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

Abstract

To provide a synthesis method that is efficient and desirable in terms of green chemistry for producing 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine and a salt thereof.SOLUTION: 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is safely and efficiently synthesized by a method including a step of adding 4,4-dimethylcyclohexanone to the 6-position of the compound represented by the following formula [where Hal represents a halogen].SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 The present invention relates to a method for producing [2-methylthieno[2,3-d]pyrimidine or a salt thereof. [Background technology]

[0002] Patent Document 1 (International Publication No. 2015 / 056771A1) describes GABA B As a positive allosteric modulator of the receptor, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ]-1,1-dioxo ... 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is described.

[0003] [ka] [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2015 / 056771A1 Summary of the Invention [Problem to be solved by the invention]

[0005] Although WO 2015 / 056771A1 describes a method for synthesizing the compound represented by formula I, the method involves thiophene cyclization from a cyclohexane derivative and finally formation of a thienopyrimidine skeleton, which requires many steps and results in a low yield of the target compound. Furthermore, the method described in WO 2015 / 056771A1 requires the use of toxic compounds, so from the perspective of green chemistry, it is desirable to establish a method for synthesizing the target substance using as few harmful substances as possible.

[0006] The subject of the present invention is 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 The objective of the present invention is to develop an efficient and more favorable synthetic method for [(2-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or its salt from the viewpoint of green chemistry. [Means for solving the problem]

[0007] As a result of extensive investigation into the above-mentioned problems, the present inventors have discovered that 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 We have established an efficient and green chemistry-oriented synthetic method for [(2-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or its salts.

[0008] The present invention includes, but is not limited to, the following aspects. [1] 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 1. A method for synthesizing [-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or a salt thereof, comprising: Below formula:

[0009] [ka]

[0010] [wherein Hal is a halogen],

[0011] [ka]

[0012] to form a compound represented by the following formula:

[0013] [ka]

[0014] The above method, comprising a step of obtaining a compound represented by the formula: [2] Below formula:

[0015] [ka]

[0016] is cyanated to give a compound represented by the following formula:

[0017] [ka]

[0018] The method according to [1], further comprising a step of obtaining a compound represented by the formula: [3] Below formula:

[0019] [ka]

[0020] From a compound represented by the following formula:

[0021] [ka]

[0022] The method according to [2], further comprising a step of obtaining a compound represented by the formula: [wherein R is an alkyl group]. [4] (1) Below formula:

[0023] [ka]

[0024] [wherein R is an alkyl group], the compound represented by the following formula:

[0025] [ka]

[0026] After obtaining a compound represented by the formula:

[0027] [ka]

[0028] obtaining a compound represented by the formula: (2) Below formula:

[0029] [ka]

[0030] The compound represented by the formula:

[0031] [ka]

[0032] to form a compound represented by the following formula:

[0033] [ka]

[0034] obtaining a compound represented by the formula: The method according to [3], further comprising: [5] (1) Below formula:

[0035] [ka]

[0036] [wherein R is an alkyl group], the compound represented by the following formula:

[0037] [ka]

[0038] After obtaining a compound represented by the formula:

[0039] [ka]

[0040] obtaining a compound represented by the formula: (2) Below formula:

[0041] [ka]

[0042] The compound represented by the formula:

[0043] [ka]

[0044] to form a compound represented by the following formula:

[0045] [ka]

[0046] After obtaining a compound represented by the formula:

[0047] [ka]

[0048] obtaining a compound represented by the formula: The method according to [3], further comprising: [6] (1) Below formula:

[0049] [ka]

[0050] From a compound represented by the following formula:

[0051] [ka]

[0052] obtaining a compound represented by the formula: (2) Below formula:

[0053] [ka]

[0054] with divinyl sulfone to obtain a compound represented by the following formula:

[0055] [ka]

[0056] obtaining a compound represented by the formula: The method according to [2], further comprising: [7] Below formula:

[0057] [ka]

[0058] From a compound represented by the following formula:

[0059] [ka]

[0060] After obtaining a compound represented by the formula:

[0061] [ka]

[0062] obtaining a compound represented by the formula: The method according to [6], comprising: [8] Below formula:

[0063] [ka]

[0064] to obtain a compound represented by the following formula:

[0065] [ka]

[0066] obtaining a compound represented by the formula: The method according to [6], comprising: [Effects of the Invention]

[0067] According to the present invention, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6

[0023] It is possible to synthesize [(2-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or a salt thereof in an efficient manner and more preferably from the viewpoint of green chemistry. DETAILED DESCRIPTION OF THE INVENTION

[0068] 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is a compound represented by the following formula I:

[0069] [ka]

[0070] The compound represented by Formula I may be in a free form not forming an ester or a salt, or may form a salt with an acid, etc. Such salts are preferably pharmaceutically acceptable salts, and include, but are not limited to, acid addition salts with inorganic acids or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, 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, and carbonic acid.

[0071] In this specification, a compound may be described using a structural formula such as "a compound represented by formula X," but may also be simply referred to as compound X. Therefore, a compound represented by formula I may also be simply referred to as "compound I."

[0072] In one embodiment, the present invention provides 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 The present invention relates to a method for producing [2-methylthieno[2,3-d]pyrimidine or a salt thereof.

[0073] When various hydrates, solvates, crystalline polymorphs, etc. of the compound represented by formula I are produced, the hydrates, etc. may be obtained by an appropriate known method. Furthermore, when various radioactive or non-radioactive isotope-labeled compounds of the compound represented by formula I are produced, the compounds may be labeled by an appropriate known method.

[0074] 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 to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include, but are not limited to, those described in "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006), and may be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary.

[0075] As used herein, "lower alkyl" refers to a group that is typically straight-chain or branched and has 1 to 6 carbon atoms (hereinafter, C 1-6 The number of carbon atoms will be expressed in the same manner hereinafter.) and examples thereof include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Typical examples of "lower alkyl" include a methyl group, an ethyl group, a propyl group, etc., and an ethyl group is more preferred.

[0076] "Cycloalkanes" are typically C 3-8 Examples of "cycloalkane" include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. 5-6 Cycloalkanes are preferred, cyclohexane or cyclopropane are more preferred, and cyclopropane is even more preferred. "Halogen" means F, Cl, Br, or I.

[0077] In this specification, the concentration unit mol / L may be expressed as M. For example, a 1M NaOH aqueous solution means a 1 mol / L NaOH aqueous solution.

[0078] In addition, the following abbreviations may be used in this specification: AcCl = acetyl chloride, AcOH = acetic acid, AlCl3 = aluminum chloride, brine = saturated brine, CDI = 1,1'-carbonyldiimidazole, DCE = 1,2-dichloroethane, DCM = dichloromethane, Boc2O = di-tert-butyl dicarbonate, DIPEA = N,N-diisopropylethylamine, DME = dimethoxyethane, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, DPPA = diphenylphosphoryl azide, Et2O = diethyl ether, EtOAc = ethyl acetate, EtOH = ethanol, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-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 = diisopropyl ethyl ether, KCN = potassium cyanide, MeCN = acetonitrile, MEK = methyl ethyl ketone, MeOH = methanol, MgSO4 = anhydrous magnesium sulfate, MsCl = methanesulfonyl chloride, Na2SO4 = anhydrous sodium sulfate, NaBH(OAc)3 = sodium triacetoxyborohydride, n-BuLi = n-butyllithium, p-TolSO2Na = sodium p-toluenesulfinate, Pd(OAc)2 = palladium(II) acetate, Pd(OH)2 / C = palladium hydroxide on carbon, Pd / C = palladium on 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 sodium bicarbonate solution = saturated aqueous NaHCO3 solution, Ac = acetyl, Bn = benzyl, Boc = tert-butoxycarbonyl, Et = ethyl, Me = methyl, Ms = methanesulfonyl (SO2CH3), Ph = phenyl, tBu or But = tert-butyl.

[0079] The manufacturing method of the present invention will be described in detail below, but it should be understood that the manufacturing method of the present invention is not limited to the specific embodiments shown below and can be changed or modified as appropriate.

[0080] 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, a compound represented by the following formula:

[0081] [ka]

[0082] For 4-chloro-2-methylthieno[2,3-d]pyrimidine or a derivative thereof represented by the following formula:

[0083] [ka]

[0084] The compound represented by the following formula:

[0085] [ka]

[0086] A compound represented by the formula: Although WO 2015 / 056771A1 describes a method for synthesizing the compound represented by Formula I, the method requires many steps, including thiophene cyclization from a cyclohexane derivative and finally formation of a thienopyrimidine skeleton, and the yield of the target compound is 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, thereby reducing the number of steps and significantly improving the yield compared to conventionally known methods.

[0087] When 4-chloro-2-methylthieno[2,3-d]pyrimidine (A-100) and 4,4-dimethylcyclohexanone (A-10) are reacted to obtain 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 the reaction proceeds, but for example, ethers such as THF can be preferably used. The base is not limited thereto, but typical examples include organolithium compounds such as n-BuLi, sec-BuLi, and lithium diisopropylamide, and n-BuLi can be preferably used.

[0088] Furthermore, when 4-chloro-2-methylthieno[2,3-d]pyrimidine (A-100) is reacted with 4,4-dimethylcyclohexanone (A-10) to obtain 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-100), the cycloalkane can be converted to a cycloalkene in one pot by adding, but not limited to, MsO or AcCl to the alkoxide obtained from Compound A-100 and Compound A-10. The solvent is not particularly limited as long as the reaction proceeds, but ethers such as THF can be suitably used. The base is not limited thereto, but typical examples include organolithium compounds such as n-BuLi, sec-BuLi, and lithium diisopropylamide. n-BuLi is suitably used, and organic amines such as DIPEA can also be used.

[0089] In the present invention, a compound represented by the following formula:

[0090] [ka]

[0091] wherein Hal is a halogen. When 4-chloro-2-methylthieno[2,3-d]pyrimidine (A-100) is used as a starting material, the reaction may need to be carried out at extremely low temperatures. However, by using a derivative halogenated at the 6-position, for example, but not limited to, a so-called Turbo Grignard reagent, the reaction can be carried out at around 0°C, and the odor derived from 4-chloro-2-methylthieno[2,3-d]pyrimidine can be suppressed.

[0092] In one embodiment, the production method according to the present invention comprises the step of:

[0093] [ka]

[0094] is cyanated to give a compound represented by the following formula:

[0095] [ka]

[0096] The method may further include a step of obtaining a compound represented by the formula: Cyanation of Compound A-200 or Compound D-100 may be carried out using, for example, a CN source such as NaCN, KCN, or Zn(CN)2 together with p-TolSO2Na or CH3SO2Na, etc. The solvent is not particularly limited as long as it does not interfere with the reaction, and typical examples include MeCN and DMF, with MeCN being preferred.

[0097] In one embodiment, the present invention provides a compound of the formula:

[0098] [ka]

[0099] From a compound represented by the following formula:

[0100] [ka]

[0101] wherein R is an alkyl group. The method may further include a step of obtaining a compound represented by the formula:

[0102] This reaction is typically carried out with 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300) in the presence of an alkyl alcohol and an acid or acid halide (optionally in a suitable solvent). Suitable acids or acid halide include HCl, acyl chloride, etc., and solvents include EtOH or any mixed solvent containing EtOH. Typically, the alkyl alcohol and acid are added under cooling, followed by reaction at around room temperature and stirring at 40°C to 60°C for several hours to overnight, but this is not limiting.

[0103] In one embodiment, the present invention provides a compound of the formula:

[0104] [ka]

[0105] to obtain a compound represented by the following formula:

[0106] [ka]

[0107] After obtaining a compound represented by the formula:

[0108] [ka]

[0109] The method may include a step of obtaining a compound represented by the formula: The step of reducing ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400) to obtain [6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500) can be carried out in the presence of a reducing agent using a solvent inert to the reaction. The reaction conditions are not particularly limited, but can be, for example, cooling or heating, preferably at −20°C to 80°C, for 0.1 hours to 3 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but suitable solvents include ethers, aromatic hydrocarbons, alcohols, halogenated hydrocarbons, and mixtures thereof. Examples of reducing agents that can be used include, but are not limited to, sodium borohydride (NaBH), lithium aluminum hydride (LiAlH), borane (BH), and reducing agents described in the following documents: NaBH may be used in combination with CaCl, and in a particularly preferred embodiment, KBH may be used in combination with MgCl. [Literature] M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)", ACS, 1996 RC Larock, “Comprehensive Organic Transformations”, 2nd edition, VCH Publishers, Inc., 1999; TJ Donohoe, “Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)”, Oxford Science Publications, 2000; "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

[0110] Furthermore, the step of reducing [6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500) to obtain 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600) may be carried out by hydrogenating compound A-500. This reaction may be carried out, for example, by stirring compound A-500 in a reaction-inert solvent with a metal catalyst in a hydrogen atmosphere, either cooled or heated, preferably at room temperature, typically for 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, and alcohols, ethers, and the like are suitable. The metal catalyst may be, but is not limited to, a palladium catalyst such as Pd or Pd(OH), a platinum catalyst such as PtO, or a rhodium catalyst such as Wilkinson's catalyst. As the hydrogen source, formic acid or ammonium formate can be used in an amount equal to or in excess of Compound A-500 instead of hydrogen gas. [Literature] M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996; "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 19 (2005) (Maruzen)

[0111] Also in this aspect, the present invention provides a compound of the formula:

[0112] [ka]

[0113] The compound represented by the formula:

[0114] [ka]

[0115] to form a compound represented by the following formula:

[0116] [ka]

[0117] The method may further comprise a step of obtaining a target compound represented by the formula: This amination step can be carried out by any suitable method known in the art, such as direct amination using a catalyst or by converting the hydroxyl group into a leaving group. Preferably, the hydroxyl group of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600) is converted into a leaving group, such as a halogen, alkyl sulfonate, or fluoroalkyl sulfonate, followed by stirring in a solvent inert to the reaction with thiomorpholine-1,1-dioxide (A-20) or without a solvent, with cooling or heating, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, and examples include aromatic hydrocarbons such as toluene and xylene, ethers such as EtO, THF, DME, and dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, DMF, DMSO, EtOAc, MeCN, and mixtures thereof. In this step, an organic base such as TEA, DIPEA or NMO, or an inorganic base such as K2CO3, Na2CO3 or KOH may help the reaction proceed more smoothly. [Literature] S.R. Sandler and W. Karo, "Organic Functional Group Preparations," 2nd ed., Vol. 1, Academic Press Inc., 1991; "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

[0118] In yet another aspect, the present invention provides a compound of formula:

[0119] [ka]

[0120] From a compound represented by the following formula:

[0121] [ka]

[0122] After obtaining a compound represented by the formula:

[0123] [ka]

[0124] The method may include a step of obtaining a compound represented by the formula: The step of hydrolyzing the ethyl ester of ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400) to obtain 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) can be carried out by any suitable method known in the art, for example, using a reaction-inert solvent in the presence of an aqueous alkali solution. The reaction conditions are not particularly limited, but can be, for example, cooling or heating, preferably at 0°C to 50°C, for 0.1 hours to 3 days. The solvent is not particularly limited as long as it does not interfere with the reaction, and suitable solvents include alcohols such as MeOH and EtOH, ethers such as THF, and mixtures thereof. The aqueous alkali solution is not limited to, but examples of suitable solutions include aqueous NaOH, aqueous KOH, and aqueous LiOH.

[0125] Furthermore, the step of reducing 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) to obtain 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) may be carried out by hydrogenating compound (B-100). This reaction may be carried out, for example, by stirring compound B-100 in a reaction-inert solvent with a metal catalyst under a hydrogen atmosphere, either cooled or heated, preferably at room temperature, typically for 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 alcohols, ethers, and the like are suitable. The metal catalyst may be, but is not limited to, a palladium catalyst such as Pd or Pd(OH), a platinum catalyst such as PtO, or a rhodium catalyst such as Wilkinson's catalyst. As the hydrogen source, formic acid or ammonium formate can be used in an amount equal to or in excess of Compound B-100 instead of hydrogen gas. [Literature] M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996; "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 19 (2005) (Maruzen)

[0126] Also in this aspect, the present invention provides a compound of the formula:

[0127] [ka]

[0128] The compound represented by the formula:

[0129] [ka]

[0130] to form a compound represented by the following formula:

[0131] [ka]

[0132] After obtaining a compound represented by the formula:

[0133] [ka]

[0134] The method may include a step of obtaining a target compound represented by the formula: 4-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonyl]-1λ 6 Thiomorpholine-1,1-dione (B-300) is prepared from 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) and thiomorpholine-1-dioxide (A-20). In this reaction, compounds B-200 and A-20 are used in equal amounts, or in excess of one. The mixture is stirred in a reaction-inert solvent in the presence of a condensing agent, cooled or heated, preferably at temperatures between -20°C and 60°C, for typically 0.1 hours to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but examples include aromatic hydrocarbons, halogenated hydrocarbons such as DCM, ethers, DMF, DMSO, EtOAc, CHCN, water, and mixtures thereof. Condensing agents include, but are not limited to, WSC, CDI, HATU, DCC, DMTMM, phosphorus oxychloride, thionyl chloride, and ethyl chloroformate. Additives such as HOBt may facilitate the reaction, as may organic bases such as pyridine, TEA, DIPEA, or NMO, or inorganic bases such as K2CO3, Na2CO3, or KOH.

[0135] Compound B-300 can also be produced from a reactive derivative of a carboxylic acid and Compound A-20. Examples of reactive derivatives include, but are not limited to, acid halides obtained by reacting the carboxylic acid of Compound B-200 with a halogenating agent such as phosphorus oxychloride or thionyl chloride; mixed acid anhydrides obtained by reacting with isobutyl chloroformate (ethyl chlorocarbonate); and activated esters obtained by condensing with HOBt. The reaction of the reactive derivative with Compound A-20 can be carried out by stirring in a reaction-inert solvent with an organic base such as pyridine, TEA, DIPEA, or NMO, with cooling or heating, preferably at −20°C to 60°C, for typically 0.1 hours to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, and examples include halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, CH3CN, water, and mixtures thereof. The organic base can also serve as the solvent. [Literature] S.R. Sandler and W. Karo, "Organic Functional Group Preparations," 2nd ed., Vol. 1, Academic Press Inc., 1991; "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen)

[0136] Furthermore, in the reaction for obtaining the target compound represented by formula I from compound B-300, the solvent is not particularly limited as long as the reaction proceeds, and examples of the solvent that can be used include THF, aromatic hydrocarbons, etc. The reducing agent is not limited to, but examples of the reducing agent that can be used include a combination of LiAlH4 and aluminum chloride (AlCl3), Red-Al, DIBAL, BH3, Et3SiH, etc.

[0137] In one embodiment, the present invention provides a compound of the formula:

[0138] [ka]

[0139] From a compound represented by the following formula:

[0140] [ka]

[0141] or a salt thereof such as hydrochloride (C-300). In this aspect, the present invention provides a compound of formula:

[0142] [ka]

[0143] From a compound represented by the following formula:

[0144] [ka]

[0145] or a salt thereof such as hydrochloride (C-200), the compound is reduced to give a compound represented by the following formula:

[0146] [ka]

[0147] or a salt thereof such as hydrochloride (C-300). The reaction for obtaining 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300) or a salt thereof such as 1-[6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its hydrochloride (C-200) can be carried out, but is not limited to, by reducing the cyano group using a nickel catalyst such as Raney nickel in the presence of (Boc)O to obtain a Boc-protected primary amine, followed by simultaneous dehydration and Boc-removal using a MeOH hydrochloric acid solution or the like to obtain a cycloalkene.

[0148] The step of reducing 1-[6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or a salt thereof, such as its hydrochloride (C-200), to obtain 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or a salt thereof, such as its hydrochloride (C-300), may be carried out by a hydrogenation reaction. This reaction may be carried out, for example, by stirring compound (C-200) in a hydrogen atmosphere in a reaction-inert solvent with a metal catalyst at a temperature ranging from cooling to heating, preferably at room temperature, for typically 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 alcohols, ethers, and the like are preferably used, such as EtOH. Examples of metal catalysts include, but are not limited to, palladium catalysts such as Pd and Pd(OH)2, platinum catalysts such as PtO2, and rhodium catalysts such as Wilkinson's catalyst. As the hydrogen source, formic acid or ammonium formate can also be used instead of hydrogen gas.

[0149] Also in this aspect, the present invention provides a compound of the formula:

[0150] [ka]

[0151] to obtain a compound represented by the following formula:

[0152] [ka]

[0153] A compound represented by the formula: The reduction of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-200) to obtain 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or a salt thereof, such as its hydrochloride (C-300), may be carried out by hydrogenation. This reaction may be carried out, for example, by stirring compound D-200 in a reaction-inert solvent with a metal catalyst under a hydrogen atmosphere, with cooling or heating, preferably at room temperature, typically for 1 hour to 5 days. The solvent is not particularly limited as long as it does not interfere with the reaction, but alcohols and ethers are suitable. Examples of metal catalysts include, but are not limited to, palladium catalysts such as Pd and Pd(OH), platinum catalysts such as PtO, and rhodium catalysts such as Wilkinson's catalyst. Instead of hydrogen gas, formic acid, ammonium formate, etc. can also be used as the hydrogen source. In a particularly preferred embodiment, but not limited to, catalytic reduction using a palladium catalyst such as Pd(OH)2 can reduce the cyano group of compound D-200 and the alkene simultaneously in one pot, thereby shortening the synthesis process.

[0154] In this aspect, the present invention provides a compound of formula:

[0155] [ka]

[0156] with divinyl sulfone to obtain a compound represented by the following formula:

[0157] [ka]

[0158] The method may include a step of obtaining a compound represented by the formula: When 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine-hydrogen chloride (C-300) is reacted with divinyl sulfone to obtain the target compound of Formula I, the solvent is not particularly limited as long as the reaction proceeds, but for example, MeOH can be suitably used. In this reaction, an organic amine such as DIPEA can be suitably used as a base.

[0159] Furthermore, the compounds described herein may exist in the form of tautomers or geometric isomers depending on the type of substituents. Although only one form of an isomer of a compound may be described herein, it should be understood that the present invention also encompasses other isomers, and encompasses isolated isomers or mixtures thereof.

[0160] Similarly, the compounds described herein may have asymmetric carbon atoms or axial chirality, and therefore may have optical isomers. In such cases, the present invention encompasses the separated optical isomers of the compounds, as well as mixtures thereof.

[0161] The present invention will be described in more detail below with reference to 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 their endpoints. [Example]

[0162] Reference example WO 2015 / 056771A1 discloses a method for the preparation of 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ]-methylcyclohexyl] ... 6 The synthesis of [-thiomorpholin-4-yl]methyl-2-methylthieno[2,3-d]pyrimidine is described.

[0163] [ka]

[0164] Process 1 Under an argon atmosphere, 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). The internal temperature was maintained below 10°C under ice cooling, and sulfur trioxide pyridine complex (77.7 g) was added in small portions. After stirring at room temperature for 2 hours, ice water was added to the reaction mixture, which was then concentrated under reduced pressure and extracted with chloroform. The organic layer was washed sequentially with 1M HCl and brine. MgSO4 was added to the organic layer, followed by stirring, filtration, and concentration under reduced pressure to give (4,4-dimethylcyclohexyl)acetaldehyde (27.3 g).

[0165] Process 2 To a mixture of (4,4-dimethylcyclohexyl)acetaldehyde (27.3 g) and DMF (100 mL), 2-cyanoacetamide (12 g), sulfur (5 g), and TEA (24 mL) were added and the mixture was heated and stirred at 60°C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed successively with water and brine, then NaSO and activated carbon (2 g) were added and the mixture was stirred. After filtration through Celite, the mixture was concentrated under reduced pressure to give 2-amino-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide (33.0 g).

[0166] Process 3 To a mixture of 2-amino-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide (33 g), pyridine (40 mL), and DCM (200 mL), AcCl (14 mL) was added dropwise at 0°C and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of water and 1M HCl and extraction with chloroform. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and brine. MgSO4, activated carbon (2 g), and basic silica gel (100 mL) were added to the organic layer and stirred. After filtration through Celite, the mixture was concentrated under reduced pressure to give 2-acetamido-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide (37.3 g).

[0167] Process 4 To a mixture of 2-acetamido-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide (37.3 g) and EtOH (200 mL), 2M aqueous NaOH (200 mL) was added and stirred at 80°C for 2 hours. 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 give 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (26.3 g).

[0168] Process 5 To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (30.0 g) and toluene (240 mL), phosphorus oxychloride (40 mL) and DMF (1.0 mL) were added and the mixture was heated to 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. MgSO4, activated carbon (10 g), and silica gel (100 mL) were added to the organic layer and stirred. After filtration through Celite, the mixture was concentrated under reduced pressure to give 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.3 g).

[0169] 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), CHSONa (11 g) and KCN (10 g) were added and the mixture was heated and stirred at 70 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to approximately half its volume, diluted with water (300 mL), and stirred. The precipitate was collected by filtration. Chloroform was added to the precipitate, and the mixture was dissolved. MgSO, activated carbon (10 g), and silica gel (100 mL) were added and stirred. The mixture was filtered through Celite and concentrated under reduced pressure to give 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (27.4 g).

[0170] 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), 4M hydrogen chloride in dioxane (200 mL) was added and stirred at 80 °C overnight. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. EtOH (200 mL) and water (200 mL) were added to the residue and stirred. The precipitate was collected by filtration. The resulting precipitate was dissolved in chloroform, and MgSO4, activated carbon (10 g), and basic silica gel (100 mL) were added and stirred. After filtration through Celite, the mixture was concentrated under reduced pressure to give ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (23.3 g).

[0171] Process 8 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) was added calcium chloride (6.6 g). The mixture was stirred at room temperature for 30 minutes, and then NaBH (1.8 g) was added in small portions over 15 minutes under ice-cooling. After stirring at room temperature for 4.5 hours, water (100 mL) and EtOAc (100 mL) were added to the reaction mixture under ice-cooling. 1M HCl (100 mL) was added until the suspension became a solution, followed by concentration under reduced pressure and extraction with EtOAc. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform / Et0Ac) to give [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]MeOH (9.35 g).

[0172] Process 9 To a mixture of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]MeOH (16.0 g), TEA (10 mL), and DCM (200 mL) was added MsCl (5.0 mL) dropwise over 15 minutes at 0°C and stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine. MgSO4, activated carbon (5 g), and basic silica gel (20 mL) were added to the organic layer, which was stirred. After filtration through Celite, the mixture was concentrated under reduced pressure to give [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (18.9 g).

[0173] Step 10 To a mixture of thiomorpholine-1,1-dioxide (70 mg) and DMF (4 mL), [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (120 mg) and TEA (150 μL) were added, followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified using 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.

[0174] Considerations regarding the reference example The method described in WO 2015 / 056771A1 converts the starting material 2-(4,4-dimethylcyclohexyl)EtOH into the target material 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 The overall yield of [(2-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine was approximately 5%, which is not an efficient synthetic method.

[0175] Furthermore, when synthesizing the starting material, 2-(4,4-dimethylcyclohexyl)EtOH, from 4,4-dimethyl-2-cyclohexen-1-one (CAS 1073-13-8), which is readily available from reagent companies, the yield is approximately 68% according to the scheme below, and a large amount of raw material is required to synthesize the target substance (Bioorganic & Medicinal Chemistry Letters (2011), 21(15), pp. 4409-4415).

[0176] [ka]

[0177] Furthermore, in the method described in WO 2015 / 056771A1, an oxidation reaction using SO3·pyridine / DMSO in step 1 generates dimethyl sulfide, which is toxic and has a foul odor, and phosphoryl chloride (POCl3), a poisonous substance under the Poisonous and Deleterious Substances Control Act, is used for chlorination in step 5. From the perspective of green chemistry, it is desirable to establish a method for synthesizing target substances using as few harmful substances as possible.

[0178] Example 1 (1-1) Preparation of 1-(4-chloro-2-methylthieno[2,3-d]pyrimidin-6-yl)-4,4-dimethylcyclohexan-1-ol (A-200)

[0179] [ka]

[0180] 4-Chloro-2-methylthieno[2,3-d]pyrimidine (A-100) (21.1 kg) and THF (186.9 kg) were charged into a nitrogen-purged reactor 1, stirred, and cooled. At an internal temperature of -79°C to -74°C, an n-BuLi / n-hexane solution (15 w / w%, 50.9 kg) was added dropwise, and the mixture was stirred at an internal temperature of -80°C to -79°C for 30 minutes. 4,4-Dimethylcyclohexanone (A-10) (14.4 kg) and THF (70.1 kg) were mixed in a nitrogen-purged vessel, and the mixed solution was added dropwise to the reactor 1 at an internal temperature of -79°C to -76°C. The vessel containing the compound A-10 and THF solution was rinsed with THF (9.3 kg) and transferred to the reactor 1. The reaction solution was stirred at an internal temperature of -76°C to -74°C for 30 minutes. The completion of the reaction was confirmed by HPLC.

[0181] Next, AcOH (9.1 kg) and THF (18.0 kg) were mixed in a nitrogen-purged container to prepare an AcOH / THF solution. This AcOH / THF solution (50 w / w%, 22.4 kg) was charged into reaction vessel 1 at an internal temperature of -74°C to -59°C. The vessel in which the AcOH / THF solution was prepared was rinsed with THF (3.7 kg) and transferred to reaction vessel 1. The reaction solution in reaction vessel 1 was heated and transferred to reaction vessel 2, which was purged with nitrogen. Reaction vessel 1 was rinsed with THF (28.3 kg) and transferred to reaction vessel 2. Reaction vessel 2 was charged with normal water (42.3 kg), stirred for 10 minutes, allowed to stand, and the aqueous layer was separated. An aqueous NaCl solution (10 w / w%, 52.7 kg) was charged to the organic layer, stirred for 10 minutes, allowed to stand, and the aqueous layer was separated. The organic layer was transferred to reaction vessel 3, which was purged with nitrogen. Reaction vessel 2 was washed with THF (10.0 kg) and transferred to reaction vessel 3, and organic layer 1 was obtained. The above-mentioned procedure of obtaining organic layer 1 from A-100 was repeated twice, and organic layer 2 and organic layer 3 were obtained, respectively.

[0182] Organic layers 1 to 3 were mixed, and activated carbon (Purified Shirasagi W50, manufactured by Osaka Gas Chemicals, 63.0 kg) and THF (82.0 kg) were charged into reaction tank 3, followed by stirring 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 the solution was transferred to reaction tank 2 via a filter.

[0183] The solution was concentrated under reduced pressure at an external temperature of 50°C or below until the remaining volume was 252 L. THF (224.4 kg) was charged, and the solution was concentrated under reduced pressure at an external temperature of 50°C or below until the remaining volume was 252 L. The solution was heated, MeCN (198.1 kg) was added at an internal temperature of 48°C to 51°C, and then ordinary water (504.2 kg) was charged at an internal temperature of 49°C to 51°C. The suspension containing the precipitated crystals was stirred at 49°C to 51°C for 1 hour, then cooled, and stirred at 26°C to 30°C for 10 hours.

[0184] 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, yielding 92.17 kg of compound A-200. The yield of compound A-200 relative to the compound A-100 charged as a raw material was 86.6%. Compound A-200 1 H 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, 2H), 1.00(s, 3H), 0.97(s, 3H) HRMS (ESI) of compound A-200: [M+H + ] Calcd for 311.0985, Found 311.0969

[0185] (1-2) Preparation of 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300)

[0186] [ka]

[0187] Compound A-200 (91.5 kg), p-TolSO2Na (15.7 kg), MeCN (719.6 kg), purified water (10.7 kg), and KCN (38.3 kg) were charged into a nitrogen-purged reactor 1 and stirred. The suspension was heated and stirred at an internal temperature of 78°C to 81°C for 24 hours. The completion of the reaction was confirmed by HPLC.

[0188] The reaction solution was then cooled, and ordinary water (457.7 kg) was added at an internal temperature of 34° C., followed by stirring for 5 hours at an internal temperature of 5 to 10° C. 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).

[0189] The washed crystals (total amount) and an aqueous MeCN solution (33 v / v%, 510.4 kg) were charged into a nitrogen-purged reactor 1 and stirred at an internal temperature of 40°C to 45°C for 2 hours. The suspension was cooled and stirred at an internal temperature of 27°C to 30°C for 30 minutes. 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 relative to the charged compound A-200 was 92.4%. 1 H 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

[0190] (1-3) Preparation of ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400)

[0191] [ka]

[0192] Compound A-300 (81.5 kg) and EtOH (643.8 kg) were charged into a nitrogen-purged reactor 1, followed by stirring and cooling. AcCl (319.1 kg) was added dropwise at an internal temperature of -10°C to 12°C, followed by heating and stirring at an internal temperature of 55°C to 62°C for 15 hours. The reaction solution was cooled and concentrated under reduced pressure at an external temperature of 40°C or below until the residual volume reached 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. Furthermore, ordinary water (285.6 kg) was added dropwise at an internal temperature of 4°C to 6°C, followed by stirring at an internal temperature of 4 to 5°C for 3 hours.

[0193] The suspension was filtered, and the crystals were washed with an aqueous EtOH solution (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 less for 27 hours to obtain 80.81 kg of compound A-400. The yield of compound A-400 relative to the amount of compound A-300 used was 90.5%. Compound A-400 1 H 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) HRMS (ESI) of compound A-400: [M+Na + ] Calcd for 353.1300, Found 353.1280

[0194] (1-4) Preparation of [6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500)

[0195] [ka]

[0196] EtOH (285.6 kg) and normal water (39.9 kg) were charged into a nitrogen-purged reactor 1 and stirred. Calcium chloride dihydrate (35.6 kg) was charged at an internal temperature of 29°C to 33°C to prepare a CaCl2 solution. Compound A-400 (80.0 kg) and THF (356.2 kg) were charged into reaction vessel 2, which had been purged with nitrogen, and stirred. The CaCl2 solution (359.7 kg) was added dropwise to reaction vessel 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 vessel 2, NaBH4 (7.32 kg) was charged at an internal temperature of 0°C to 1°C, and stirred for 5 hours at an internal temperature of 0°C to 2°C. NaBH4 (0.11 kg) was charged at an internal temperature of 0°C, and stirred for 2 hours at an internal temperature of 0°C to 1°C. The completion of the reaction was confirmed by HPLC.

[0197] Ammonium chloride (60.0 kg) and tap water (601.7 kg) were charged into reactor 3, which had been purged with nitrogen, followed by stirring and cooling. Isopropyl acetate (353.8 kg) was charged into reactor 3 at an internal temperature of 6°C, and the reaction solution from reactor 2 was added dropwise to reactor 3 at an internal temperature of 4-5°C. Reactor 2 was rinsed with isopropyl acetate (353.1 kg) and transferred to reactor 3. The reaction solution in reactor 3 was stirred for 30 minutes, then allowed to stand, and the aqueous layer was separated. Aqueous potassium carbonate solution (10% v / v, 440.2 kg) was charged into the organic layer, stirred for 10 minutes, then 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 below until the remaining volume was 310 L. EtOH (317.8 kg) was charged, and the mixture was concentrated under reduced pressure at an external temperature of 50°C or below 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 below 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.

[0198] 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 relative to the amount of compound A-400 used was 90.4%. Compound A-500 1 H 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) HRMS (ESI) of compound A-500: [M+Na + ] Calcd for 311.1194, Found 311.1171

[0199] (1-5) Preparation of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600)

[0200] [ka]

[0201] Compound A-500 (62.9 kg) and EtOH (249.3 kg) were charged into a nitrogen-purged reactor 1, and the atmosphere was then purged with nitrogen. Subsequently, 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 charged into reactor 1 at an internal temperature of 7°C to 10°C. The atmosphere in reactor 1 was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred for 1 hour at an internal temperature of 25°C to 26°C under a hydrogen pressure of 0.15 MPa. After increasing the hydrogen pressure to 0.7 MPa, the reaction mixture was heated and stirred for 5 hours at an internal temperature of 65°C to 70°C. The reaction mixture was cooled, the pressure was released, and the mixture was purged 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 reactor 1 at an internal temperature of 28°C. The atmosphere in reactor 1 was purged with nitrogen three times and then 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 purged with nitrogen three times.

[0202] The suspension was filtered through radiolite, and the solution was transferred to reactor 2, which had been purged with nitrogen. Reaction vessel 1 was washed with EtOH (151.1 kg), and the solution was transferred to reactor 2 via a filter. The solution was stirred, and ordinary water (283.2 kg) was added at an internal temperature of 24°C to 25°C. Seed crystals of compound A-600 (63 g) were added at an internal temperature of 25°C, and the mixture was stirred at an internal temperature of 23°C to 25°C for 1 hour. Furthermore, ordinary water (628.8 kg) was added at an internal temperature of 22°C to 27°C, and the mixture was stirred at an internal temperature of 25°C to 27°C for 1 hour. The suspension was filtered, and the crystals were washed with an aqueous EtOH solution (33 v / v%, 177.8 kg).

[0203] EtOH (148.7 kg), tap water (377.4 kg), and AcOH (6.56 kg) were charged into a nitrogen-substituted reaction vessel 3 and stirred to prepare an EtOH / AcOH aqueous solution. The atmosphere in reactor 2 was replaced with nitrogen, and the washed crystals (total amount) and the prepared EtOH / AcOH aqueous solution (531.1 kg) were charged. The mixture was stirred at an internal temperature of 35°C to 41°C for 2 hours and at an internal temperature of 26°C to 30°C for 2 hours. The suspension was filtered, and the crystals were washed with an EtOH aqueous solution (33 v / v%, 175.8 kg). The crystals were dried under reduced pressure at an external temperature of 50°C or less for 12 hours to obtain 47.7 kg of compound A-600. The yield of compound A-600 relative to the amount of compound A-500 charged was 75.3%. Compound A-600 1 H 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) HRMS (ESI) of compound A-600: [M+Na + ] Calcd for 313.1351, Found 313.1329

[0204] (1-6) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6Preparation of [(4-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (A-800)

[0205] [ka]

[0206] Compound A-600 (47.4 kg), DIPEA (67.5 kg), and DMF (312.2 kg) were charged into a nitrogen-purged reaction vessel 1 and stirred. The solution was cooled, and a mixed solution of methanesulfonic anhydride (42.6 kg) and DMF (89.1 kg) was added dropwise to the reaction vessel 1 at an internal temperature of -2°C to 2°C. The vessel was rinsed with DMF (44.6 kg) and transferred to the reaction vessel 1. The reaction solution was stirred at 0°C for 10 minutes.

[0207] Then, thiomorpholine-1-dioxide (28.6 kg) was added 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. Then, 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).

[0208] The atmosphere in reactor 1 was replaced with nitrogen, and the washed crystals (total amount) and an aqueous MeCN solution (30 v / v%, 1330 kg) were charged and 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 at an external temperature of 50°C or below for 30 hours. The vacuum-dried crystals (total amount) and a solution of MEK (114.7 kg) and n-heptane (548.5 kg) were charged into a nitrogen-purged reactor 2 and stirred. The suspension was heated and stirred at 40-45°C for 1 hour. It was then cooled and stirred at -3-5°C for 15 hours. The suspension was filtered, and the crystals were washed with an 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 less for 15 hours, yielding 54.9 kg of crude compound A-800. The yield of crude compound A-800 relative to the charged compound A-600 was 82.6%. Compound A-800 1 H 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) HRMS (ESI) of compound A-800: [M+Na + ] Calcd for 430.1599, Found 430.1589

[0209] Next, crude compound A-800 (54.6 kg) and MEK (265.9 kg) were charged into reactor 1, which had been purged with nitrogen, and stirred. The suspension was heated, and dissolution was confirmed at an internal temperature of 71°C. The suspension was then transferred to reactor 2, which had been purged with nitrogen, via a cartridge filter. MEK (22.4 kg) and n-heptane (18.9 kg) were charged into reactor 1, and stirred. The solution was heated to an internal temperature of 73°C and transferred to reactor 2, which had been purged with nitrogen, via a cartridge filter. n-heptane (632.9 kg) was charged into reactor 2 at an internal temperature of 68°C to 71°C, and stirred at an internal temperature of 69°C to 70°C for 1 hour. 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 at an internal temperature of 0°C to 1°C for 1 hour.

[0210] MEK (22.1 kg) and n-heptane (93.4 kg) were placed in a separate nitrogen-purged vessel and stirred to prepare an 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 less for 12 hours to obtain 49.3 kg of compound A-800. The yield in this purification step, i.e., the yield of compound A-800 relative to the amount of crude compound A-800 charged, was 90.3%. The total yield in Example 1, i.e., the yield of the target compound, compound A-800, relative to compound A-100 charged as a starting material, was 36.8%.

[0211] 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)

[0212] [ka]

[0213] EtOH (50 mL), THF (50 mL), and a 5M aqueous NaOH 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 stirred for 13 hours at an internal temperature of 21° C. to 25° C. 6M HCl (4.5 mL), water (50 mL), and compound B-100 (5.2 mg) were added to the reaction mixture, and the mixture was stirred for 32 minutes at an internal temperature of 8° C. to 9° C. Water (50 mL) was added, and the mixture was stirred for 1 hour at an internal temperature of 8° C. to 16° C. to obtain a suspension containing crystals.

[0214] The suspension was filtered, and the crystals were washed with water (50 mL). Then, water (150 mL) was added and stirred at room temperature for 1 hour. The suspension was filtered, and the crystals were washed with 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 relative to the amount of compound A-400 added was 85.5%. Compound B-100 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)

[0215] (2-2) 4-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonyl]-1λ 6 Preparation of 1,1-thiomorpholine-1,1-dione (B-300)

[0216] [ka]

[0217] Compound B-100 (1.06 g) was added to Pd / C (gross amount 1.18 g), EtOH (17 mL), and TEA (4.24 mL), and the mixture was purged with nitrogen and hydrogen. The mixture was stirred at an internal temperature of 70°C and a hydrogen pressure of 7.0 bar for 5 hours, after which the mixture was purged with nitrogen and the Pd / C was removed by filtration.

[0218] The solution was concentrated, and then THF was added and concentrated. This process of adding n-hexane and concentrating was repeated 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 obtain 1 g of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200).

[0219] To compound B-200 (1 g), THF (10.6 mL), DIPEA (2.4 mL), and ethyl chlorocarbonate (668 μL) were added under ice cooling, and the mixture was stirred at room temperature for 35 minutes. Thiomorpholine-1,1-dioxide (A-20, 1.42 g) was added, and the mixture was stirred at room temperature for 1.5 hours.

[0220] The reaction mixture was partitioned between brine (20 w / w%) and t-butyl methyl ether, 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. The mixture was cooled at a rate of 15°C / hour and stirred at 0°C overnight.

[0221] 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 relative to the amount of compound B-100 was 54.2%. Compound B-300 1 H 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)

[0222] (2-3) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 Preparation of [(4-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (A-800)

[0223] [ka]

[0224] LiAlH (90 mg) and THF (5 mL) were mixed in a nitrogen-substituted vessel, and AlCl (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.

[0225] To the reaction mixture, an aqueous solution of ammonium chloride (15 w / w%) and t-butyl methyl ether were added, and the organic layer was washed with water and then concentrated. MEK (234 μL) and n-heptane (630 μL, 612 μL) were added, and the mixture was stirred at 0° C. for 3 hours.

[0226] 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 in Example 2, i.e., the yield of the target compound, compound A-800, relative to compound A-100 charged as the starting material, was 25.4%.

[0227] Example 3 (3-1) Preparation of tert-butyl {[6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}carbamate (C-100)

[0228] [ka]

[0229] To compound A-300 (26.1 g) obtained in the same manner as in Example 1, THF (390 mL), EtOH (190 mL), and Boc2O (56.7 g) were added, and the mixture was washed down with EtOH (100 mL). Raney nickel (78 mL) was added, and the mixture was washed in with EtOH (100 mL), followed by stirring under a hydrogen stream at an internal temperature of 25°C to 27°C for 3.5 hours.

[0230] The suspension was filtered through Celite and washed with EtOH (390 mL) and EtOAc (390 mL). The filtrate was concentrated. n-Hexane (156 mL) was added and concentrated twice, and n-hexane (156 mL) was added and concentrated. n-Hexane (156 mL) was added and stirred at an internal temperature of 0°C to 5°C for 1 hour.

[0231] 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 relative to the amount of compound A-300 used was 82.3%.

[0232] (3-2) Preparation of 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine hydrochloride (C-300)

[0233] [ka]

[0234] Compound C-100 (28.8 g) was added to a hydrogen chloride methanol solution (5 to 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 mixture was concentrated, and IPA (116 mL) was added and concentrated twice. IPA (116 mL) was added and concentrated. IPA (116 mL) was added and stirred under ice-cooling for 15 minutes.

[0235] 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 then at room temperature for 17 hours to obtain 23.8 g of 1-[6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine hydrochloride (C-200).

[0236] Compound C-200 (5.15 g) was added to EtOH (77 mL), purified water (22 mL), and Pd(OH)2 / C (2 g, 51.6 w / w% water-wet product), and the atmosphere was purged with nitrogen and hydrogen. The mixture was stirred for 18 hours at an external temperature of 70 °C and a hydrogen pressure of 0.7 MPa. The atmosphere in the reactor was purged with nitrogen, and the 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.

[0237] 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 relative to the amount of compound C-100 used was 68.0%.

[0238] (3-3) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 Preparation of [(4-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (A-800)

[0239] [ka]

[0240] Divinyl sulfone (0.15 mL) and MeOH (3.5 mL) were charged into vessel 1 and stirred. Compound C-300 (0.5 g), DIPEA (0.32 mL), and MeOH (3 mL) were charged into a separate vessel and added dropwise to vessel 1 over 1 hour at an internal temperature of 0 to 5°C. After the addition was complete, the mixture was washed with MeOH (0.5 mL). The mixture was stirred for 1.5 hours at an internal temperature of 5°C or below, and then ordinary water (7 mL) was slowly added dropwise at the same temperature and stirred for 1.5 hours. The suspension was filtered, and the crystals were washed with an aqueous MeOH solution (50 v / v%, 2 mL). The crystals were then dried under reduced pressure.

[0241] In a separate vessel, the vacuum-dried crystals (total amount), MEK (1.5 mL), and n-heptane (8.5 mL) were charged and stirred at an internal temperature of 45°C for 1 hour. The internal temperature was cooled to 5°C and stirred at the same temperature for an additional 1 hour. The suspension was filtered, and the crystals were washed with an 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 relative to the amount of compound C-300 charged was 85.4%. The total yield in Example 3, i.e., the yield of the target compound, compound A-800, relative to the amount of compound A-100 charged as the starting material, was 38.2%.

[0242] Example 4 (4-1) Preparation of 4-chloro-6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine (D-100)

[0243] [ka]

[0244] Compound A-100 (10.0 g) and THF (100 mL) were placed in a nitrogen-purged vessel, 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 at an internal temperature of −65° C. or lower for 30 minutes.

[0245] Compound A-10 (6.83 g) and THF (37.5 mL) were charged into a separate vessel, stirred, and slowly added dropwise to the reaction solution at an internal temperature of -65°C or lower. The vessel 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.

[0246] The reaction mixture was quenched by the addition of 1 M HCl (54.2 mL). The reaction mixture was transferred to a separatory 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). Activated carbon (10 g) and THF (20 mL) were added to the resulting organic layer, and the mixture was stirred overnight at an internal temperature of 24°C.

[0247] The suspension was filtered, and the filtrate was concentrated under reduced pressure at an external temperature of 50°C or below until the residual 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 below until the residual volume was 50 mL. This process was repeated four times, and the concentrated solution was stirred at 50°C for 1 hour. Regular water (50 mL) was added dropwise at an internal temperature of 50°C over 1 hour, and then the mixture was stirred at the same temperature for 1 hour. The solution was cooled to 20°C over 1 hour and stirred at the same temperature for 2 hours.

[0248] 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 less for 15 hours to obtain 13 g of compound D-100. The yield of compound D-100 relative to the amount of compound A-100 used was 63.9%. Compound D-100 1 H 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)

[0249] (4-2) Preparation of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-200)

[0250] [ka]

[0251] Compound D-100 (10.0 g), p-TolSO2Na (1.83 g), MeCN (100 mL), purified water (1.2 mL), and KCN (4.45 g) were added and stirred, then heated and stirred at an internal temperature of 81°C 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).

[0252] In a separate vessel, the washed crystals (total amount) and an aqueous MeCN solution (33 v / v%, approximately 60 mL) were charged and stirred at an internal temperature of 45°C for 2 hours, then cooled and stirred at an internal temperature of 25°C for 30 minutes. 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 relative to the amount of compound D-100 charged was 81.0%. Compound D-200 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)

[0253] (4-3) Preparation of 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine hydrochloride (C-300)

[0254] [ka]

[0255] Compound D-200 (1.0 g) and EtOH (15 mL) were placed in a vessel and purged with nitrogen. Pd(OH)2 / C (palladium 20 w / w%, 500 mg) was suspended in normal water (1 mL) and added. The hydrogen pressure was then increased to 0.7 MPa, and the reaction mixture was heated and stirred at an internal temperature of 70°C for 26 hours. After cooling, the reaction mixture was filtered and washed with EtOH (2 mL). The filtrate was concentrated under reduced pressure to 5 mL, and then EtOAc (10 mL) was added and the mixture was again concentrated under reduced pressure to 5 mL. Another 10 mL of EtOAc was added and the mixture was again concentrated under reduced pressure to 5 mL.

[0256] EtOAc (5 mL) was added to the concentrated solution, which was stirred and cooled to 3°C. A 4 M solution of hydrogen chloride in ethyl acetate (1.3 mL) was added dropwise 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.

[0257] The washed crystals (total amount) and THF (approximately 20 mL) were placed in a separate container and 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 crude compound C-300. The yield of compound C-300 relative to the amount of compound D-200 added was 56.0%.

[0258] Next, the crude compound C-300 crystals (total amount) and THF (approximately 20 mL) were charged into a separate vessel and 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 relative to the charged compound D-200 was 54.1%. Compound C-300 1 H 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)

[0259] (4-4) 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 Preparation of [(4-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (A-800)

[0260] [ka]

[0261] Divinyl sulfone (0.15 mL) and MeOH (3.5 mL) were charged into vessel 1 and stirred. Compound C-300 (0.5 g), DIPEA (0.32 mL), and MeOH (3 mL) were charged into a separate vessel and added dropwise to vessel 1 over 1 hour at an internal temperature of 0°C. After the addition was complete, the vessel was washed with MeOH (0.5 mL). The mixture was stirred for 1.5 hours at an internal temperature of 5°C or below, and then ordinary water (7 mL) was slowly added dropwise at the same temperature and stirred for 1.5 hours. The suspension was filtered, and the crystals were washed with an aqueous MeOH solution (50 v / v%, 2 mL). The crystals were then dried under reduced pressure.

[0262] In a separate vessel, the vacuum-dried crystals (total amount), MEK (1.5 mL), and n-heptane (8.5 mL) were charged and stirred at an internal temperature of 45°C for 1 hour. The internal temperature was cooled to 5°C and stirred at the same temperature for an additional 1 hour. The suspension was filtered, and the crystals were washed with an 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 relative to the amount of compound C-300 charged was 85.4%. The total yield in Example 4, i.e., the yield of the target compound, compound A-800, relative to the amount of compound A-100 charged as the starting material, was 23.9%.

[0263] Consideration For the methods described in the Reference Example (the method described in WO2015 / 056771A1) and Examples 1 to 4, the yield (total yield) of the target compound, the compound of formula I, is shown below.

[0264] [Table 1] [Industrial Applicability]

[0265] According to the present invention, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6

[0010] The present invention provides an efficient and green chemistry-oriented synthetic method for [(2-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine and its salts.

Claims

1. 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1λ 6 1. A method for synthesizing [-thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or a salt thereof, comprising: Below formula: 【Chemical 1】 [wherein Hal is a halogen], 【Chemistry 2】 to form a compound represented by the following formula: 【Chemistry 3】 The above method, comprising a step of obtaining a compound represented by the formula:

2. Below formula: 【Chemistry 4】 to cyanate a compound represented by the following formula: 【Chemistry 5】 The method of claim 1, further comprising obtaining a compound represented by the formula:

3. Below formula: 【Chemistry 6】 From a compound represented by the following formula: 【Chemistry 7】 The method of claim 2, further comprising obtaining a compound represented by the formula:

4. (1) Below formula: 【Chemistry 8】 [wherein R is an alkyl group], the compound represented by the following formula: 【Chemistry 9】 After obtaining a compound represented by the formula: 【Chemistry 10】 obtaining a compound represented by the formula: (2) Below formula: 【Chemistry 11】 The compound represented by the following formula: 【Chemistry 12】 to form a compound represented by the following formula: 【Chemistry 13】 obtaining a compound represented by the formula: The method of claim 3 further comprising:

5. (1) Below formula: 【Chemistry 14】 [wherein R is an alkyl group], the compound represented by the following formula: 【Chemistry 15】 After obtaining a compound represented by the formula: 【Chemistry 16】 obtaining a compound represented by the formula: (2) Below formula: 【Chemistry 17】 The compound represented by the following formula: 【Chemistry 18】 to form a compound represented by the following formula: 【Chemistry 19】 After obtaining a compound represented by the formula: 【Chemistry 20】 obtaining a compound represented by the formula: The method of claim 3 further comprising:

6. (1) Below formula: 【Chemical 21】 From a compound represented by the following formula: 【Chemical 22】 obtaining a compound represented by the formula: (2) Below formula: 【Chemical 23】 with divinyl sulfone to obtain a compound represented by the following formula: 【Chemistry 24】 obtaining a compound represented by the formula: The method of claim 2 further comprising:

7. Below formula: 【Chemistry 25】 From a compound represented by the following formula: 【Chemical 26】 After obtaining a compound represented by the formula: 【Chemical 27】 obtaining a compound represented by the formula: The method of claim 6, comprising:

8. Below formula: 【Chemical Formula 28】 to obtain a compound represented by the following formula: 【Chemical 29】 obtaining a compound represented by the formula: The method of claim 6, comprising:

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