JPWO2005019225A1

JPWO2005019225A1 - Method for producing compound having NK1 receptor antagonistic activity and production intermediate thereof

Info

Publication number: JPWO2005019225A1
Application number: JP2005513299A
Authority: JP
Inventors: 一郎荒谷; 信太郎金澤
Original assignee: Kyorin Pharmaceutical Co Ltd
Current assignee: Kyorin Pharmaceutical Co Ltd
Priority date: 2003-08-21
Filing date: 2004-08-20
Publication date: 2007-11-01
Also published as: WO2005019225A1

Abstract

本発明は、タキキニン受容体に対して優れた拮抗作用、特にＮＫ１受容体拮抗作用を有する化合物を工業的に生産するための２−（４−アセチルピペラジン−１−イル）−６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（化合物Ｉ）の製造方法であって、４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸（７）を中間体として、これにクロル化剤を作用させた後、３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノールと反応、続いて塩基を作用させて環化させ、次いでこれを酸化した後、Ｎ−アセチルピペラジンと反応することを特徴とする化合物Ｉの製造方法に関する。The present invention relates to 2- (4-acetylpiperazin-1-yl) -6- [3, for industrially producing a compound having an excellent antagonistic action on a tachykinin receptor, particularly an NK1 receptor antagonistic action. 5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5] oxazosin-5 A method for producing ON (compound I) comprising 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid (7) as an intermediate, After the action of a chlorinating agent, reaction with 3- [3,5-bis (trifluoromethyl) benzylamino] -1-propanol, followed by cyclization with the action of a base, followed by oxidation, N-acetylpi The method for the preparation of compounds I, characterized by reacting with Rajin.

Description

本発明は、タキキニン受容体に対して優れた拮抗作用、特にＮＫ１受容体拮抗作用を有する２−（４−アセチルピペラジン−１−イル）−６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（以下、「化合物Ｉ」と略す）の製造方法及びその新規な製造中間体に関する。 The present invention relates to 2- (4-acetylpiperazin-1-yl) -6- [3,5-bis (trifluoromethyl) phenyl having excellent antagonism against tachykinin receptors, particularly NK1 receptor antagonism. Methyl] -4- (2-methylphenyl) -6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5] oxazosin-5-one (hereinafter referred to as “Compound I”) Abbreviated) and a novel production intermediate thereof.

上記化合物Ｉはタキキニン受容体に対して優れた拮抗作用、特にＮＫ１受容体拮抗作用を有する縮合二環式ピリミジン誘導体であり、タキキニン受容体が関与する種々の病態（頻尿、尿失禁、嘔吐、炎症、アレルギー、気道疾患、痛み、中枢神経系疾患等）の治療等の医薬用途に有用であることが知られている（特許文献１の実施例１６の化合物）。また化合物Ｉの製造方法についても、特許文献１の国際公開パンフレット中に具体的に記載されている。しかしながら特許文献１に示された製造方法は工業的規模で実施することが難しく、製造の操作性、精製効率及び収率等について更なる改善工夫を行い、実生産に適合する製造法を見出す必要があった。
ＷＯ０３／０６２２４５パンフレット The above compound I is a condensed bicyclic pyrimidine derivative having an excellent antagonistic action on the tachykinin receptor, particularly an NK1 receptor antagonistic action, and various pathological conditions involving tachykinin receptor (frequent urine, urinary incontinence, vomiting, It is known to be useful for pharmaceutical use such as treatment of inflammation, allergy, respiratory tract disease, pain, central nervous system disease and the like (compound of Example 16 of Patent Document 1). The production method of Compound I is also specifically described in the international publication pamphlet of Patent Document 1. However, the production method disclosed in Patent Document 1 is difficult to implement on an industrial scale, and it is necessary to further improve the operability of production, purification efficiency, yield, etc., and find a production method suitable for actual production. was there.
WO03 / 062245 brochure

医薬品として高品質の化合物Ｉを工業的に生産していくためには、実生産レベルに適う製造工程の操作性や収率の改善、純度の向上或いは有害な溶剤等の削減と言った課題を解決する必要がある。 In order to industrially produce high-quality compound I as a pharmaceutical product, it is necessary to improve the operability and yield of the manufacturing process suitable for the actual production level, improve the purity, or reduce harmful solvents. It needs to be solved.

本発明者らは、上記課題を解決するため、鋭意研究を重ねた結果、新規化合物４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸を製造中間体に用いることにより化合物Ｉが簡便な操作で、収率良く製造できることを見出し、本発明を完成させたものである。 In order to solve the above-mentioned problems, the present inventors have made extensive studies and as a result, a novel compound 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid. It was found that Compound I can be produced in a high yield by a simple operation by using as a production intermediate, and the present invention has been completed.

すなわち、本発明は、
１）４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸にクロル化剤を作用させた後、３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノールと反応、続いて塩基を用いて閉環させ、次いでこれを酸化、Ｎ−アセチルピペラジンと反応することを特徴とする２−（４−アセチルピペラジン−１−イル）−６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン又はその水和物の製造方法、
２）４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸又はその水和物からなる２−（４−アセチルピペラジン−１−イル）−６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン又はその水和物の製造中間体、
３）２−（２−メチルベンジリデン）マロン酸ジエチルエステルと過剰量の２−メチル−２−チオプソイド尿素硫酸塩を溶媒中、塩基の存在下に反応させ、４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，４，５，６−テトラヒドロ−５−ピリミジンカルボン酸エチルエステルとし、次いでこの化合物を脱水素化し４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸エチルエステルとした後、この化合物を加水分解することを特徴とする４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸またはその水和物の製造方法、に関するものである。That is, the present invention
1) After reacting 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid with a chlorinating agent, 3- [3,5-bis (tri 2- (4-acetylpiperazin-1-yl, characterized by reacting with fluoromethyl) benzylamino] -1-propanol, followed by ring closure with a base, then oxidizing and reacting with N-acetylpiperazine ) -6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1 , 5] process for producing oxazosin-5-one or a hydrate thereof,
2) 2- (4-acetylpiperazin-1-yl)-consisting of 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid or a hydrate thereof 6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5 Intermediate for producing oxazosin-5-one or its hydrate,
3) 2- (2-methylbenzylidene) malonic acid diethyl ester and an excess amount of 2-methyl-2-thiopseudourea sulfate were reacted in a solvent in the presence of a base to give 4- (2-methylphenyl) -2 -Methylthio-6-oxo-1,4,5,6-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester, then dehydrogenating this compound to 4- (2-methylphenyl) -2-methylthio-6-oxo- 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro, characterized in that 1,6-dihydro-5-pyrimidinecarboxylic acid ethyl ester is obtained and then this compound is hydrolyzed. The present invention relates to a process for producing 5-pyrimidinecarboxylic acid or a hydrate thereof.

本発明の原料化合物４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸又はその水和物は具体的開示の無い新規化合物であり、かつその有用性についても知られていなかった。この４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸を製造中間体として用いることにより、不純物が少なく、収率が向上し、その後の精製も簡便になることを見出し、化合物Ｉの工業的製造方法を提供するものである。 The starting compound 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid of the present invention or a hydrate thereof is a novel compound without specific disclosure, and It was also unknown about its usefulness. By using this 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid as a production intermediate, there are few impurities and the yield is improved. The inventors have found that the purification can be simplified and provide an industrial production method of Compound I.

本発明は４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸にオキシ塩化リン、塩化チオニル等のクロル化剤を作用させ４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボン酸クロリドとした後、３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノールと反応、続いて塩基を用いて閉環させ、６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルチオ−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オンとし、次いでこれを酸化、６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルスルホニル−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オンとした後、Ｎ−アセチルピペラジンと反応することを特徴とする化合物Ｉの工業的スケールの製造方法である（下記スキームを参照）。 In the present invention, 4-chloro- (4-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid is reacted with a chlorinating agent such as phosphorus oxychloride or thionyl chloride. 6- (2-Methylphenyl) -2-methylthio-5-pyrimidinecarboxylic acid chloride was reacted with 3- [3,5-bis (trifluoromethyl) benzylamino] -1-propanol, followed by base reaction. And 6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido [4 , 5-b] [1,5] oxazosin-5-one, which is then oxidized to 6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) 2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5] oxazosin-5-one, and then reacted with N-acetylpiperazine And an industrial scale production method of Compound I (see the following scheme).

本発明の新規な原料化合物である４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸（７）又はその水和物は次のようにして得られる。 The novel starting compound of the present invention, 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid (7) or a hydrate thereof, is as follows. Obtained.

すなわち、ｏ−トルアルデヒド（３）とマロン酸ジエチルエステルとの縮合で得られる２−（２−メチルベンジリデン）マロン酸ジエチルエステル（４）と過剰量の２−メチル−２−チオプソイド尿素硫酸塩をエタノール、２−プロパノール、ジメチルホルムアミド、Ｎ−メチルピロリドン、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシドなどの有機溶媒及びその含水溶媒中、炭酸水素カリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸ナトリウム等の塩基の存在下、４０℃から８０℃に加温し１から８時間撹拌後、反応混合物を冷却水に２２℃以下で滴下撹拌、析出結晶を濾過乾燥、次いで２−プロパノール−水にて再結晶することにより４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，４，５，６−テトラヒドロ−５−ピリミジンカルボン酸エチルエステル（５）を得る。これを酢酸エチル、ジメチルスルホキシドなどの有機溶媒中、２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン（ＤＤＱ）等の酸化剤存在下、室温から５０℃にて反応後、処理し得られる粗結晶をエタノール−水により再結晶することにより４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸エチルエステル（６）を得る。更にこれを水酸化ナトリウム水溶液などのアルカリ水溶液で加水分解した後、２−プロパノールで再結晶又は熱時懸濁洗浄することにより４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸（７）またはその水和物を得ることができる。 That is, 2- (2-methylbenzylidene) malonic acid diethyl ester (4) obtained by condensation of o-tolualdehyde (3) and malonic acid diethyl ester and an excess amount of 2-methyl-2-thiopseidourea sulfate In organic solvents such as ethanol, 2-propanol, dimethylformamide, N-methylpyrrolidone, N, N′-dimethylimidazolidinone, dimethyl sulfoxide, and water-containing solvents thereof, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc. In the presence of the base, the mixture was heated from 40 ° C. to 80 ° C. and stirred for 1 to 8 hours. By crystallization, 4- (2-methylphenyl) -2-methylthio-6-oxo-1,4,5,6-te Rahidoro 5-pyrimidine carboxylic acid ethyl ester is obtained (5). This was treated in an organic solvent such as ethyl acetate and dimethyl sulfoxide in the presence of an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room temperature to 50 ° C., and then treated. The resulting crude crystals are recrystallized from ethanol-water to obtain 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid ethyl ester (6). . Further, this was hydrolyzed with an aqueous alkali solution such as an aqueous sodium hydroxide solution, and then recrystallized with 2-propanol or suspended and washed with heat to give 4- (2-methylphenyl) -2-methylthio-6-oxo-1 , 6-dihydro-5-pyrimidinecarboxylic acid (7) or a hydrate thereof can be obtained.

次いで、４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸（７）にクロル化剤、好ましくはオキシ塩化リンもしくは酢酸エチル等の有機溶媒中Ｎ，Ｎ−ジメチルホルムアミド存在下の塩化チオニルを加え加熱撹拌（７０℃〜９０℃、１〜３時間）、有機溶媒未使用の場合冷却後氷水中に投入後濾過、使用の場合アルカリ水溶液（例えば炭酸水素ナトリウム水溶液）で洗浄し、それぞれ４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボン酸クロリドを固体又は有機溶媒溶液として得る。これに３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノール（２）を酢酸エチル等の有機溶媒中、トリエチルアミン等の塩基存在下、０〜１０℃で反応させた後、反応液を水、酸及びアルカリ水溶液で洗浄、無水硫酸ナトリウムで乾燥、溶媒留去することによりＮ−［３，５−ビス（トリフルオロメチル）フェニルメチル］−Ｎ−（３−ヒドロキシプロピル）−４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボキサミドを得る。この油状物又は結晶をジメチルスルホキシド、ジメチルホルムアミド、トルエン等の有機溶媒中、１，８−ジアザビシクロ［５，４，０］ウンデカ−７−エン（ＤＢＵ）、ｔ−ブトキシカリウム等の塩基の存在下、反応温度５０〜８０℃、反応時間１〜３時間で反応を行い、６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルチオ−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（８）を得る。次いでこれをモノペルオキシフタル酸マグネシウム・６水和物（ＭＭＰＰ）、メタクロロ過安息香酸（ｍ−ＣＰＢＡ）、過酸化水素（タングステン等の触媒存在下）などの酸化剤を用いて酸化を行い、６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルスルホニル−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（９）とした後、ジメチルホルムアミド、ジメチルスルホキシド等の有機溶媒中、トリメチルアミン、トリエチルアミン、トリプロピルアミン等の塩基の存在下、４０〜６０℃、３〜８時間、Ｎ−アセチルピペラジンと反応することにより、簡便な操作で収率良く、かつ高純度の化合物Ｉの原薬を得ることができる。本発明により化合物Ｉの優れた工業的生産方法が提供されたものである。 Subsequently, 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid (7) is converted into a chlorinating agent, preferably an organic solvent such as phosphorus oxychloride or ethyl acetate. Add thionyl chloride in the presence of medium N, N-dimethylformamide and heat and stir (70 ° C. to 90 ° C., 1 to 3 hours). For example, 4-chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxylic acid chloride is obtained as a solid or an organic solvent solution. This was reacted with 3- [3,5-bis (trifluoromethyl) benzylamino] -1-propanol (2) in an organic solvent such as ethyl acetate at 0 to 10 ° C. in the presence of a base such as triethylamine. The reaction solution is washed with water, acid and aqueous alkali solution, dried over anhydrous sodium sulfate, and evaporated to remove N- [3,5-bis (trifluoromethyl) phenylmethyl] -N- (3-hydroxypropyl). -4-Chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxamide is obtained. This oil or crystal is obtained in the presence of a base such as 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) or t-butoxy potassium in an organic solvent such as dimethyl sulfoxide, dimethylformamide or toluene. The reaction is carried out at a reaction temperature of 50 to 80 ° C. for a reaction time of 1 to 3 hours to give 6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylthio-6. , 7,8,9-Tetrahydro-5H-pyrimido [4,5-b] [1,5] oxazin-5-one (8). Next, this is oxidized using an oxidizing agent such as magnesium monoperoxyphthalate hexahydrate (MMPP), metachloroperbenzoic acid (m-CPBA), hydrogen peroxide (in the presence of a catalyst such as tungsten), and the like. -[3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] After [1,5] oxazosin-5-one (9), in an organic solvent such as dimethylformamide and dimethylsulfoxide, in the presence of a base such as trimethylamine, triethylamine and tripropylamine, 40 to 60 ° C., 3 to 8 By reacting with N-acetylpiperazine for a long time, the drug substance of Compound I with high yield and high purity can be obtained by a simple operation. The present invention provides an excellent industrial production method for Compound I.

次に本発明を具体例によって説明するが、これらの例によって本発明が限定されるものではない。 Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

＜参考例１＞３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノール（２）
２−プロパノール４．９４Ｌに３，５−ビス（トリフルオロメチル）ベンズアルデヒド（１）１．６５ｋｇ（６．８０ｍｏｌ）と３−アミノ−１−プロパノール０．７７ｋｇ（１０．２ｍｏｌ）を投入し、内温３２〜４０℃で３時間撹拌した。反応液に水素化ホウ素ナトリウム０．２８ｋｇ（７．４８ｍｏｌ）を加え、内温５０〜５５℃で３時間撹拌した。反応液に熱時水１１．５Ｌを加えた後、氷水冷却して内温１５℃とし、内温３０℃以下で４ｍｏｌ／Ｌ塩酸４．７５Ｌを加えｐＨ＝１とした後、０．５時間撹拌し、室温で一夜放置した。混合物に内温２５〜２８℃で４ｍｏｌ／Ｌ水酸化ナトリウム溶液４．７４Ｌを加えｐＨ＝１２とした後、氷水冷却し内温１６℃で結晶種を加え結晶晶析後、水４．９４Ｌを加え、内温４〜１０℃で１時間撹拌した。析出した結晶をろ取し、５％２−プロパノール水１３．６Ｌで洗浄した後、２時間通気乾燥した。得られた湿潤粗結晶（２．５６ｋｇ）を水１３．６Ｌに懸濁し、水冷下、内温２４〜２７℃で塩酸０．５６Ｌを加えｐＨ＝１．５とした後、酢酸エチル（５．４４Ｌ、２．７２Ｌ×２）で３回、ｎ−ヘキサン（２．７２Ｌ）で一回洗浄した。水層を減圧濃縮して残存する有機溶媒を除去した後、内温２５〜２８℃で４ｍｏｌ／Ｌ水酸化ナトリウム溶液１．６０Ｌを加え、１０分間撹拌して結晶晶析させた後、４ｍｏｌ／Ｌ水酸化ナトリウム溶液０．４０Ｌを加えｐＨ＝１２とし、氷水冷却して内温１２〜１５℃で１時間撹拌した。析出た結晶をろ取し、水１１．５Ｌで洗浄した後、２時間通気乾燥した。続いて４０℃で１３時間、４８℃で１０時間送風乾燥し、白色粉末の（２）を１．７３ｋｇ（収率８５％）得た。
ＥＩ−ＭＳｍ／ｚ：２２７（ｂａｓｅｐｅａｋ），３０１（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．７７（２Ｈ，ｑｕｉｎｔ，Ｊ＝５．４Ｈｚ），２．８９（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），３．８２（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），３．９３（２Ｈ，ｓ），７．２８（３Ｈ，ｓ）．Reference Example 1 3- [3,5-Bis (trifluoromethyl) benzylamino] -1-propanol (2)
To 1.94 L of 2-propanol, 1.65 kg (6.80 mol) of 3,5-bis (trifluoromethyl) benzaldehyde (1) and 0.77 kg (10.2 mol) of 3-amino-1-propanol were added. The mixture was stirred at a temperature of 32 to 40 ° C. for 3 hours. To the reaction solution, 0.28 kg (7.48 mol) of sodium borohydride was added and stirred at an internal temperature of 50 to 55 ° C. for 3 hours. After adding 11.5 L of hot water to the reaction solution, cooling with ice water to an internal temperature of 15 ° C., adding 4.75 L of 4 mol / L hydrochloric acid at an internal temperature of 30 ° C. or lower to pH = 1, 0.5 hour Stir and leave at room temperature overnight. To the mixture, 4.74 L of 4 mol / L sodium hydroxide solution was added at an internal temperature of 25 to 28 ° C. to adjust the pH = 12, then cooled with ice water, crystal seeds were added at an internal temperature of 16 ° C., and after crystal crystallization, 4.94 L of water was added. In addition, the mixture was stirred at an internal temperature of 4 to 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 13.6 L of 5% 2-propanol water, and then air-dried for 2 hours. The obtained wet crude crystals (2.56 kg) were suspended in 13.6 L of water, and under water cooling, 0.56 L of hydrochloric acid was added at an internal temperature of 24-27 ° C. to adjust to pH = 1.5, followed by ethyl acetate (5. It was washed 3 times with 44 L, 2.72 L × 2) and once with n-hexane (2.72 L). The aqueous layer was concentrated under reduced pressure to remove the remaining organic solvent, then 1.60 L of 4 mol / L sodium hydroxide solution was added at an internal temperature of 25 to 28 ° C., and the mixture was stirred for 10 minutes for crystal crystallization. 0.40 L of L sodium hydroxide solution was added to adjust the pH to 12, followed by cooling with ice water and stirring at an internal temperature of 12 to 15 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 11.5 L of water, and then air-dried for 2 hours. Subsequently, it was blown and dried at 40 ° C. for 13 hours and at 48 ° C. for 10 hours to obtain 1.73 kg (yield 85%) of (2) as a white powder.
EI-MS m / z: 227 (base peak), 301 (M) ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.77 (2H, quint, J = 5.4 Hz), 2.89 (2H, t, J = 5.9 Hz), 3.82 (2H, t, J = 5.4 Hz), 3.93 (2H, s), 7.28 (3H, s).

＜参考例２＞２−（２−メチルベンジリデン）マロン酸ジエチルエステル（４）
トルエン４．５０Ｌにｏ−トルアルデヒド（３）０．９０ｋｇ（７．４９ｍｏｌ）、マロン酸ジエチルエステル１．２０ｋｇ（７．４９ｍｏｌ）とピペリジン０．１９ｋｇ（２．２５ｍｏｌ）を加え溶解し、ディーンスターク管を付け、共沸脱水しながら６時間加熱還流した（０．５時間と１時間後にピペリジン０．０６ｋｇ（０．７５ｍｏｌ）を追加した）。反応液を減圧濃縮後、得られた残留物を減圧蒸留し、淡黄色油状の（４）を１．６７ｋｇ（１４７〜１６０℃／２６７〜３３３Ｐａ、収率８５％）得た。
ＥＩ−ＭＳｍ／ｚ：２１７（ｂａｓｅｐｅａｋ），２６２（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．１７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．３４（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．３８（３Ｈ，ｓ），４．２２（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），４．３２（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），７．１５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．２１（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２５−７．２９（１Ｈ，ｍ），７．３３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９７（１Ｈ，ｓ）．
実施例１Reference Example 2 2- (2-Methylbenzylidene) malonic acid diethyl ester (4)
Dean Stark was dissolved by adding 0.90 kg (7.49 mol) of o-tolualdehyde (3), 1.20 kg (7.49 mol) of malonic acid diethyl ester and 0.19 kg (2.25 mol) of piperidine to 4.50 L of toluene. A tube was attached and the mixture was heated to reflux for 6 hours with azeotropic dehydration (added 0.06 kg (0.75 mol) of piperidine after 0.5 and 1 hour). The reaction mixture was concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain 1.67 kg (147 to 160 ° C./267 to 333 Pa, yield 85%) of pale yellow oil (4).
EI-MS m / z: 217 (base peak), 262 (M) ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.17 (3H, t, J = 7.3 Hz), 1.34 (3H, t, J = 7.3 Hz), 2.38 (3H, s) , 4.22 (2H, q, J = 7.3 Hz), 4.32 (2H, q, J = 7.3 Hz), 7.15 (1H, t, J = 7.8 Hz), 7.21 ( 1H, d, J = 6.8 Hz), 7.25-7.29 (1H, m), 7.33 (1H, d, J = 7.8 Hz), 7.97 (1H, s).
Example 1

４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，４，５，６−テトラヒドロ−５−ピリミジンカルボン酸エチルエステル（５）
ジメチルスルホキシド１２．７Ｌに化合物（４）１．６７ｋｇ（６．３５ｍｏｌ）、２−メチル−２−チオプソイド尿素硫酸塩３．５４ｋｇ（１２．７ｍｏｌ）と炭酸水素カリウム２．５４ｋｇ（２５．４ｍｏｌ）を投入し、内温５０〜５５℃で４時間撹拌した。反応液を２０℃まで水冷した後、５℃に冷却した水６３．５Ｌに内温２２℃以下で徐々に滴下した後、内温５〜１１℃で１時間撹拌した。析出した結晶をろ取し、水４．９９Ｌで洗浄した後、０．５時間通気乾燥した。２−プロパノール９．３２Ｌに得られた湿潤粗結晶（４．１０ｋｇ）を加えた後、加熱溶解し（７３℃で完溶）、水２．３４Ｌを加えた後、内温３０℃まで水冷し、続いて内温１０℃まで氷水冷却した後、内温８〜１０℃で０．５時間撹拌した。析出した結晶をろ取し、氷水冷却した８０％２−プロパノール水３．３３Ｌで洗浄した後、０．５時間通気乾燥した。湿潤晶（１．９９ｋｇ）を６０℃で７時間送風乾燥し、白色粉末の（５）を１．６２ｋｇ（収率８３％）得た。
ＥＩ−ＭＳｍ／ｚ：２３３（ｂａｓｅｐｅａｋ），３０６（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．１５（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．４２（３Ｈ，ｓ），２．４４（３Ｈ，ｓ），３．６６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），４．１５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），５．４４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．０７−７．１０（１Ｈ，ｍ），７．１６−７．２０（３Ｈ，ｍ），８．００（１Ｈ，ｓ）．
実施例２4- (2-Methylphenyl) -2-methylthio-6-oxo-1,4,5,6-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester (5)
1.67 kg (6.35 mol) of compound (4), 3.54 kg (12.7 mol) of 2-methyl-2-thiopsoid urea sulfate and 2.54 kg (25.4 mol) of potassium hydrogen carbonate were added to 12.7 L of dimethyl sulfoxide. The mixture was charged and stirred at an internal temperature of 50 to 55 ° C. for 4 hours. The reaction solution was water-cooled to 20 ° C., and then gradually dropped into 63.5 L of water cooled to 5 ° C. at an internal temperature of 22 ° C. or lower, and then stirred at an internal temperature of 5 to 11 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 4.99 L of water, and then air-dried for 0.5 hours. After adding wet crude crystals (4.10 kg) obtained in 9.32 L of 2-propanol, the mixture was dissolved by heating (completely dissolved at 73 ° C.), and 2.34 L of water was added, followed by water cooling to an internal temperature of 30 ° C. Subsequently, after cooling with ice water to an internal temperature of 10 ° C., the mixture was stirred at an internal temperature of 8 to 10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 3.33 L of 80% 2-propanol water cooled with ice water, and then air-dried for 0.5 hours. The wet crystals (1.99 kg) were blown and dried at 60 ° C. for 7 hours to obtain 1.62 kg (yield 83%) of white powder (5).
EI-MS m / z: 233 (base peak), 306 (M) ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.15 (3H, t, J = 7.3 Hz), 2.42 (3H, s), 2.44 (3H, s), 3.66 (1H , D, J = 8.3 Hz), 4.15 (2H, q, J = 7.3 Hz), 5.44 (1H, d, J = 8.3 Hz), 7.07-7.10 (1H, m), 7.16-7.20 (3H, m), 8.00 (1H, s).
Example 2

４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸エチルエステル（６）
酢酸エチル８．０８Ｌに化合物（５）１．６２ｋｇ（５．２７ｍｏｌ）を投入し、この懸濁溶液に２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン１．３２ｋｇ（ＤＤＱ、５．８０ｍｏｌ）を加え、室温で２．５時間撹拌した（４３℃まで発熱した）。反応液を内温２５℃まで水冷し、析出固体をろ別した後、固体を酢酸エチル１．６２Ｌで洗浄した。ろ液と洗液を合わせた後、炭酸水素ナトリウム水溶液８．０８Ｌ（炭酸水素ナトリウム０．２３ｋｇを水に溶解し、８．０８Ｌとした）で洗浄した。水層を酢酸エチル２．０２Ｌで抽出し、先の有機層と合わせ、水２．５３Ｌで２回洗浄した後、減圧濃縮した。得られた粗結晶にエタノール４．２２Ｌを加え加熱溶解し（６３℃で完溶）、水４．２２Ｌを加えた後、４０℃まで放冷し、続いて３０℃まで水冷した後、氷水冷却し、内温６〜１０℃で１時間撹拌した。析出した結晶をろ取し、氷水冷却した３０％エタノール水４．８５Ｌで洗浄した後、０．５時間通気乾燥した。
湿潤晶（１．８５ｋｇ）を６０℃で１７時間送風乾燥し、淡褐色粉末の（６）を１．４４ｋｇ（収率９０％）得た。
ＥＩ−ＭＳｍ／ｚ：２３１（ｂａｓｅｐｅａｋ），３０４（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．８４（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．２４（３Ｈ，ｓ），２．５８（３Ｈ，ｓ），４．０２（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．１３−７．１５（１Ｈ，ｍ），７．１８−７．２４（２Ｈ，ｍ），７．２８−７．３３（１Ｈ，ｍ），１２．４３（１Ｈ，ｂｒ）．
実施例３4- (2-Methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid ethyl ester (6)
To 8.08 L of ethyl acetate, 1.62 kg (5.27 mol) of the compound (5) was charged, and 1.32 kg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 5.80 mol) was added and stirred at room temperature for 2.5 hours (exothermic to 43 ° C.). The reaction solution was water-cooled to an internal temperature of 25 ° C., the precipitated solid was filtered off, and the solid was washed with 1.62 L of ethyl acetate. The filtrate and the washing solution were combined, and then washed with 8.08 L of an aqueous sodium hydrogen carbonate solution (0.23 kg of sodium bicarbonate was dissolved in water to make 8.08 L). The aqueous layer was extracted with 2.02 L of ethyl acetate, combined with the previous organic layer, washed twice with 2.53 L of water, and concentrated under reduced pressure. 4.22 L of ethanol was added to the obtained crude crystals and dissolved by heating (complete dissolution at 63 ° C.). After adding 4.22 L of water, the mixture was allowed to cool to 40 ° C., then cooled to 30 ° C., and then cooled with ice water. The mixture was stirred at an internal temperature of 6 to 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 4.85 L of 30% ethanol water cooled with ice water, and then air-dried for 0.5 hours.
The wet crystals (1.85 kg) were blown and dried at 60 ° C. for 17 hours to obtain 1.44 kg (yield 90%) of light brown powder (6).
EI-MS m / z: 231 (base peak), 304 (M) ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.84 (3H, t, J = 7.1 Hz), 2.24 (3H, s), 2.58 (3H, s), 4.02 (2H , Q, J = 7.1 Hz), 7.13-7.15 (1H, m), 7.18-7.24 (2H, m), 7.28-7.33 (1H, m), 12 .43 (1H, br).
Example 3

４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸（７）
１ｍｏｌ／Ｌ水酸化ナトリウム溶液１８．９Ｌに化合物（６）１．４４ｋｇ（４．７１ｍｏｌ）を投入し溶解した後、内温８０〜８５℃で２時間撹拌した。反応液を内温３０℃まで水冷し、その後氷水冷却して内温７℃とした。反応液に内温５〜１５℃で２ｍｏｌ／Ｌ塩酸７．８２Ｌを加えｐＨ＝４とした後２０分間撹拌し、続いて２ｍｏｌ／Ｌ塩酸５．３０Ｌを加えｐＨ＝２とした後、内温７〜１０℃で１時間撹拌した。析出した結晶をろ取し、水５．７４Ｌで洗浄した後、０．５時間通気乾燥した。２−プロパノール１０．０Ｌに得られた湿潤粗結晶（１．９１ｋｇ）を投入し、この懸濁溶液を１時間加熱還流した。混合物を３０℃まで水冷し、その後氷水冷冷却して、内温６〜１０℃で１時間撹拌した。結晶をろ取し、２−プロパノール２．８７Ｌで洗浄した後、０．５時間通気乾燥した。湿潤晶（１．６１ｋｇ）を６０℃で８時間送風乾燥し、淡褐白色粉末の（７）を１．２６ｋｇ（収率９７％）得た。
ＥＩ−ＭＳｍ／ｚ：２３１（ｂａｓｅｐｅａｋ），２７６（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：２．２２（３Ｈ，ｓ），２．４９（３Ｈ，ｓ），７．１９−７．３５（４Ｈ，ｍ），１３．３５（１Ｈ，ｂｒ）．
実施例４4- (2-Methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid (7)
After dissolving 1.44 kg (4.71 mol) of the compound (6) in 18.9 L of 1 mol / L sodium hydroxide solution, the mixture was stirred at an internal temperature of 80 to 85 ° C. for 2 hours. The reaction solution was water-cooled to an internal temperature of 30 ° C, and then cooled with ice water to an internal temperature of 7 ° C. To the reaction solution, 7.82 L of 2 mol / L hydrochloric acid was added at an internal temperature of 5 to 15 ° C. to adjust pH = 4, followed by stirring for 20 minutes. Subsequently, 5.30 L of 2 mol / L hydrochloric acid was added to adjust pH = 2, and then the internal temperature was increased. It stirred at 7-10 degreeC for 1 hour. The precipitated crystals were collected by filtration, washed with 5.74 L of water, and then air-dried for 0.5 hours. The obtained wet crude crystals (1.91 kg) were added to 10.0 L of 2-propanol, and the suspension was heated to reflux for 1 hour. The mixture was cooled with water to 30 ° C., then cooled with ice water and stirred at an internal temperature of 6 to 10 ° C. for 1 hour. The crystals were collected by filtration, washed with 2.87 L of 2-propanol, and then air-dried for 0.5 hours. The wet crystals (1.61 kg) were blown and dried at 60 ° C. for 8 hours to obtain 1.26 kg (yield 97%) of light brown white powder (7).
EI-MS m / z: 231 (base peak), 276 (M) ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.22 (3H, s), 2.49 (3H, s), 7.19-7.35 (4H, m), 13.35 (1H , Br).
Example 4

６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルチオ−６，７，８，９，−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（８）
化合物（７）１．２６ｋｇ（４．５５ｍｏｌ）にオキシ塩化リン２．８０ｋｇ（１８．３ｍｏｌ）を加え、内温７５〜８０℃で１時間撹拌した。反応液を内温２４℃まで水冷した後、氷水８．８１Ｌに内温１８℃以下で加え、その後１８〜２４℃で０．５時間撹拌した。析出した結晶をろ取し、水２．５２Ｌで洗浄した後、０．５時間通気乾燥して白色粉末の４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボン酸クロリドを２．３４ｋｇ（湿潤粗結晶）得た。この粗結晶を酢酸エチル２２．７Ｌに溶解した後、水５．０３Ｌ×２、１０％炭酸水素ナトリウム水溶液３．７７Ｌ及び２８％食塩水２．５２Ｌで順次洗浄した。この溶液を３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノール（２）１．６５ｋｇ（５．４６ｍｏｌ）及びトリエチルアミン０．９２ｋｇ（９．１１ｍｏｌ）の酢酸エチル２．５２Ｌ溶液に内温１０℃以下で滴下し、その後内温４〜１０℃で０．５時間撹拌した。反応液を水３．７７Ｌ、０．５ｍｏｌ／Ｌ塩酸３．７７Ｌ、１０％炭酸水素ナトリウム水溶液３．７７Ｌ及び２８％食塩水２．５２Ｌで順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、黄色油状のＮ−［３，５−ビス（トリフルオロメチル）フェニルメチル］−Ｎ−（３−ヒドロキシプロピル）−４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボキサミドを２．８４ｋｇ得た。この油状物をジメチルスルホキシド８．８１Ｌに溶解し、１，８−ジアザビシクロ［５，４，０］ウンデカ−７−エン０．８３ｋｇ（ＤＢＵ、５．４６ｍｏｌ）を加えた後、内温５５〜６０℃で１時間撹拌し、一夜放置した。反応液を１０℃以下に冷却した水１７．６Ｌに内温１９℃以下で注加した後、氷水冷却し、内温１０℃以下で０．５時間撹拌した。析出した結晶をろ取し、水６．２９Ｌで洗浄した後、１時間通気乾燥し、湿潤粗結晶（７．８９ｋｇ）得た。この湿潤粗結晶を２−プロパノール１２．６Ｌに加え、６０℃に加熱して溶解した後、水２．５２Ｌを加え空冷し（内温５２℃で結晶晶析した）、続いて内温５０℃で水冷した後、内温１９〜２５℃で１時間撹拌した。析出した結晶をろ取し、５０％２−プロパノール水３．７７Ｌで洗浄した後、０．５時間通気乾燥し、湿潤黄色結晶（２．２２ｋｇ）得た。この湿潤結晶を２−プロパノール９．４６Ｌに加え、６０℃に加熱して溶解した後、水３．７７Ｌを加え空冷し、続いて内温５０℃で水冷し、内温２０〜２５℃で１時間撹拌した。析出した結晶をろ取し、５０％２−プロパノール水３．７７Ｌで洗浄した後、０．５時間通気乾燥し、湿潤黄色結晶（１．８８ｋｇ）を得た。この湿潤結晶を２−プロパノール５．６６Ｌに加え、６０℃に加熱して溶解した後、水１．８９Ｌを加え空冷し、続いて内温５０℃で水冷し、内温２２〜２５℃で１時間撹拌した。析出した結晶をろ取し、５０％２−プロパノール水２．８３Ｌで洗浄した後、０．５時間通気乾燥し、続いて６０℃で１９時間送風乾燥して黄色粉末の（８）を１．３３ｋｇ（収率５４％）得た。
ＥＩ−ＭＳｍ／ｚ：２５９（ｂａｓｅｐｅａｋ），５４１（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．９６−２．０６（１Ｈ，ｍ），２．１５−２．２１（１Ｈ，ｍ），２．２４（３Ｈ，ｓ），２．５６（３Ｈ，ｓ），３．３１−３．３６（１Ｈ，ｍ），３．７２−３．８０（１Ｈ，ｍ），３．８７（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），４．３７−４．４８（２Ｈ，ｍ），５．３１（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），６．９２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０２−７．０６（１Ｈ，ｍ），７．２１−７．２５（２Ｈ，ｍ），７．５６（２Ｈ，ｓ），７．８２（１Ｈ，ｓ）．
一部単離精製した中間体２化合物の機器データを記す。
・４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボン酸クロリド
ＦＡＢ^＋ｍ／ｚ：３１３［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：２．３０（３Ｈ，ｓ），２．６１（３Ｈ，ｓ），７．１９（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．２５−７．３６（２Ｈ，ｍ），７．４１（１Ｈ，ｔｄ，Ｊ＝１．５，７．６Ｈｚ）．
・Ｎ−［３，５−ビス（トリフルオロメチル）フェニルメチル］−Ｎ−（３−ヒドロキシプロピル）−４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボキサミド
ＦＡＢ^＋ｍ／ｚ：５７８［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．２２（１Ｈ，ｔ，Ｊ＝４．２Ｈｚ），１．４４−１．４８（１Ｈ，ｍ），１．６０−１．６７（１Ｈ，ｍ），２．２９（３Ｈ，ｓ），２．５９（３Ｈ，ｓ），２．８８−３．１８（１Ｈ，ｍ），３．２０−３．２６（１Ｈ，ｍ），３．５１（２Ｈ，ｑ，Ｊ＝５．６Ｈｚ），４．４８（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），４．７８（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），７．０４（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．１９−７．３１（３Ｈ，ｍ），７．５９（２Ｈ，ｓ），７．７７（１Ｈ，ｓ）．
実施例５6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylthio-6,7,8,9, -tetrahydro-5H-pyrimido [4,5-b ] [1,5] oxazosin-5-one (8)
To 1.26 kg (4.55 mol) of compound (7), 2.80 kg (18.3 mol) of phosphorus oxychloride was added, and the mixture was stirred at an internal temperature of 75 to 80 ° C. for 1 hour. The reaction solution was water-cooled to an internal temperature of 24 ° C., then added to 8.81 L of ice water at an internal temperature of 18 ° C. or lower, and then stirred at 18-24 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 2.52 L of water, and then dried by aeration for 0.5 hours to give 4-chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxylic acid as white powder. 2.34 kg (wet crude crystals) of chloride was obtained. The crude crystals were dissolved in 22.7 L of ethyl acetate and then washed successively with water 5.03 L × 2, 3.77 L of 10% aqueous sodium hydrogen carbonate solution and 2.52 L of 28% brine. This solution was mixed with 1.65 kg (5.46 mol) of 3- [3,5-bis (trifluoromethyl) benzylamino] -1-propanol (2) and 0.92 kg (9.11 mol) of triethylamine 2.52 L of ethyl acetate. The solution was added dropwise at an internal temperature of 10 ° C. or lower, and then stirred at an internal temperature of 4 to 10 ° C. for 0.5 hour. The reaction solution was washed successively with 3.77 L of water, 3.77 L of 0.5 mol / L hydrochloric acid, 3.77 L of 10% aqueous sodium hydrogen carbonate solution and 2.52 L of 28% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. N- [3,5-bis (trifluoromethyl) phenylmethyl] -N- (3-hydroxypropyl) -4-chloro-6- (2-methylphenyl) -2-methylthio-5- 2.84 kg of pyrimidinecarboxamide was obtained. This oily substance was dissolved in dimethyl sulfoxide (8.81 L), 1,8-diazabicyclo [5,4,0] undec-7-ene (0.83 kg (DBU, 5.46 mol)) was added, and the internal temperature was 55-60. Stir at 1 ° C. for 1 hour and let stand overnight. The reaction solution was poured into 17.6 L of water cooled to 10 ° C. or lower at an internal temperature of 19 ° C. or lower, cooled with ice water, and stirred at an internal temperature of 10 ° C. or lower for 0.5 hours. The precipitated crystals were collected by filtration, washed with 6.29 L of water, and then air-dried for 1 hour to obtain wet crude crystals (7.89 kg). This wet crude crystal was added to 12.6 L of 2-propanol and dissolved by heating to 60 ° C., then 2.52 L of water was added and air-cooled (crystal crystallization was performed at an internal temperature of 52 ° C.), followed by an internal temperature of 50 ° C. After cooling with water, the mixture was stirred at an internal temperature of 19 to 25 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 3.77 L of 50% 2-propanol water, and then air-dried for 0.5 hours to obtain wet yellow crystals (2.22 kg). The wet crystals are added to 9.46 L of 2-propanol and dissolved by heating to 60 ° C., then 3.77 L of water is added and air-cooled, followed by water cooling at an internal temperature of 50 ° C., and 1 at an internal temperature of 20-25 ° C. Stir for hours. The precipitated crystals were collected by filtration, washed with 3.77 L of 50% 2-propanol water, and then air-dried for 0.5 hours to obtain wet yellow crystals (1.88 kg). This wet crystal was added to 5.66 L of 2-propanol and dissolved by heating to 60 ° C., then 1.89 L of water was added and air-cooled, followed by water cooling at an internal temperature of 50 ° C., and 1 at an internal temperature of 22-25 ° C. Stir for hours. The precipitated crystals were collected by filtration, washed with 2.83 L of 50% 2-propanol water, then air-dried for 0.5 hours, and then air-dried at 60 ° C. for 19 hours to obtain yellow powder (8) as 1. 33 kg (yield 54%) was obtained.
EI-MS m / z: 259 (base peak), 541 (M) ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.96-2.06 (1H, m), 2.15-2.21 (1H, m), 2.24 (3H, s), 2.56 (3H, s), 3.31-3.36 (1H, m), 3.72-3.80 (1H, m), 3.87 (1H, d, J = 14.6 Hz), 4.37 -4.48 (2H, m), 5.31 (1H, d, J = 15.1 Hz), 6.92 (1 H, d, J = 7.3 Hz), 7.02-7.06 (1 H, m), 7.21-7.25 (2H, m), 7.56 (2H, s), 7.82 (1H, s).
The instrument data of the intermediate 2 compound partially isolated and purified are described.
4-chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxylic acid chloride FAB ⁺ m / z: 313 [M + H] ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.30 (3H, s), 2.61 (3H, s), 7.19 (1H, d, J = 1.5 Hz), 7.25-7 .36 (2H, m), 7.41 (1H, td, J = 1.5, 7.6 Hz).
N- [3,5-bis (trifluoromethyl) phenylmethyl] -N- (3-hydroxypropyl) -4-chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxamide FAB ⁺ m / z: 578 [M + H] ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22 (1H, t, J = 4.2 Hz), 1.44 to 1.48 (1H, m), 1.60 to 1.67 (1H, m), 2.29 (3H, s), 2.59 (3H, s), 2.88-3.18 (1H, m), 3.20-3.26 (1H, m), 3.51 (2H, q, J = 5.6 Hz), 4.48 (1H, d, J = 15.1 Hz), 4.78 (1H, d, J = 15.1 Hz), 7.04 (1H, t, J = 7.6 Hz), 7.19-7.31 (3H, m), 7.59 (2H, s), 7.77 (1H, s).
Example 5

６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルスルホニル−６，７，８，９，−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（９）
アセトニトリル／エタノール（２：１）混液７．９８Ｌに化合物（８）１．３３ｋｇ（２．４６ｍｏｌ）を加え溶解し、水冷する。この溶液にモノペルオキシフタル酸マグネシウム・６水和物１．８２ｋｇ（ＭＭＰＰ、３．６８ｍｏｌ）を内温２１〜２８℃で加えた後、１８〜２７℃で１５．５時間撹拌した（８．５時間後にアセトニトリル／エタノール（２：１）混液３．９９Ｌを、１０．５時間後にＭＭＰＰ９１．１ｇ（０．１８ｍｏｌ）を追加した）。反応液に水１６．０Ｌを加え、内温１３〜１５℃で１時間撹拌した後、析出した結晶をろ取し、水３．９９Ｌで洗浄した後、０．５時間通気乾燥した。得られた湿潤粗結晶（３．３１ｋｇ）に酢酸エチル７．９８Ｌを加え、加熱溶解した後（６８℃）、２−プロパノール２３．９Ｌと水６．６５Ｌを加え、水冷し、内温２３〜２５℃で１時間撹拌した。析出した結晶をろ取し、５０％２−プロパノール水３．３３Ｌで洗浄した後、０．５時間通気乾燥し、続いて６０℃で２４時間送風乾燥して白色粉末の（９）を１．２３ｋｇ（収率８７％）得た。
ＥＩ−ＭＳｍ／ｚ：４９４（ｂａｓｅｐｅａｋ），５７３（Ｍ）^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：２．０４−２．１３（１Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２５−２．３２（１Ｈ，ｍ），３．３４（３Ｈ，ｓ），３．４４（１Ｈ，ｄｄ，Ｊ＝４．９，１５．６Ｈｚ），３．６７−３．７６（１Ｈ，ｍ），３．９１（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），４．４８−４．５９（２Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），６．６８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．００−７．０４（１Ｈ，ｍ），７．２４−７．３１（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８４（１Ｈ，ｓ）．
実施例６6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylsulfonyl-6,7,8,9, -tetrahydro-5H-pyrimido [4,5- b] [1,5] oxazosin-5-one (9)
Add 1.33 kg (2.46 mol) of the compound (8) to 7.98 L of acetonitrile / ethanol (2: 1) mixture, dissolve and cool with water. To this solution, 1.82 kg (MMPP, 3.68 mol) of magnesium monoperoxyphthalate hexahydrate was added at an internal temperature of 21 to 28 ° C., and then stirred at 18 to 27 ° C. for 15.5 hours (8.5). After that time, 3.99 L of acetonitrile / ethanol (2: 1) mixture was added, and after 10.5 hours, 91.1 g (0.18 mol) of MMPP was added. After adding 16.0 L of water to the reaction solution and stirring at an internal temperature of 13 to 15 ° C. for 1 hour, the precipitated crystals were collected by filtration, washed with 3.99 L of water, and then air-dried for 0.5 hour. To the obtained wet crude crystals (3.31 kg), 7.98 L of ethyl acetate was added and dissolved by heating (68 ° C.). Then, 23.9 L of 2-propanol and 6.65 L of water were added, and the mixture was cooled with water. Stir at 25 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 3.33 L of 50% 2-propanol water, then air-dried for 0.5 hours, and then air-dried at 60 ° C. for 24 hours to obtain (1) as white powder (9). 23 kg (yield 87%) was obtained.
EI-MS m / z: 494 (base peak), 573 (M) ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.13 (1H, m), 2.23 (3H, s), 2.25-2.32 (1H, m), 3.34 (3H, s), 3.44 (1H, dd, J = 4.9, 15.6 Hz), 3.67-3.76 (1H, m), 3.91 (1H, d, J = 14. 6Hz), 4.48-4.59 (2H, m), 5.29 (1H, d, J = 14.6 Hz), 6.68 (1H, d, J = 7.3 Hz), 7.00- 7.04 (1H, m), 7.24-7.31 (2H, m), 7.57 (2H, s), 7.84 (1H, s).
Example 6

２−（４−アセチルピペラジン−１−イル）−６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−６，７，８，９，−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（化合物Ｉ）
ジメチルスルホキシド６．１２Ｌに化合物（９）１．２２ｋｇ（２．１４ｍｏｌ）、Ｎ−アセチルピペラジン０．３８ｋｇ（２．９９ｍｏｌ）及びトリエチルアミン０．３２ｋｇ（３．２０ｍｏｌ）を投入し、内温５０〜５５℃で３．５時間撹拌した。反応液を水冷して内温２５℃まで冷却した後、氷水１８．４Ｌに内温３〜１８℃で注加し、その後内温１７〜１８℃で０．５時間撹拌した。析出した結晶をろ取し、水２．４５Ｌで洗浄した後、０．５時間通気乾燥した。得られた湿潤粗結晶（３．７４ｋｇ）に酢酸エチル１２．２Ｌを加え溶解し、１０％食塩水３．０６Ｌで洗浄した後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた淡黄色油状物（１．４８ｋｇ）に酢酸エチル２．４５Ｌを加え、加熱溶解した後（５２℃）、内温３５℃まで水冷し、内温２８〜３５℃でｎ−ヘキサン４．９０Ｌを加えた後、水冷し、内温１８〜２５℃で１時間撹拌した。析出した結晶をろ取し、ｎ−ヘキサン／酢酸エチル（４：１）混液３．０６Ｌで洗浄した後、６０℃で１７時間送風乾燥し、白色固体を０．９１ｋｇ得た。この固体にアセトン２．７２Ｌを加え、加熱溶解した後、ろ過し、ろ過器をアセトン０．９１Ｌで洗浄した。ろ液と洗液を合わせ、内温４０℃に加熱した後、水３．２０Ｌを加え、３５〜４０℃で０．５時間撹拌する（結晶晶析）。更に水４．０４Ｌを加えた後、水冷し、内温２３〜２５℃で１時間撹拌した。析出した結晶をろ取し、２０％アセトン水２．２６Ｌで洗浄した後、６０℃で２５時間送風乾燥、続いて６５℃で９．５時間減圧乾燥して白色粉末の（１０）を０．９１ｋｇ（収率６４％）得た。
ｍｐ．：１８６〜１８７℃（熱板法）
ＩＲ（ＫＢｒ）ｃｍ^−１：１６３１，１５６５，１２８６．
Ａｎａｌ．ＣａｌｃｄＣ_３０Ｈ_２９Ｆ_６Ｎ_５Ｏ_３：
Ｃ，５７．９７；Ｈ，４．７０；Ｎ，１１．２７．
Ｆｏｕｎｄ：Ｃ，５７．８７；Ｈ，４．６０；Ｎ，１１．３９．
ＦＡＢ^＋ｍ／ｚ：６２２［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．９４−２．０２（１Ｈ，ｍ），２．１３−２．１９（１Ｈ，ｍ），２．１３（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），３．３０（１Ｈ，ｄｄ，Ｊ＝４．９，１５．１Ｈｚ），３．５０（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），３．６２−３．６８（２Ｈ，ｍ），３．７１−３．９３（６Ｈ，ｍ），４．３２−４．４２（２Ｈ，ｍ），５．３２（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），６．９５（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０４−７．０８（１Ｈ，ｍ），７．２１−７．２５（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８１（１Ｈ，ｓ）．
ＨＰＬＣ相対純度：９９．７％
カラム：（商品名：ＩｎｅｒｔｓｉｌＯＤＳ−３、ジーエルサイエンス（株）製、４．６φ×２５０ｍｍ）、
プレカラム：（商品名：ＩｎｅｒｔｓｉｌＯＤＳ−３、ジーエルサイエンス（株）製、４．０φ×１０ｍｍ）、
測定波長：２１０ｎｍ、
流速：１．０ｍＬ／ｍｉｎ、
カラム温度：３０℃、
移動相：アセトニトリル／リン酸水溶液（１→１０００）＝６０：４０、
注入量：１０μｇ．2- (4-acetylpiperazin-1-yl) -6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9, -tetrahydro- 5H-pyrimido [4,5-b] [1,5] oxazosin-5-one (Compound I)
Compound (9) 1.22 kg (2.14 mol), N-acetylpiperazine 0.38 kg (2.99 mol) and triethylamine 0.32 kg (3.20 mol) were added to 6.12 L of dimethyl sulfoxide, and the internal temperature was 50 to 55. Stir at 3.5 ° C. for 3.5 hours. The reaction solution was cooled with water and cooled to an internal temperature of 25 ° C., then, poured into 18.4 L of ice water at an internal temperature of 3 to 18 ° C., and then stirred at an internal temperature of 17 to 18 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 2.45 L of water, and then air-dried for 0.5 hours. The obtained wet crude crystals (3.74 kg) were dissolved by adding 12.2 L of ethyl acetate, washed with 3.06 L of 10% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained pale yellow oil (1.48 kg), 2.45 L of ethyl acetate was added and dissolved by heating (52 ° C.), then water-cooled to an internal temperature of 35 ° C., and n-hexane 4. After adding 90 L, the mixture was cooled with water and stirred at an internal temperature of 18 to 25 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 3.06 L of a mixture of n-hexane / ethyl acetate (4: 1), and then air-dried at 60 ° C. for 17 hours to obtain 0.91 kg of a white solid. To this solid, 2.72 L of acetone was added and dissolved by heating, followed by filtration. The filter was washed with 0.91 L of acetone. The filtrate and washing solution are combined and heated to an internal temperature of 40 ° C., and then 3.20 L of water is added and stirred at 35 to 40 ° C. for 0.5 hour (crystal crystallization). Further, 4.04 L of water was added, followed by cooling with water and stirring at an internal temperature of 23 to 25 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 2.26 L of 20% acetone water, then air-dried at 60 ° C. for 25 hours, and then dried under reduced pressure at 65 ° C. for 9.5 hours to give (10) as a white powder in an amount of 0.00. 91 kg (yield 64%) was obtained.
mp. 186-187 ° C (hot plate method)
IR (KBr) cm ⁻¹ : 1631, 1565, 1286.
Anal. _{_{_{Calcd C 30 H 29 F 6 N}}} 5 O 3:
C, 57.97; H, 4.70; N, 11.27.
Found: C, 57.87; H, 4.60; N, 11.39.
FAB ⁺ m / z: 622 [M + H] ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.94-2.02 (1H, m), 2.13-2.19 (1H, m), 2.13 (3H, s), 2.25 (3H, s), 3.30 (1H, dd, J = 4.9, 15.1 Hz), 3.50 (2H, t, J = 4.9 Hz), 3.62-3.68 (2H, m), 3.71-3.93 (6H, m), 4.32-4.42 (2H, m), 5.32 (1H, d, J = 15.1 Hz), 6.95 (1H, d, J = 7.3 Hz), 7.04-7.08 (1H, m), 7.21-7.25 (2H, m), 7.57 (2H, s), 7.81 (1H, s).
HPLC relative purity: 99.7%
Column: (trade name: Inertsil ODS-3, manufactured by GL Sciences Inc., 4.6φ × 250 mm),
Precolumn: (trade name: Inertsil ODS-3, manufactured by GL Sciences, Inc., 4.0φ × 10 mm),
Measurement wavelength: 210 nm,
Flow rate: 1.0 mL / min,
Column temperature: 30 ° C.
Mobile phase: acetonitrile / phosphoric acid aqueous solution (1 → 1000) = 60: 40,
Injection volume: 10 μg.

〈参考例３〉３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノール（２）
３，５−ビス（トリフルオロメチル）ベンズアルデヒド（１）２４２ｇ（１．００ｍｏｌ）を２−プロパノール７２６ｍＬに溶解し、撹拌しながら３−アミノ−１−プロパノール９０．１ｇ（１．２０ｍｏｌ）を加え、内温２６〜３５℃で１時間撹拌した。混合物に水素化ホウ素ナトリウム３７．８ｇ（１．００ｍｏｌ）を加え、４５〜５３℃で５時間撹拌した。反応液に精製水１．７０Ｌを加えた後、内温３０℃まで冷却し、内温２６〜３０℃で４ｍｏｌ／Ｌ塩酸６６０ｍＬを加えｐＨ１．２に調整した後、室温で０．５時間撹拌し、一晩放置した。混合物に内温２３〜２８℃で４ｍｏｌ／Ｌ水酸化ナトリウム水溶液６７５ｍＬを加えてｐＨ１２．０に調整し、内温１６℃まで冷却した後、結晶種を加え晶析させた後、精製水７２６ｍＬを加え、内温４〜１０℃で１時間撹拌した。析出した結晶をろ取し、５％２−プロパノール水溶液７２６ｍＬで洗浄し、１時間通気乾燥して湿潤結晶３３８ｇを得た。この湿潤結晶に２−プロパノール６０５ｍＬ及び精製水１．８２Ｌを懸濁し、撹拌しながら濃塩酸Ｌ６０ｍＬを加え溶解し、ｐＨ１．２に調整した。混合物に内温２０〜２６℃で４ｍｏｌ／Ｌ水酸化ナトリウム水溶液５５０ｍＬを加えｐＨ１２．０に調整し、冷却し内温１６℃で結晶種を加え、内温１０〜１６℃で撹拌した。結晶晶析後内温６〜１０℃で１時間撹拌し、析出した結晶をろ取した後、５％２−プロパノール水溶液７２６ｍＬで洗浄し、１時間通気乾燥して湿潤結晶３３４ｇを得た。この湿潤結晶を２−プロパノール６０５ｍＬ及び精製水１．８２Ｌに懸濁し、撹拌しながら濃塩酸８５ｍＬを加えて溶解し、ｐＨ１．２に調整した。混合物に内温２０〜２４℃で４ｍｏｌ／Ｌ水酸化ナトリウム水溶液３００ｍＬを加えてｐＨ１２．０に調整した後、冷却して内温１２〜２４℃で撹拌し、結晶晶析後、冷却して内温６〜１０℃で１時間撹拌した。析出した結晶をろ取し、５％２−プロパノール水溶液７２６ｍＬで洗浄した後、１時間通気乾燥して湿潤結晶３４０ｇを得た。この湿潤結晶を４日間風乾後、３８℃で７時間送風乾燥し、４８℃で１７時間送風乾燥し、白色粉末の（２）を２６６ｇ（収率８８％）を得た。
ｍｐ（熱板法）：６０〜６１℃
ＥＩ−ＭＳｍ／ｚ：３０１（Ｍ^＋），２５６（ｂａｓｅｐｅａｋ）．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：１．７７（２Ｈ，ｑｕｉｎｔ，５．９Ｈｚ），２．８９（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），３．８２（２Ｈ，ｔ，Ｊ＝５．６Ｈｚ），３．９３（２Ｈ，ｓ），７．７８（３Ｈ，ｓ）．
実施例７Reference Example 3 3- [3,5-Bis (trifluoromethyl) benzylamino] -1-propanol (2)
242 g (1.00 mol) of 3,5-bis (trifluoromethyl) benzaldehyde (1) was dissolved in 726 mL of 2-propanol, and 90.1 g (1.20 mol) of 3-amino-1-propanol was added while stirring. The mixture was stirred at an internal temperature of 26 to 35 ° C. for 1 hour. 37.8 g (1.00 mol) of sodium borohydride was added to the mixture and stirred at 45-53 ° C. for 5 hours. After adding 1.70 L of purified water to the reaction solution, it was cooled to an internal temperature of 30 ° C., adjusted to pH 1.2 by adding 660 mL of 4 mol / L hydrochloric acid at an internal temperature of 26-30 ° C., and then stirred at room temperature for 0.5 hour. And left overnight. The mixture was adjusted to pH 12.0 by adding 675 mL of a 4 mol / L aqueous sodium hydroxide solution at an internal temperature of 23 to 28 ° C., cooled to an internal temperature of 16 ° C., crystallized by adding crystal seeds, and then purified water (726 mL) was added. In addition, the mixture was stirred at an internal temperature of 4 to 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 726 mL of a 5% 2-propanol aqueous solution, and air-dried for 1 hour to obtain 338 g of wet crystals. To this wet crystal, 605 mL of 2-propanol and 1.82 L of purified water were suspended, and dissolved by adding 60 mL of concentrated hydrochloric acid with stirring to adjust the pH to 1.2. The mixture was adjusted to pH 12.0 by adding 550 mL of a 4 mol / L aqueous sodium hydroxide solution at an internal temperature of 20 to 26 ° C., cooled, added crystal seeds at an internal temperature of 16 ° C., and stirred at an internal temperature of 10 to 16 ° C. After crystal crystallization, the mixture was stirred for 1 hour at an internal temperature of 6 to 10 ° C., and the precipitated crystals were collected by filtration, washed with 726 mL of 5% 2-propanol aqueous solution, and air-dried for 1 hour to obtain 334 g of wet crystals. The wet crystals were suspended in 605 mL of 2-propanol and 1.82 L of purified water, and dissolved by adding 85 mL of concentrated hydrochloric acid while stirring to adjust the pH to 1.2. The mixture was adjusted to pH 12.0 by adding 300 mL of 4 mol / L sodium hydroxide aqueous solution at an internal temperature of 20-24 ° C., then cooled and stirred at an internal temperature of 12-24 ° C. The mixture was stirred at a temperature of 6 to 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 726 mL of 5% 2-propanol aqueous solution, and then air-dried for 1 hour to obtain 340 g of wet crystals. The wet crystals were air-dried for 4 days, then air-dried at 38 ° C. for 7 hours, and air-dried at 48 ° C. for 17 hours to obtain 266 g of white powder (2) (yield 88%).
mp (hot plate method): 60-61 ° C
EI-MS m / z: 301 (M ^<+> ), 256 (base peak).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.77 (2H, quint, 5.9 Hz), 2.89 (2H, t, J = 5.9 Hz), 3.82 (2H, t, J = 5.6 Hz), 3.93 (2H, s), 7.78 (3H, s).
Example 7

４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，４，５，６−テトラヒドロ−５−ピリミジンカルボン酸エチルエステル（５）
ｏ−トルアルデヒド１２０ｇ（１．００ｍｏｌ）、マロン酸ジエチルエステル１６０ｇ（１．００ｍｏｌ）及びピペリジン８．５２ｇ（１００ｍｍｏｌ）をトルエン６００ｍＬに溶解し、酢酸６．０１ｇ（１００ｍｍｏｌ）を加え、ディーンスターク管を付け共沸脱水しながら５時間加熱還流した。内温３０℃まで冷却した後、反応液を減圧濃縮した。濃縮残渣を９０％ジメチルスルホキシド水溶液９６１ｍＬに溶解した後、２−メチル−２−チオプソイド尿素硫酸塩１３９ｇ（５００ｍｍｏｌ）及び炭酸ナトリウム５３．０ｇ（５００ｍｍｏｌ）を加え、内温５０〜５５℃で６時間撹拌した。反応液を内温３０℃まで冷却し、精製水４．２２Ｌに加えた後、内温６〜１０℃で１時間撹拌した。析出した結晶をろ取し、精製水３６０ｍＬで洗浄した後、０．５時間通気乾燥し、湿潤結晶３６９ｇを得た。この湿潤結晶を２−プロパノール９６０ｍＬに加熱溶解後（内温５９℃で溶解）、精製水２４０ｍＬを加えた。内温１０℃まで冷却した後（内温４２℃で晶析開始）、内温８〜１０℃で０．５時間撹拌した。析出した結晶をろ取し、水冷した８０％２−プロパノール水溶液３６０ｍＬで洗浄し、０．５時間通気乾燥して湿潤結晶３３３ｇを得た。この湿潤結晶を６０℃で１７時間送風乾燥し白色粉末の（５）を２２４ｇ（収率７３％）を得た。
ｍｐ（熱板法）：１３４〜１３５℃
ＥＩ−ＭＳｍ／ｚ：３０６（Ｍ^＋），２３３（ｂａｓｅｐｅａｋ）．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：１．１５（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．４３（３Ｈ，ｓ），２．４４（３Ｈ，ｓ），３．６６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），４．１５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），５．４４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．０７−７．１０（１Ｈ，ｍ），７．１６−７．２２（３Ｈ，ｍ），７．８３（１Ｈ，ｂｒ）．
実施例８4- (2-Methylphenyl) -2-methylthio-6-oxo-1,4,5,6-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester (5)
120 g (1.00 mol) of o-tolualdehyde, 160 g (1.00 mol) of malonic acid diethyl ester and 8.52 g (100 mmol) of piperidine were dissolved in 600 mL of toluene, 6.01 g (100 mmol) of acetic acid was added, and a Dean-Stark tube was added. The mixture was heated to reflux for 5 hours with azeotropic dehydration. After cooling to an internal temperature of 30 ° C., the reaction solution was concentrated under reduced pressure. The concentrated residue was dissolved in 961 mL of 90% dimethyl sulfoxide aqueous solution, and then 139 g (500 mmol) of 2-methyl-2-thiopseudourea sulfate and 53.0 g (500 mmol) of sodium carbonate were added and stirred at an internal temperature of 50 to 55 ° C. for 6 hours. did. The reaction solution was cooled to an internal temperature of 30 ° C., added to 4.22 L of purified water, and then stirred at an internal temperature of 6 to 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 360 mL of purified water, and then air-dried for 0.5 hours to obtain 369 g of wet crystals. The wet crystals were dissolved in 960 mL of 2-propanol by heating (dissolved at an internal temperature of 59 ° C.), and 240 mL of purified water was added. After cooling to an internal temperature of 10 ° C. (crystallization started at an internal temperature of 42 ° C.), the mixture was stirred at an internal temperature of 8 to 10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 360 mL of a water-cooled 80% 2-propanol aqueous solution, and air-dried for 0.5 hours to obtain 333 g of wet crystals. This wet crystal was blown and dried at 60 ° C. for 17 hours to obtain 224 g of white powder (5) (yield 73%).
mp (hot plate method): 134-135 ° C
EI-MS m / z: 306 (M ^<+> ), 233 (base peak).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.15 (3H, t, J = 7.3 Hz), 2.43 (3H, s), 2.44 (3H, s), 3.66 (1H , D, J = 8.3 Hz), 4.15 (2H, q, J = 7.3 Hz), 5.44 (1H, d, J = 8.3 Hz), 7.07-7.10 (1H, m), 7.16-7.22 (3H, m), 7.83 (1H, br).
Example 8

４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸エチルエステル（６）
ジメチルスルホキシド６６９ｍＬに化合物（５）２２３ｇ（７２８ｍｍｏｌ）を溶解し、２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン３３．０ｇ（１４６ｍｍｏｌ）及び無水酢酸１４９ｇ（１．４６ｍｏｌ）を加え、内温５０℃〜６０℃で２時間撹拌した。炭酸水素ナトリウム２７５ｇ（３．２８ｍｏｌ）を精製水３．３５Ｌに溶解した溶液に、反応液に加え、内温２１〜２５℃で０．５時間撹拌した。析出した結晶をろ取し、結晶を精製水６６９ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶２９６ｇを得た。この湿潤結晶をエタノール５５８ｍＬに熱時溶解し（内温４５℃で溶解）、内温５０〜５５℃で精製水５５８ｍＬを加えた後、冷却して（４９℃で晶析開始）内温６〜１０℃で１時間撹拌した。析出した結晶をろ取し、３０％エタノール水溶液６６９ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶２４０ｇを得た。この湿潤結晶を６０℃で２０時間送風乾燥し、褐色粉末の（６）を１６６ｇ（収率７５％）を得た。
ｍｐ（熱板法）：１３１〜１３５℃
ＥＩ−ＭＳｍ／ｚ：３０４（Ｍ^＋），２３１（ｂａｓｅｐｅａｋ）．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：０．８３（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．２３（３Ｈ，ｓ），２．５８（３Ｈ，ｓ），４．０２（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．１２−７．１４（１Ｈ，ｍ），７．１８−７．２４（２Ｈ，ｍ），７．３０（１Ｈ，ｄｔ，Ｊ＝１．２Ｈｚ，７．３Ｈｚ）．
実施例９4- (2-Methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid ethyl ester (6)
223 g (728 mmol) of the compound (5) is dissolved in 669 mL of dimethyl sulfoxide, and 33.0 g (146 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 149 g (1.46 mol) of acetic anhydride are added. The mixture was stirred at an internal temperature of 50 ° C. to 60 ° C. for 2 hours. To a solution obtained by dissolving 275 g (3.28 mol) of sodium hydrogen carbonate in 3.35 L of purified water was added to the reaction solution, followed by stirring at an internal temperature of 21 to 25 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 669 mL of purified water, and then air-dried for 0.5 hours to obtain 296 g of wet crystals. This wet crystal was dissolved in 558 mL of ethanol when heated (dissolved at an internal temperature of 45 ° C.), 558 mL of purified water was added at an internal temperature of 50 to 55 ° C., and then cooled (crystallization started at 49 ° C.). Stir at 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 669 mL of a 30% aqueous ethanol solution, and then air-dried for 0.5 hours to obtain 240 g of wet crystals. This wet crystal was blown and dried at 60 ° C. for 20 hours to obtain 166 g (yield 75%) of brown powder (6).
mp (hot plate method): 131-135 ° C
EI-MS m / z: 304 (M ^<+> ), 231 (base peak).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.83 (3H, t, J = 7.1 Hz), 2.23 (3H, s), 2.58 (3H, s), 4.02 (2H , Q, J = 7.1 Hz), 7.12-7.14 (1H, m), 7.18-7.24 (2H, m), 7.30 (1H, dt, J = 1.2 Hz, 7.3 Hz).
Example 9

Ｎ−［３，５−ビス（トリフルオロメチル）フェニルメチル］−Ｎ−（４−ヒドロキシプロピル）−４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボキサミド
化合物（７）１３４ｇ（４８５ｍｍｏｌ）に酢酸エチル６７０ｍＬを懸濁し、Ｎ，Ｎ−ジメチルホルムアミド６．７ｍＬを加えた。この溶液に塩化チオニル１２７ｇ（１．０７ｍｏｌ）の酢酸エチル６７０ｍＬ溶液を内温６３〜６７℃で滴下し、滴下後２時間加熱還流した。反応液を冷却し、内温２０℃で精製水６７０ｍＬを加え、室温で０．５時間撹拌した。有機層を分取し、精製水６７０ｍＬ、１０％炭酸水素ナトリウム水溶液６７０ｍＬ及び２８％食塩水２６８ｍＬで順次洗浄した。この溶液を、化合物（２）１４６ｇ（４８５ｍｍｏｌ）及びトリエチルアミン７３．６ｇ（７２７ｍｍｏｌ）の酢酸エチル６７０ｍＬ溶液に内温６〜１５℃で滴下し、滴下後内温６〜１０℃で０．５時間撹拌した。反応液を０．５ｍｏｌ／Ｌ塩酸６７０ｍＬ、１０％炭酸水素ナトリウム水溶液４００ｍＬ及び２８％食塩水２７０ｍＬで順次洗浄した後、減圧濃縮した。残渣を２−プロパノール１．３４Ｌに加熱溶解し、内温５５〜６０℃で精製水２．６８Ｌを加えた後、冷却して（５３℃で晶析開始）内温８〜１０℃で０．５時間撹拌した。析出した結晶をろ取し、精製水４００ｍＬで洗浄し、０．５時間通気乾燥後、湿潤結晶３６３ｇを得た。この湿潤結晶を２−プロパノール１．３４Ｌに加熱溶解し、内温５５〜６０℃で精製水１．３４Ｌを加えた後、冷却して（５５℃で晶析開始）内温８〜１０℃で０．５時間撹拌した。析出した結晶をろ取し、３０％２−プロパノール水溶液４００ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶３０７ｇを得た。この湿潤結晶を６０℃で１４時間送風乾燥し、淡褐色粉末のＮ−［３，５−ビス（トリフルオロメチル）フェニルメチル］−Ｎ−（４−ヒドロキシプロピル）−４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボキサミドを２４７ｇ（収率８８％）を得た。
ｍｐ（熱板法）：１５３〜１５７℃
ＦＡＢ−ＭＳ^＋ｍ／ｚ：５７８［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：１．４４−１．６６（２Ｈ，ｍ），２．２９（３Ｈ，ｓ），２．５９（３Ｈ，ｓ），２．９１（１Ｈ，ｄｄｄ，Ｊ＝４．９Ｈｚ，９．８Ｈｚ，１４．６Ｈｚ），３．１６−３．３０（１Ｈ，ｍ），３．５２（２Ｈ，ｑ，Ｊ＝４．９Ｈｚ），４．４８（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），４．７８（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），７．０４（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．１９−７．３０（３Ｈ，ｍ），７．５９（２Ｈ，ｓ），７．７７（１Ｈ，ｓ）．
実施例１０N- [3,5-bis (trifluoromethyl) phenylmethyl] -N- (4-hydroxypropyl) -4-chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxamide Compound (7 ) 670 mL of ethyl acetate was suspended in 134 g (485 mmol), and 6.7 mL of N, N-dimethylformamide was added. To this solution, a solution of 127 g (1.07 mol) of thionyl chloride in 670 mL of ethyl acetate was added dropwise at an internal temperature of 63 to 67 ° C., followed by heating to reflux for 2 hours. The reaction solution was cooled, 670 mL of purified water was added at an internal temperature of 20 ° C., and the mixture was stirred at room temperature for 0.5 hour. The organic layer was separated and washed sequentially with 670 mL of purified water, 670 mL of 10% aqueous sodium hydrogen carbonate solution and 268 mL of 28% brine. This solution was added dropwise to a solution of compound (2) 146 g (485 mmol) and triethylamine 73.6 g (727 mmol) in ethyl acetate 670 mL at an internal temperature of 6 to 15 ° C. After the dropwise addition, the solution was stirred at an internal temperature of 6 to 10 ° C. for 0.5 hour. did. The reaction mixture was washed sequentially with 670 mL of 0.5 mol / L hydrochloric acid, 400 mL of 10% aqueous sodium hydrogen carbonate solution and 270 mL of 28% brine, and then concentrated under reduced pressure. The residue was dissolved by heating in 1.34 L of 2-propanol, and 2.68 L of purified water was added at an internal temperature of 55-60 ° C., and then cooled (crystallization started at 53 ° C.). Stir for 5 hours. The precipitated crystals were collected by filtration, washed with 400 mL of purified water, and dried by aeration for 0.5 hour to obtain 363 g of wet crystals. This wet crystal is dissolved by heating in 1.34 L of 2-propanol, 1.34 L of purified water is added at an internal temperature of 55-60 ° C., and then cooled (crystallization starts at 55 ° C.) at an internal temperature of 8-10 ° C. Stir for 0.5 hour. The precipitated crystals were collected by filtration, washed with 400 mL of 30% 2-propanol aqueous solution, and then air-dried for 0.5 hours to obtain 307 g of wet crystals. The wet crystals were air-dried at 60 ° C. for 14 hours, and light brown powder N- [3,5-bis (trifluoromethyl) phenylmethyl] -N- (4-hydroxypropyl) -4-chloro-6- ( 247 g (yield 88%) of 2-methylphenyl) -2-methylthio-5-pyrimidinecarboxamide was obtained.
mp (hot plate method): 153 to 157 ° C
FAB-MS ⁺ m / z: 578 [M + H] ⁺ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.44 to 1.66 (2H, m), 2.29 (3H, s), 2.59 (3H, s), 2.91 (1H, ddd) , J = 4.9 Hz, 9.8 Hz, 14.6 Hz), 3.16-3.30 (1H, m), 3.52 (2H, q, J = 4.9 Hz), 4.48 (1H, d, J = 14.6 Hz), 4.78 (1H, d, J = 15.1 Hz), 7.04 (1H, t, J = 7.3 Hz), 7.19-7.30 (3H, m ), 7.59 (2H, s), 7.77 (1H, s).
Example 10

６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルチオ−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（８）
Ｎ−［３，５−ビス（トリフルオロメチル）フェニルメチル］−Ｎ−（４−ヒドロキシプロピル）−４−クロロ−６−（２−メチルフェニル）−２−メチルチオ−５−ピリミジンカルボキサミド２４６ｇ（４２６ｍｍｏｌ）をアセトン７４０ｍＬに溶解し、１，８−ジアザビシクロ［５，４，０］ウンデカ−７−エン７７．８ｇ（５１１ｍｍｏｌ）を加え、内温５２〜５５℃で２時間加熱還流した。反応液を内温３０℃まで冷却した後、氷水冷却した精製水３．６９Ｌに内温１０〜１６℃で加え、その後内温６〜１０℃で１時間撹拌した。析出した結晶をろ取し、精製水７４０ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶３３１ｇを得た。この湿潤結晶を２−プロパノール２．４６Ｌに加熱溶解し（５７℃で完溶）、内温５５〜６０℃で精製水１．２３Ｌを加えた後、冷却し（５３℃で晶析開始）て内温１３〜２０℃で０．５時間撹拌した。析出した結晶をろ取し、５０％２−プロパノール水溶液７４０ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶２３６ｇを得た。この湿潤結晶を６０℃で１７時間送風乾燥し、淡黄色粉末の（８）１９６ｇ（収率８５％）を得た。
ｍｐ（熱板法）：１４６〜１４７℃
ＦＡＢ−ＭＳ^＋ｍ／ｚ：５４２［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：１．９７−２．０７（１Ｈ，ｍ），２．１６−２．２４（１Ｈ，ｍ），２．２４（３Ｈ，ｓ），２．５５（３Ｈ，ｓ），３．３４（１Ｈ，ｄｄ，Ｊ＝５．４Ｈｚ，１５．６Ｈｚ），３．７２−３．８０（１Ｈ，ｍ），３．８７（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），４．３７−４．４８（２Ｈ，ｍ），５．３２（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），６．９３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０５（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．２１−７．２５（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８２（１Ｈ，ｓ）．
実施例１１6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5] Oxazosin-5-one (8)
246 g (426 mmol) of N- [3,5-bis (trifluoromethyl) phenylmethyl] -N- (4-hydroxypropyl) -4-chloro-6- (2-methylphenyl) -2-methylthio-5-pyrimidinecarboxamide ) Was dissolved in 740 mL of acetone, 77.8 g (511 mmol) of 1,8-diazabicyclo [5,4,0] undec-7-ene was added, and the mixture was heated to reflux at an internal temperature of 52 to 55 ° C. for 2 hours. The reaction solution was cooled to an internal temperature of 30 ° C., then added to 3.69 L of purified water cooled with ice water at an internal temperature of 10 to 16 ° C., and then stirred at an internal temperature of 6 to 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with 740 mL of purified water, and then air-dried for 0.5 hours to obtain 331 g of wet crystals. This wet crystal was dissolved in 2.46 L of 2-propanol by heating (completely dissolved at 57 ° C.), 1.23 L of purified water was added at an internal temperature of 55-60 ° C., and then cooled (crystallization started at 53 ° C.). The mixture was stirred at an internal temperature of 13 to 20 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 740 mL of a 50% 2-propanol aqueous solution, and then air-dried for 0.5 hours to obtain 236 g of wet crystals. This wet crystal was blown and dried at 60 ° C. for 17 hours to obtain 196 g (yield 85%) of (8) as a pale yellow powder.
mp (hot plate method): 146-147 ° C
FAB-MS ⁺ m / z: 542 [M + H] ⁺ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.97-2.07 (1H, m), 2.16-2.24 (1H, m), 2.24 (3H, s), 2.55 (3H, s), 3.34 (1H, dd, J = 5.4 Hz, 15.6 Hz), 3.72-3.80 (1H, m), 3.87 (1H, d, J = 15. 1 Hz), 4.37-4.48 (2 H, m), 5.32 (1 H, d, J = 14.6 Hz), 6.93 (1 H, d, J = 7.8 Hz), 7.05 ( 1H, t, J = 7.3 Hz), 7.21-7.25 (2H, m), 7.57 (2H, s), 7.82 (1H, s).
Example 11

６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルスルホニル−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（９）
化合物（８）１０．０ｇ（１８．５ｍｍｏｌ）をアセトニトリル５３．３ｍＬ及びエタノール２６．７ｍＬに溶解し、モノペルオキシフタル酸マグネシウム・６水和物１７．１ｇ（２７．７ｍｍｏｌ）を内温１６〜２８℃で加え、内温１８〜２７℃で５．５時間撹拌した。反応液を水１７２ｍＬに加え、内温２５℃以下で１時間撹拌した。析出した結晶をろ取し、精製水３０．０ｍＬで洗浄した後、０．５時間通気乾燥、６０℃で１５時間送風乾燥し、白色粉末の（９）を１０．４ｇ（収率９８％）を得た。
ｍｐ（熱板法）：２１１〜２１２℃
ＦＡＢ−ＭＳ^＋ｍ／ｚ：５７４［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：２．０６−２．１１（１Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２３−２．２７（１Ｈ，ｍ），３．３４（３Ｈ，ｓ），３．４４（１Ｈ，ｄｄ，Ｊ＝５．４Ｈｚ，１５．９Ｈｚ），３．６７−３．７４（１Ｈ，ｍ），３．９１（１Ｈ，ｄ，Ｊ＝１４．９Ｈｚ），４．４８−４．５７（２Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝１４．９Ｈｚ），６．８７（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．０２（１Ｈ，ｔ，Ｊ＝７．１Ｈｚ），７．２４−７．３１（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８４（１Ｈ，ｓ）．
実施例１２6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b ] [1,5] Oxazosin-5-one (9)
10.0 g (18.5 mmol) of the compound (8) is dissolved in 53.3 mL of acetonitrile and 26.7 mL of ethanol, and 17.1 g (27.7 mmol) of monoperoxyphthalic acid magnesium hexahydrate is dissolved at an internal temperature of 16 to 28. The mixture was added at ° C and stirred at an internal temperature of 18 to 27 ° C for 5.5 hours. The reaction solution was added to 172 mL of water and stirred at an internal temperature of 25 ° C. or lower for 1 hour. The precipitated crystals were collected by filtration and washed with 30.0 mL of purified water, and then dried by aeration for 0.5 hours and blown and dried at 60 ° C. for 15 hours to give 10.4 g (98% yield) of white powder (9). Got.
mp (hot plate method): 211-212 ° C
FAB-MS ⁺ m / z: 574 [M + H] ⁺ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.06-2.11 (1H, m), 2.23 (3H, s), 2.23 to 2.27 (1H, m), 3.34 (3H, s), 3.44 (1H, dd, J = 5.4 Hz, 15.9 Hz), 3.67-3.74 (1H, m), 3.91 (1H, d, J = 14. 9 Hz), 4.48-4.57 (2 H, m), 5.29 (1 H, d, J = 14.9 Hz), 6.87 (1 H, d, J = 7.6 Hz), 7.02 ( 1H, t, J = 7.1 Hz), 7.24-7.31 (2H, m), 7.57 (2H, s), 7.84 (1H, s).
Example 12

２−（４−アセチルピペラジン−１−イル）−６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−６，７，８，９，−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（化合物Ｉ）
実施例１１に記載した方法により得られた粗精製の化合物（９）５．００ｇ（８．７２ｍｍｏｌ）、Ｎ−アセチルピペラジン１．５６ｇ（１２．２ｍｍｏｌ）及びトリエチルアミン１．３２ｇ（１３．１ｍｍｏｌ）をジメチルスルホキシド２５ｍＬに溶解し、内温５０〜５８℃で４．５時間撹拌した。反応液を精製水９４．５ｍＬに内温３０℃〜４０℃で加え、内温２０℃以下で０．５時間撹拌した。析出した結晶をろ取し、精製水２０ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶１０．４ｇを得た。この湿潤結晶を６０℃で１５時間送風乾燥し粗結晶５．１２ｇを得た。この粗結晶をアセトン２５ｍＬに溶解し、内温４５℃〜５０℃で精製水２ｍＬを加えた後（白濁する）、内温４５〜５０℃で１．５時間撹拌し、更に精製水１３．０ｍＬを加えた。結晶晶析後、内温４５〜５０℃で０．５時間撹拌し、内温２５℃以下で１時間撹拌した。析出した結晶をろ取し、２０％アセトン水溶液２５．０ｍＬで洗浄した後、０．５時間通気乾燥、続いて６０℃で１６時間送風乾燥し、白色結晶を４．６５ｇ得た。この結晶をアセトン２０．０ｍＬに溶解し、ろ過した後、アセトン５．０ｍＬで洗浄した。ろ液及び洗液を合わせ、内温４５〜５０℃で精製水２７ｍＬを加え（白濁する）、内温４５〜５０℃で１．５時間撹拌し、更に精製水１３．０ｍＬを加え後、内温４５〜５０℃で０．５時間続いて内温２５℃以下で１時間撹拌した。析出した結晶をろ取し、２０％アセトン水溶液２５．０ｍＬで洗浄した後、０．５時間通気乾燥、続いて６０℃で１５時間送風乾燥し、白色粉末の化合物（１）を４．５３ｇ（収率８４％）を得た。
ｍｐ（熱板法）：１８２〜１８４℃
ＦＡＢ−ＭＳ^＋ｍ／ｚ：６２２［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：１．９５−２．０２（１Ｈ，ｍ），２．１０−２．１９（１Ｈ，ｍ），２．１４（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），３．３０（１Ｈ，ｄｄ，Ｊ＝４．９Ｈｚ，１５．１Ｈｚ），３．５０（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），３．６５−３．６８（２Ｈ，ｍ），３．７８−３．９３（６Ｈ，ｍ），４．３２−４．４１（２Ｈ，ｍ），５．３２（１Ｈ，ｄ，Ｊ＝１４．９Ｈｚ），６．９５（１Ｈ，ｄ，Ｊ＝７．１Ｈｚ），７．０６（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．２１−７．２５（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８１（１Ｈ，ｓ）．
実施例１３2- (4-acetylpiperazin-1-yl) -6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9, -tetrahydro- 5H-pyrimido [4,5-b] [1,5] oxazosin-5-one (Compound I)
5.00 g (8.72 mmol) of the crude compound (9) obtained by the method described in Example 11, 1.56 g (12.2 mmol) of N-acetylpiperazine and 1.32 g (13.1 mmol) of triethylamine were obtained. It melt | dissolved in 25 mL of dimethyl sulfoxide, and stirred at the internal temperature of 50-58 degreeC for 4.5 hours. The reaction solution was added to 94.5 mL of purified water at an internal temperature of 30 ° C. to 40 ° C. and stirred at an internal temperature of 20 ° C. or lower for 0.5 hour. The precipitated crystals were collected by filtration, washed with 20 mL of purified water, and then air-dried for 0.5 hours to obtain 10.4 g of wet crystals. The wet crystals were blown and dried at 60 ° C. for 15 hours to obtain 5.12 g of crude crystals. The crude crystals were dissolved in 25 mL of acetone, and 2 mL of purified water was added at an internal temperature of 45 ° C. to 50 ° C. (white turbidity), followed by stirring at an internal temperature of 45-50 ° C. for 1.5 hours, and further purified water of 13.0 mL Was added. After crystal crystallization, the mixture was stirred at an internal temperature of 45 to 50 ° C. for 0.5 hour, and stirred at an internal temperature of 25 ° C. or lower for 1 hour. The precipitated crystals were collected by filtration, washed with 25.0 mL of 20% acetone aqueous solution, dried by aeration for 0.5 hours, and then air-dried at 60 ° C. for 16 hours to obtain 4.65 g of white crystals. The crystals were dissolved in 20.0 mL of acetone, filtered, and washed with 5.0 mL of acetone. The filtrate and the washing solution were combined, 27 mL of purified water was added at an internal temperature of 45 to 50 ° C. (white turbidity), stirred for 1.5 hours at an internal temperature of 45 to 50 ° C., and further 13.0 mL of purified water was added. The mixture was stirred at a temperature of 45 to 50 ° C for 0.5 hour and then at an internal temperature of 25 ° C or less for 1 hour. The precipitated crystals were collected by filtration, washed with 25.0 mL of a 20% aqueous acetone solution, dried by aeration for 0.5 hours, and then air-dried at 60 ° C. for 15 hours to obtain 4.53 g of a white powder of compound (1) ( Yield 84%) was obtained.
mp (hot plate method): 182-184 ° C
FAB-MS ⁺ m / z: 622 [M + H] ⁺ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.95-2.02 (1H, m), 2.10-2.19 (1H, m), 2.14 (3H, s), 2.25 (3H, s), 3.30 (1H, dd, J = 4.9 Hz, 15.1 Hz), 3.50 (2H, t, J = 4.9 Hz), 3.65-3.68 (2H, m), 3.78-3.93 (6H, m), 4.32-4.41 (2H, m), 5.32 (1H, d, J = 14.9 Hz), 6.95 (1H, d, J = 7.1 Hz), 7.06 (1H, t, J = 7.6 Hz), 7.21-7.25 (2H, m), 7.57 (2H, s), 7.81 ( 1H, s).
Example 13

６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルスルホニル−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（９）
化合物（８）２．００ｇ（３．６９ｍｍｏｌ）、タングステン（ＶＩ）酸ナトリウム・２水和物１２．２ｍｇ（０．０３７１ｍｍｏｌ）、硫酸水素セチルトリメチルアンモニウム１４．１ｍｇ（０．０３７１ｍｍｏｌ）、フェニルホスホン酸５．８０ｍｇ（０．０３６７ｍｍｏｌ）及び３１％過酸化水素水１．０１ｇ（９．２３ｍｍｏｌ）を酢酸エチル２０ｍＬに懸濁し、５０℃で２時間撹拌した。反応液を冷却した後、水３０ｍＬ及び酢酸エチル４０ｍＬを加え、有機層を分取した。有機層を減圧濃縮し、白色結晶の（９）を２．０６ｇ（収率９７％）を得た。
ｍｐ（熱板法）：２１２〜２１３℃
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：２．０４−２．１３（１Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２３−２．３２（１Ｈ，ｍ），３．３４（３Ｈ，ｓ），３．４４（１Ｈ，ｄｄ，Ｊ＝４．９Ｈｚ，１６．１Ｈｚ），３．６８−３．７６（１Ｈ，ｍ），３．９１（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），４．４８−４．５９（２Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），６．８８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．００−７．０４（１Ｈ，ｍ），７．２４−７．３１（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８４（１Ｈ，ｓ）．
実施例１４6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b ] [1,5] Oxazosin-5-one (9)
Compound (8) 2.00 g (3.69 mmol), sodium tungsten (VI) dihydrate 12.2 mg (0.0371 mmol), cetyltrimethylammonium hydrogen sulfate 14.1 mg (0.0371 mmol), phenylphosphonic acid 5.80 mg (0.0367 mmol) and 31% aqueous hydrogen peroxide 1.01 g (9.23 mmol) were suspended in 20 mL of ethyl acetate and stirred at 50 ° C. for 2 hours. After cooling the reaction solution, 30 mL of water and 40 mL of ethyl acetate were added, and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain 2.06 g (yield 97%) of (9) as white crystals.
mp (hot plate method): 212-213 ° C
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.04-2.13 (1H, m), 2.23 (3H, s), 2.23-2.32 (1H, m), 3.34 (3H, s), 3.44 (1H, dd, J = 4.9 Hz, 16.1 Hz), 3.68-3.76 (1H, m), 3.91 (1H, d, J = 14. 6Hz), 4.48-4.59 (2H, m), 5.29 (1H, d, J = 15.1 Hz), 6.88 (1H, d, J = 7.3 Hz), 7.00- 7.04 (1H, m), 7.24-7.31 (2H, m), 7.57 (2H, s), 7.84 (1H, s).
Example 14

６−［３，５−ビス（トリフルオロメチル）フェニルメチル］−４−（２−メチルフェニル）−２−メチルスルホニル−６，７，８，９−テトラヒドロ−５Ｈ−ピリミド［４，５−ｂ］［１，５］オキサゾシン−５−オン（９）
化合物（８）２０．０ｇ（３６．９ｍｍｏｌ）をアセトニトリル８０ｍＬに溶解し、タングステン（ＶＩ）酸ナトリウム・２水和物１２２ｍｇ（０．３６９ｍｍｏｌ）、酢酸８．８７ｇ（１４８ｍｍｏｌ）及び３５％過酸化水素水１４．４ｇ（１４８ｍｍｏｌ）を加え、内温５０〜６０℃で４．５時間撹拌した。反応液を３０℃まで冷却した後、精製水３２０ｍＬに加え、内温１０〜１５℃で０．５時間撹拌した。析出した結晶をろ取し、精製水６０ｍＬで洗浄した後、０．５時間通気乾燥して湿潤結晶２８．６ｇを得た。この湿潤結晶を６０℃で１６時間送風乾燥し、白色粉末の（９）を２０．６ｇ（収率９７％）を得た。
ｍｐ（熱板法）：２１０〜２１５℃
ＦＡＢ−ＭＳ^＋ｍ／ｚ：５７４［Ｍ＋Ｈ］^＋．
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：２．０４−２．１３（１Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２３−２．３２（１Ｈ，ｍ），３．３４（３Ｈ，ｓ），３．４４（１Ｈ，ｄｄ，Ｊ＝５．４Ｈｚ，１５．６Ｈｚ），３．６７−３．７５（１Ｈ，ｍ），３．９１（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），４．４８−４．５９（２Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝１４．６Ｈｚ），６．８８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．００−７．０４（１Ｈ，ｍ），７．２２−７．３１（２Ｈ，ｍ），７．５７（２Ｈ，ｓ），７．８４（１Ｈ，ｓ）．6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b ] [1,5] Oxazosin-5-one (9)
Compound (8) 20.0 g (36.9 mmol) was dissolved in acetonitrile 80 mL, and tungsten (VI) sodium dihydrate 122 mg (0.369 mmol), acetic acid 8.87 g (148 mmol) and 35% hydrogen peroxide 14.4 g (148 mmol) of water was added, and the mixture was stirred at an internal temperature of 50 to 60 ° C. for 4.5 hours. The reaction solution was cooled to 30 ° C., added to 320 mL of purified water, and stirred at an internal temperature of 10 to 15 ° C. for 0.5 hour. The precipitated crystals were collected by filtration, washed with 60 mL of purified water, and then air-dried for 0.5 hours to obtain 28.6 g of wet crystals. This wet crystal was blown and dried at 60 ° C. for 16 hours to obtain 20.6 g (yield 97%) of white powder (9).
mp (hot plate method): 210-215 ° C
FAB-MS ⁺ m / z: 574 [M + H] ⁺ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.04-2.13 (1H, m), 2.23 (3H, s), 2.23-2.32 (1H, m), 3.34 (3H, s), 3.44 (1H, dd, J = 5.4 Hz, 15.6 Hz), 3.67-3.75 (1H, m), 3.91 (1H, d, J = 15. 1 Hz), 4.48-4.59 (2 H, m), 5.29 (1 H, d, J = 14.6 Hz), 6.88 (1 H, d, J = 7.8 Hz), 7.00- 7.04 (1H, m), 7.22-7.31 (2H, m), 7.57 (2H, s), 7.84 (1H, s).

ＮＫ１受容体拮抗薬として有望な化合物Ｉを製造するにあたり、中間体として４−（２−メチルフェニル）−２−メチルチオ−６−オキソ−１，６−ジヒドロ−５−ピリミジンカルボン酸を用い、クロル化剤を作用させた後、３−［３，５−ビス（トリフルオロメチル）ベンジルアミノ］−１−プロパノールと反応させ、次いでこれを酸化した後Ｎ−アセチルピペラジンと反応すると多量の不純物の生成を伴う事無く、高収率で反応が進行することが明らかとなった。これにより高品質な化合物Ｉを収率良く提供できることが明らかとなった。 In producing promising compound I as an NK1 receptor antagonist, 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid is used as an intermediate, and chloro After reacting with an agent, it is reacted with 3- [3,5-bis (trifluoromethyl) benzylamino] -1-propanol, then oxidized and then reacted with N-acetylpiperazine to produce a large amount of impurities. It was revealed that the reaction proceeds in a high yield without accompanying. As a result, it has been clarified that a high-quality compound I can be provided in good yield.

Claims

After allowing a chlorinating agent to act on 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid, 3- [3,5-bis (trifluoromethyl) 2- (4-acetylpiperazin-1-yl)-, characterized by reacting with benzylamino] -1-propanol, followed by ring closure with a base, then oxidizing and reacting with N-acetylpiperazine 6- [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5 ] The manufacturing method of oxazosin-5-one or its hydrate.

2- (4-acetylpiperazin-1-yl) -6 consisting of 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid or its hydrate [3,5-Bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5] oxazocine Intermediate for producing -5-one or its hydrate.

2- (2-methylbenzylidene) malonate diethyl and an excess amount of 2-methyl-2-thiopseudourea sulfate are reacted in a solvent in the presence of a base to give 4- (2-methylphenyl) -2-methylthio- 6-Oxo-1,4,5,6-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester is obtained, which is then dehydrogenated to 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-characterized by hydrolysis of the compound after conversion to dihydro-5-pyrimidinecarboxylic acid ethyl ester A method for producing pyrimidinecarboxylic acid or a hydrate thereof.