH 3 ), reducing agents described in the following literature, etc. are used. NaBH4 may be used with CaCl2 . Furthermore, in a particularly preferred embodiment, side reactions such as nuclear reduction can be suppressed by using KBH 4 together with MgCl 2 at 0°C to 5°C.
[Literature]
M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)", ACS, 1996
R. C. Larock, Comprehensive Organic Transformations, 2nd edition, VCH Publishers, Inc., 1999;
T. J. Donohoe, "Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)", Oxford Science Publications, 2000;
“Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 14 (2005) (Maruzen)
　また、[6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタノール（A-500）を還元して6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタノール（A-600）を得る工程は、反応が進行すれば特に制限されないが、化合物A-500の水素添加反応によればよい。この反応は、例えば、化合物A-500を、水素雰囲気中、反応に不活性な溶媒中、金属触媒と、典型的には冷却～加熱、好適には室温で、通常１時間～５日間撹拌すればよいが、これに限定されない。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはEtOH、MeOHなどのアルコール類、THFなどのエーテル類などを使用することができる。金属触媒は、これに限定されないが、例えば、典型的にはPdやPd(OH)2などのパラジウム触媒、PtO2などの白金触媒、Wilkinson触媒などのロジウム触媒などを使用することができ、好適にはPd(OH)2を使用することができる。水素源は、水素ガスの代わりに、化合物A-500に対し等量～過剰量のギ酸やギ酸アンモニウムなども使用することができる。
〔文献〕
M. Hudlicky著, 「Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)」, ACS, 1996年;
日本化学会編「実験化学講座(第5版)」19巻(2005年)(丸善) In addition, [6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500) was reduced to 6 The process of obtaining -(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600) is not particularly limited as long as the reaction proceeds, but compound A- 500 hydrogenation reaction may be used. This reaction can be carried out, for example, by stirring compound A-500 with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, typically between cooling and heating, preferably at room temperature, usually for 1 hour to 5 days. Good, but not limited to this. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as EtOH and MeOH, ethers such as THF, etc. can be used. Metal catalysts include, but are not limited to, typically palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , rhodium catalysts such as Wilkinson catalysts, etc., and are suitable. Pd(OH) 2 can be used for. As the hydrogen source, formic acid, ammonium formate, etc. can also be used in an equivalent to excess amount of compound A-500, instead of hydrogen gas.
[Literature]
M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996;
“Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 19 (2005) (Maruzen)
　また、この態様において本発明は、下式：
で表される化合物に、下式：
で表される化合物を付加させて、下式：
で表される目的化合物を得る工程をさらに含んでいてよい。
　このアミノ化の工程は、当技術分野で知られている適切な方法で行えばよく、例えば、典型的には触媒を用いた直接アミノ化によって、または水酸基を脱離基に変換することによって行うことができる。好適には6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタノール（A-600）の水酸基を、例えば、ハロゲン、アルキルスルホネート、フルオロアルキルスルホネートなどの脱離基としてから、チオモルホリン-1,1-ジオキシド（A-20）との反応に不活性な溶媒中または無溶媒で、典型的には冷却～加熱で、好適には0℃～80℃で、通常0.1時間～5日間撹拌して行うことができるが、これに限定されない。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的には、トルエン、キシレンなどの芳香族炭化水素類、Et2O、THF、DME、ジオキサンなどのエーテル類、DCM、DCE、クロロホルムなどのハロゲン化炭化水素類、DMF、DMSO、EtOAc、MeCN及びこれらの混合溶媒などを使用することができる。この工程においては、TEA、DIPEAまたはNMOなどの有機塩基、K2CO3、Na2CO3またはKOHなどの無機塩基が、反応をより円滑に進行させる場合がある。
〔文献〕
S. R. Sandler及びW. Karo著, 「Organic Functional Group Preparations」, 第2版, 第1巻, Academic Press Inc., 1991年;
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) Furthermore, in this aspect, the present invention provides the following formula:
For the compound represented by the following formula:
By adding the compound represented by the following formula:
The method may further include a step of obtaining a target compound represented by:
This amination step may be carried out by any suitable method known in the art, for example by direct amination, typically with a catalyst, or by converting the hydroxyl group into a leaving group. be able to. Suitably, the hydroxyl group of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600) is substituted with a halogen, an alkylsulfonate, a fluoroalkylsulfonate, etc. as a leaving group such as thiomorpholine-1,1-dioxide (A-20) in an inert solvent or without solvent, typically by cooling to heating, preferably from 0°C to It can be carried out by stirring at 80°C for usually 0.1 hour to 5 days, but is not limited thereto. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes aromatic hydrocarbons such as toluene and xylene, ethers such as Et 2 O, THF, DME, and dioxane, DCM, DCE, Halogenated hydrocarbons such as chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof can be used. In this step, an organic base such as TEA, DIPEA or NMO, or an inorganic base such as K 2 CO 3 , Na 2 CO 3 or KOH may make the reaction proceed more smoothly.
[Literature]
S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, Volume 1, Academic Press Inc., 1991;
“Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 14 (2005) (Maruzen)
　また別の態様において本発明は、下式：
で表される化合物から、下式：
で表される化合物を得た後、その化合物を還元して、下式：
で表される化合物を得る工程を含んでいてよい。
　6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸エチル（A-400）のエチルエステルを加水分解して6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸（B-100）を得る工程は、当技術分野で知られている適切な方法で行えばよく、反応が進行すれば特に制限されないが、例えば、典型的には反応に不活性な溶媒を用いて、アルカリ水溶液の存在下で行えばよい。反応条件は特に制限されないが、例えば、典型的には冷却～加熱、好適には0℃～50℃で、0.1時間～3日間とすることができる。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはMeOH、EtOHなどのアルコール類、THFなどのエーテル類、あるいはこれらの混合溶媒などを使用することができる。アルカリ水溶液は、反応が進行すれば特に制限されないが、、例えば、典型的にはNaOH水溶液、KOH水溶液、LiOH水溶液などを使用することができる。
　また、6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸（B-100）を還元して6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸（B-200）を得る工程は、化合物(B-100)の水素添加反応によればよい。この反応は、反応が進行すれば特に制限されないが、例えば、化合物B-100を、水素雰囲気中、反応に不活性な溶媒中、金属触媒と、典型的には冷却～加熱で、好適には室温で、通常１時間～５日間撹拌すればよい。溶媒は、反応を妨げなければ特に限定はないが、典型的にはMeOH、EtOHなどのアルコール類、THFなどのエーテル類などを使用することができる。金属触媒は、これに限定されないが、例えば、PdやPd(OH)2などのパラジウム触媒、PtO2などの白金触媒、Wilkinson触媒などのロジウム触媒などを使用することができる。水素源は、水素ガスの代わりに、化合物B-100に対し等量～過剰量のギ酸やギ酸アンモニウムなども使用することができる。
〔文献〕
M. Hudlicky著, 「Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)」, ACS, 1996年;
日本化学会編「実験化学講座(第5版)」19巻(2005年)(丸善) In another aspect, the present invention provides the following formula:
From the compound represented by the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
The method may include a step of obtaining a compound represented by:
Hydrolysis of ethyl ester of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400) The process for obtaining 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) is well known in the art. It may be carried out by any known appropriate method, and is not particularly limited as long as the reaction proceeds, but for example, it may be carried out typically in the presence of an aqueous alkaline solution using a solvent inert to the reaction. The reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at 0° C. to 50° C., for 0.1 hour to 3 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, or mixed solvents thereof can be used. The alkaline aqueous solution is not particularly limited as long as the reaction proceeds, but typically, for example, a NaOH aqueous solution, a KOH aqueous solution, a LiOH aqueous solution, etc. can be used.
Additionally, 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) is reduced to The step of obtaining 4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) may be performed by hydrogenation reaction of compound (B-100). This reaction is not particularly limited as long as the reaction proceeds, but for example, compound B-100 is preferably mixed with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, and typically by cooling to heating. The mixture may be stirred at room temperature, usually for 1 hour to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, etc. can be used. Examples of the metal catalyst include, but are not limited to, palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst. As the hydrogen source, formic acid, ammonium formate, etc. can also be used in an equivalent to excess amount of compound B-100, instead of hydrogen gas.
[Literature]
M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996;
“Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 19 (2005) (Maruzen)
　また、この態様において本発明は、下式：
で表される化合物に、下式：
で表される化合物を付加して、下式：
で表される化合物を得た後、その化合物を還元して、下式：
で表される目的化合物を得る工程を含んでいてよい。
　4-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニル]-1λ6-チオモルホリン-1,1-ジオン（B-300）は、6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸（B-200）とチオモルホリン-1-ジオキシド（A-20）から製造される。この反応では、化合物B-200と化合物A-20を等量もしくは一方を過剰量で用い、縮合剤の存在下、反応に不活性な溶媒中、典型的には冷却～加熱で、好適には-20℃～60℃で、通常0.1時間～5日間撹拌する。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的には芳香族炭化水素類、DCMなどのハロゲン化炭化水素類、エーテル類、DMF、DMSO、EtOAc、CH3CNまたは水、これらの混合溶媒などを使用することができる。縮合剤は、これに限定されないが、例えば、典型的にはWSC、CDI、HATU、DCC、DMTMMなどを使用することができる。HOBtなどの添加剤が反応を円滑に進行させる場合がある。ピリジン、TEA、DIPEAもしくはNMOなどの有機塩基、K2CO3、Na2CO3もしくはKOHなどの無機塩基が、反応を円滑に進行させる場合がある。
　また、化合物B-300は、カルボン酸の反応性誘導体と化合物A-20からも製造できる。反応性誘導体としては、これに限定されないが、化合物B-200のカルボン酸を、例えば、典型的にはオキシ塩化リン、塩化チオニルなどのハロゲン化剤と反応させて得られる酸ハロゲン化物；クロロギ酸イソブチル、クロロ炭酸エチルなどと反応して得られる混合酸無水物；HOBtなどと縮合して得られる活性エステル；などが挙げることができ、好適にはクロロ炭酸エチルである。反応性誘導体と化合物A-20との反応は、反応に不活性な溶媒中、ピリジン、TEA、DIPEA若しくはNMOなどの有機塩基と、典型的には冷却～加熱、好適には-20℃～60℃で、通常0.1時間～5日間撹拌することができる。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、DMF、CH3CN、水、若しくはこれらの混合溶媒などを使用できる。また、上記有機塩基が溶媒を兼ねることもできる。
〔文献〕
S. R. Sandler及びW. Karo著, 「Organic Functional Group Preparations」、第2版, 第1巻, Academic Press Inc., 1991年;
日本化学会編「実験化学講座(第5版)」16巻(2005年)(丸善) Furthermore, in this aspect, the present invention provides the following formula:
For the compound represented by the following formula:
By adding the compound represented by the following formula:
After obtaining the compound represented by, the compound is reduced to form the following formula:
The method may include a step of obtaining a target compound represented by
4-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonyl]-1λ 6 -thiomorpholine-1,1-dione (B-300) is 6 -(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) and thiomorpholine-1-dioxide (A-20). In this reaction, Compound B-200 and Compound A-20 are used in equal amounts or in excess of one of them, in the presence of a condensing agent, in a solvent inert to the reaction, typically by cooling to heating, and preferably Stir at -20℃ to 60℃, usually for 0.1 hour to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes aromatic hydrocarbons, halogenated hydrocarbons such as DCM, ethers, DMF, DMSO, EtOAc, CH 3 CN, or water, Mixed solvents of these can be used. Although the condensing agent is not limited thereto, for example, typically WSC, CDI, HATU, DCC, DMTMM, etc. can be used. Additives such as HOBt may facilitate the reaction. Organic bases such as pyridine, TEA, DIPEA or NMO, inorganic bases such as K 2 CO 3 , Na 2 CO 3 or KOH may facilitate the reaction.
Compound B-300 can also be produced from a reactive derivative of carboxylic acid and compound A-20. Reactive derivatives include, but are not limited to, acid halides obtained by reacting the carboxylic acid of compound B-200 with a halogenating agent, typically phosphorus oxychloride, thionyl chloride; chloroformic acid; Examples include mixed acid anhydrides obtained by reacting with isobutyl, ethyl chlorocarbonate, etc.; active esters obtained by condensation with HOBt, etc.; preferred is ethyl chlorocarbonate. The reaction of the reactive derivative with compound A-20 is carried out with an organic base such as pyridine, TEA, DIPEA or NMO in a solvent inert to the reaction, typically by cooling to heating, preferably from -20°C to 60°C. It can be stirred at ℃ for usually 0.1 hour to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, CH 3 CN, water, or a mixed solvent thereof. Can be used. Moreover, the above organic base can also serve as a solvent.
[Literature]
S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, Volume 1, Academic Press Inc., 1991;
“Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)
　さらに、化合物B-300から式Ｉで示される目的化合物を得る反応について、溶媒は、反応が進行すれば特に制限されないが、例えば、THF、芳香族炭化水素類などを使用することができる。還元剤としては、これに限定されないが、例えば、典型的にはLiAlH4と塩化アルミニウム（AlCl3）の併用、 Red-Al、DIBAL、BH3、Et3SiHなどを使用することができ、好適にはLiAlH4と塩化アルミニウム（AlCl3）の併用を使用することができる。
　一つの態様において本発明は、下式：
で表される化合物から、下式：
で表される化合物またはその塩酸塩（C-300）などの塩を得る工程を含んでいてよい。
　この態様において本発明は、下式：
で表される化合物から、下式：
で表される化合物またはその塩酸塩（C-200）などの塩を得た後、その化合物を還元して、下式：
で表される化合物またはその塩酸塩（C-300）などの塩を得る工程を含んでいてよい。
　6-(1-ヒドロキシ-4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル（A-300）から1-[6-（4,4-ジメチルシクロヘキサ-1-エン-1-イル）-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミンまたはその塩酸塩（C-200）などの塩を得る反応は、これに限定されないが、水素雰囲気下中で反応に不活性な溶媒中、ラネーニッケルなどのニッケル触媒やPd、Pd(OH)2などのパラジウム触媒を用いてシアノ基を還元し、続いて、MeOH塩酸溶液、塩酸、硫酸などを用いて脱水を行い、シクロアルケンを得ればよい。反応条件は、特に制限されないが、例えば、典型的には冷却～加熱、好適には0℃～50℃で、0.1時間～3日間とすることができる。溶媒は反応を妨げなければ特に限定はないが、例えば、典型的にはMeOH、EtOHなどのアルコール類、THFなどのエーテル類、あるいは、これらの混合溶媒などを使用できる。別の様態として、(Boc)2O存在下でラネーニッケルを用いてシアノ基還元と1級アミンのBoc保護を一挙に行い、さらにMeOH塩酸溶液で脱水と脱Bocを同時に行うことで、1級アミンの求核性由来の副反応を抑制しながら反応を進行させることができる。
　1-[6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミンまたはその塩酸塩（C-200）などの塩を還元して1-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミンまたはその塩酸塩（C-300）などの塩を得る工程は、水素添加反応によればよい。この反応は、例えば、化合物（C-200）を、水素雰囲気中、反応に不活性な溶媒中、金属触媒と、冷却～加熱、好ましくは室温で、通常1時間～5日間撹拌すればよいが、これに限定されない。溶媒は、反応を妨げなければ特に限定はないが、典型的にはMeOH、EtOHなどのアルコール類、THF、CPMEなどのエーテル類などを使用でき、好適にはEtOHを使用することができる。金属触媒は、これに限定されないが、例えば、PdやPd(OH)2などのパラジウム触媒、PtO2などの白金触媒、Wilkinson触媒などのロジウム触媒などを使用することができる。水素源は、水素ガスの代わりに、ギ酸やギ酸アンモニウムなども使用することができる。
　また、この態様において本発明は、下式：
で表される化合物を還元して、下式：
で表される化合物を得てもよい。
　6-（4,4-ジメチルシクロヘキサ-1-エン-1-イル）-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル（D-200）を還元して1-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミンまたはその塩酸塩（C-300）などの塩を得る工程は、水素添加反応によればよい。この反応は、例えば、化合物D-200を、水素雰囲気中、反応に不活性な溶媒中、金属触媒と、典型的には冷却～加熱、好適には0℃～80℃で、通常１時間～５日間撹拌すればよいが、これに限定されない。溶媒は、反応を妨げなければ特に限定はないが、例えば、典型的にはMeOH、EtOHなどのアルコール類、THF、CPMEなどのエーテル類などを使用でき、MeOHまたはEtOHを好適に使用することができる。金属触媒は、これに限定されないが、例えば、典型的にはPdやPd(OH)2などのパラジウム触媒、PtO2などの白金触媒、Wilkinson触媒などのロジウム触媒などが挙げられる。水素源は、水素ガスの代わりに、ギ酸やギ酸アンモニウムなども使用できる。特に好ましい態様において、これに限定されないが、例えば、Pd(OH)2などのパラジウム触媒などを用いた接触還元を70℃の加熱条件下によれば、化合物D-200のシアノ基と同時にアルケンをワンポットで還元することができるため、合成工程を短縮することができる。
　この態様において本発明は、下式：
で表される化合物をジビニルスルホンと反応させて、下式：
で表される化合物を得る工程を含んでいてよい。
　1-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミン-塩化水素（C-300）とジビニルスルホンを反応させて目的化合物である式Ｉの化合物を得る場合、溶媒は、反応が進行すれば特に制限されないが、例えば、典型的にはMeOH、EtOHなどのアルコール類、トルエン、キシレンなどの芳香族炭化水素類、Et2O、THF、DME、ジオキサンなどのエーテル類、DCM、DCE、クロロホルムなどのハロゲン化炭化水素類、DMF、DMSO、EtOAc、MeCN及びこれらの混合溶媒などを使用することができ、好適にはMeOHを使用することができる。この反応においては、塩基として、例えば、典型的にはTEA、DIPEA、DBU、NMIなどの有機アミンを使用することができ、好適にはDIPEAを使用することができる。特に好ましい様態において、ジビニルスルホンをMeOHに溶解させた反応液に、C-300とDIPEAのMeOH溶液をゆっくりと滴下していくことで良好に反応を進行させることができる。
　また、本明細書に記載する化合物には、置換基の種類によって、互変異性体や幾何異性体が存在しうる。本明細書において化合物が異性体の一形態のみが記載されることがあるが、本発明は、それ以外の異性体も包含し、異性体の分離されたもの、あるいはそれらの混合物も包含すると理解すべきである。
　同様に、本明細書に記載する化合物には、不斉炭素原子や軸不斉を有する場合があり、これに基づく光学異性体が存在しうる。そのような場合、本発明は、当該化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。
　以下、具体例を挙げて本発明をより詳細に説明するが、本発明は下記の具体例に限定されるものではない。なお、本明細書において、特に記載しない場合、濃度などは重量基準であり、数値範囲はその端点を含むものとする。 Further, in the reaction to obtain the target compound represented by formula I from compound B-300, the solvent is not particularly limited as long as the reaction proceeds, and for example, THF, aromatic hydrocarbons, etc. can be used. The reducing agent is not limited to this, but typically a combination of LiAlH 4 and aluminum chloride (AlCl 3 ), Red-Al, DIBAL, BH 3 , Et 3 SiH, etc. can be used, and are suitable. A combination of LiAlH 4 and aluminum chloride (AlCl 3 ) can be used.
In one embodiment, the present invention provides the following formula:
From the compound represented by the following formula:
The method may include a step of obtaining a compound represented by or a salt such as its hydrochloride (C-300).
In this aspect, the invention provides the following formula:
From the compound represented by the following formula:
After obtaining a compound represented by or a salt such as its hydrochloride (C-200), the compound is reduced to form the following formula:
The method may include a step of obtaining a compound represented by or a salt such as its hydrochloride (C-300).
6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300) to 1-[6-(4,4-dimethylcyclohexyl) Reactions to obtain salts such as -1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its hydrochloride (C-200) include, but are not limited to, The cyano group is reduced using a nickel catalyst such as Raney nickel or a palladium catalyst such as Pd, Pd(OH) 2 in a reaction-inert solvent under a hydrogen atmosphere, followed by MeOH hydrochloric acid solution, hydrochloric acid, sulfuric acid, etc. The cycloalkene can be obtained by dehydration using . The reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at 0° C. to 50° C., for 0.1 hour to 3 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, or mixed solvents thereof can be used. In another embodiment, cyano group reduction and Boc protection of the primary amine are performed at once using Raney nickel in the presence of (Boc) 2 O, and then dehydration and Boc removal are simultaneously performed with MeOH hydrochloric acid solution, thereby converting the primary amine into The reaction can proceed while suppressing side reactions derived from the nucleophilicity of .
1-[6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its hydrochloride (C-200), etc. to give a salt such as 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its hydrochloride (C-300). The step of obtaining it may be a hydrogenation reaction. This reaction can be carried out, for example, by stirring the compound (C-200) with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, by cooling to heating, preferably at room temperature, usually for 1 hour to 5 days. , but not limited to. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF and CPME, etc. can be used, and EtOH can be preferably used. Examples of the metal catalyst include, but are not limited to, palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst. As the hydrogen source, formic acid, ammonium formate, etc. can also be used instead of hydrogen gas.
Furthermore, in this aspect, the present invention provides the following formula:
By reducing the compound represented by the following formula:
You may obtain a compound represented by
6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-200) is reduced to 1-[6- The process of obtaining (4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its salt such as hydrochloride (C-300) may be carried out by hydrogenation reaction. . This reaction is carried out, for example, by combining compound D-200 with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, typically between cooling and heating, preferably between 0°C and 80°C, usually for 1 hour to 80°C. It may be stirred for 5 days, but is not limited thereto. The solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF and CPME, etc. can be used, and MeOH or EtOH is preferably used. can. Examples of metal catalysts include, but are not limited to, typically palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst. As a hydrogen source, formic acid, ammonium formate, etc. can also be used instead of hydrogen gas. In a particularly preferred embodiment, catalytic reduction using a palladium catalyst such as Pd(OH) 2 is carried out under heating conditions of 70°C, for example, but not limited thereto, to simultaneously convert the alkene into the cyano group of compound D-200. Since the reduction can be performed in one pot, the synthesis process can be shortened.
In this aspect, the invention provides the following formula:
The compound represented by is reacted with divinyl sulfone to form the following formula:
The method may include a step of obtaining a compound represented by:
The target compound is obtained by reacting 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine-hydrogen chloride (C-300) with divinyl sulfone. When obtaining the compound of formula I, the solvent is not particularly limited as long as the reaction proceeds, but typically includes alcohols such as MeOH and EtOH, aromatic hydrocarbons such as toluene and xylene, Et 2 O, Ethers such as THF, DME, and dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof can be used, and MeOH is preferably used. be able to. In this reaction, as a base, for example, typically an organic amine such as TEA, DIPEA, DBU, NMI, etc. can be used, preferably DIPEA. In a particularly preferred embodiment, the reaction can proceed favorably by slowly dropping a MeOH solution of C-300 and DIPEA into a reaction solution in which divinyl sulfone is dissolved in MeOH.
Further, the compounds described in this specification may exist as tautomers or geometric isomers depending on the type of substituent. Although only one isomer form of a compound may be described herein, it is understood that the present invention includes other isomers as well as separated isomers or mixtures thereof. Should.
Similarly, the compounds described in this specification may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on this may exist. In such cases, the present invention also includes separated optical isomers of the compound or mixtures thereof.
Hereinafter, the present invention will be explained in more detail by giving specific examples, but the present invention is not limited to the following specific examples. In this specification, unless otherwise specified, concentrations and the like are based on weight, and numerical ranges include the end points.
　参考例
　国際公開２０１５／０５６７７１Ａ１には、下記のスキームに基づいて6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンを合成することが記載されている。
　工程1
　アルゴン雰囲気下で、2-(4,4-ジメチルシクロヘキシル)EtOH (25.3 g)及びDCM (200 mL)の混合物に、DMSO (50 mL)及びTEA (100 mL)を加え、更に氷冷下で内温を10℃以下に保ち、三酸化硫黄ピリジン錯体 (77.7 g)を小分けして加えた。室温で2時間撹拌した後、反応混合物に氷水を加え、減圧下濃縮後、クロロホルムで抽出した。有機層を1M HCl及びbrineで順次洗浄した。有機層にMgSO4を加えて撹拌後、濾過し、減圧下濃縮し、(4,4-ジメチルシクロヘキシル)アセトアルデヒド (27.3 g)を得た。
　工程2
　(4,4-ジメチルシクロヘキシル)アセトアルデヒド (27.3 g)及びDMF (100 mL)の混合物に、2-シアノアセトアミド (12 g)、硫黄 (5 g)及びTEA (24 mL)を加え、60℃で12時間加熱撹拌した。反応混合物に水を加え、EtOAcで抽出した。有機層を水及びbrineで順次洗浄後、Na2SO4及び活性炭 (2 g)を加えて撹拌し、セライト濾過後、減圧下濃縮し、2-アミノ-5-(4,4-ジメチルシクロヘキシル)チオフェン-3-カルボキサミド (33.0 g)を得た。
　工程3
　2-アミノ-5-(4,4-ジメチルシクロヘキシル)チオフェン-3-カルボキサミド (33 g)、ピリジン (40 mL)及びDCM (200 mL)の混合物に、AcCl (14 mL)を0℃で滴下して加え、室温で1.5時間撹拌した。反応混合物を減圧下濃縮後、水と1M HClを加え、クロロホルムで抽出した。有機層を水、飽和重曹水及びbrineで順次洗浄した。有機層にMgSO4、活性炭 (2 g)及び塩基性シリカゲル (100 mL)を加えて撹拌し、セライト濾過後、減圧下濃縮し、2-アセトアミド-5-(4,4-ジメチルシクロヘキシル)チオフェン-3-カルボキサミド(37.3 g)を得た。
　工程4
　2-アセトアミド-5-(4,4-ジメチルシクロヘキシル)チオフェン-3-カルボキサミド (37.3 g)及びEtOH (200 mL)の混合物に、2M NaOH水溶液 (200 mL)を加え、80℃で2時間加熱撹拌した。反応混合物を室温まで放冷後、1M HCl (500 mL)を加え、室温で撹拌した。析出物をろ取し、6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4(3H)-オン(26.3 g)を得た。
　工程5
　6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4(3H)-オン (30.0 g)及びトルエン (240 mL)の混合物に、オキシ塩化リン (40 mL)及びDMF (1.0 mL)を加え、130℃で2時間加熱還流した。反応混合物を室温まで放冷後、減圧下濃縮した。残渣にクロロホルム及び飽和重曹水を加えて撹拌した。有機層を水及びbrineで順次洗浄した。有機層にMgSO4、活性炭 (10 g)、シリカゲル (100 mL)を加え撹拌し、セライト濾過後、減圧下濃縮し、4-クロロ-6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン (31.3 g)を得た。
　工程6
　4-クロロ-6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン (31.1 g)及びDMF (220 mL)の混合物に、CH3SO2Na (11 g)及びKCN (10 g)を加え、70℃で15時間加熱撹拌した。反応混合物を約半量まで減圧下濃縮し、水 (300 mL)で希釈した後、撹拌した。析出物をろ取した。析出物にクロロホルムを加えて溶解し、MgSO4、活性炭 (10 g)及びシリカゲル (100 mL)を加えて撹拌し、セライト濾過後、減圧下濃縮し、6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル (27.4 g)を得た。
　工程7
　6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル (27.4 g)及びEtOH (200 mL)の混合物に、4M 塩化水素ジオキサン溶液 (200 mL)を加え、80℃で終夜撹拌した。反応混合物を室温まで放冷した後、減圧下濃縮し、残渣にEtOH (200 mL)と水 (200 mL)を加えて撹拌した。析出物をろ取した。得られた析出物をクロロホルムに溶解させ、MgSO4、活性炭 (10 g)及び塩基性シリカゲル (100 mL)を加えて撹拌し、セライト濾過後、減圧下濃縮し、6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸エチル (23.3 g)を得た。
　工程8
　6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸エチル (13.0 g)、THF (150 mL)及びEtOH (150 mL)の混合物に、塩化カルシウム (6.6 g)を加え、室温で30分間撹拌後、氷冷下、NaBH4 (1.8 g)を小分けして15分間かけて加えた。室温で4.5時間撹拌した後、反応混合物に氷冷下で水 (100 mL)及びEtOAc (100 mL)を加え、さらに懸濁液が溶液になるまで1M HCl (100 mL)を加えた後、減圧下濃縮し、EtOAcで抽出した。有機層を、水、飽和重曹水及びbrineで順次洗浄し、MgSO4で乾燥後、減圧下濃縮した。残渣をシリカゲルカラム(クロロホルム/EtOAc)で精製し、[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]MeOH (9.35 g)を得た。
　工程9
　[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]MeOH(16.0 g)、TEA (10 mL)及びDCM (200 mL)の混合物に、MsCl (5.0 mL)を0℃で15分間かけて滴下し、同温で1時間撹拌した。反応混合物に飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和重曹水及びbrineで順次洗浄した。有機層をMgSO4、活性炭 (5 g)及び塩基性シリカゲル (20 mL)を加えて撹拌し、セライト濾過後、減圧下濃縮し、メタンスルホン酸 [6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メチル (18.9 g)を得た。
　工程10
　チオモルホリン-1,1-ジオキシド (70 mg)及びDMF (4 mL)の混合物に、メタンスルホン酸 [6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メチル (120 mg)及びTEA (150μL)を加え、室温で終夜撹拌した。反応混合物に水を加えてEtOAcで抽出した。有機層をbrineで洗浄し、MgSO4で乾燥後、減圧下濃縮した。残渣を塩基性シリカゲルカラム(ヘキサン/EtOAc)で精製し、6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジン (102 mg)を得た。
　参考例に関する考察
　国際公開２０１５／０５６７７１Ａ１に記載された方法は、出発物質である2-(4,4-ジメチルシクロヘキシル)EtOHから目的物質である6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまでの全収率は約５％であり、効率のよい合成方法とはいえない。
　また、出発物質である2-(4,4-ジメチルシクロヘキシル)EtOHを、試薬会社から容易に入手できる4,4-ジメチル-2-シクロヘキセン-1-オン（CAS 1073-13-8）から合成する場合、下記のスキームによると収率は約６８％であり、目的物質を合成するためには多くの原料が必要となる（Bioorganic & Medicinal Chemistry Letters (2011), 21(15), pp. 4409-4415）。
　さらに、国際公開２０１５／０５６７７１Ａ１に記載された方法では、工程１において、SO3・ピリジン/DMSOを用いた酸化反応によって、毒性があり悪臭のするジメチルスルフィドが発生することになり、また、工程５において、毒物及び劇物取締法上の毒物である塩化ホスホリル (POCl3）を塩素処理に使用することになる。グリーンケミストリーの観点から、有害な物質をなるべく使用せずに目的物質を合成する方法の確立が望まれる。 Reference example International Publication 2015/056771A1 contains 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]- based on the scheme below. The synthesis of 2-methylthieno[2,3-d]pyrimidine has been described.
Process 1
DMSO (50 mL) and TEA (100 mL) were added to a mixture of 2-(4,4-dimethylcyclohexyl)EtOH (25.3 g) and DCM (200 mL) under an argon atmosphere, and the mixture was further cooled on ice. Sulfur trioxide pyridine complex (77.7 g) was added in portions while keeping the temperature below 10°C. After stirring at room temperature for 2 hours, ice water was added to the reaction mixture, concentrated under reduced pressure, and extracted with chloroform. The organic layer was washed sequentially with 1M HCl and brine. MgSO 4 was added to the organic layer, the mixture was stirred, filtered, and concentrated under reduced pressure to obtain (4,4-dimethylcyclohexyl)acetaldehyde (27.3 g).
Process 2
To a mixture of (4,4-dimethylcyclohexyl)acetaldehyde (27.3 g) and DMF (100 mL) were added 2-cyanoacetamide (12 g), sulfur (5 g) and TEA (24 mL), and the mixture was incubated at 60 °C for 12 The mixture was heated and stirred for hours. Water was added to the reaction mixture and extracted with EtOAc. After washing the organic layer sequentially with water and brine, Na 2 SO 4 and activated carbon (2 g) were added and stirred, filtered through Celite, concentrated under reduced pressure, and 2-amino-5-(4,4-dimethylcyclohexyl) Thiophene-3-carboxamide (33.0 g) was obtained.
Process 3
AcCl (14 mL) was added dropwise to a mixture of 2-amino-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide (33 g), pyridine (40 mL) and DCM (200 mL) at 0 °C. and stirred at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, water and 1M HCl were added, and the mixture was extracted with chloroform. The organic layer was washed successively with water, saturated sodium bicarbonate solution, and brine. MgSO 4 , activated carbon (2 g) and basic silica gel (100 mL) were added to the organic layer, the mixture was stirred, filtered through Celite, concentrated under reduced pressure, and 2-acetamido-5-(4,4-dimethylcyclohexyl)thiophene- 3-carboxamide (37.3 g) was obtained.
Process 4
Add 2M NaOH aqueous solution (200 mL) to a mixture of 2-acetamido-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide (37.3 g) and EtOH (200 mL), and heat and stir at 80°C for 2 hours. did. After the reaction mixture was allowed to cool to room temperature, 1M HCl (500 mL) was added and stirred at room temperature. The precipitate was collected by filtration to obtain 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (26.3 g).
Process 5
Phosphorus oxychloride (40 mL) was added to a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (30.0 g) and toluene (240 mL). and DMF (1.0 mL) were added, and the mixture was heated under reflux at 130°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then concentrated under reduced pressure. Chloroform and saturated aqueous sodium bicarbonate were added to the residue and stirred. The organic layer was washed successively with water and brine. MgSO 4 , activated carbon (10 g), and silica gel (100 mL) were added to the organic layer, stirred, filtered through Celite, concentrated under reduced pressure, and 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[ 2,3-d]pyrimidine (31.3 g) was obtained.
Process 6
To a mixture of 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.1 g) and DMF (220 mL) were added CH 3 SO 2 Na (11 g) KCN (10 g) was added, and the mixture was heated and stirred at 70°C for 15 hours. The reaction mixture was concentrated to about half its volume under reduced pressure, diluted with water (300 mL), and then stirred. The precipitate was collected by filtration. Chloroform was added to the precipitate to dissolve it, MgSO 4 , activated carbon (10 g) and silica gel (100 mL) were added and stirred, filtered through Celite, concentrated under reduced pressure, and 6-(4,4-dimethylcyclohexyl)- 2-Methylthieno[2,3-d]pyrimidine-4-carbonitrile (27.4 g) was obtained.
Process 7
To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (27.4 g) and EtOH (200 mL) was added 4M hydrogen chloride in dioxane (200 mL). was added and stirred at 80°C overnight. After the reaction mixture was allowed to cool to room temperature, it was concentrated under reduced pressure, and EtOH (200 mL) and water (200 mL) were added to the residue, followed by stirring. The precipitate was collected by filtration. The obtained precipitate was dissolved in chloroform, stirred with the addition of MgSO 4 , activated carbon (10 g) and basic silica gel (100 mL), filtered through Celite, concentrated under reduced pressure, and dissolved in 6-(4,4-dimethyl Ethyl cyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (23.3 g) was obtained.
Process 8
Calcium chloride was added to a mixture of ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (13.0 g), THF (150 mL) and EtOH (150 mL). (6.6 g) was added thereto, and after stirring at room temperature for 30 minutes, NaBH 4 (1.8 g) was added in small portions over 15 minutes under ice cooling. After stirring at room temperature for 4.5 h, water (100 mL) and EtOAc (100 mL) were added to the reaction mixture under ice-cooling, and 1M HCl (100 mL) was added until the suspension became a solution, followed by vacuum reduction. It was concentrated and extracted with EtOAc. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform/EtOAc) to obtain [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]MeOH (9.35 g).
Process 9
MsCl (5.0 mL) was added dropwise at 0°C over 15 minutes, and the mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with saturated sodium bicarbonate solution and brine. The organic layer was stirred by adding MgSO 4 , activated carbon (5 g) and basic silica gel (20 mL), filtered through Celite, concentrated under reduced pressure, and diluted with methanesulfonic acid [6-(4,4-dimethylcyclohexyl)-2 -Methylthieno[2,3-d]pyrimidin-4-yl]methyl (18.9 g) was obtained.
Step 10
Methanesulfonic acid [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4 was added to a mixture of thiomorpholine-1,1-dioxide (70 mg) and DMF (4 mL). -yl]methyl (120 mg) and TEA (150 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2 -Methylthieno[2,3-d]pyrimidine (102 mg) was obtained.
Consideration regarding reference examples The method described in International Publication 2015/056771A1 converts the starting material 2-(4,4-dimethylcyclohexyl)EtOH to the target material 6-(4,4-dimethylcyclohexyl)-4-[ The total yield to (1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is about 5%, and it is an efficient synthesis method. I can't say that.
In addition, the starting material 2-(4,4-dimethylcyclohexyl)EtOH is synthesized from 4,4-dimethyl-2-cyclohexen-1-one (CAS 1073-13-8), which is easily available from reagent companies. According to the scheme below, the yield is about 68%, and many raw materials are required to synthesize the target substance (Bioorganic & Medicinal Chemistry Letters (2011), 21(15), pp. 4409- 4415).
Furthermore, in the method described in International Publication 2015/056771A1, in step 1, the oxidation reaction using SO 3 pyridine/DMSO generates toxic and foul-smelling dimethyl sulfide, and in step 5, In this process, phosphoryl chloride (POCl 3 ), which is a poisonous substance under the Poisonous and Deleterious Substances Control Law, will be used for chlorination. From the perspective of green chemistry, it is desirable to establish a method for synthesizing target substances without using as many harmful substances as possible.
　実施例1
　（1-1）　1-(4-クロロ-2-メチルチエノ[2,3-d]ピリミジン-6-イル)-4,4-ジメチルシクロヘキサン-1-オール（A-200）の調製
 Example 1
(1-1) Preparation of 1-(4-chloro-2-methylthieno[2,3-d]pyrimidin-6-yl)-4,4-dimethylcyclohexan-1-ol (A-200)
　窒素置換した反応槽１に4-クロロ-2-メチルチエノ[2,3-d]ピリミジン (A-100）（21.1 kg）及びTHF (186.9 kg）を仕込み、撹拌、冷却した。内温-79℃～-74℃でn-BuLi/n-ヘキサン溶液 (15 w/w%, 50.9 kg）を滴下し、内温-80℃～-79℃で30分間撹拌した。窒素置換した容器で4,4-ジメチルシクロヘキサノン（A-10）(14.4 kg）及びTHF (70.1 kg）を混合し、混合した溶液を内温-79℃～-76℃で反応槽１に滴下した。化合物A-10とTHF溶液を混合した容器をTHF (9.3 kg）で洗い込み、反応槽１に移送し、反応液を内温-76℃～-74℃で30分間撹拌した。反応終了をHPLCで確認した。
　次いで、窒素置換した容器にてAcOH (9.1 kg）及びTHF (18.0 kg）を混合してAcOH/THF溶液を調製し、このAcOH/THF溶液 (50 w/w%, 22.4 kg）を内温-74℃～-59℃で反応槽１に仕込んだ。AcOH/THF溶液を調製した容器をTHF (3.7 kg）で洗い込み、反応槽１に移送した。反応槽１の反応液を昇温し、窒素置換した反応槽２に移送した。反応槽１をTHF (28.3 kg）で洗い込み、反応槽２に移送した。反応槽２に常水 (42.3 kg）を仕込み、10分間撹拌後、静置し、水層を分液した。有機層にNaCl水溶液 (10 w/w%, 52.7 kg）を仕込み、10分間撹拌後、静置し、水層を分液した。有機層を窒素置換した反応槽３に移送した。反応槽２をTHF (10.0 kg）で洗い込み、反応槽３に移送し、有機層１を取得した。前述のA-100より有機層1を取得する操作を2回繰り返し、それぞれ有機層２、有機層３を取得した。
　有機層１～３を混合し、反応槽３に活性炭 (精製白鷺W50, 大阪ガスケミカル社製, 63.0 kg）及びTHF (82.0 kg）を仕込み、内温23℃～26℃で3時間撹拌した。懸濁液を濾過し、溶液を反応槽２に移送した。反応槽３をTHF (112.5 kg）で洗い込み、濾過機を経由して反応槽２に移送した。
　溶液を外温50℃以下で、残量が252 Lになるまで減圧濃縮した。THF (224.4 kg）を仕込み、外温50℃以下で、残量が252 Lになるまで減圧濃縮した。溶液を昇温し、MeCN (198.1 kg）を内温48℃～51℃で投入してから、常水 (504.2 kg）を内温49℃～51℃で仕込み、析出した結晶を含む懸濁液を49℃～51℃で1時間撹拌した後、冷却し、26℃～30℃で10時間撹拌した。 4-chloro-2-methylthieno[2,3-d]pyrimidine (A-100) (21.1 kg) and THF (186.9 kg) were charged into a reaction tank 1 purged with nitrogen, stirred, and cooled. An n-BuLi/n-hexane solution (15 w/w%, 50.9 kg) was added dropwise at an internal temperature of -79°C to -74°C, and the mixture was stirred for 30 minutes at an internal temperature of -80°C to -79°C. 4,4-dimethylcyclohexanone (A-10) (14.4 kg) and THF (70.1 kg) were mixed in a nitrogen-purged container, and the mixed solution was dropped into reaction tank 1 at an internal temperature of -79°C to -76°C. . The container in which Compound A-10 and THF solution were mixed was washed with THF (9.3 kg), transferred to reaction tank 1, and the reaction solution was stirred at an internal temperature of -76°C to -74°C for 30 minutes. Completion of the reaction was confirmed by HPLC.
Next, in a nitrogen-purged container, AcOH (9.1 kg) and THF (18.0 kg) were mixed to prepare an AcOH/THF solution, and this AcOH/THF solution (50 w/w%, 22.4 kg) was heated to - Reactor 1 was charged at 74°C to -59°C. The container in which the AcOH/THF solution was prepared was washed with THF (3.7 kg) and transferred to reaction tank 1. The reaction solution in reaction tank 1 was heated and transferred to reaction tank 2, which was purged with nitrogen. Reaction tank 1 was washed with THF (28.3 kg) and transferred to reaction tank 2. Reaction tank 2 was charged with ordinary water (42.3 kg), stirred for 10 minutes, and then allowed to stand to separate the aqueous layer. An aqueous NaCl solution (10 w/w%, 52.7 kg) was added to the organic layer, and after stirring for 10 minutes, the mixture was allowed to stand, and the aqueous layer was separated. The organic layer was transferred to reaction tank 3, which was purged with nitrogen. Reaction tank 2 was washed with THF (10.0 kg) and transferred to reaction tank 3 to obtain organic layer 1. The above-described operation for obtaining organic layer 1 from A-100 was repeated twice to obtain organic layer 2 and organic layer 3, respectively.
Organic layers 1 to 3 were mixed, activated carbon (purified Shirasagi W50, manufactured by Osaka Gas Chemical Co., Ltd., 63.0 kg) and THF (82.0 kg) were charged into reaction tank 3, and the mixture was stirred at an internal temperature of 23°C to 26°C for 3 hours. The suspension was filtered and the solution was transferred to reaction tank 2. Reaction tank 3 was washed with THF (112.5 kg) and transferred to reaction tank 2 via a filter.
The solution was concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 252 L. THF (224.4 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 252 L. Raise the temperature of the solution, add MeCN (198.1 kg) at an internal temperature of 48°C to 51°C, and then add ordinary water (504.2 kg) at an internal temperature of 49°C to 51°C to create a suspension containing precipitated crystals. The mixture was stirred at 49°C to 51°C for 1 hour, then cooled and stirred at 26°C to 30°C for 10 hours.
　結晶を含む懸濁液を濾過し、MeCN水溶液 (25 v/v%, 238.5 kg）で結晶を洗浄した。結晶を外温50℃以下で43時間減圧乾燥し、化合物A-200を92.17 kg得た。原料として仕込んだ化合物A-100に対する化合物A-200の収率は86.6％であった。
化合物A-200の1H NMR（CDCl3, 400 MHz）：δ ppm 7.18（s, 1H)、2.77（s, 3H)、2.17（s, 1H)、2.05（td, J = 13.3, 4.1 Hz, 2H)、1.88（brd, J = 13.7 Hz、2H)、1.67（td, J = 13.2, 3.9 Hz, 2H)、1.35（dt, J = 13.6、2.8 Hz, 2 H)、1.00（s, 3H)、0.97（s, 3H)
化合物A-200のHRMS（ESI)：［M+H+］ Calcd for 311.0985、Found 311.0969 The suspension containing the crystals was filtered, and the crystals were washed with an aqueous MeCN solution (25 v/v%, 238.5 kg). The crystals were dried under reduced pressure at an external temperature of 50° C. or less for 43 hours to obtain 92.17 kg of Compound A-200. The yield of compound A-200 based on compound A-100 charged as a raw material was 86.6%.
1H NMR (CDCl 3 , 400 MHz) of compound A-200: δ ppm 7.18 (s, 1H), 2.77 (s, 3H), 2.17 (s, 1H), 2.05 (td, J = 13.3, 4.1 Hz, 2H), 1.88 (brd, J = 13.7 Hz, 2H), 1.67 (td, J = 13.2, 3.9 Hz, 2H), 1.35 (dt, J = 13.6, 2.8 Hz, 2H), 1.00 (s, 3H) , 0.97 (s, 3H)
HRMS (ESI) of compound A-200: [M+H + ] Calcd for 311.0985, Found 311.0969
　（1-2）　6-(1-ヒドロキシ-4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル（A-300）の調製
 (1-2) Preparation of 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300)
　窒素置換した反応槽１に化合物A-200（91.5 kg)、p-TolSO2Na（15.7 kg)、MeCN（719.6 kg)、精製水（10.7 kg)、及びKCN（38.3 kg）を仕込み、撹拌した。懸濁液を加熱し、内温78℃～81℃にて24時間撹拌した。反応終了をHPLCで確認した。
　次いで、反応液を冷却し、内温34℃で常水 (457.7 kg）を仕込み、内温5℃～10℃にて5時間撹拌した。懸濁液を濾過し、MeCN水溶液 (50 v/v%, 408.8 kg）で結晶を洗浄し、さらに常水（457.9 kg）で結晶を洗浄した。
　窒素置換した反応槽１に、洗浄した結晶（全量）、MeCN水溶液（33 v/v%, 510.4 kg）を仕込み、内温40℃～45℃で2時間撹拌した。懸濁液を冷却し、内温27℃～30℃で30分間撹拌した。懸濁液を濾過し、MeCN水溶液（33 v/v%, 256.7 kg）で結晶を洗浄した。結晶を外温50℃以下で29.5時間減圧乾燥し、化合物A-300を81.99 kg得た。仕込んだ化合物A-200に対する化合物A-300の収率は92.4％であった。
1H NMR（CDCl3, 400 MHz）：δ ppm 7.29（s, 1H)、2.85（s, 3H)、2.18（s, 1H)、2.12-2.00（m, 2H)、1.93-1.85（m, 2H)、1.72-1.63（m, 2H)、1.42-1.38（m, 2H)、1.01（s, 3H)、1.00（s, 3H)
HRMS（ESI)：［M+H+］ Calcd for 302.1327、Found 302.1303 Compound A-200 (91.5 kg), p-TolSO 2 Na (15.7 kg), MeCN (719.6 kg), purified water (10.7 kg), and KCN (38.3 kg) were charged into reaction tank 1, which was purged with nitrogen, and stirred. . The suspension was heated and stirred at an internal temperature of 78°C to 81°C for 24 hours. Completion of the reaction was confirmed by HPLC.
Next, the reaction solution was cooled, and ordinary water (457.7 kg) was charged at an internal temperature of 34°C, followed by stirring at an internal temperature of 5°C to 10°C for 5 hours. The suspension was filtered, and the crystals were washed with an aqueous MeCN solution (50 v/v%, 408.8 kg), and then with ordinary water (457.9 kg).
The washed crystals (total amount) and an aqueous MeCN solution (33 v/v%, 510.4 kg) were charged into a reaction tank 1 purged with nitrogen, and stirred at an internal temperature of 40°C to 45°C for 2 hours. The suspension was cooled and stirred for 30 minutes at an internal temperature of 27°C to 30°C. The suspension was filtered and the crystals were washed with an aqueous MeCN solution (33 v/v%, 256.7 kg). The crystals were dried under reduced pressure at an external temperature of 50°C or less for 29.5 hours to obtain 81.99 kg of Compound A-300. The yield of compound A-300 based on the charged compound A-200 was 92.4%.
1H NMR (CDCl 3 , 400 MHz): δ ppm 7.29 (s, 1H), 2.85 (s, 3H), 2.18 (s, 1H), 2.12-2.00 (m, 2H), 1.93-1.85 (m, 2H) ), 1.72-1.63 (m, 2H), 1.42-1.38 (m, 2H), 1.01 (s, 3H), 1.00 (s, 3H)
HRMS (ESI): [M+H + ] Calcd for 302.1327, Found 302.1303
　（1-3）　6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸エチル（A-400）の調製
 (1-3) Preparation of ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400)
　窒素置換した反応槽１に化合物A-300（81.5 kg）及びEtOH（643.8 kg）を仕込み、撹拌、冷却した。内温-10℃～12℃にてAcCl（319.1 kg）を滴下後、加熱し、内温55℃～62℃で15時間撹拌した。反応液を冷却し、外温40℃以下にて残量が408 Lになるまで減圧濃縮した。EtOH（322.5 kg）を仕込み、溶液を冷却し、内温5℃～8℃にて常水（122.4 kg）を滴下した。さらに内温4℃～6℃にて常水（285.6 kg）を滴下し、内温4～5℃にて3時間撹拌した。 Compound A-300 (81.5 kg) and EtOH (643.8 kg) were charged into reaction tank 1 that was purged with nitrogen, stirred, and cooled. AcCl (319.1 kg) was added dropwise at an internal temperature of -10°C to 12°C, then heated and stirred for 15 hours at an internal temperature of 55°C to 62°C. The reaction solution was cooled and concentrated under reduced pressure at an external temperature of 40°C or lower until the remaining volume was 408 L. EtOH (322.5 kg) was charged, the solution was cooled, and ordinary water (122.4 kg) was added dropwise at an internal temperature of 5°C to 8°C. Further, ordinary water (285.6 kg) was added dropwise at an internal temperature of 4°C to 6°C, and the mixture was stirred for 3 hours at an internal temperature of 4°C to 5°C.
　懸濁液を濾過し、EtOH水溶液（67 v/v%, 282.9 kg）で結晶を洗浄した。結晶を常水（244.8 kg）で３回洗浄し、外温50℃以下で27時間減圧乾燥し、化合物A-400を80.81 kg得た。仕込んだ化合物A-300に対する化合物A-400の収率は90.5％であった。
化合物A-400の1H NMR（CDCl3, 400 MHz）：δ ppm 7.69（s, 1H)、6.34（t, J = 4.1 Hz, 1H)、4.54（q, J = 6.9 Hz, 2H)、2.88（s, 3H)、2.53（ddt, J = 6.4, 4.4, 2.0, 2.0 Hz, 2H)、2.08-2.04（m, 2H)、1.55（t, J = 6.4 Hz, 2H)、 1.48（t, J = 7.1 Hz, 3H)、0.97（s, 6H)
化合物A-400のHRMS（ESI)：［M+Na+］ Calcd for 353.1300, Found 353.1280 The suspension was filtered and the crystals were washed with aqueous EtOH (67 v/v%, 282.9 kg). The crystals were washed three times with ordinary water (244.8 kg) and dried under reduced pressure at an external temperature of 50° C. or lower for 27 hours to obtain 80.81 kg of Compound A-400. The yield of compound A-400 based on the charged compound A-300 was 90.5%.
1H NMR of compound A-400 (CDCl 3 , 400 MHz): δ ppm 7.69 (s, 1H), 6.34 (t, J = 4.1 Hz, 1H), 4.54 (q, J = 6.9 Hz, 2H), 2.88 (s, 3H), 2.53 (ddt, J = 6.4, 4.4, 2.0, 2.0 Hz, 2H), 2.08-2.04 (m, 2H), 1.55 (t, J = 6.4 Hz, 2H), 1.48 (t, J = 7.1Hz, 3H), 0.97(s, 6H)
HRMS (ESI) of compound A-400: [M+Na + ] Calcd for 353.1300, Found 353.1280
　（1-4）　[6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタノール（A-500）の調製
 (1-4) Preparation of [6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500)
　窒素置換した反応槽１にEtOH（285.6 kg）及び常水（39.9 kg）を仕込み、撹拌した。内温29℃～33℃で塩化カルシウム二水和物（35.6 kg）を仕込み、CaCl2溶液を調製した。
　窒素置換した反応槽２に化合物A-400（80.0 kg）及びTHF（356.2 kg)を仕込み、撹拌した。前記CaCl2溶液（359.7 kg）を内温22℃～25℃で反応槽２に滴下した。反応槽１をEtOH（33.0 kg）で洗い込み、反応槽２に移送した。反応槽２中の反応液を冷却後、内温0℃～1℃でNaBH4（7.32 kg）を仕込み、内温0～2℃で5時間撹拌した。内温0℃でNaBH4（0.11 kg）を仕込み、内温0℃～1℃で2時間撹拌した。反応終了をHPLCで確認した。
　窒素置換した反応槽３に塩化アンモニウム（60.0 kg）及び常水（601.7 kg）を仕込み、撹拌、冷却した。反応槽３に酢酸イソプロピル（353.8 kg）を内温6℃で仕込み、反応槽２の反応液を内温4℃～5℃で反応槽３に滴下した。反応槽２を酢酸イソプロピル（353.1 kg）で洗い込み、反応槽３に移送した。反応槽３の反応液を30分間撹拌後、静置し、水層を分液した。有機層に炭酸カリウム水溶液（10 v/v%、440.2 kg）を仕込み、10分間撹拌後、静置し、水層を分液した。有機層を外温50℃以下で、残量が310 Lになるまで減圧濃縮した。EtOH（317.8 kg）を仕込み、外温50℃以下で、残量が310 Lになるまで減圧濃縮した。EtOH（316.8 kg）を仕込み、外温50℃以下で、残量が280 Lになるまで減圧濃縮した。EtOH（95.7 kg）を仕込み、次いで常水（480.0 kg）を24℃～30℃にて仕込んだ。懸濁液を内温24℃～25℃にて12時間撹拌した。 EtOH (285.6 kg) and ordinary water (39.9 kg) were charged into reaction tank 1, which was purged with nitrogen, and stirred. Calcium chloride dihydrate (35.6 kg) was charged at an internal temperature of 29°C to 33°C to prepare a CaCl 2 solution.
Compound A-400 (80.0 kg) and THF (356.2 kg) were charged into reaction tank 2, which was purged with nitrogen, and stirred. The CaCl 2 solution (359.7 kg) was dropped into reaction tank 2 at an internal temperature of 22°C to 25°C. Reaction vessel 1 was washed with EtOH (33.0 kg) and transferred to reaction vessel 2. After cooling the reaction solution in reaction tank 2, NaBH 4 (7.32 kg) was charged at an internal temperature of 0°C to 1°C, and the mixture was stirred for 5 hours at an internal temperature of 0°C to 2°C. NaBH 4 (0.11 kg) was charged at an internal temperature of 0°C, and the mixture was stirred for 2 hours at an internal temperature of 0°C to 1°C. Completion of the reaction was confirmed by HPLC.
Ammonium chloride (60.0 kg) and ordinary water (601.7 kg) were charged into a reaction tank 3 purged with nitrogen, stirred, and cooled. Isopropyl acetate (353.8 kg) was charged into reaction tank 3 at an internal temperature of 6°C, and the reaction solution in reaction tank 2 was dropped into reaction tank 3 at an internal temperature of 4°C to 5°C. Reaction tank 2 was washed with isopropyl acetate (353.1 kg) and transferred to reaction tank 3. After stirring the reaction solution in reaction tank 3 for 30 minutes, it was allowed to stand still, and the aqueous layer was separated. An aqueous potassium carbonate solution (10 v/v%, 440.2 kg) was added to the organic layer, and after stirring for 10 minutes, the mixture was allowed to stand, and the aqueous layer was separated. The organic layer was concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 310 L. EtOH (317.8 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 310 L. EtOH (316.8 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 280 L. EtOH (95.7 kg) was charged, and then ordinary water (480.0 kg) was charged at 24°C to 30°C. The suspension was stirred at an internal temperature of 24°C to 25°C for 12 hours.
　懸濁液を濾過し、EtOH水溶液（40 v/v%, 221.0 kg）で結晶を洗浄した。結晶を外温50℃以下で15時間減圧乾燥し、化合物A-500を63.1 kg得た。仕込んだ化合物A-400に対する化合物A-500の収率は90.4％であった。
化合物A-500の1H NMR（CDCl3, 400 MHz）：δ ppm 6.96（s, 1H)、6.29 - 6.26（m, 1H)、4.94（s, 2H)、4.29（brs, 1H)、 2.78（s, 3H)、2.50-2.45（m, 2H)、2.05-2.02（m, 2H)、1.54（t, J = 6.4 Hz, 2H)、 0.96（s, 6H)
化合物A-500のHRMS（ESI)：［M+Na+］ Calcd for 311.1194、Found 311.1171 The suspension was filtered and the crystals were washed with an aqueous EtOH solution (40 v/v%, 221.0 kg). The crystals were dried under reduced pressure at an external temperature of 50°C or less for 15 hours to obtain 63.1 kg of Compound A-500. The yield of compound A-500 based on the charged compound A-400 was 90.4%.
1H NMR (CDCl 3 , 400 MHz) of compound A-500: δ ppm 6.96 (s, 1H), 6.29 - 6.26 (m, 1H), 4.94 (s, 2H), 4.29 (brs, 1H), 2.78 ( s, 3H), 2.50-2.45 (m, 2H), 2.05-2.02 (m, 2H), 1.54 (t, J = 6.4 Hz, 2H), 0.96 (s, 6H)
HRMS (ESI) of compound A-500: [M+Na + ] Calcd for 311.1194, Found 311.1171
　（1-5）　6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタノール（A-600）の調製
 (1-5) Preparation of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600)
　窒素置換した反応槽１に化合物A-500 (62.9 kg）及びEtOH (249.3 kg）を仕込み、窒素置換した。続いてPd(OH)2/C（川研ファインケミカル, パラジウム含量 20 w/w%, 水湿潤品、26.6 kg）を精製水 (75.6 kg）に懸濁させ、内温7℃～10℃で反応槽１に仕込んだ。反応槽１を３回窒素置換、さらに３回水素置換し、内温25℃～26℃、水素圧0.15 MPaで1時間撹拌した。水素圧を0.7 MPaまで加圧した後、反応液を昇温し、内温65℃～70℃で5時間撹拌した。反応液を冷却し、放圧した後に４回窒素置換した。Pd(OH)2/C (パラジウム含量 20 w/w%, 水湿潤品, 6.6 kg)を精製水 (19.1 kg)に懸濁させ、内温28℃で反応槽１に仕込んだ。反応槽１を３回窒素置換、さらに３回水素置換し、反応液を昇温し、内温65℃～70℃で6時間撹拌した。反応終了を確認後、反応液を冷却し、放圧した後に３回窒素置換した。
　懸濁液をラヂオライト濾過し、溶液を窒素置換した反応槽２に移送した。反応槽１をEtOH (151.1 kg)で洗い込み、濾過機を経由して反応槽２に移送した。溶液を撹拌し、常水 (283.2 kg)を内温24℃～25℃で仕込んだ。化合物A-600の種晶 (63 g)を内温25℃で仕込み、内温23℃～25℃で1時間撹拌した。さらに常水 (628.8 kg)を内温22℃～27℃で仕込み、内温25℃～27℃で1時間撹拌した。懸濁液を濾過し、EtOH水溶液 (33 v/v%, 177.8 kg)で結晶を洗浄した。 Compound A-500 (62.9 kg) and EtOH (249.3 kg) were charged into reaction tank 1, which was purged with nitrogen, and the tank was purged with nitrogen. Next, Pd(OH) 2 /C (Kawaken Fine Chemicals, palladium content 20 w/w%, water wet product, 26.6 kg) was suspended in purified water (75.6 kg) and reacted at an internal temperature of 7°C to 10°C. It was placed in tank 1. Reaction tank 1 was purged with nitrogen three times and further with hydrogen three times, and stirred for 1 hour at an internal temperature of 25° C. to 26° C. and a hydrogen pressure of 0.15 MPa. After increasing the hydrogen pressure to 0.7 MPa, the reaction solution was heated and stirred at an internal temperature of 65°C to 70°C for 5 hours. After the reaction solution was cooled and the pressure was released, the atmosphere was replaced with nitrogen four times. Pd(OH) 2 /C (palladium content 20 w/w%, water wet product, 6.6 kg) was suspended in purified water (19.1 kg) and charged into reaction tank 1 at an internal temperature of 28°C. Reaction tank 1 was purged with nitrogen three times and further with hydrogen three times, and the reaction solution was heated and stirred at an internal temperature of 65°C to 70°C for 6 hours. After confirming the completion of the reaction, the reaction solution was cooled, the pressure was released, and the atmosphere was replaced with nitrogen three times.
The suspension was filtered through radiolite, and the solution was transferred to reaction tank 2, which was purged with nitrogen. Reaction tank 1 was washed with EtOH (151.1 kg) and transferred to reaction tank 2 via a filter. The solution was stirred and ordinary water (283.2 kg) was charged at an internal temperature of 24°C to 25°C. Seed crystals (63 g) of compound A-600 were charged at an internal temperature of 25°C, and stirred for 1 hour at an internal temperature of 23°C to 25°C. Further, ordinary water (628.8 kg) was charged at an internal temperature of 22°C to 27°C, and the mixture was stirred for 1 hour at an internal temperature of 25°C to 27°C. The suspension was filtered and the crystals were washed with aqueous EtOH (33 v/v%, 177.8 kg).
　窒素置換した反応槽３にEtOH (148.7 kg）、常水 (377.4 kg）、及びAcOH (6.56 kg)を仕込み、撹拌し、EtOH/AcOH水溶液を調製した。
　反応槽２を窒素置換し、洗浄した結晶 (全量)及び調製したEtOH/AcOH水溶液 (531.1 kg)を仕込み、内温35℃～41℃で2時間、内温26℃～30℃で2時間撹拌した。懸濁液を濾過し、EtOH水溶液 (33 v/v%, 175.8 kg)で結晶を洗浄した。結晶を外温50℃以下で12時間減圧乾燥し、化合物A-600を47.7 kg得た。仕込んだ化合物A-500に対する化合物A-600の収率は75.3％であった。
化合物A-600の1H NMR（CDCl3, 400 MHz）：δ ppm 6.92（d, J = 1.4 Hz, 1H)、4.95（s, 2H)、4.34（brs, 1H)、 2.81-2.74（m, 4H)、1.95-1.88（m, 2H)、1.74-1.63（m, 2H)、1.51-1.48（m, 1H)、 1.38-1.29（m, 2H)、0.95（s, 3H)、0.95（s, 3H)
化合物A-600のHRMS（ESI)：［M+Na+］ Calcd for 313.1351、Found 313.1329 EtOH (148.7 kg), ordinary water (377.4 kg), and AcOH (6.56 kg) were charged into reaction tank 3 purged with nitrogen and stirred to prepare an EtOH/AcOH aqueous solution.
Reaction tank 2 was purged with nitrogen, the washed crystals (total amount) and the prepared EtOH/AcOH aqueous solution (531.1 kg) were charged, and the mixture was stirred at an internal temperature of 35°C to 41°C for 2 hours and an internal temperature of 26°C to 30°C for 2 hours. did. The suspension was filtered and the crystals were washed with aqueous EtOH (33 v/v%, 175.8 kg). The crystals were dried under reduced pressure at an external temperature of 50°C or lower for 12 hours to obtain 47.7 kg of Compound A-600. The yield of compound A-600 based on the charged compound A-500 was 75.3%.
1H NMR (CDCl 3 , 400 MHz) of compound A-600: δ ppm 6.92 (d, J = 1.4 Hz, 1H), 4.95 (s, 2H), 4.34 (brs, 1H), 2.81-2.74 (m, 4H), 1.95-1.88 (m, 2H), 1.74-1.63 (m, 2H), 1.51-1.48 (m, 1H), 1.38-1.29 (m, 2H), 0.95 (s, 3H), 0.95 (s, 3H)
HRMS (ESI) of compound A-600: [M+Na + ] Calcd for 313.1351, Found 313.1329
　（1-6）　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジン（A-800）の調製
 (1-6) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine Preparation of (A-800)
　窒素置換した反応槽１に、化合物A-600 (47.4 kg）、DIPEA (67.5 kg）、及びDMF (312.2 kg)を仕込み、撹拌した。溶液を冷却し、メタンスルホン酸無水物 (42.6 kg)とDMF (89.1 kg)を混合した溶液を内温-2℃～2℃で反応槽１に滴下した。DMF (44.6 kg)で容器を洗い込み、反応槽１に移送した。反応液を0℃で10分間撹拌した。
　次いで、チオモルホリン-,1-ジオキシド (28.6 kg)を内温0℃で仕込み、内温20℃～27℃で24時間撹拌した。
　その後、MeCN (297.5 kg)を26℃～27℃で仕込み、常水 (853.8 kg)を26℃～28℃で仕込んだ。懸濁液を内温25℃～26℃で1時間撹拌した。懸濁液を濾過し、MeCN水溶液 (40 v/v%, 215.1 kg)で結晶を洗浄した。 Compound A-600 (47.4 kg), DIPEA (67.5 kg), and DMF (312.2 kg) were charged into reaction tank 1, which was purged with nitrogen, and stirred. The solution was cooled, and a mixed solution of methanesulfonic anhydride (42.6 kg) and DMF (89.1 kg) was dropped into reaction tank 1 at an internal temperature of -2°C to 2°C. The container was washed with DMF (44.6 kg) and transferred to reaction tank 1. The reaction solution was stirred at 0°C for 10 minutes.
Next, thiomorpholine-,1-dioxide (28.6 kg) was charged at an internal temperature of 0°C, and the mixture was stirred at an internal temperature of 20°C to 27°C for 24 hours.
Thereafter, MeCN (297.5 kg) was charged at 26°C to 27°C, and ordinary water (853.8 kg) was charged at 26°C to 28°C. The suspension was stirred for 1 hour at an internal temperature of 25°C to 26°C. The suspension was filtered and the crystals were washed with an aqueous MeCN solution (40 v/v%, 215.1 kg).
　反応槽１を窒素置換し、洗浄した結晶（全量)及びMeCN水溶液 (30 v/v%, 1330 kg)を仕込み、内温22℃～23℃で1時間撹拌した。懸濁液を濾過し、MeCN水溶液 (30 v/v%, 221.7 kg)で結晶を洗浄した。結晶を外温50℃以下で30時間減圧乾燥した。
　窒素置換した反応槽２に、減圧乾燥した結晶 (全量）、及び、MEK (114.7 kg)とn-ヘプタン (548.5 kg)を混合した溶液を仕込み、撹拌した。懸濁液を昇温し40℃～45℃で1時間撹拌した。次いで冷却し、-3℃～5℃で15時間撹拌した。懸濁液を濾過し、MEK/n-ヘプタン溶液 (15 v/v%, 63.5 kg)で結晶を洗浄した。結晶を外温50℃以下で15時間減圧乾燥し、未精製の化合物A-800を54.9 kg得た。仕込んだ化合物A-600に対する未精製の化合物A-800の収率は82.6％であった。
化合物A-800の1H NMR（CDCl3, 400 MHz）：δ ppm 7.14（d, J = 0.92 Hz, 1H)、4.00（s, 2 H)、3.10（s, 8H)、 2.80-2.75（m, 4H)、1.95-1.89（m, 2H)、1.64-1.73（m, 2H)、1.55（m, 1H)、 1.32-1.37（m, 2H)、0.97（s, 6H)
化合物A-800のHRMS（ESI)：［M+Na+］ Calcd for 430.1599, Found 430.1589 Reaction tank 1 was purged with nitrogen, washed crystals (total amount) and MeCN aqueous solution (30 v/v%, 1330 kg) were charged, and the mixture was stirred at an internal temperature of 22°C to 23°C for 1 hour. The suspension was filtered and the crystals were washed with an aqueous MeCN solution (30 v/v%, 221.7 kg). The crystals were dried under reduced pressure for 30 hours at an external temperature of 50°C or less.
The vacuum-dried crystals (total amount) and a mixed solution of MEK (114.7 kg) and n-heptane (548.5 kg) were charged into reaction tank 2, which was purged with nitrogen, and stirred. The suspension was heated to 40°C to 45°C and stirred for 1 hour. It was then cooled and stirred at -3°C to 5°C for 15 hours. The suspension was filtered and the crystals were washed with MEK/n-heptane solution (15 v/v%, 63.5 kg). The crystals were dried under reduced pressure at an external temperature of 50° C. or lower for 15 hours to obtain 54.9 kg of unpurified compound A-800. The yield of unpurified compound A-800 relative to the charged compound A-600 was 82.6%.
1 H NMR (CDCl 3 , 400 MHz) of compound A-800: δ ppm 7.14 (d, J = 0.92 Hz, 1H), 4.00 (s, 2 H), 3.10 (s, 8H), 2.80-2.75 (m , 4H), 1.95-1.89 (m, 2H), 1.64-1.73 (m, 2H), 1.55 (m, 1H), 1.32-1.37 (m, 2H), 0.97 (s, 6H)
HRMS (ESI) of compound A-800: [M+Na + ] Calcd for 430.1599, Found 430.1589
　次いで、窒素置換した反応槽１に、未精製の化合物A-800 (54.6 kg)及びMEK (265.9 kg)を仕込み、撹拌した。懸濁液を昇温し、内温71℃で溶解を確認し、カートリッジフィルターを経由して窒素置換した反応槽２に移送した。反応槽１にMEK (22.4 kg)及びn-ヘプタン (18.9 kg)を仕込み、撹拌した。溶液を内温73℃に昇温し、カートリッジフィルターを経由して窒素置換した反応槽２に移送した。反応槽２にn-ヘプタン (632.9 kg)を内温68℃～71℃で仕込み、内温69℃～70℃で1時間撹拌した。懸濁液を冷却し、内温-1℃～5℃にて1時間撹拌した。n-ヘプタン (633.1 kg)を内温-3℃～1℃で仕込み、内温0℃～1℃で1時間撹拌した。
　窒素置換した別の容器にMEK (22.1 kg)及びn-ヘプタン (93.4 kg)を入れて撹拌し、MEK/n-ヘプタン溶液を調製した。懸濁液を濾過し、調製したMEK/n-ヘプタン溶液全量で結晶を洗浄した。結晶を外温50℃以下で12時間減圧乾燥し、化合物A-800を49.3 kg得た。この精製工程における収率、すなわち、仕込んだ未精製の化合物A-800に対する化合物A-800の収率は90.3％であった。また、実施例１におけるトータルの収率（全収率）、すなわち、出発物質として仕込んだ化合物A-100に対する目的化合物である化合物A-800の収率は36.8％であった。 Next, unpurified compound A-800 (54.6 kg) and MEK (265.9 kg) were charged into reaction tank 1 which was purged with nitrogen and stirred. The temperature of the suspension was raised, dissolution was confirmed at an internal temperature of 71°C, and the suspension was transferred to reaction tank 2 which was purged with nitrogen via a cartridge filter. MEK (22.4 kg) and n-heptane (18.9 kg) were charged into reaction tank 1 and stirred. The solution was heated to an internal temperature of 73° C. and transferred to reaction tank 2, which was purged with nitrogen via a cartridge filter. N-heptane (632.9 kg) was charged into reaction tank 2 at an internal temperature of 68°C to 71°C, and stirred for 1 hour at an internal temperature of 69°C to 70°C. The suspension was cooled and stirred at an internal temperature of -1°C to 5°C for 1 hour. N-heptane (633.1 kg) was charged at an internal temperature of -3°C to 1°C, and stirred for 1 hour at an internal temperature of 0°C to 1°C.
MEK (22.1 kg) and n-heptane (93.4 kg) were placed in another container purged with nitrogen and stirred to prepare a MEK/n-heptane solution. The suspension was filtered, and the crystals were washed with the entire amount of the prepared MEK/n-heptane solution. The crystals were dried under reduced pressure at an external temperature of 50°C or lower for 12 hours to obtain 49.3 kg of Compound A-800. The yield in this purification step, that is, the yield of compound A-800 based on the charged unpurified compound A-800, was 90.3%. Further, the total yield (total yield) in Example 1, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 36.8%.
　実施例2
　（2-1）　6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸（B-100）の調製
 Example 2
(2-1) Preparation of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100)
　実施例１と同様の方法で得た化合物A-400 (5.02 g)にEtOH (50 mL）、THF (50 mL）、及び5M NaOH水溶液 (5.00 mL)を加え、内温21℃～25℃で13時間撹拌した。反応液に6M HCl (4.5 mL）、常水 (50 mL）、及び化合物B-100 (5.2 mg)を加え、内温8℃～9℃で32分間撹拌し、常水 (50 mL)を加え、内温8℃～16℃で1時間撹拌し、結晶を含む懸濁液を得た。 EtOH (50 mL), THF (50 mL), and 5M NaOH aqueous solution (5.00 mL) were added to compound A-400 (5.02 g) obtained in the same manner as in Example 1, and the mixture was heated at an internal temperature of 21°C to 25°C. Stirred for 13 hours. Add 6M HCl (4.5 mL), ordinary water (50 mL), and compound B-100 (5.2 mg) to the reaction solution, stir at an internal temperature of 8℃ to 9℃ for 32 minutes, and add ordinary water (50 mL). The mixture was stirred for 1 hour at an internal temperature of 8°C to 16°C to obtain a suspension containing crystals.
　懸濁液を濾過し、常水 (50 mL)で結晶を洗浄してから、常水 (150 mL)を加え、室温で1時間撹拌した。懸濁液を濾過し、常水 (50 mL)で結晶を洗浄した。結晶を外温50℃で減圧乾燥し、化合物B-100を3.93 g得た。仕込んだ化合物A-400に対する化合物B-100の収率は85.5％であった。
化合物B-100の1H NMR（CDCl3, 400 MHz）：δ ppm 7.90（s, 1H)、6.41（t, J = 4.12 Hz, 1H)、2.87（s, 3H)、2.57（td, J = 6.41, 1.83 Hz, 2H)、2.12-2.07（m, 2H)、1.59（t, J = 6.41 Hz, 2H)、1.00（s, 6H) The suspension was filtered, the crystals were washed with ordinary water (50 mL), ordinary water (150 mL) was added, and the mixture was stirred at room temperature for 1 hour. The suspension was filtered and the crystals were washed with ordinary water (50 mL). The crystals were dried under reduced pressure at an external temperature of 50°C to obtain 3.93 g of Compound B-100. The yield of compound B-100 based on the charged compound A-400 was 85.5%.
1H NMR (CDCl 3 , 400 MHz) of compound B-100: δ ppm 7.90 (s, 1H), 6.41 (t, J = 4.12 Hz, 1H), 2.87 (s, 3H), 2.57 (td, J = 6.41, 1.83 Hz, 2H), 2.12-2.07 (m, 2H), 1.59 (t, J = 6.41 Hz, 2H), 1.00 (s, 6H)
　（2-2）　4-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニル]-1λ6-チオモルホリン-1,1-ジオン（B-300）の調製
 (2-2) 4-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonyl]-1λ 6 -thiomorpholine-1,1-dione (B- 300) Preparation
　化合物B-100 (1.06 g）にPd/C (gross量1.18 g）、EtOH (17 mL）、TEA (4.24 mL)を加え、窒素置換、水素置換を行った。内温70℃、水素圧7.0 barで5時間撹拌した後、窒素置換し、Pd/Cを濾去した。
　溶液を濃縮し、THFを添加して濃縮した。n-ヘキサンを加えて濃縮する操作を２回実施した。EtOH (5 mL)、精製水 (5 mL)を添加して濃縮した。IPA (3 mL）、n-ヘキサン (10 mL)を加えて濃縮し、6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボン酸（B-200）を1 g得た。
　化合物B-200 (1 g)に氷冷下、THF (10.6 mL）、DIPEA (2.4 mL）、クロロ炭酸エチル (668μL)を加え、室温で35分間撹拌し、チオモルホリン-1,1-ジオキシド (A-20, 1.42 g)を添加し、室温で1.5時間撹拌した。
　反応液に食塩水 (20 w/w%）、t-ブチルメチルエーテルを加えて分液し、有機層を濃縮した。MEK (12 mL)及びn-ヘプタン(24 mL)を加え、内温70℃で1時間撹拌した。15℃/時間の速度で冷却し、0℃で1晩撹拌した。 Pd/C (gross amount 1.18 g), EtOH (17 mL), and TEA (4.24 mL) were added to compound B-100 (1.06 g), and the mixture was replaced with nitrogen and hydrogen. After stirring for 5 hours at an internal temperature of 70°C and a hydrogen pressure of 7.0 bar, the mixture was purged with nitrogen and Pd/C was removed by filtration.
The solution was concentrated, THF was added and concentrated. The operation of adding n-hexane and concentrating was performed twice. EtOH (5 mL) and purified water (5 mL) were added and concentrated. IPA (3 mL) and n-hexane (10 mL) were added and concentrated to give 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200 ) was obtained.
THF (10.6 mL), DIPEA (2.4 mL), and ethyl chlorocarbonate (668 μL) were added to compound B-200 (1 g) under ice-cooling, and the mixture was stirred at room temperature for 35 minutes to dissolve thiomorpholine-1,1-dioxide ( A-20, 1.42 g) was added and stirred at room temperature for 1.5 hours.
Brine (20 w/w%) and t-butyl methyl ether were added to the reaction solution to separate the layers, and the organic layer was concentrated. MEK (12 mL) and n-heptane (24 mL) were added, and the mixture was stirred at an internal temperature of 70°C for 1 hour. It was cooled at a rate of 15°C/hour and stirred at 0°C overnight.
　懸濁液を濾過し、適量のMEK/n-ヘプタン溶液 (1:2 v/v)で結晶を洗浄した。結晶を外温50℃で減圧乾燥し、化合物B-300を800.7 mg得た。仕込んだ化合物B-100に対する化合物B-300の収率は54.2％であった。
化合物B-300の1H NMR（CDCl3, 400 MHz）：δ ppm 7.12（d, J = 0.92 Hz, 1H)、4.39-4.29（m, 2H)、4.04-3.96（m, 2H)、3.36-3.31（m, 2H)、3.25（brt, J = 5.50 Hz, 2H)、2.85-2.77（m, 4H)、1.99-1.91（m, 2H)、1.77-1.66（m, 2H)、1.56（brs, 1H)、1.52（brs, 1H)、1.44-1.29（m, 2H)、0.98（s, 3H)、0.97（s, 3H) The suspension was filtered and the crystals were washed with an appropriate amount of MEK/n-heptane solution (1:2 v/v). The crystals were dried under reduced pressure at an external temperature of 50°C to obtain 800.7 mg of Compound B-300. The yield of compound B-300 based on the charged compound B-100 was 54.2%.
1H NMR (CDCl 3 , 400 MHz) of compound B-300: δ ppm 7.12 (d, J = 0.92 Hz, 1H), 4.39-4.29 (m, 2H), 4.04-3.96 (m, 2H), 3.36- 3.31 (m, 2H), 3.25 (brt, J = 5.50 Hz, 2H), 2.85-2.77 (m, 4H), 1.99-1.91 (m, 2H), 1.77-1.66 (m, 2H), 1.56 (brs, 1H), 1.52 (brs, 1H), 1.44-1.29 (m, 2H), 0.98 (s, 3H), 0.97 (s, 3H)
　（2-3）　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジン（A-800）の調製
 (2-3) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine Preparation of (A-800)
　窒素置換した容器に、LiAlH4 (90 mg）、THF (5 mL)を混合し、内温0℃でAlCl3 (474 mg)を添加した。この溶液500μLを化合物B-300 (50 mg)のTHF (1 mL)溶液に滴下し、室温で2時間撹拌した。
　反応液に塩化アンモニウム水溶液 (15 w/w%）、t-ブチルメチルエーテルを加え、有機層を水で洗浄後、濃縮した。MEK（234μL）、n-ヘプタン (630μL, 612μL)を加え、0℃で3時間撹拌した。
　懸濁液を濾過し、MEK/ n-ヘプタン溶液 (15 v/v%)で結晶を洗浄した。結晶を減圧乾燥し、化合物A-800を36.64 mg得た。化合物B-300に対する化合物A-800の収率は75.8％であった。また、実施例２におけるトータルの収率（全収率）、すなわち、出発物質として仕込んだ化合物A-100に対する目的化合物である化合物A-800の収率は25.4％であった。 LiAlH 4 (90 mg) and THF (5 mL) were mixed in a container purged with nitrogen, and AlCl 3 (474 mg) was added at an internal temperature of 0°C. 500 μL of this solution was added dropwise to a solution of compound B-300 (50 mg) in THF (1 mL), and the mixture was stirred at room temperature for 2 hours.
An aqueous ammonium chloride solution (15 w/w%) and t-butyl methyl ether were added to the reaction mixture, and the organic layer was washed with water and concentrated. MEK (234 μL) and n-heptane (630 μL, 612 μL) were added, and the mixture was stirred at 0° C. for 3 hours.
The suspension was filtered and the crystals were washed with MEK/n-heptane solution (15 v/v%). The crystals were dried under reduced pressure to obtain 36.64 mg of Compound A-800. The yield of compound A-800 relative to compound B-300 was 75.8%. Further, the total yield (total yield) in Example 2, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 25.4%.
　実施例3
　（3-1）　tert-ブチル{[6-(1-ヒドロキシ-4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メチル}カルバメート（C-100）の調製
 Example 3
(3-1) Tert-butyl {[6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}carbamate (C-100) preparation
　実施例１と同様の方法で得た化合物A-300 (26.1 g)にTHF (390 mL）、EtOH (190 mL）、及びBoc2O (56.7 g)を加え、EtOH (100 mL)で洗いこんだ。
　ラネーニッケル (78 mL)を加え、EtOH (100 mL)で洗いこんだ。水素気流下、内温25℃～27℃で3.5時間撹拌した。
　懸濁液をセライト濾過し、EtOH (390 mL）、EtOAc (390 mL)で洗浄し、濾液を濃縮した。n-ヘキサン (156 mL)を添加して濃縮を２回繰り返し、n-ヘキサン (156 mL)を添加して濃縮した。n-ヘキサン (156 mL)を加え、内温0℃～5℃で1時間撹拌した。
　懸濁液を濾過し、冷n-ヘキサン (52 mL)で結晶を洗浄した。結晶を外温40℃で2時間減圧乾燥し、化合物C-100を28.9 g得た。仕込んだ化合物A-300に対する化合物C-100の収率は82.3％であった。 THF (390 mL), EtOH (190 mL), and Boc 2 O (56.7 g) were added to compound A-300 (26.1 g) obtained in the same manner as in Example 1, and the mixture was washed with EtOH (100 mL). is.
Raney nickel (78 mL) was added and washed with EtOH (100 mL). The mixture was stirred for 3.5 hours at an internal temperature of 25°C to 27°C under a hydrogen stream.
The suspension was filtered through Celite, washed with EtOH (390 mL) and EtOAc (390 mL), and the filtrate was concentrated. Concentration was repeated twice by adding n-hexane (156 mL), and then concentrating by adding n-hexane (156 mL). N-hexane (156 mL) was added, and the mixture was stirred at an internal temperature of 0°C to 5°C for 1 hour.
The suspension was filtered and the crystals were washed with cold n-hexane (52 mL). The crystals were dried under reduced pressure at an external temperature of 40°C for 2 hours to obtain 28.9 g of Compound C-100. The yield of compound C-100 based on the charged compound A-300 was 82.3%.
　（3-2）　1-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミン塩酸塩（C-300）の調製
 (3-2) Preparation of 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine hydrochloride (C-300)
　塩化水素メタノール溶液 (5～10 w/w%, 720 mL)に化合物C-100 (28.8 g)を加え、内温55℃～66℃で7時間撹拌した。
　反応液を濃縮し、IPA (116 mL)を添加して濃縮を２回繰り返した。IPA (116 mL)を添加して濃縮した。IPA (116 mL)を加え、氷冷下15分間撹拌した。
　懸濁液を濾過し、IPA (29 mL)で結晶を2回洗浄した。結晶を外温40℃で2時間、室温で17時間減圧乾燥し、1-[6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミン塩酸塩（C-200）を23.8 g得た。
　化合物C-200 (5.15 g)にEtOH（77 mL）、精製水（22 mL）、及びPd(OH)2/C（2 g、51.6 w/w%水湿潤品）を加え、窒素置換、水素置換を行った。外温70℃、水素圧0.7 MPaで18時間撹拌した。反応器内を窒素置換し、Pd(OH)2/Cをセライト濾過し、MeOH (50 mL)で2回洗浄した。溶液を濃縮し、精製水 (20 mL)を加え、25℃で30分間撹拌した。
　懸濁液を濾過し、結晶を室温で1時間、外温40℃で4時間減圧乾燥し、化合物C-300を3.4 g得た。仕込んだ化合物C-100に対する化合物C-300の収率は68.0％であった。 Compound C-100 (28.8 g) was added to a hydrogen chloride methanol solution (5-10 w/w%, 720 mL), and the mixture was stirred at an internal temperature of 55°C to 66°C for 7 hours.
The reaction solution was concentrated, IPA (116 mL) was added, and the concentration was repeated twice. IPA (116 mL) was added and concentrated. IPA (116 mL) was added and stirred for 15 minutes under ice cooling.
The suspension was filtered and the crystals were washed twice with IPA (29 mL). The crystals were dried under reduced pressure at an external temperature of 40°C for 2 hours and at room temperature for 17 hours to obtain 1-[6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d ]pyrimidin-4-yl]methanamine hydrochloride (C-200) was obtained.
EtOH (77 mL), purified water (22 mL), and Pd(OH) 2 /C (2 g, 51.6 w/w% water wet product) were added to compound C-200 (5.15 g), and the mixture was replaced with nitrogen and hydrogen. Replacement was made. The mixture was stirred for 18 hours at an external temperature of 70°C and a hydrogen pressure of 0.7 MPa. The inside of the reactor was purged with nitrogen, and Pd(OH) 2 /C was filtered through Celite and washed twice with MeOH (50 mL). The solution was concentrated, purified water (20 mL) was added, and the mixture was stirred at 25°C for 30 minutes.
The suspension was filtered, and the crystals were dried under reduced pressure at room temperature for 1 hour and at an external temperature of 40°C for 4 hours to obtain 3.4 g of compound C-300. The yield of compound C-300 based on the charged compound C-100 was 68.0%.
　（3-3）　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジン (A-800）の調製
 (3-3) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine Preparation of (A-800)
　容器１にジビニルスルホン (0.15 mL)及びMeOH（3.5 mL)を仕込み、撹拌した。別の容器に化合物C-300 (0.5 g）、DIPEA (0.32 mL）、及びMeOH (3 mL)を仕込み、容器１に内温0℃～5℃にて1時間かけて滴下した。滴下終了後，MeOH (0.5 mL)で洗いこみを行った。内温5℃以下にて1.5時間撹拌し、同温にて常水 (7 mL)をゆっくりと滴下し、1.5時間撹拌した。懸濁液を濾過し、MeOH水溶液 (50 v/v%, 2 mL)で結晶を洗浄した。続いて結晶を減圧乾燥した。
　別の容器に、減圧乾燥した結晶 (全量)、MEK (1.5 mL)、及びn-ヘプタン (8.5 mL)を仕込み、内温45℃にて1時間撹拌した。内温5℃まで冷却し同温にてさらに1時間撹拌した。懸濁液を濾過し、MEK/n-ヘプタン溶液 (25 v/v%，1 mL)で結晶を洗浄した。結晶を15時間減圧乾燥し、化合物A-800を534 mg得た。仕込んだ化合物C-300に対する化合物A-800の収率は85.4％であった。また、実施例３におけるトータルの収率（全収率）、すなわち、出発物質として仕込んだ化合物A-100に対する目的化合物である化合物A-800の収率は38.2％であった。 Divinylsulfone (0.15 mL) and MeOH (3.5 mL) were charged into Container 1 and stirred. Compound C-300 (0.5 g), DIPEA (0.32 mL), and MeOH (3 mL) were placed in another container, and added dropwise to Container 1 over 1 hour at an internal temperature of 0°C to 5°C. After the dropwise addition was completed, the sample was washed with MeOH (0.5 mL). The mixture was stirred for 1.5 hours at an internal temperature of 5°C or less, and ordinary water (7 mL) was slowly added dropwise at the same temperature, followed by stirring for 1.5 hours. The suspension was filtered and the crystals were washed with an aqueous MeOH solution (50 v/v%, 2 mL). Subsequently, the crystals were dried under reduced pressure.
In a separate container, the crystals (total amount) dried under reduced pressure, MEK (1.5 mL), and n-heptane (8.5 mL) were charged, and the mixture was stirred at an internal temperature of 45°C for 1 hour. The mixture was cooled to an internal temperature of 5°C and further stirred at the same temperature for 1 hour. The suspension was filtered and the crystals were washed with MEK/n-heptane solution (25 v/v%, 1 mL). The crystals were dried under reduced pressure for 15 hours to obtain 534 mg of Compound A-800. The yield of compound A-800 based on the charged compound C-300 was 85.4%. Further, the total yield (total yield) in Example 3, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 38.2%.
　実施例4
　（4-1）　4-クロロ-6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル）-2-メチルチエノ[2,3-d]ピリミジン（D-100）の調製
 Example 4
(4-1) Preparation of 4-chloro-6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine (D-100)
　窒素置換した容器に化合物A-100 (10.0 g)及びTHF (100 mL)を仕込み、撹拌、冷却した。内温-65℃以下2.6 M　n-BuLi/n-ヘキサン溶液 (21.5 mL)をゆっくり滴下し、内温- 65℃以下で30分間撹拌した。
　別の容器に化合物A-10 (6.83 g)及びTHF (37.5 mL)を仕込み、撹拌し、内温-65℃以下で反応液にゆっくり滴下した。容器をTHF (5.0 mL)で0洗い込み、反応液に移送した。反応液を内温-65℃で30分間撹拌した。同温にてDIPEA (18.5 mL)及びメタンスルホン酸無水物 (28.3 g)を仕込み、室温で1時間撹拌した。
　反応液に1 M HCl (54.2 mL)を加えクエンチした。反応液を分液ロートに移し、有機層を分取した。有機層を、炭酸カリウム水溶液（15 w/w%，57.5 g)とNaCl水溶液 (10 w/w%、25.0 g)で順次洗浄し、得られた有機層に活性炭 (10 g)、THF (20 mL)を仕込み、内温24℃で終夜撹拌した。
　懸濁液を濾過し、濾液を外温50℃以下で、残量が30 mLになるまで減圧濃縮した。MeCN (50 mL)を加え外温50℃以下で、残量が50 mLになるまで減圧濃縮した。これを4回繰り返し、濃縮液を50℃にて1時間撹拌した。内温50℃にて常水 (50 mL)を1時間かけて滴下し、その後同温にて1時間撹拌した。この溶液を1時間かけて20℃に冷却し、同温にて2時間撹拌した。 Compound A-100 (10.0 g) and THF (100 mL) were placed in a nitrogen-purged container, stirred, and cooled. A 2.6 M n-BuLi/n-hexane solution (21.5 mL) was slowly added dropwise at an internal temperature of -65°C or lower, and the mixture was stirred for 30 minutes at an internal temperature of -65°C or lower.
Compound A-10 (6.83 g) and THF (37.5 mL) were placed in another container, stirred, and slowly added dropwise to the reaction solution at an internal temperature of -65°C or lower. The container was rinsed with THF (5.0 mL) and transferred to the reaction solution. The reaction solution was stirred at an internal temperature of -65°C for 30 minutes. DIPEA (18.5 mL) and methanesulfonic anhydride (28.3 g) were charged at the same temperature, and the mixture was stirred at room temperature for 1 hour.
The reaction solution was quenched by adding 1 M HCl (54.2 mL). The reaction solution was transferred to a separating funnel, and the organic layer was separated. The organic layer was washed sequentially with an aqueous potassium carbonate solution (15 w/w%, 57.5 g) and an aqueous NaCl solution (10 w/w%, 25.0 g), and the resulting organic layer was added with activated carbon (10 g) and THF (20 g). mL) and stirred overnight at an internal temperature of 24°C.
The suspension was filtered, and the filtrate was concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 30 mL. MeCN (50 mL) was added, and the mixture was concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 50 mL. This was repeated four times, and the concentrated solution was stirred at 50°C for 1 hour. At an internal temperature of 50°C, ordinary water (50 mL) was added dropwise over 1 hour, and then stirred at the same temperature for 1 hour. This solution was cooled to 20°C over 1 hour and stirred at the same temperature for 2 hours.
　懸濁液を濾過し、MeCN水溶液 (50 v/v%, 20 mL)で結晶を洗浄した。結晶を外温50℃以下で15時間減圧乾燥し、化合物D-100を13 g得た。仕込んだ化合物A-100に対する化合物D-100の収率は63.9％であった。
化合物D-100の1H NMR（CDCl3, 400 MHz）：δ ppm 7.07（s, 1H)、6.30（m, 1H)、2.76（s, 3H)、2.51-2.48（m, 2H)、2.06-2.05（m,  2H)、1.57-1.54（m, 2H)、0.97（s, 6H) The suspension was filtered and the crystals were washed with an aqueous MeCN solution (50 v/v%, 20 mL). The crystals were dried under reduced pressure at an external temperature of 50°C or lower for 15 hours to obtain 13 g of Compound D-100. The yield of compound D-100 based on the charged compound A-100 was 63.9%.
1H NMR (CDCl 3 , 400 MHz) of compound D-100: δ ppm 7.07 (s, 1H), 6.30 (m, 1H), 2.76 (s, 3H), 2.51-2.48 (m, 2H), 2.06- 2.05 (m, 2H), 1.57-1.54 (m, 2H), 0.97 (s, 6H)
　（4-2）　6-(4,4-ジメチルシクロヘキサ-1-エン-1-イル)-2-メチルチエノ[2,3-d]ピリミジン-4-カルボニトリル（D-200）の調製
 (4-2) Preparation of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-200)
　化合物D-100 (10.0 g）、p-TolSO2Na (1.83 g）、MeCN (100 mL）、精製水 (1.2 mL）、及びKCN (4.45 g)を仕込み、撹拌後、加熱し、内温81℃にて23時間撹拌した。反応液を冷却し、内温35℃で常水 (50 mL)を仕込み、内温2℃にて3時間撹拌した。懸濁液を濾過し、MeCN水溶液 (50 v/v%，50 mL)で結晶を洗浄し、常水 (50 mL)で結晶を洗浄した。 Compound D-100 (10.0 g), p-TolSO 2 Na (1.83 g), MeCN (100 mL), purified water (1.2 mL), and KCN (4.45 g) were charged, stirred, and then heated to an internal temperature of 81 Stirred at ℃ for 23 hours. The reaction solution was cooled, and ordinary water (50 mL) was added at an internal temperature of 35°C, followed by stirring at an internal temperature of 2°C for 3 hours. The suspension was filtered, and the crystals were washed with an aqueous MeCN solution (50 v/v%, 50 mL), and then with ordinary water (50 mL).
　別の容器に、洗浄した結晶（全量)、MeCN水溶液 (33 v/v%, 約60 mL)を仕込み、内温45℃で2時間撹拌後、冷却し、内温25℃で30分間撹拌した。懸濁液を濾過し、MeCN水溶液 (33 v/v%, 30 mL)で結晶を洗浄した。結晶を減圧乾燥し、化合物D-200を7.84 g得た。仕込んだ化合物D-100に対する化合物D-200の収率は81.0％であった。
化合物D-200の1H NMR（CDCl3, 400 MHz）：δ ppm 7.17（s, 1H)、6.40（m, 1H)、2.83（s, 3H)、2.53-2.49（m, 2H)、2.10-2.07（m,  2H)、1.59-1.52（m, 2H)、0.98（s, 6H) In a separate container, the washed crystals (total amount) and MeCN aqueous solution (33 v/v%, approximately 60 mL) were charged, and after stirring at an internal temperature of 45°C for 2 hours, it was cooled and stirred for 30 minutes at an internal temperature of 25°C. . The suspension was filtered and the crystals were washed with an aqueous MeCN solution (33 v/v%, 30 mL). The crystals were dried under reduced pressure to obtain 7.84 g of Compound D-200. The yield of compound D-200 based on the charged compound D-100 was 81.0%.
1H NMR (CDCl 3 , 400 MHz) of compound D-200: δ ppm 7.17 (s, 1H), 6.40 (m, 1H), 2.83 (s, 3H), 2.53-2.49 (m, 2H), 2.10- 2.07 (m, 2H), 1.59-1.52 (m, 2H), 0.98 (s, 6H)
　（4-3）　1-[6-(4,4-ジメチルシクロヘキシル)-2-メチルチエノ[2,3-d]ピリミジン-4-イル]メタンアミン塩酸塩（C-300）の調製
 (4-3) Preparation of 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine hydrochloride (C-300)
　容器に化合物D-200 (1.0 g）、EtOH (15 mL)を仕込み、窒素置換した。Pd(OH)2/C (パラジウム20 w/w%, 500 mg)を常水 (1 mL)に懸濁させ仕込んだ。続いて水素圧を0.7 MPaまで加圧した後、反応液を昇温し、内温70℃で26時間撹拌した。反応液を冷却した後、懸濁液を濾過し、EtOH (2 mL)で洗浄した。濾液を5 mLまで減圧濃縮した後、EtOAc (10 mL)を添加し、再び5 mLまで減圧濃縮した。さらにEtOAc (10 mL)を添加し、再び5 mLまで減圧濃縮した。
　濃縮液にEtOAc (5 mL)を加えて撹拌し、3℃まで冷却した。これに4 M 塩化水素酢酸エチル溶液 (1.3 mL)を1時間かけて滴下し、同温にて3時間撹拌した。懸濁液を濾過し、別の容器にてEtOH (2 mL)及びTHF (4 mL)を混合して調製したEtOH/THF溶液 (1:2 v/v, 6 mL)で結晶を洗浄した。
　別の容器に洗浄した結晶 (全量)及びTHF (約20 mL)を仕込み、室温にて1時間撹拌した。懸濁液を濾過し、THF (2 mL)で結晶を洗浄した。結晶を終夜減圧乾燥し、未精製の化合物C-300を643 mg得た。仕込んだ化合物D-200に対する化合物C-300の収率は56.0％であった。 Compound D-200 (1.0 g) and EtOH (15 mL) were placed in a container, and the atmosphere was replaced with nitrogen. Pd(OH) 2 /C (palladium 20 w/w%, 500 mg) was suspended in ordinary water (1 mL) and charged. Subsequently, the hydrogen pressure was increased to 0.7 MPa, and then the reaction solution was heated and stirred at an internal temperature of 70° C. for 26 hours. After cooling the reaction solution, the suspension was filtered and washed with EtOH (2 mL). After the filtrate was concentrated to 5 mL under reduced pressure, EtOAc (10 mL) was added and concentrated again to 5 mL under reduced pressure. Further EtOAc (10 mL) was added, and the mixture was again concentrated under reduced pressure to 5 mL.
EtOAc (5 mL) was added to the concentrated solution, stirred, and cooled to 3°C. A 4 M hydrogen chloride ethyl acetate solution (1.3 mL) was added dropwise to this over 1 hour, and the mixture was stirred at the same temperature for 3 hours. The suspension was filtered and the crystals were washed with an EtOH/THF solution (1:2 v/v, 6 mL) prepared by mixing EtOH (2 mL) and THF (4 mL) in a separate container.
The washed crystals (total amount) and THF (about 20 mL) were placed in a separate container, and the mixture was stirred at room temperature for 1 hour. The suspension was filtered and the crystals were washed with THF (2 mL). The crystals were dried under reduced pressure overnight to obtain 643 mg of unpurified compound C-300. The yield of compound C-300 based on the charged compound D-200 was 56.0%.
　続いて別の容器に未精製の化合物C-300結晶 (全量)及びTHF (約20 mL)を仕込み、室温にて2時間撹拌した。懸濁液を濾過し、THF (2 mL)で結晶を洗浄した。結晶を終夜減圧乾燥し、化合物C-300を622 mg得た。仕込んだ化合物D-200に対する懸濁精製後の化合物C-300の収率は54.1％であった。
化合物C-300の1H NMR（CD3OD, 400 MHz）：δ ppm 7.27（s, 1H)、3.31（s, 2H)、2.91（m, 1H)、2.79（s, 3H)、2.40-1.95（m, 2H)、1.81-1.74（m, 2H)、1.58-1.54（m, 2H)、1.47-1.39（m, 2H)、1.00（s, 3H),0.99 (s,3H) Subsequently, unpurified Compound C-300 crystals (total amount) and THF (about 20 mL) were charged into another container, and the mixture was stirred at room temperature for 2 hours. The suspension was filtered and the crystals were washed with THF (2 mL). The crystals were dried under reduced pressure overnight to obtain 622 mg of Compound C-300. The yield of compound C-300 after suspension purification with respect to the charged compound D-200 was 54.1%.
1H NMR (CD 3 OD, 400 MHz) of compound C-300: δ ppm 7.27 (s, 1H), 3.31 (s, 2H), 2.91 (m, 1H), 2.79 (s, 3H), 2.40-1.95 (m, 2H), 1.81-1.74 (m, 2H), 1.58-1.54 (m, 2H), 1.47-1.39 (m, 2H), 1.00 (s, 3H),0.99 (s,3H)
　（4-4）　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジン（A-800）の調製
　容器１にジビニルスルホン (0.15 mL)及びMeOH (3.5 mL)を仕込み、撹拌した。別の容器に化合物C-300 (0.5 g）、DIPEA (0.32 mL）、及びMeOH (3 mL)を仕込み、容器１に内温0℃にて1時間かけて滴下した。滴下終了後、MeOH (0.5 mL)で洗い込みを行った。内温5℃以下にて1.5時間撹拌し、同温にて常水 (7 mL)をゆっくり滴下し、1.5時間撹拌した。懸濁液を濾過し、MeOH水溶液 (50 v/v%, 2 mL)で結晶を洗浄した。続いて結晶を減圧乾燥した。
　別の容器に、減圧乾燥した結晶 (全量）、MEK (1.5 mL）、及びn-ヘプタン (8.5 mL)を仕込み、内温45℃にて1時間撹拌した。内温5℃まで冷却し同温にてさらに1時間撹拌した。懸濁液を濾過し、MEK/n-ヘプタン溶液 (25 v/v%, 1 mL)で結晶を洗浄した。結晶を15時間減圧乾燥し、化合物A-800を534 mg得た。仕込んだ化合物C-300に対する化合物A-800の収率は85.4％であった。また、実施例４におけるトータルの収率（全収率）、すなわち、出発物質として仕込んだ化合物A-100に対する目的化合物である化合物A-800の収率は23.9％であった。
　考察
　参考例（WO2015/056771A1に記載された方法）と実施例１～４に記載した方法について、目的化合物である式Ｉの化合物の収率（全収率）を以下に示す。
 (4-4) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine Preparation of (A-800)
Divinylsulfone (0.15 mL) and MeOH (3.5 mL) were charged into Container 1 and stirred. Compound C-300 (0.5 g), DIPEA (0.32 mL), and MeOH (3 mL) were placed in another container, and added dropwise to container 1 at an internal temperature of 0° C. over 1 hour. After completion of the dropwise addition, washing was performed with MeOH (0.5 mL). The mixture was stirred for 1.5 hours at an internal temperature of 5°C or less, and ordinary water (7 mL) was slowly added dropwise at the same temperature, followed by stirring for 1.5 hours. The suspension was filtered and the crystals were washed with an aqueous MeOH solution (50 v/v%, 2 mL). Subsequently, the crystals were dried under reduced pressure.
In a separate container, the crystals (total amount) dried under reduced pressure, MEK (1.5 mL), and n-heptane (8.5 mL) were charged, and the mixture was stirred at an internal temperature of 45°C for 1 hour. The mixture was cooled to an internal temperature of 5°C and further stirred at the same temperature for 1 hour. The suspension was filtered and the crystals were washed with MEK/n-heptane solution (25 v/v%, 1 mL). The crystals were dried under reduced pressure for 15 hours to obtain 534 mg of Compound A-800. The yield of compound A-800 based on the charged compound C-300 was 85.4%. Further, the total yield (total yield) in Example 4, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 23.9%.
Discussion Regarding the reference example (method described in WO2015/056771A1) and the methods described in Examples 1 to 4, the yield (total yield) of the compound of formula I, which is the target compound, is shown below.
　本発明によって6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジン及びその塩に関する効率的でグリーンケミストリーの観点でより好ましい合成方法が提供される。
  The present invention provides 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine and its A more preferable synthesis method from the viewpoint of efficient and green chemistry regarding salts is provided.

Claims (8)

  1. 　6-(4,4-ジメチルシクロヘキシル)-4-[(1,1-ジオキソ-1λ6-チオモルホリン-4-イル)メチル]-2-メチルチエノ[2,3-d]ピリミジンまたはその塩を合成する方法であって、
    　下式：
    で表される化合物［式中、Halはハロゲンである］の６位に、下式：
    で表される化合物を付加させて、下式：
    で表される化合物を得る工程を含む、上記方法。     Synthesis of 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or its salt A method of
    Below formula:
    At the 6th position of the compound represented by [in the formula, Hal is a halogen], the following formula:
    By adding the compound represented by the following formula:
    The above method, comprising the step of obtaining a compound represented by:
  2. 　下式：
    で表される化合物をシアノ化して、下式：
    で表される化合物を得る工程をさらに含む、請求項１に記載の方法。     Below formula:
    By cyanating the compound represented by the following formula:
    The method according to claim 1, further comprising the step of obtaining a compound represented by:
  3. 　下式：
    で表される化合物から、下式：
    で表される化合物を得る工程をさらに含む、請求項２に記載の方法。     Below formula:
    From the compound represented by the following formula:
    The method according to claim 2, further comprising the step of obtaining a compound represented by:
  4. （１）下式：
    で表される化合物［式中、Rはアルキル基である］から、下式：
    で表される化合物を得た後、その化合物を還元して、下式：
    で表される化合物を得る工程；次いで、
    （２）下式：
    で表される化合物に、下式：
    で表される化合物を付加して、下式：
    で表される化合物を得る工程；
    をさらに含む、請求項３に記載の方法。     (1) Below formula:
    From the compound represented by [wherein R is an alkyl group], the following formula:
    After obtaining the compound represented by, the compound is reduced to form the following formula:
    A step of obtaining a compound represented by;
    (2) Below formula:
    For the compound represented by the following formula:
    By adding the compound represented by the following formula:
    A step of obtaining a compound represented by;
    4. The method of claim 3, further comprising:
  5. （１）下式：
    で表される化合物［式中、Rはアルキル基である］から、下式：
    で表される化合物を得た後、その化合物を還元して、下式：
    で表される化合物を得る工程；次いで、
    （２）下式：
    で表される化合物に、下式：
    で表される化合物を付加して、下式：
    で表される化合物を得た後、その化合物を還元して、下式：
    で表される化合物を得る工程；
    をさらに含む、請求項３に記載の方法。     (1) Below formula:
    From the compound represented by [wherein R is an alkyl group], the following formula:
    After obtaining the compound represented by, the compound is reduced to form the following formula:
    A step of obtaining a compound represented by;
    (2) Below formula:
    For the compound represented by the following formula:
    By adding the compound represented by the following formula:
    After obtaining the compound represented by, the compound is reduced to form the following formula:
    A step of obtaining a compound represented by;
    4. The method of claim 3, further comprising:
  6. （１）下式：
    で表される化合物から、下式：
    で表される化合物を得る工程；及び、
    （２）下式：
    で表される化合物をジビニルスルホンと反応させて、下式：
    で表される化合物を得る工程；
    をさらに含む、請求項２に記載の方法。     (1) Below formula:
    From the compound represented by the following formula:
    A step of obtaining a compound represented by; and
    (2) Below formula:
    The compound represented by is reacted with divinyl sulfone to form the following formula:
    A step of obtaining a compound represented by;
    3. The method of claim 2, further comprising:
  7. 　下式：
    で表される化合物から、下式：
    で表される化合物を得た後、その化合物を還元して、下式：
    で表される化合物を得る工程；
    を含む、請求項６に記載の方法。     Below formula:
    From the compound represented by the following formula:
    After obtaining the compound represented by, the compound is reduced to form the following formula:
    A step of obtaining a compound represented by;
    7. The method of claim 6, comprising:
  8. 　下式：
    で表される化合物を還元して、下式：
    で表される化合物を得る工程；
    を含む、請求項６に記載の方法。
          Below formula:
    By reducing the compound represented by the following formula:
    A step of obtaining a compound represented by;
    7. The method of claim 6, comprising:
PCT/JP2023/031795 2022-09-01 2023-08-31 METHOD FOR PRODUCING 6-(4,4-DIMETHYLCYCLOHEXYL)-4-[(1,1-DIOXO-1λ6-THIOMORPHOLIN-4-YL)METHYL]-2-METHYLTHIENO[2,3-D]PYRIMIDINE OR SALT THEREOF WO2024048714A1 (en)

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