JPWO2015093586A1 - Optically active compound having thrombopoietin receptor agonist activity and method for producing the intermediate - Google Patents

Abstract

Method for producing intermediate with high chemical purity and / or optical purity, crystal of intermediate with high chemical purity and / or optical purity, method for producing intermediate capable of carrying out two reactions substantially in one step, and thrombopoietin The present invention relates to a method for producing an optically active 1,3-thiazole derivative having a receptor agonistic action.

Description

  The present invention relates to a method for producing an optically active 1,3-thiazole derivative having a thrombopoietin receptor agonistic action. More specifically, the present invention relates to a compound useful as a production intermediate, a crystal of the production intermediate compound, a production method thereof, and the like.

Thrombopoietin is a polypeptide cytokine consisting of 332 amino acids, and stimulates the differentiation and proliferation of megakaryocytes via the receptor, thereby enhancing platelet production. It is expected as a drug for the pathology of accompanying blood diseases. Non-patent document 1 describes the base sequence of the gene encoding the thrombopoietin receptor. Although low molecular weight peptides having affinity for the thrombopoietin receptor are also known in Patent Document 1 and Patent Document 2, oral administration of these peptide derivatives is generally not practical.
Examples of low molecular weight compounds having affinity for the thrombopoietin receptor include 1,4-benzothiazepine derivatives in Patent Document 3 and Patent Document 4, 1-azonaphthalene derivatives in Patent Document 5, and 1 in Patent Documents 6-22. 1,3-thiazole derivatives are described. Patent Document 23 describes a pharmaceutical composition containing a 1,3-thiazole derivative and crystals thereof.
Non-Patent Document 1 describes a formylation reaction, and Non-Patent Document 2 describes a formylation reaction using N-formylmorpholine.
Non-patent documents 3 and 4 describe a synthesis method in which a formylation reaction and a Horner-Wadsworth-Emmons reaction are performed in one step, but the substrates and reagents are different.

JP-A-10-72492 International Publication No. 96/40750 Pamphlet Japanese Patent Laid-Open No. 11-1477 Japanese Patent Laid-Open No. 11-152276 International Publication No. 00/35446 Pamphlet JP-A-10-287634 International Publication No. 01/07423 Pamphlet International Publication No. 01/53267 Pamphlet International Publication No. 02/059099 Pamphlet WO 02/059100 pamphlet WO 02/059100 pamphlet International Publication No. 02/062775 Pamphlet International Publication No. 2003/062233 Pamphlet International Publication No. 2004/029049 Pamphlet International Publication No. 2005/007651 Pamphlet International Publication No. 2005/014561 Pamphlet JP 2005-47905 A JP 2006-219480 A JP 2006-219482 A International Publication No. 2007/004038 Pamphlet International Publication No. 2007/036709 Pamphlet International Publication No. 2007/054783 Pamphlet International Publication No. 2009/017098 Pamphlet

Proc. Of the National Academy of Science of the United State of America (Proc. Natl. Acad. Sci. USA) 1992, 89, p. 5640-5644 Journal of Organic Chemistry (J. Org. Chem.) 1984, 49, p. 3856-3857 Journal of Organic Chemistry (J. Org. Chem.) 1992, 57, p. 6667-6669 Synlett 2004, Vol. 6, p. 1092-1094

  Patent Document 8, Patent Document 16, and Patent Document 23 describe methods for producing 1,3-thiazole derivatives.

で表される１，３−チアゾール誘導体が、トロンボポエチン受容体に親和性を有する化合物として有用であることが記載されている。１，３−チアゾール誘導体の製造方法としては、例えば、実施例１に以下の式：

が記載されている。詳しくは、ホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）、次いで、アミド化反応により、１，３−チアゾール誘導体を合成する製造方法が開示されている。In Patent Document 8, the following formula:

It is described that the 1,3-thiazole derivative represented by the above formula is useful as a compound having affinity for the thrombopoietin receptor. As a manufacturing method of a 1, 3-thiazole derivative, for example, the following formula:

Is described. In detail, the manufacturing method which synthesize | combines a 1, 3- thiazole derivative by Horner-Wadsworth-Emmons reaction (Horner-Wadsworth-Emmons reaction) and then amidation reaction is disclosed.

で表される１，３−チアゾール誘導体が、トロンボポエチン受容体に親和性を有する化合物として有用であることが記載されている。１，３−チアゾール誘導体の製造方法としては、例えば、実施例８０に以下の式：

が記載されている。詳しくは、ホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）、次いで、アミド化反応により、１，３−チアゾール誘導体を合成する製造方法が開示されている。Patent Document 16 includes the following formula:

It is described that the 1,3-thiazole derivative represented by the above formula is useful as a compound having affinity for the thrombopoietin receptor. As a method for producing a 1,3-thiazole derivative, for example, in Example 80, the following formula:

Is described. In detail, the manufacturing method which synthesize | combines a 1, 3- thiazole derivative by Horner-Wadsworth-Emmons reaction (Horner-Wadsworth-Emmons reaction) and then amidation reaction is disclosed.

で表される１，３−チアゾール誘導体が、トロンボポエチン受容体に親和性を示し、その誘導体を有効成分として含有する医薬組成物およびその結晶について記載されている。１，３−チアゾール誘導体の製造方法としては、例えば、実施例４に以下の式：

が記載されている。詳しくは、１，３−チアゾール環の形成、次いで、アミド化反応により、１，３−チアゾール誘導体を合成する製造方法が開示されている。
上記化合物１３の製造方法は、実施例３の第Ａ工程として、下記式：

が記載されている。詳しくは、ホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）により、化合物１３は製造されている。
さらに詳しくは、上記化合物２０は、実施例３の第４工程と同様な方法を用いて得られたことが記載されている。実施例３の第４工程において、該当するアミン化合物は、シリカゲルクロマトグラフィーにより精製して得られたことが記載されているため、上記化合物２０も同様にシリカゲルクロマトグラフィーにより精製して得られたと考えられる。
上記化合物２１は、上記化合物２０と上記化合物１３とのアミド化反応により製造されることが記載されており、上記化合物２１は、結晶として得られたとの記載はない。
これら特許文献に、トロンボポエチン受容体アゴニスト作用を有する光学活性な１，３−チアゾール誘導体の製造方法は既に開示されているものの、医薬品として使用または医薬品として工業的に製造するために、より好ましい製造方法の確立が望まれていた。
In Patent Document 23, the following formula:

1,3-thiazole derivatives having an affinity for thrombopoietin receptors, and pharmaceutical compositions containing the derivatives as active ingredients and crystals thereof are described. As a method for producing a 1,3-thiazole derivative, for example, in Example 4, the following formula:

Is described. Specifically, a production method for synthesizing a 1,3-thiazole derivative by forming a 1,3-thiazole ring and then amidating reaction is disclosed.
The production method of the compound 13 is the following formula:

Is described. Specifically, compound 13 is produced by the Horner-Wadsworth-Emmons reaction.
More specifically, it is described that the compound 20 was obtained using the same method as in the fourth step of Example 3. In the fourth step of Example 3, since it is described that the corresponding amine compound was obtained by purification by silica gel chromatography, it is considered that the compound 20 was also obtained by purification by silica gel chromatography. It is done.
It is described that the compound 21 is produced by an amidation reaction between the compound 20 and the compound 13, and there is no description that the compound 21 was obtained as a crystal.
Although these patent documents have already disclosed a method for producing an optically active 1,3-thiazole derivative having a thrombopoietin receptor agonistic activity, a more preferred production method for use as a pharmaceutical or industrial production as a pharmaceutical The establishment of was desired.

（式中、Ｘ^１は、脱離基；Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）で示される化合物をチオウレアと反応させ、式（ＩＩ）：

（式中、Ｒ^１、Ｒ^２およびＲ^３は上記と同義）で示される化合物を得、
得られた上記式（ＩＩ）で示される化合物を結晶化することを特徴とする、式（ＩＩ）で示される化合物の結晶の製造方法。
（２）非極性溶媒により結晶化することを特徴とする、上記項目（１）記載の結晶の製造方法。
（３）トルエン、キシレン、ヘプタンおよびヘキサンからなる群から１以上選択される非極性溶媒により結晶化することを特徴とする、上記項目（１）または（２）記載の結晶の製造方法。
（４）トルエンまたはキシレンから選択される１または２の溶媒、および、ヘプタンまたはヘキサンから選択される１または２の溶媒の混合溶媒により結晶化することを特徴とする、上記項目（１）〜（３）のいずれかに記載の結晶の製造方法。
（５）トルエンおよびヘプタンの混合溶媒により結晶化することを特徴とする、上記項目（１）〜（４）のいずれかに記載の結晶の製造方法。
（６）Ｒ^１が、メチルオキシであり；
Ｒ^２が、メチルであり；かつ
Ｒ^３が、ｎ−ヘキシルである、上記項目（１）〜（５）のいずれかに記載の式（ＩＩ）で示される化合物の結晶の製造方法。
（７）結晶化により、式（ＸＩ）で示される化合物の結晶の有機不純物を１．５重量％以下に除去することを特徴とする、上記項目（６）記載の結晶の製造方法。
（８）式（ＩＩ）で示される化合物の結晶の光学純度が、９７％ｅ．ｅ．以上である、上記項目（６）または（７）記載の結晶の製造方法。
（８Ａ）光学純度が９７％ｅ．ｅ．以上である、化合物（ＩＩ’）：

の結晶。
（８Ｂ）化合物（ＩＩ’’）：

（式中、＊は不斉炭素原子を示す。）
で示される光学異性体混合物の結晶において、化合物（ＩＩ’）：

の結晶を、９７％ｅ．ｅ．以上の光学純度で包含する結晶。
（８Ｃ）有機不純物の含有量が、１．５重量％以下である、化合物（ＩＩ’）：

の結晶。
（８Ｄ）式（ＩＩ）で示される化合物の結晶の光学純度が、９９％ｅ．ｅ．以上である、上記項目（６）または（７）記載の結晶の製造方法。
（８Ｅ）光学純度が９９％ｅ．ｅ．以上である、化合物（ＩＩ’）：

の結晶。
（８Ｆ）化合物（ＩＩ’’）：

（式中、＊は不斉炭素原子を示す。）
で示される光学異性体混合物の結晶において、化合物（ＩＩ’）：

の結晶を、９９％ｅ．ｅ．以上の光学純度で包含する結晶。
（９）塩基の存在下、式（Ｖ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子）
で示される化合物と、ホルミル化試薬として、Ｎ−ホルミルモルホリン、Ｎ−ホルミルピペリジンまたはＮ，Ｎ−ジメチルホルムアミドを反応させる工程、
および、上記工程の生成物に、式（ＶＩ）：

（式中、Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル；Ｒ^８は、各々独立してＣ１−Ｃ３アルキル）で示される化合物を反応させる工程を、実質上の一工程として連続的に行うことを特徴とする、式（ＶＩＩ）：

（式中、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同義）で示される化合物の製造方法。
（１０）塩基がＬＤＡ、ＫＨＭＤＳ、ＬＨＭＤＳ、ｎ−ブチルリチウムまたはフェニルリチウムである、上記項目（９）記載の式（ＶＩＩ）で示される化合物の製造方法。
（１０Ａ）塩基がＬＤＡ、ＫＨＭＤＳまたはＬＨＭＤＳである、上記項目（９）記載の式（ＶＩＩ）で示される化合物の製造方法。
（１０Ｂ）塩基がＬＤＡである、上記項目（９）記載の式（ＶＩＩ）で示される化合物の製造方法。
（１０Ｃ）ホルミル化試薬が、Ｎ−ホルミルモルホリンまたはＮ−ホルミルピペリジンである、上記項目（９）、（１０）、（１０Ａ）または（１０Ｂ）記載の式（ＶＩＩ）で示される化合物の製造方法。
（１０Ｄ）ホルミル化試薬が、Ｎ−ホルミルモルホリンである、上記項目（９）、（１０）、（１０Ａ）または（１０Ｂ）記載の式（ＶＩＩ）で示される化合物の製造方法。
（１０Ｅ）反応に使用する溶媒が、１，２−ジメトキシエタン、テトラヒドロフラン、またはメチルｔｅｒｔ-ブチルエーテルである、上記項目（９）、（１０）および（１０Ａ）〜（１０Ｄ）のいずれかに記載の式（ＶＩＩ）で示される化合物の製造方法。
（１０Ｆ）反応に使用する溶媒が、１，２−ジメトキシエタンである、上記項目（９）、（１０）および（１０Ａ）〜（１０Ｄ）のいずれかに記載の式（ＶＩＩ）で示される化合物の製造方法。
（１１）Ｒ^４およびＲ^５が、共に塩素原子であり；
Ｒ^６が、メチルであり；かつ
Ｒ^７が、エチルである、上記項目（９）、（１０）および（１０Ａ）〜（１０Ｆ）のいずれかに記載の式（ＶＩＩ）で示される化合物の製造方法。
（１２）式（ＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）で示される化合物を、式（ＶＩＩ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）で示される化合物と反応させ、式（ＶＩＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同義）で示される化合物を得、
得られた上記式（ＶＩＩＩ）で示される化合物を、結晶化することを特徴とする、式（ＶＩＩＩ）で示される化合物の結晶の製造方法。
（１３）Ｒ^１が、メチルオキシであり；
Ｒ^２が、メチルであり；
Ｒ^３が、ｎ−ヘキシルであり；
Ｒ^４およびＲ^５が、共に塩素原子であり；
Ｒ^６が、メチルであり；かつ
Ｒ^７が、エチルである、上記項目（１２）記載の式（ＶＩＩＩ）で示される化合物の結晶の製造方法。
（１４）結晶化により、式（ＶＩＩＩ）で示される化合物の結晶の有機不純物を２．０重量％以下に除去することを特徴とする、上記項目（１３）記載の結晶の製造方法。
（１４Ａ）ジメチルスルホキシドまたはアセトンにより結晶化することを特徴とする、上記項目（１３）または（１４）記載の結晶の製造方法。
（１４Ｂ）ジメチルスルホキシドにより結晶化することを特徴とする、上記項目（１３）、（１４）および（１４Ａ）のいずれかに記載の結晶の製造方法。
（１４Ｃ）酸により結晶化することを特徴とする、上記項目（１３）または（１４）記載の結晶の製造方法。
（１４Ｄ）酸が塩酸、リン酸、硫酸、安息香酸、ゲンチジン酸、ｐ−トルイル酸、３−クロロ安息香酸または３，５−ジクロロ安息香酸である、上記項目（１３）、（１４）および（１４Ｃ）のいずれかに記載の結晶の製造方法。
（１４Ｅ）酸が塩酸、安息香酸またはｐ−トルイル酸である、上記項目（１３）、（１４）、（１４Ｃ）および（１４Ｄ）のいずれかに記載の結晶の製造方法。
（１５）化合物（ＶＩＩＩ’）：

またはその付加物の結晶。
（１５Ａ）有機不純物の含有量が、２．０重量％以下である、上記項目（１５）記載の結晶。
（１６）ジメチルスルホキシド付加物の結晶である、上記項目（１５）記載の結晶。
（１７）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．２°±０．２°、１０．５°±０．２°、１５．８°±０．２°、１９．３°±０．２°、２４．１°±０．２°にピークを有する、上記項目（１６）記載の結晶。
（１８）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．２°±０．２°、７．０°±０．２°、８．７°±０．２°、１０．５°±０．２°、１２．３°±０．２°、１４．０°±０．２°、１５．８°±０．２°、１９．３°±０．２°、２２．５°±０．２°、２４．１°±０．２°にピークを有する、上記項目（１６）記載の結晶。
（１８Ａ）安息香酸付加物の結晶である、上記項目（１５）記載の結晶。
（１８Ｂ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．７°±０．２°、５．８°±０．２°、６．８°±０．２°、１３．６°±０．２°、２０．２°±０．２°にピークを有する、上記項目（１８Ａ）記載の結晶。
（１８Ｃ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．７°±０．２°、５．８°±０．２°、６．８°±０．２°、１１．７°±０．２°、１３．６°±０．２°、１８．３°±０．２°、２０．２°±０．２°、２４．０°±０．２°、２４．３°±０．２°、３０．１°±０．２°にピークを有する、上記項目（１８Ａ）記載の結晶。
（１８Ｄ）ｐ−トルイル酸付加物である、上記項目（１５）記載の結晶。
（１８Ｅ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．５°±０．２°、５．９°±０．２°、６．８°±０．２°、１１．８°±０．２°、１３．６°±０．２°にピークを有する、上記項目（１８Ｄ）記載の結晶。
（１８Ｆ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．５°±０．２°、５．９°±０．２°、６．８°±０．２°、１１．８°±０．２°、１３．６°±０．２°、１６．３°±０．２°、１８．０°±０．２°、１９．９°±０．２°、２１．５°±０．２°、２３．８°±０．２°にピークを有する、（１８Ｄ）記載の結晶。
（１８Ｇ）塩酸付加物である、上記項目（１５）記載の結晶。
（１８Ｈ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．６°±０．２°、１０．８°±０．２°、２０．５°±０．２°、２３．７°±０．２°、２４．８°±０．２°にピークを有する、上記項目（１８Ｇ）記載の結晶。
（１８Ｉ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．６°±０．２°、１０．８°±０．２°、１４．０°±０．２°、１８．０°±０．２°、１９．７°±０．２°、２０．５°±０．２°、２２．６°±０．２°、２３．７°±０．２°、２４．８°±０．２°、２７．２°±０．２°にピークを有する、上記項目（１８Ｇ）記載の結晶。
（１８Ｊ）アセトン付加物である、上記項目（１５）記載の結晶。
（１８Ｋ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：６．９°±０．２°、１０．４°±０．２°、１５．６°±０．２°、１９．１°±０．２°、２４．３°±０．２°にピークを有する、上記項目（１８Ｊ）記載の結晶。
（１８Ｌ）粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．２°±０．２°、６．９°±０．２°、１０．４°±０．２°、１２．１°±０．２°、１３．８°±０．２°、１５．６°±０．２°、１７．３°±０．２°、１９．１°±０．２°、２０．８°±０．２°、２４．３°±０．２°にピークを有する、上記項目（１８Ｊ）記載の結晶。
（１９）上記項目（１）記載の製造方法により、式（ＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）で示される化合物の結晶を製造する工程を包含する、式（ＶＩＩＩ）：

（式中、Ｒ^１、Ｒ^２およびＲ^３は、上記と同義；Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）で示される化合物の結晶の製造方法。
（２０）上記項目（９）記載の製造方法により、式（ＶＩＩ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）で示される化合物を製造する工程を包含する、式（ＶＩＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル；Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同義）で示される化合物の結晶の製造方法。
（２１）上記項目（１）記載の製造方法により、式（ＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）で示される化合物の結晶を製造する工程、
および、上記項目（９）記載の製造方法により、式（ＶＩＩ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）で示される化合物を製造する工程を包含する、式（ＶＩＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同義）で示される化合物の結晶の製造方法。
（２１Ａ）上記項目（１）記載の製造方法により、式（ＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）で示される化合物の結晶を製造し、
および、上記項目（９）記載の製造方法により、式（ＶＩＩ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）で示される化合物を製造し、得られた式（ＩＩ）で示される結晶と式（ＶＩＩ）で示される化合物をアミド化反応に付することを特徴とする上記項目（２１）記載の製造方法。
（２２）上記項目（１２）、（１９）、（２０）、（２１）および（２１Ａ）のいずれかに記載の方法により式（ＶＩＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル；Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）で示される化合物の結晶を得、得られた式（ＶＩＩＩ）で示される化合物の結晶を加水分解することを特徴とする、式（ＸＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、上記と同義）で示される化合物の結晶の製造方法。
（２３）Ｒ^１が、メチルオキシであり；
Ｒ^２が、メチルであり；
Ｒ^３が、ｎ−ヘキシルであり；
Ｒ^４およびＲ^５が、共に塩素原子であり；
Ｒ^６が、メチルであり；かつ
Ｒ^７が、エチルである、上記項目（２２）記載の式（ＸＩ）で示される化合物の結晶の製造方法。
（２４）式（ＸＩ）で示される化合物の結晶の有機不純物の含有量が１．０重量％以下である、上記項目（２３）記載の結晶の製造方法。
（２５）式（ＸＩ）で示される化合物の結晶の光学純度が、９５％ｅ．ｅ．以上である、上記項目（２３）または（２４）記載の結晶の製造方法。
（２５Ａ）有機不純物の含有量が１．０重量％以下である、化合物（ＸＩ’）：

の結晶。
（２５Ｂ）光学純度が９５％ｅ．ｅ．以上である、化合物（ＸＩ’）：

の結晶。
（２５Ｃ）式（ＸＩ）で示される化合物のの結晶の光学純度が、９９％ｅ．ｅ．以上である、上記項目（２３）または（２４）記載の結晶の製造方法。
（２５Ｄ）光学純度が９９％ｅ．ｅ．以上である、化合物（ＸＩ’）：

の結晶。The present invention relates to a method for producing an intermediate having high chemical purity and / or optical purity, an intermediate crystal having high chemical purity and / or optical purity, and production of an intermediate in which two reactions can be carried out substantially in one step. The present invention relates to a method and a method for producing an optically active 1,3-thiazole derivative having a thrombopoietin receptor agonistic action.
The present invention relates to the following items (1) to (25D).
(1) Formula (I):

(Wherein X ¹ is a leaving group; R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl) and a compound represented by thiourea is reacted. Formula (II):

(Wherein R ¹ , R ² and R ³ are as defined above),
A method for producing a crystal of a compound represented by formula (II), wherein the obtained compound represented by formula (II) is crystallized.
(2) The method for producing a crystal according to item (1), wherein the crystal is crystallized with a nonpolar solvent.
(3) The method for producing a crystal according to the above item (1) or (2), wherein crystallization is performed with a nonpolar solvent selected from the group consisting of toluene, xylene, heptane and hexane.
(4) Crystallization with a mixed solvent of 1 or 2 solvent selected from toluene or xylene and 1 or 2 solvent selected from heptane or hexane, 3) The manufacturing method of the crystal | crystallization in any one.
(5) The method for producing a crystal according to any one of the above items (1) to (4), wherein the crystal is crystallized with a mixed solvent of toluene and heptane.
(6) R ¹ is methyloxy;
The manufacturing method of the crystal | crystallization of the compound shown by the formula (II) in any one of said item (1)-(5) whose R < ² > is methyl; and R < ³ > is n-hexyl.
(7) The method for producing a crystal according to the above item (6), wherein organic impurities of the crystal of the compound represented by the formula (XI) are removed to 1.5% by weight or less by crystallization.
(8) The optical purity of the crystal of the compound represented by the formula (II) is 97% e.e. e. The method for producing a crystal according to item (6) or (7) above.
(8A) Optical purity is 97% e.e. e. Compound (II ′):

Crystal.
(8B) Compound (II ″):

(In the formula, * represents an asymmetric carbon atom.)
In the crystal of the optical isomer mixture represented by the compound (II ′):

Of 97% e.e. e. Crystals included in the above optical purity.
(8C) Compound (II ′) having an organic impurity content of 1.5% by weight or less:

Crystal.
(8D) The optical purity of the crystal of the compound represented by formula (II) is 99% e.e. e. The method for producing a crystal according to item (6) or (7) above.
(8E) 99% optical purity e.e. e. Compound (II ′):

Crystal.
(8F) Compound (II ″):

(In the formula, * represents an asymmetric carbon atom.)
In the crystal of the optical isomer mixture represented by the compound (II ′):

Of 99% e.e. e. Crystals included in the above optical purity.
(9) In the presence of a base, formula (V):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom)
Reacting N-formylmorpholine, N-formylpiperidine or N, N-dimethylformamide as a formylation reagent,
And the product of the above step includes formula (VI):

(Wherein R ⁶ and R ⁷ are each independently C 1 -C 3 alkyl; R ⁸ is each independently C 1 -C 3 alkyl). Formula (VII), characterized in that

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above).
(10) The method for producing a compound represented by the formula (VII) according to the above item (9), wherein the base is LDA, KHMDS, LHMDS, n-butyllithium or phenyllithium.
(10A) A method for producing a compound represented by formula (VII) according to item (9), wherein the base is LDA, KHMDS or LHMDS.
(10B) A method for producing a compound represented by formula (VII) according to item (9), wherein the base is LDA.
(10C) A method for producing a compound represented by the formula (VII) according to the above item (9), (10), (10A) or (10B), wherein the formylation reagent is N-formylmorpholine or N-formylpiperidine .
(10D) A method for producing a compound represented by the formula (VII) according to the above item (9), (10), (10A) or (10B), wherein the formylation reagent is N-formylmorpholine.
(10E) The solvent used in the reaction is 1,2-dimethoxyethane, tetrahydrofuran, or methyl tert-butyl ether, according to any one of the above items (9), (10), and (10A) to (10D) A method for producing a compound represented by formula (VII).
(10F) The compound represented by formula (VII) according to any one of (9), (10) and (10A) to (10D) above, wherein the solvent used in the reaction is 1,2-dimethoxyethane Manufacturing method.
(11) R ⁴ and R ⁵ are both chlorine atoms;
Production of a compound represented by the formula (VII) according to any one of the above items (9), (10) and (10A) to (10F), wherein R ⁶ is methyl; and R ⁷ is ethyl Method.
(12) Formula (II):

(Wherein R ¹ is C1-C3 alkyloxy or a halogen atom; R ² and R ³ are each independently C1-C8 alkyl), a compound represented by formula (VII):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C 1 -C 3 alkyl) and are reacted with a compound of formula (VIII):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above),
A method for producing a crystal of a compound represented by formula (VIII), wherein the obtained compound represented by formula (VIII) is crystallized.
(13) R ¹ is methyloxy;
R ² is methyl;
R ³ is n-hexyl;
R ⁴ and R ⁵ are both chlorine atoms;
A method for producing a crystal of a compound represented by formula (VIII) according to item (12), wherein R ⁶ is methyl; and R ⁷ is ethyl.
(14) The method for producing a crystal according to the above item (13), wherein organic impurities of the crystal of the compound represented by formula (VIII) are removed to 2.0% by weight or less by crystallization.
(14A) The method for producing a crystal according to item (13) or (14), wherein the crystal is crystallized with dimethyl sulfoxide or acetone.
(14B) The method for producing a crystal according to any one of the items (13), (14) and (14A), characterized by crystallization with dimethyl sulfoxide.
(14C) The method for producing a crystal according to item (13) or (14), wherein the crystal is crystallized with an acid.
(14D) The above items (13), (14) and (14), wherein the acid is hydrochloric acid, phosphoric acid, sulfuric acid, benzoic acid, gentisic acid, p-toluic acid, 3-chlorobenzoic acid or 3,5-dichlorobenzoic acid. 14C) The manufacturing method of the crystal | crystallization in any one.
(14E) The method for producing a crystal according to any one of the above items (13), (14), (14C) and (14D), wherein the acid is hydrochloric acid, benzoic acid or p-toluic acid.
(15) Compound (VIII ′):

Or crystals of its adduct.
(15A) The crystal according to item (15), wherein the content of organic impurities is 2.0% by weight or less.
(16) The crystal according to the above item (15), which is a crystal of a dimethyl sulfoxide adduct.
(17) In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° The crystal according to item (16) above, having peaks at ± 0.2 ° and 24.1 ° ± 0.2 °.
(18) In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° The crystal according to item (16) above, having peaks at ± 0.2 ° and 24.1 ° ± 0.2 °.
(18A) The crystal according to item (15), which is a crystal of a benzoic acid adduct.
(18B) In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.7 ° ± 0.2 °, 5.8 ° ± 0.2 °, 6.8 ° ± 0.2 °, 13.6 ° The crystal according to item (18A), having a peak at ± 0.2 °, 20.2 ° ± 0.2 °.
(18C) In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.7 ° ± 0.2 °, 5.8 ° ± 0.2 °, 6.8 ° ± 0.2 °, 11.7 ° ± 0.2 °, 13.6 ° ± 0.2 °, 18.3 ° ± 0.2 °, 20.2 ° ± 0.2 °, 24.0 ° ± 0.2 °, 24.3 ° The crystal according to item (18A), having a peak at ± 0.2 °, 30.1 ° ± 0.2 °.
(18D) The crystal according to item (15), which is a p-toluic acid adduct.
(18E) In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.5 ° ± 0.2 °, 5.9 ° ± 0.2 °, 6.8 ° ± 0.2 °, 11.8 ° The crystal according to item (18D) above, having peaks at ± 0.2 ° and 13.6 ° ± 0.2 °.
(18F) In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.5 ° ± 0.2 °, 5.9 ° ± 0.2 °, 6.8 ° ± 0.2 °, 11.8 ° ± 0.2 °, 13.6 ° ± 0.2 °, 16.3 ° ± 0.2 °, 18.0 ° ± 0.2 °, 19.9 ° ± 0.2 °, 21.5 ° The crystal according to (18D), having a peak at ± 0.2 °, 23.8 ° ± 0.2 °.
(18G) The crystal according to item (15), which is a hydrochloric acid adduct.
(18H) In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.6 ° ± 0.2 °, 10.8 ° ± 0.2 °, 20.5 ° ± 0.2 °, 23.7 ° The crystal according to the above item (18G), having a peak at ± 0.2 °, 24.8 ° ± 0.2 °.
(18I) In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.6 ° ± 0.2 °, 10.8 ° ± 0.2 °, 14.0 ° ± 0.2 °, 18.0 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.6 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.8 ° The crystal according to the above item (18G), having a peak at ± 0.2 °, 27.2 ° ± 0.2 °.
(18J) The crystal according to item (15), which is an acetone adduct.
(18K) In powder X-ray diffraction spectrum, diffraction angle (2θ): 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.6 ° ± 0.2 °, 19.1 ° The crystal according to item (18J), which has peaks at ± 0.2 ° and 24.3 ° ± 0.2 °.
(18L) In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 12.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 15.6 ° ± 0.2 °, 17.3 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.8 ° The crystal according to item (18J), which has peaks at ± 0.2 ° and 24.3 ° ± 0.2 °.
(19) According to the production method described in item (1) above, formula (II):

(Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl). ):

(Wherein R ¹ , R ² and R ³ are as defined above; R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl) A method for producing a crystal of a compound.
(20) According to the production method described in item (9) above, formula (VII):

Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl). :

(Wherein R ¹ is C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl; R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above) The manufacturing method of the crystal | crystallization of the compound shown by these.
(21) According to the production method described in item (1) above, formula (II):

(Wherein R ¹ is C1-C3 alkyloxy or a halogen atom; R ² and R ³ are each independently C1-C8 alkyl),
And by the production method described in item (9) above, the formula (VII):

Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl). :

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as described above).
(21A) According to the production method described in item (1) above, formula (II):

(Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently a C1-C8 alkyl),
And by the production method described in item (9) above, the formula (VII):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl), and the resulting compound represented by formula (II) The method according to item (21), wherein the crystal shown and the compound represented by formula (VII) are subjected to an amidation reaction.
(22) Formula (VIII): by the method according to any one of the items (12), (19), (20), (21) and (21A)

Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl; R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ is each independently a crystal of a compound represented by C1-C3 alkyl), and the resulting crystal of the compound represented by formula (VIII) is hydrolyzed, wherein formula (XI):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above).
(23) R ¹ is methyloxy;
R ² is methyl;
R ³ is n-hexyl;
R ⁴ and R ⁵ are both chlorine atoms;
A method for producing a crystal of a compound represented by formula (XI) according to item (22), wherein R ⁶ is methyl; and R ⁷ is ethyl.
(24) The method for producing a crystal according to item (23), wherein the content of organic impurities in the crystal of the compound represented by formula (XI) is 1.0% by weight or less.
(25) The optical purity of the crystal of the compound represented by the formula (XI) is 95% e.e. e. The method for producing a crystal according to item (23) or (24) above.
(25A) Compound (XI ′) having an organic impurity content of 1.0% by weight or less:

Crystal.
(25B) 95% optical purity e.e. e. Compound (XI ′):

Crystal.
(25C) The optical purity of the crystal of the compound represented by the formula (XI) is 99% e.e. e. The method for producing a crystal according to item (23) or (24) above.
(25D) 99% optical purity e.e. e. Compound (XI ′):

Crystal.

  The meaning of each term is explained below. In the present specification, each term is used in a unified meaning, and is used in the same meaning when used alone or in combination with other terms.

  In the present specification, the “adduct” includes salts, co-crystals, hydrates, solvates, clathrates, inclusion compounds, chelates, and complexes. The adduct includes one or more adducts selected from the group consisting of salts, cocrystals, hydrates, solvates, clathrates, inclusion compounds, chelates and complexes. Examples include adducts of salts and solvates, adducts of co-crystals and hydrates, and the like.

  The “leaving group” includes a halogen atom, p-toluenesulfonyl, trifluoromethanesulfonyl and methanesulfonyl. For example, a halogen atom is mentioned.

  In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A fluorine atom, a chlorine atom, and a bromine atom are preferable.

  In the present specification, “alkyl” includes a straight-chain or branched monovalent hydrocarbon group having 1 to 8 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. It is done. Preferably, C1-C6 alkyl is mentioned. More preferably, C1-C4 alkyl is mentioned. In particular, when a carbon number is specified, it means “alkyl” having a carbon number within the range.

  In the present specification, “alkyloxy” includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, 2 -Pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy and the like. Preferably, C1-C6 alkyloxy is mentioned. More preferably, C1-C4 alkyloxy is mentioned. In particular, when a carbon number is specified, it means “alkyloxy” having a carbon number within the range of the number.

  In the present specification, the “nonpolar solvent” is defined as follows. When the charge in a molecule is distributed so that the molecule does not have a permanent dipole moment, this molecule is called a nonpolar molecule. When a liquid composed of such molecules is used as a solvent, this is called a nonpolar solvent. (See Biochemical Dictionary, 3rd edition) Examples include hydrocarbons and aromatic hydrocarbons, hexane (eg, cyclohexane, n-hexane), heptane (eg, n-heptane), tetrachloromethane, toluene, xylene , Benzene, dichloromethane, diethyl ether, dioxane and the like. For example, hexane (example: cyclohexane, n-hexane), heptane, toluene, xylene may be mentioned.

  In this specification, “crystallize” means that when crystals are precipitated from the solution after the reaction and when the crude crystals obtained by the post-treatment after the reaction are dissolved in an appropriate solvent, the crystals are precipitated from the solvent. Including the case.

  In the present specification, “organic impurities” include impurities derived from the production process. It means impurities produced as a by-product in the production process and impurities contained in the starting material of the production process.

  In the present specification, “performed continuously” is a step of reacting a compound represented by the formula (V) with N-formylmorpholine, N-formylpiperidine or N, N-dimethylformamide as a formylation reagent. It means reacting with the compound of formula (VI) without isolating the resulting product.

  In the present specification, “compound represented by formula (II)”, “compound (II ′)”, “compound represented by formula (VII)”, “compound (VII ′)”, “shown by formula (VIII)” The “compound”, “compound (VIII ′)”, “compound of formula (XI)” and “compound (XI ′)” may form a salt. For example, the compound and an alkali metal (eg, lithium, sodium, potassium, etc.), an alkaline earth metal (eg, calcium, barium, etc.), magnesium, a transition metal (eg, zinc, iron, etc.), ammonia, an organic base (eg, , Trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, Hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid , Glutaric acid, malic acid Benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

  Moreover, the said compound may form the solvate. For example, solvates (eg, hydrates, etc.) and / or crystal polymorphs may be formed, and the present invention also includes such various solvates and crystal polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound. When the compound or a salt thereof is left in the air, moisture may be absorbed and adsorbed water may adhere or a hydrate may be formed. Moreover, the crystalline polymorph may be formed by recrystallizing the compound or a salt thereof.

In the compound represented by the formula (I), X ¹ includes a halogen atom. For example, a chlorine atom is mentioned.
R ¹ includes C1-C3 alkyloxy. For example, C1 alkyloxy (methyloxy) is mentioned.
R ² includes C1-C8 alkyl. An example is C1 alkyl (methyl).
R ³ includes C1-C8 alkyl. An example is C6 alkyl (hexyl).

In the compound represented by the formula (II), examples of R ¹ include C1-C3 alkyloxy. For example, C1 alkyloxy (methyloxy) is mentioned.
R ² includes C1-C8 alkyl. An example is C1 alkyl (methyl).
R ³ includes C1-C8 alkyl. An example is C6 alkyl (hexyl).

In the compound represented by the formula (V), examples of R ⁴ include a halogen atom. For example, a chlorine atom is mentioned.
R ⁵ includes a halogen atom. For example, a chlorine atom is mentioned.

In the compound represented by the formula (VI), examples of R ⁶ include C1-C3 alkyl. An example is C1 alkyl (methyl).
R ⁷ includes C1-C3 alkyl. An example is C2 alkyl (ethyl).
R ⁸ includes C1-C3 alkyl. An example is C2 alkyl (ethyl).

In the compound represented by the formula (VII), examples of R ⁴ include a halogen atom. For example, a chlorine atom is mentioned.
R ⁵ includes a halogen atom. For example, a chlorine atom is mentioned.
R ⁶ includes C1-C3 alkyl. An example is C1 alkyl (methyl).
R ⁷ includes C1-C3 alkyl. An example is C2 alkyl (ethyl).

In the compound represented by the formula (VIII), examples of R ¹ include C1-C3 alkyloxy. For example, C1 alkyloxy (methyloxy) is mentioned.
R ² includes C1-C8 alkyl. An example is C1 alkyl (methyl).
R ³ includes C1-C8 alkyl. An example is C6 alkyl (hexyl).
R ⁴ includes a halogen atom. For example, a chlorine atom is mentioned.
R ⁵ includes a halogen atom. For example, a chlorine atom is mentioned.
R ⁶ includes C1-C3 alkyl. An example is C1 alkyl (methyl).
R ⁷ includes C1-C3 alkyl. An example is C2 alkyl (ethyl).

In the compound represented by the formula (XI), examples of R ¹ include C1-C3 alkyloxy. For example, C1 alkyloxy (methyloxy) is mentioned.
R ² includes C1-C8 alkyl. An example is C1 alkyl (methyl).
R ³ includes C1-C8 alkyl. An example is C6 alkyl (hexyl).
R ⁴ includes a halogen atom. For example, a chlorine atom is mentioned.
R ⁵ includes a halogen atom. For example, a chlorine atom is mentioned.
R ⁶ includes C1-C3 alkyl. An example is C1 alkyl (methyl).

Crystals of the compound represented by the formula (II) and the compound represented by the formula (VIII) with high chemical purity and / or optical purity can be produced.
Further, a formylation reaction step of the compound represented by the formula (V), and a Horner-Wadsworth-Emmons reaction step between the obtained product and the compound represented by the formula (VI) Can be carried out continuously as a substantially single step.
Furthermore, crystals of compound (VIII ′) and its adduct can be produced.
According to the above, the compound represented by the formula (XI) or the compound (XI ′) having high chemical purity and / or optical purity, and crystals thereof can be produced.

1 shows a powder X-ray diffraction pattern of a crystal of compound (VII ′). 1 shows a powder X-ray diffraction pattern of a crystal of Compound (II ′). 1 shows HPLC in which the optical purity of a crude crystal of compound (II ′) was measured. The HPLC which measured the optical purity of the crystal | crystallization of compound (II ') after recrystallization by ethanol / water system is shown. 2 shows HPLC in which the optical purity of a crystal of compound (II ′) after recrystallization by a toluene / heptane system was measured. 1 shows an HPLC of crude crystals of compound (II ′). 2 shows an HPLC of crystals of compound (II ′) after recrystallization in an ethanol / water system. 2 shows an HPLC of crystals of compound (II ′) after recrystallization from a toluene / heptane system. 1 shows a powder X-ray diffraction pattern of a DMSO adduct crystal of compound (VIII ′). The TG / DTA analysis result of the DMSO adduct crystal | crystallization of compound (VIII ') is shown. The HPLC chart of the extract of compound (VIII ') is shown. The HPLC peak table of the extract of compound (VIII ') is shown. The HPLC chart of the DMSO adduct crystal | crystallization of compound (VIII ') is shown. The HPLC peak table of the DMSO adduct crystal | crystallization of compound (VIII ') is shown. 1 shows a powder X-ray diffraction pattern of a crystal of compound (XI ′). 1 shows a powder X-ray diffraction pattern of an acetone adduct crystal of compound (VIII ′). The TG / DTA analysis result of the acetone adduct crystal | crystallization of compound (VIII ') is shown. 1 shows a powder X-ray diffraction pattern of a hydrochloric acid adduct crystal of compound (VIII ′). The TG / DTA analysis result of the hydrochloric acid adduct crystal | crystallization of compound (VIII ') is shown. 1 shows a powder X-ray diffraction pattern of a benzoic acid adduct crystal of Compound (VIII ′). The TG / DTA analysis result of the benzoic acid adduct crystal | crystallization of compound (VIII ') is shown. 1 shows a powder X-ray diffraction pattern of a p-toluic acid adduct crystal of compound (VIII ′). The TG / DTA analysis result of the p-toluic acid adduct crystal | crystallization of compound (VIII ') is shown. The HPLC chart of the acetone adduct crystal | crystallization of compound (VIII ') is shown. The HPLC peak table of the acetone adduct crystal | crystallization of compound (VIII ') is shown. 2 shows an HPLC chart of a hydrochloric acid adduct crystal of compound (VIII ′). The HPLC peak table of the hydrochloric acid adduct crystal | crystallization of compound (VIII ') is shown. 1 shows an HPLC chart of a benzoic acid adduct crystal of compound (VIII ′). The HPLC peak table of the benzoic acid adduct crystal | crystallization of compound (VIII ') is shown. The HPLC chart of the p-toluic acid adduct crystal | crystallization of compound (VIII ') is shown. The HPLC peak table of the p-toluic acid adduct crystal | crystallization of compound (VIII ') is shown.

（式中、Ｘ^１は、脱離基；Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）で示される化合物をチオウレアと反応させ、式（ＩＩ）：

（式中、Ｒ^１、Ｒ^２およびＲ^３は上記と同義）で示される化合物を得る工程を包含する。
出発化合物の式（Ｉ）で示される化合物は、特許文献２３の記載の方法に従い製造することができる。
溶媒としては、反応を阻害しない限り特に限定はされないが、メタノール、エタノール、イソプロパノール、トルエン、キシレン等が挙げられる。例えば、エタノールとトルエンの混合溶媒を用いることができる。
反応温度は、通常、室温から溶媒が還流する温度の範囲で実施される。例えば、５０℃〜１００℃の範囲で行うことができる。
式（Ｉ）で示される化合物に対して、チオウレアの使用量は、通常、１．０〜５．０当量、例えば、１．５〜３．０当量を使用すればよい。
本発明は、得られた上記式（ＩＩ）で示される化合物を、結晶化する工程を包含する。
結晶化に用いる溶媒としては、非極性溶媒を用いることができる。例えば、トルエン、キシレン、ヘプタン、ヘキサン等が挙げられる。該溶媒は、単独溶媒および混合溶媒として用いることができる。例えば、トルエンまたはキシレンから選択される１または２の溶媒、および、ヘプタンまたはヘキサンから選択される１または２の溶媒の混合溶媒を用いることができる。例えば、トルエンおよびヘプタンの混合溶媒、トルエンおよびヘキサンの混合溶媒、キシレンおよびヘプタンの混合溶媒、ならびにキシレンおよびヘキサンの混合溶媒を用いることができる。好ましくは、トルエンおよびヘプタンの混合溶媒を用いることができる。
ＡおよびＢの混合溶媒と記載した場合、結晶化に影響を与えない限り、ＡおよびＢ以外の溶媒を少量含んでいてもよい。
結晶化に混合溶媒を用いる場合には、溶媒の添加順序は特に限定されない。例えば、得られた粗結晶を良溶媒に溶解させた後に、貧溶媒を添加して結晶を析出させてもよい。また、例えば、得られた粗結晶を良溶媒と貧溶媒を含む混合溶媒に溶解させた後に、貧溶媒を添加して結晶を析出させてもよい。
結晶化に用いる溶媒量の比率は特に限定されない。トルエンまたはキシレンから選択される１または２の溶媒の体積をｖ（ｍＬ）としたとき、ヘプタンまたはヘキサンから選択される１または２の溶媒量は、例えば約１５ｖ（ｍＬ）〜１ｖ（ｍＬ）、約１１ｖ（ｍＬ）〜４ｖ（ｍＬ）、約９ｖ（ｍＬ）〜４ｖ（ｍＬ）、約７ｖ（ｍＬ）〜５ｖ（ｍＬ）、約６ｖ（ｍＬ）が挙げられる。トルエンおよびヘプタンの混合溶媒、トルエンおよびヘキサンの混合溶媒、キシレンおよびヘプタンの混合溶媒、ならびにキシレンおよびヘキサンの混合溶媒の比率も前記と同様である。
晶析温度は、結晶化を阻害しない限り特に限定はされないが、例えば、０℃〜３０℃の範囲で行うことができる。好ましくは、１５℃〜２５℃の範囲で行うことができ、より好ましくは、２０℃で行うことができる。
また、本発明は、該結晶化工程により、有機不純物を除去することができる。該有機不純物としては、出発原料である式（Ｉ）で示される化合物中に存在する有機不純物が、チオウレアと反応して生成した副生成物を包含する。例えば、有機不純物Ａおよび有機不純物Ｂが挙げられる。
さらに、該結晶化工程により、高い光学純度を有する化合物（ＩＩ’）を製造することができる。例えば、該結晶化工程により、化合物（ＩＩ’）中に存在する有機不純物を１．５重量％以下に除去することができる。また、光学純度が９７％ｅ．ｅ．以上の化合物（ＩＩ’）を製造することができる。例えば、光学純度が９９％ｅ．ｅ．以上の化合物（ＩＩ’）を製造することができる。
次に、本発明は、塩基の存在下、式（Ｖ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子）
で示される化合物と、ホルミル化試薬として、Ｎ−ホルミルモルホリン、Ｎ−ホルミルピペリジンまたはＮ，Ｎ−ジメチルホルムアミドを反応させる工程を包含する。
出発化合物の式（Ｖ）で示される化合物は、市販品を用いることができる。
溶媒としては、反応を阻害しない限り特に限定はされないが、１，２−ジメトキシエタン、テトラヒドロフラン、シクロペンチルメチルエーテル、ジエチルエーテル、メチルｔｅｒｔ-ブチルエーテル、ジクロロメタン、トルエン、キシレンが挙げられる。例えば、１，２−ジメトキシエタンが挙げられる。
反応温度は、通常、−７８℃〜室温の範囲で実施される。例えば、−７８℃〜５℃の範囲、より望ましくは、−７８℃〜−３０℃の範囲で行うことができる。
塩基としては、ＬＤＡ、ＫＨＭＤＳ、ＬＨＭＤＳ、ｎ−ブチルリチウムまたはフェニルリチウムが挙げられる。例えば、ＬＤＡが挙げられる。式（Ｖ）で示される化合物に対して、塩基は、２．０〜５．０当量、例えば２．５〜３．５当量を使用すればよい。
ホルミル化試薬としては、Ｎ−ホルミルモルホリン、Ｎ−ホルミルピペリジンまたはＮ，Ｎ−ジメチルホルムアミドが挙げられる。例えば、Ｎ−ホルミルモルホリンまたはＮ−ホルミルピペリジンが挙げられる。例えば、Ｎ−ホルミルモルホリンが挙げられる。
式（Ｖ）で示される化合物に対して、Ｎ−ホルミルモルホリン、Ｎ−ホルミルピペリジンまたはＮ，Ｎ−ジメチルホルムアミドの使用量は、通常、２．０〜５．０当量、例えば２．５〜３．５当量を使用すればよい。
また、本工程は、上記工程の生成物に、式（ＶＩ）：

（式中、Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル；Ｒ^８は、各々独立してＣ１−Ｃ３アルキル）で示される化合物を反応させる工程を、実質上の一工程として連続的に行うことを特徴とする、式（ＶＩＩ）：

（式中、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同義）で示される化合物の製造方法を包含する。
式（ＶＩ）で示される化合物は、市販品を用いることができる。
反応温度は、通常、−７８℃〜室温の範囲で実施される。例えば、−１０℃〜１０℃の範囲で行うことができる。
式（Ｖ）で示される化合物に対して、式（ＶＩ）で示される化合物は、１．０〜５．０当量、例えば１．２〜２．０当量を使用すればよい。
通常、式（Ｖ）で示される化合物とＮ−ホルミルモルホリンを反応させる工程（ホルミル化反応）は、非特許文献２に記載されているように、後処理で酸を加えてホルミル化合物を製造する。しかしながら、本発明は、ホルミル化反応の後、酸を加えることなく、式（ＶＩ）で示される化合物とのホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）を行い、式（ＶＩＩ）で示される化合物を実質上の一工程として連続的に製造することができる。
特許文献２３には、水酸化リチウム・１水和物の存在下、化合物１５とトリエチルホスホノプロピオネートとのホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）により、化合物１３が得られたことが記載されている。しかしながら、該反応において、反応系中の水によって化合物１３のカルボン酸エステルが加水分解され、カルボン酸化合物が副生成物として生成することが明らかとなった。
本発明は、水酸化リチウム・１水和物を用いることなくホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）が進行し、反応系中に水が存在しないため、副反応のエステル加水分解は起こらないという利点がある。また、通常、ホルミル化およびホーナー・ワズワース・エモンズ反応（Horner-Wadsworth-Emmons reaction）の２段階反応により式（ＶＩＩ）で示される化合物および化合物（ＶＩＩ’）を製造するが、本発明は実質上の一工程として連続的に製造できるため、工業製造法として優れている。
さらに本発明は、式（ＩＩ）：

（式中、Ｒ^１は、Ｃ１−Ｃ３アルキルオキシまたはハロゲン原子；Ｒ^２およびＲ^３は、各々独立してＣ１−Ｃ８アルキル）
で示される化合物を、式（ＶＩＩ）：

（式中、Ｒ^４およびＲ^５は、各々独立してハロゲン原子；Ｒ^６およびＲ^７は、各々独立してＣ１−Ｃ３アルキル）
で示される化合物と反応させ、式（ＶＩＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同義）で示される化合物を得る工程を包含する。
溶媒としては、反応を阻害しない限り特に限定はされないが、トルエン、キシレン、酢酸エチル、酢酸イソプロピル、ジメチルアセトアミド、Ｎ-メチルピロリジノン等が挙げられる。例えば、酢酸エチルを用いることができる。
反応温度は、通常、室温〜溶媒が還流する温度の範囲で実施される。例えば、２０℃〜７０℃の範囲で行うことができる。
式（ＩＩ）で示される化合物に対して、式（ＶＩＩ）で示される化合物の使用量は、通常、１．０〜３．０当量、例えば、１．０〜１．３当量を使用すればよい。
アミド化の活性化剤（縮合剤）としては、ジフェノキシリン酸クロリド、塩化チオニル，メタンスルホニルクロリド、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド、１-（３-ジメチルアミノプロピル）-３-エチルカルボジイミド塩酸塩等が挙げられる。例えば、ジフェノキシリン酸クロリドが挙げられる。式（ＩＩ）で示される化合物に対して、活性化剤（縮合剤）の使用量は、通常、１．０〜５．０当量、例えば、１．０〜２．０当量を使用すればよい。
塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、モルホリン、ピリジン等が挙げられる。例えば、トリエチルアミンを用いることができる。式（ＩＩ）で示される化合物に対して、塩基の使用量は、通常、２．０〜６．０当量、例えば、２．０〜３．０当量を使用すればよい。
本発明は、得られた上記式（ＶＩＩＩ）で示される化合物を、結晶化する工程を包含する。
結晶化に用いる溶媒としては、ジメチルスルホキシド、アセトンが挙げられる。例えば、ジメチルスルホキシドを用いることができる。
また、該結晶化には、塩酸、リン酸、硫酸、安息香酸、ゲンチジン酸、ｐ−トルイル酸、３−クロロ安息香酸、３，５−ジクロロ安息香酸等の酸を使用することができる。例えば、塩酸、安息香酸、ｐ−トルイル酸を用いることができる。
また、本発明は、該結晶化工程により、有機不純物を除去することができる。該有機不純物としては、出発原料である式（ＩＩ）で示される化合物中に存在する有機不純物が、式（ＶＩＩ）で示される化合物と反応して生成した副生成物を包含する。例えば、有機不純物Ｃが挙げられる。さらに、式（ＩＩ）で示される化合物が、式（ＶＩＩ）で示される化合物中に存在する有機不純物と反応して生成した副生成物を包含する。例えば、有機不純物Ｄが挙げられる。
加えて、該結晶化工程により、化合物（ＶＩＩＩ’）の新規な結晶を製造することができる。また、該結晶化工程により、化合物（ＶＩＩＩ’）中に存在する有機不純物を、２．０重量％以下に除去することができる。The present invention relates to a compound of formula (I):

(Wherein X ¹ is a leaving group; R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl) and a compound represented by thiourea is reacted. Formula (II):

(Wherein R ¹ , R ² and R ³ are as defined above).
The starting compound represented by the formula (I) can be produced according to the method described in Patent Document 23.
The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include methanol, ethanol, isopropanol, toluene, xylene and the like. For example, a mixed solvent of ethanol and toluene can be used.
The reaction temperature is usually in the range of room temperature to the temperature at which the solvent is refluxed. For example, it can be performed in the range of 50 ° C to 100 ° C.
With respect to the compound represented by the formula (I), the amount of thiourea used is usually 1.0 to 5.0 equivalents, for example, 1.5 to 3.0 equivalents.
The present invention includes a step of crystallizing the obtained compound represented by the formula (II).
As a solvent used for crystallization, a nonpolar solvent can be used. For example, toluene, xylene, heptane, hexane, etc. are mentioned. The solvent can be used as a single solvent or a mixed solvent. For example, a mixed solvent of 1 or 2 solvent selected from toluene or xylene and 1 or 2 solvent selected from heptane or hexane can be used. For example, a mixed solvent of toluene and heptane, a mixed solvent of toluene and hexane, a mixed solvent of xylene and heptane, and a mixed solvent of xylene and hexane can be used. Preferably, a mixed solvent of toluene and heptane can be used.
When described as a mixed solvent of A and B, a small amount of a solvent other than A and B may be included as long as crystallization is not affected.
When a mixed solvent is used for crystallization, the order of addition of the solvent is not particularly limited. For example, after dissolving the obtained crude crystal in a good solvent, a poor solvent may be added to precipitate the crystal. Further, for example, after the obtained crude crystal is dissolved in a mixed solvent containing a good solvent and a poor solvent, the poor solvent may be added to precipitate the crystal.
The ratio of the amount of solvent used for crystallization is not particularly limited. When the volume of 1 or 2 solvent selected from toluene or xylene is v (mL), the amount of 1 or 2 solvent selected from heptane or hexane is, for example, about 15 v (mL) to 1 v (mL), Examples include about 11 v (mL) to 4 v (mL), about 9 v (mL) to 4 v (mL), about 7 v (mL) to 5 v (mL), and about 6 v (mL). The ratios of the mixed solvent of toluene and heptane, the mixed solvent of toluene and hexane, the mixed solvent of xylene and heptane, and the mixed solvent of xylene and hexane are the same as described above.
The crystallization temperature is not particularly limited as long as it does not inhibit crystallization, but can be performed, for example, in the range of 0 ° C to 30 ° C. Preferably, it can carry out in the range of 15 to 25 degreeC, More preferably, it can carry out at 20 degreeC.
In the present invention, organic impurities can be removed by the crystallization step. Examples of the organic impurities include by-products generated by reacting organic impurities present in the compound represented by the formula (I) as a starting material with thiourea. For example, organic impurity A and organic impurity B are mentioned.
Furthermore, compound (II ') which has high optical purity can be manufactured according to this crystallization process. For example, organic impurities present in the compound (II ′) can be removed to 1.5% by weight or less by the crystallization step. The optical purity is 97% e.e. e. The above compound (II ′) can be produced. For example, the optical purity is 99% e.e. e. The above compound (II ′) can be produced.
Next, the present invention provides a compound of formula (V):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom)
And a step of reacting N-formylmorpholine, N-formylpiperidine or N, N-dimethylformamide as a formylation reagent.
A commercial item can be used for the compound shown by the formula (V) of a starting compound.
The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include 1,2-dimethoxyethane, tetrahydrofuran, cyclopentyl methyl ether, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, and xylene. An example is 1,2-dimethoxyethane.
The reaction temperature is usually in the range of −78 ° C. to room temperature. For example, it can be carried out in the range of −78 ° C. to 5 ° C., more desirably in the range of −78 ° C. to −30 ° C.
Examples of the base include LDA, KHMDS, LHMDS, n-butyllithium, and phenyllithium. An example is LDA. The base should just use 2.0-5.0 equivalent, for example, 2.5-3.5 equivalent with respect to the compound shown by Formula (V).
Examples of the formylation reagent include N-formylmorpholine, N-formylpiperidine, or N, N-dimethylformamide. For example, N-formylmorpholine or N-formylpiperidine is mentioned. An example is N-formylmorpholine.
The amount of N-formylmorpholine, N-formylpiperidine or N, N-dimethylformamide to be used is usually 2.0 to 5.0 equivalents, for example 2.5 to 3 with respect to the compound represented by the formula (V). .5 equivalents may be used.
In addition, this step adds the product of the above step to the formula (VI):

(Wherein R ⁶ and R ⁷ are each independently C 1 -C 3 alkyl; R ⁸ is each independently C 1 -C 3 alkyl). Formula (VII), characterized in that

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above).
A commercial item can be used for the compound shown by Formula (VI).
The reaction temperature is usually in the range of −78 ° C. to room temperature. For example, it can be performed in the range of −10 ° C. to 10 ° C.
What is necessary is just to use 1.0-5.0 equivalent, for example, 1.2-2.0 equivalent for the compound shown by Formula (VI) with respect to the compound shown by Formula (V).
Usually, in the step of reacting the compound represented by formula (V) with N-formylmorpholine (formylation reaction), as described in Non-Patent Document 2, an acid is added in post-treatment to produce a formyl compound. . However, the present invention performs a Horner-Wadsworth-Emmons reaction with a compound represented by the formula (VI) without adding an acid after the formylation reaction, and the formula (VII) The compounds shown can be prepared continuously as a substantially single step.
In Patent Document 23, Compound 13 is obtained by Horner-Wadsworth-Emmons reaction between Compound 15 and triethylphosphonopropionate in the presence of lithium hydroxide monohydrate. It is described. However, in the reaction, it was revealed that the carboxylic acid ester of Compound 13 was hydrolyzed by water in the reaction system, and the carboxylic acid compound was produced as a by-product.
In the present invention, the Horner-Wadsworth-Emmons reaction proceeds without using lithium hydroxide monohydrate, and water does not exist in the reaction system. Has the advantage of not happening. In addition, the compound represented by the formula (VII) and the compound (VII ′) are usually produced by a two-stage reaction of formylation and Horner-Wadsworth-Emmons reaction. Since it can manufacture continuously as one process, it is excellent as an industrial manufacturing method.
Furthermore, the present invention provides a compound of formula (II):

(Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl)
A compound of formula (VII):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl)
With a compound of formula (VIII):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above).
The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include toluene, xylene, ethyl acetate, isopropyl acetate, dimethylacetamide, N-methylpyrrolidinone and the like. For example, ethyl acetate can be used.
The reaction temperature is usually in the range of room temperature to the temperature at which the solvent is refluxed. For example, it can be performed in the range of 20 ° C to 70 ° C.
The amount of the compound represented by the formula (VII) is usually 1.0 to 3.0 equivalents, for example, 1.0 to 1.3 equivalents with respect to the compound represented by the formula (II). Good.
Activating agents (condensing agents) for amidation include diphenoxyphosphoric chloride, thionyl chloride, methanesulfonyl chloride, N, N′-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Etc. An example is diphenoxyphosphate chloride. The amount of the activator (condensing agent) to be used is usually 1.0 to 5.0 equivalents, for example, 1.0 to 2.0 equivalents, relative to the compound represented by the formula (II). .
Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, morpholine, pyridine and the like. For example, triethylamine can be used. With respect to the compound represented by the formula (II), the amount of the base used is usually 2.0 to 6.0 equivalents, for example, 2.0 to 3.0 equivalents.
The present invention includes a step of crystallizing the obtained compound represented by the formula (VIII).
Examples of the solvent used for crystallization include dimethyl sulfoxide and acetone. For example, dimethyl sulfoxide can be used.
For the crystallization, acids such as hydrochloric acid, phosphoric acid, sulfuric acid, benzoic acid, gentisic acid, p-toluic acid, 3-chlorobenzoic acid, 3,5-dichlorobenzoic acid can be used. For example, hydrochloric acid, benzoic acid, and p-toluic acid can be used.
In the present invention, organic impurities can be removed by the crystallization step. Examples of the organic impurity include a by-product generated by reacting an organic impurity present in the compound represented by the formula (II) as a starting material with the compound represented by the formula (VII). For example, the organic impurity C is mentioned. Further, the compound represented by the formula (II) includes a by-product produced by reacting with an organic impurity present in the compound represented by the formula (VII). For example, the organic impurity D is mentioned.
In addition, a novel crystal of compound (VIII ′) can be produced by the crystallization step. Further, the crystallization step can remove organic impurities present in the compound (VIII ′) to 2.0% by weight or less.

The method for specifying the crystal of the present invention will be described below.
Unless stated otherwise, numerical values in this specification and in the claims are approximate values. Numerical fluctuations are due to instrument calibration, instrument error, substance purity, crystal size, sample size, and other factors.

  As used herein, “crystal” refers to a substance having an ordered and long range molecular structure. The crystallinity of the crystalline form can be measured by a number of techniques including, for example, powder X-ray diffraction, moisture adsorption, differential, calorimetric analysis, solution colorimetry, and dissolution characteristics.

In general, a crystalline organic compound is composed of a large number of atoms periodically arranged in a three-dimensional space. Structural periodicity typically develops physical properties that are clearly distinguishable by most spectroscopic probes (eg, X-ray diffraction, infrared spectra, Raman spectra, and solid state NMR).
Among these, powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystallinity of solids. When X-rays are irradiated on the crystal, they are reflected by the crystal lattice plane, interfere with each other, the intensity of only the diffraction lines in the direction satisfying the condition predicted by the Bragg law increases, and the rest cancel each other and are not observed. On the other hand, a wide range of ordered diffraction lines is not observed for amorphous solids. Amorphous solids typically exhibit a broad XRPD pattern, called a halo pattern, due to the absence of a wide range of repeating crystal lattices.

  The crystal of compound (II '), the crystal of compound (XI'), and the crystal of compound (VIII ') or its adducts disclosed in this application have a powder X-ray diffraction profile. For example, in the case of the dimethyl sulfoxide adduct of compound (VIII ′), the crystal can be identified by the presence of a characteristic diffraction peak. A characteristic diffraction peak as used herein is a peak selected from the observed diffraction pattern. Preferably, the characteristic peaks are selected from about 20 in the diffraction pattern, more preferably about 10 and most preferably about 5.

  In general, since the diffraction angle (2θ) in powder X-ray diffraction may cause an error within a range of ± 0.2 °, the above diffraction angle value includes a numerical value within a range of about ± 0.2 °. Need to be understood. Therefore, the present invention includes not only a crystal in which the diffraction angle of the peak in powder X-ray diffraction completely matches but also a crystal in which the diffraction angle of the peak matches with an error of about ± 0.2 °.

  In general, it is known that the relative intensities of the peaks shown in the tables and figures below can vary depending on a number of factors, such as the crystal orientation effect on the x-ray beam, the purity of the material being analyzed or the crystallinity of the sample. It has been. The peak position can also be shifted based on the variation in sample height. Furthermore, although different shifts are obtained according to the Bragg equation (nλ = 2dsin θ) when measured using different wavelengths, other XRPD patterns obtained by using such different wavelengths are also within the scope of the present invention.

  The crystal of the compound (II ′), the crystal of the compound (XI ′), and the crystal of the compound (VIII ′) or an adduct thereof produced by the above production method are stable, and the above production process is performed. Alternatively, it is a crystal useful for producing a pharmaceutical composition because it is easy to handle and has high purity in producing a pharmaceutical composition containing compound (XI ′) as an active ingredient.

The crystal of the present invention can also be specified by a thermal analysis technique.
Here, TG / DTA (differential thermothermogravimetric simultaneous measurement) is one of the main measurement methods of thermal analysis, and is a method of measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules.
TG / DTA is a method for measuring changes in weight and calorie with temperature or time of a pharmaceutically active ingredient. By plotting the obtained data against temperature or time, TG (thermogravimetric) and DTA (differential) A heat) curve is obtained. From the TG / DTA curve, it is possible to obtain information on changes in weight and calorie regarding decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of pharmaceutically active ingredients.
In TG / DTA, “melting point” refers to the onset temperature.
For TG / DTA, it is known that the observed temperature and weight changes can depend on the rate of temperature change as well as the sample preparation technique and the particular equipment used. In the identification of crystal identity, the overall pattern is important and may vary somewhat depending on the measurement conditions.

The pharmaceutical composition containing the compound (XI ′) exhibits excellent thrombopoietin receptor agonist activity, thrombocytopenia after thrombocytopenia (hematopoietic stem cell transplantation (bone marrow transplant etc.), etc., after chemotherapy, aplastic anemia, Acquired thrombocytopenia such as myelodysplastic syndrome, idiopathic thrombocytopenic purpura, congenital thrombocytopenia such as thrombopoietin deficiency, viral pneumonia (such as hepatitis C), other liver diseases (such as cirrhosis)) It can be used as an agent (platelet production regulator) for the pathology of blood diseases accompanied by abnormal platelet counts. It can be used for treatment and / or prevention of abnormal platelet counts by administration of anticancer agents for hematopoietic tumors, solid tumors and the like. It can be used for the treatment and / or prevention of thrombocytopenia during surgery such as cardiovascular system (cardiovascular, etc.).
When this pharmaceutical composition is administered to humans for the purpose of treating the above-mentioned diseases, it can be administered orally as powders, granules, tablets, capsules, pills, liquids, etc., or injections, suppositories, transdermal It can be administered parenterally as an absorbent, inhalant and the like. In addition, excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives suitable for the dosage form may be mixed with an effective amount of the present compound as necessary to obtain a pharmaceutical preparation. it can. In the case of an injection, it is sterilized with an appropriate carrier to obtain a preparation.
The dose varies depending on the disease state, administration route, patient age, or body weight, but is usually 0.01 to 100 mg / kg / day, preferably 0.02 to 10 mg / day when orally administered to an adult. kg / day, most preferably 0.05-5 mg / kg / day.

The invention is further illustrated by the following examples. These do not limit the invention. Efforts are being made to ensure accuracy with respect to numbers (eg, amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless otherwise indicated,% is weight percent of ingredients and weight percent of total weight of composition. The pressure is at or near atmospheric pressure.
Other abbreviations used herein are defined as follows:
g: gram L: liter mg: milligram mL: milliliter LDA: lithium diisopropylamide DMSO: dimethyl sulfoxide HPLC: high performance liquid chromatography

(Measurement of powder X-ray diffraction pattern)
The powder X-ray diffraction measurement of the crystals obtained in each Example was performed under the following measurement conditions in accordance with the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia.
For the powder X-ray diffraction pattern, the raw data is shown as a diagram. Further, smoothing, background removal and Kα removal were performed, and the analyzed data are shown as a table.
(apparatus)
RINT-TTRIII manufactured by Rigaku
(Method of operation)
The sample was measured under the following conditions.
Measurement method: Reflection method Light source type: Cu tube Use wavelength: CuKα ray tube current: 300 mA
Tube voltage: 50Kv
Sample plate: Aluminum X-ray incident angle: 4 °

(Measurement of TG / DTA data)
About 5 mg of each crystal obtained in each example was weighed, put into an aluminum pan, and measured in an open system. The measurement conditions are as follows.
(Measurement condition)
Equipment: TG / DTA7200 manufactured by Hitachi High-Tech Science Co., Ltd.
Measurement temperature range: 30 ° C-250 ° C
Temperature increase rate: 10 ° C / min

(NMR measurement)
When NMR data is shown, there are cases where all measured peaks are not described.

（メソッドＣ）
カラム：Unison UK-C18，φ4.6×100 mm，3 μm（Imtakt）
流量：毎分1.0 mL
ＵＶ検出波長：248nm
移動相A：トリフルオロ酢酸試液
移動相B：液体クロマトグラフィー用アセトニトリル
面積測定範囲：試料注入後約50分間
グラジエントプログラムを表１に示す。

なお、ＨＰＬＣの保持時間には、多少の誤差を含むものとして理解される必要がある。(HPLC measurement)
(Method A)
Column: CHIRALCEL OJ-H, 4.6mm x 250mm, 5μm (Daicel Chemical Industries)
Flow rate: 1.0 mL / min UV detection wavelength: 284 nm
Mobile phase: acetonitrile / diethylamine mixed solution for HPLC (1000: 1)
(Method B)
Column: Unison UK-C18, φ4.6 × 100 mm, 3 μm (Imtakt)
Flow rate: 1.0 mL per minute
UV detection wavelength: 265nm
Mobile phase A: Trifluoroacetic acid reagent / acetonitrile mixture for liquid chromatography (13: 7)
Mobile phase B: Acetonitrile area measurement range for liquid chromatography: Table 1 shows the gradient program for about 50 minutes after sample injection.

(Method C)
Column: Unison UK-C18, φ4.6 × 100 mm, 3 μm (Imtakt)
Flow rate: 1.0 mL per minute
UV detection wavelength: 248nm
Mobile phase A: Trifluoroacetic acid test solution Mobile phase B: Acetonitrile area for liquid chromatography Measurement range: Table 1 shows the gradient program for about 50 minutes after sample injection.

It should be understood that the HPLC retention time includes some errors.

（工程１）化合物（ＶＩＩ’）の合成
窒素雰囲気下、化合物１（２．００ｋｇ）を１，２−ジメトキシエタン（２８．０ｋｇ）に溶解した。２５％ＬＤＡテトラヒドロフラン−ヘプタン−エチルベンゼン溶液（１３．２０ｋｇ）を−５５℃で１時間かけて滴下し、３０分間撹拌した。Ｎ−ホルミルモルホリン(３．７４ｋｇ）の１，２−ジメトキシエタン（３．０ｋｇ）溶液を−５５℃で４０分間かけて滴下し、１時間撹拌した。２−ホスホノプロパン酸トリエチル(３．７４ｋｇ）の１，２−ジメトキシエタン（３．０ｋｇ）溶液を０℃で４５分間かけて滴下し、２時間撹拌した。反応液に３５％硫酸水溶液（１５．８ｋｇ）を４０分間かけて滴下した。水（１６．０ｋｇ）を加え、抽出した。得られた有機層を水（８．０ｋｇ）で洗浄し、溶媒を減圧留去した。アセトニトリル（１６．０ｋｇ）を加え、２５℃で１時間撹拌し、０℃に冷却して５時間３０分間撹拌した。析出した結晶を濾取し、５℃のアセトニトリル（３．２ｋｇ）で洗浄した。得られた結晶を７５℃でアセトニトリル（１６．０ｋｇ）に溶解した。６０℃に冷却し、３０分間撹拌した。１時間かけて３０℃まで冷却し、４５分間撹拌した。４０分間かけて５℃まで冷却し、３時間撹拌した。析出した結晶を濾取し、５℃のアセトニトリル（３．２ｋｇ）で洗浄した。得られた結晶を７５℃でアセトニトリル（１３．０ｋｇ）に溶解した。６０℃に冷却し、３０分間撹拌した。さらに、１時間かけて３０℃まで冷却し、７０分間撹拌した。３０分間かけて５℃まで冷却し、４時間撹拌した。析出した結晶を濾取した。５℃のアセトニトリル（３．２ｋｇ）で洗浄し、乾燥して化合物（ＶＩＩ’）（１．６３ｋｇ、収率５１．２％）を得た。
NMR（CDCl₃）δ ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz)
粉末Ｘ線回折の結果を図１および表３に示す。

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：８．１±０．２°，１６．３±０．２°，１９．２±０．２°，２０．０±０．２°，２４．８±０．２°，および３９．０±０．２°度にピークが認められた。

(Step 1) Synthesis of Compound (VII ′) Compound 1 (2.00 kg) was dissolved in 1,2-dimethoxyethane (28.0 kg) under a nitrogen atmosphere. A 25% LDA tetrahydrofuran-heptane-ethylbenzene solution (13.20 kg) was added dropwise at -55 ° C over 1 hour, and the mixture was stirred for 30 minutes. A solution of N-formylmorpholine (3.74 kg) in 1,2-dimethoxyethane (3.0 kg) was added dropwise at −55 ° C. over 40 minutes and stirred for 1 hour. A solution of triethyl 2-phosphonopropanoate (3.74 kg) in 1,2-dimethoxyethane (3.0 kg) was added dropwise at 0 ° C. over 45 minutes and stirred for 2 hours. A 35% aqueous sulfuric acid solution (15.8 kg) was added dropwise to the reaction solution over 40 minutes. Water (16.0 kg) was added and extracted. The obtained organic layer was washed with water (8.0 kg), and the solvent was distilled off under reduced pressure. Acetonitrile (16.0 kg) was added, and the mixture was stirred at 25 ° C for 1 hour, cooled to 0 ° C, and stirred for 5 hours and 30 minutes. The precipitated crystals were collected by filtration and washed with 5 ° C. acetonitrile (3.2 kg). The obtained crystals were dissolved in acetonitrile (16.0 kg) at 75 ° C. Cool to 60 ° C. and stir for 30 minutes. Cooled to 30 ° C. over 1 hour and stirred for 45 minutes. The mixture was cooled to 5 ° C. over 40 minutes and stirred for 3 hours. The precipitated crystals were collected by filtration and washed with 5 ° C. acetonitrile (3.2 kg). The obtained crystals were dissolved in acetonitrile (13.0 kg) at 75 ° C. Cool to 60 ° C. and stir for 30 minutes. Furthermore, it cooled to 30 degreeC over 1 hour, and stirred for 70 minutes. The mixture was cooled to 5 ° C. over 30 minutes and stirred for 4 hours. The precipitated crystals were collected by filtration. It was washed with acetonitrile (3.2 kg) at 5 ° C. and dried to obtain compound (VII ′) (1.63 kg, yield 51.2%).
NMR (CDCl ₃ ) δ ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz)
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 8.1 ± 0.2 °, 16.3 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0.2 °, 24 Peaks were observed at .8 ± 0.2 ° and 39.0 ± 0.2 °.

（工程２）化合物４の合成
窒素雰囲気下、化合物３（３．００ｋｇ）を１ｍｏｌ/Ｌイソプロピルマグネシウムクロリドテトラヒドロフラン溶液（１１．４０ｋｇ）に２５℃で１時間かけて滴下し、２時間撹拌した。１ｍｏｌ/Ｌイソプロピルマグネシウムクロリドテトラヒドロフラン溶液（０．５６ｋｇ）を２５℃で加え、２時間撹拌した。反応液にＮ−メトキシ−Ｎ−メチルアセトアミド（１．４５ｋｇ）を２５℃で４０分間かけて滴下し、８０分間撹拌した。反応液に７％塩酸（９．７ｋｇ）を加え、トルエン（１１．０ｋｇ）で抽出した。得られた有機層を水で２回（各７．５ｋｇ）洗浄し、溶媒を減圧留去し、化合物４（２．６３ｋｇ）を得た。
NMR（CDCl₃）δ ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H)
ppm:

（工程３）化合物５の合成
窒素雰囲気下、化合物４（２．６３ｋｇ）にクロロ[（１Ｓ、２Ｓ）−Ｎ−（ｐ−トルエンスルホニル）−１，２−ジフェニルエタンジアミン]（ｐ−シメン）ルテニウム（II）（２８．６ｇ）、テトラヒドロフラン（１．３ｋｇ）及びトリエチルアミン（８８０．０ｇ）を加えた。ギ酸（５７０．０ｇ）を４０℃で６時間かけて滴下し、１時間撹拌した。反応液に３．５％塩酸（１４．４ｋｇ）を加え、トルエン（１３．０ｋｇ）で抽出した。有機層を３．５％塩酸（１４．４ｋｇ）及び水（７．５ｋｇ）で洗浄し、溶媒を減圧濃縮し、化合物５のトルエン溶液（４．４４ｋｇ）を得た。

（工程４）化合物６の合成
窒素雰囲気下、水酸化カリウム（６．０３ｋｇ）を水（６．０ｋｇ）に溶解した。溶液に、テトラブチルアンモニウムブロマイド（１８２．０ｇ）及び化合物５のトルエン溶液（４．４４ｋｇ）を加えた。１−ブロモヘキサン（２．７９ｋｇ）を６０℃で１時間かけて滴下し、４時間撹拌した。反応液に水（４．４ｋｇ）を加えて抽出した。得られた有機層を粉末セルロースで濾過し、濾液にトルエン（３．０ｋｇ）及び水（７．６ｋｇ）を加えて抽出した。有機層から溶媒を減圧留去した。トルエン（７．８ｋｇ）を加えて溶媒を減圧留去する操作を５回繰り返し、化合物６のトルエン溶液（１０．０ｋｇ）を得た。

（工程５）化合物７の合成
窒素雰囲気下、マグネシウム粉（３０１．０ｇ）、テトラヒドロフラン（１．３ｋｇ）、トルエン（６．４ｋｇ）及び１ｍｏｌ/Ｌイソプロピルマグネシウムクロリドテトラヒドロフラン溶液（４３２．０ｇ）に化合物６のトルエン溶液（０．５０ｋｇ）を３０℃で加え、２時間撹拌した。化合物６のトルエン溶液（９．５０ｋｇ）を５０℃で３時間かけて滴下し、２時間撹拌した。１−ブロモヘキサン（７４６．０ｇ）を５０℃で加えて、１時間撹拌した。２−クロロ−Ｎ−メトキシ−Ｎ−メチルアセトアミド（１．７８ｋｇ）のトルエン（５．３ｋｇ）溶液を５℃で１時間かけて滴下し、１時間撹拌した。反応液に３．７％塩酸（１６．７ｋｇ）を加え、抽出した。得られた有機層を水（１５．０ｋｇ）で洗浄した後、減圧濃縮し、化合物７のトルエン溶液（８．２５ｋｇ）を得た。

（工程６）化合物（ＩＩ’）の合成
窒素雰囲気下、チオウレア（１．０３ｋｇ）、エタノール（１．２ｋｇ）及びトルエン（６．３ｋｇ）に化合物７のトルエン溶液（８．２５ｋｇ）を６５℃で３時間かけて滴下し、２時間撹拌した。反応液に０．７％塩酸（３０．６ｋｇ）を加えて抽出し、水（３０．０ｋｇ）で２回洗浄した。有機層にエタノール（９．５ｋｇ）、ヘプタン（１０．０ｋｇ）及び３．５％塩酸（５．９ｋｇ）を加えて抽出した。得られた水層と４％塩酸（１．５ｋｇ）及びエタノール（３．５ｋｇ）により有機層から抽出した水層を合併し、ヘプタン（１０．０ｋｇ）で洗浄してエタノール（３．１ｋｇ）を加えた。８％水酸化ナトリウム水溶液（６．０ｋｇ）を５℃で３０分間かけて滴下し、２０分間撹拌した。８％水酸化ナトリウム水溶液（５．８ｋｇ）を５℃で１５分間かけて滴下した。析出した結晶を濾取し、４５％エタノール水溶液（１０．９ｋｇ）及び水（１５．０ｋｇ）で洗浄した（化合物（ＩＩ’）の粗結晶）。得られた粗結晶をエタノール（８．１ｋｇ）に５０℃で溶解し、１時間かけて１０℃まで冷却し、３０分間撹拌した。水（１０．０ｋｇ）を２時間かけて滴下し、３０分間撹拌した。析出した結晶を濾取し、５０％エタノール水溶液（７．５ｋｇ）及び水（１０．０ｋｇ）で洗浄した（エタノール／水系による再結晶後の化合物（ＩＩ’）の結晶）。得られた結晶をトルエン（１．６ｋｇ）及びヘプタン（１．３ｋｇ）に５５℃で溶解し、１時間かけて２０℃まで冷却し、３０分間撹拌した。ヘプタン（６．３ｋｇ）を３０分間かけて滴下し、１５分間撹拌した。析出した結晶を濾取し、トルエン（０．３ｋｇ）とヘプタン（２．３ｋｇ）の混合溶媒で洗浄後、乾燥して化合物（ＩＩ’）（１．６７ｋｇ、収率４４．５％）を得た（トルエン／ヘプタン系による再結晶後の化合物（ＩＩ’）の結晶）。
NMR（CDCl₃）δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 - 1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)
粉末Ｘ線回折の結果を図２および表４に示す。

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：１２．５±０．２°，１３．０±０．２°，１３．６±０．２°，１６．４±０．２°，２３．０±０．２°，２４．３±０．２°度にピークが認められた。
上記、化合物（ＩＩ’）の粗結晶、エタノール／水系による再結晶後の化合物（ＩＩ’）の結晶およびトルエン／ヘプタン系による再結晶後の化合物（ＩＩ’）の結晶の光学純度の結果を各々、図３、図４および図５ならびに表５に示す。

（ＨＰＬＣは上記メソッドＡにて測定した。）
上記表の結果に示す通り、エタノール／水系による再結晶と比較して、トルエン／ヘプタン系による再結晶は、高い光学純度を有する化合物（ＩＩ’）の結晶を製造することができる。
次に、上記、化合物（ＩＩ’）の粗結晶、エタノール／水系による再結晶後の化合物（ＩＩ’）の結晶およびトルエン／ヘプタン系による再結晶後の化合物（ＩＩ’）の結晶のＨＰＬＣの結果を各々、図６、図７および図８ならびに表６に示す。

（単位は、ピーク面積（％）を示す。Ｎ．Ｄ．は、不検出を示す。ＨＰＬＣは上記メソッドＢにて測定した。）
上記表の結果に示す通り、エタノール／水系による再結晶と比較して、トルエン／ヘプタン系による再結晶は、有機不純物Ａおよび有機不純物Ｂを効率的に除去できることがわかる。

（工程７）化合物（ＶＩＩＩ’）のＤＭＳＯ付加物の合成
窒素雰囲気下、化合物（ＩＩ’）（１．５０ｋｇ）及び化合物（ＶＩＩ’）（１．４３ｋｇ）に酢酸エチル（１７．６ｋｇ）及びトリエチルアミン（１．０９ｋｇ）を順次加え、溶解した。ジフェニルホスホロクロリデート（１．４６ｋｇ）を５０℃で１時間かけて滴下し、３時間撹拌した。反応液を２５℃に冷却し、２．６％塩酸（８．１ｋｇ）を加えた後、抽出した。得られた有機層に６．３％水酸化ナトリウム水溶液（３．２ｋｇ）及び１４％炭酸ナトリウム水溶液（５．２ｋｇ）を加え、２０分間撹拌した。８．３％塩酸でｐＨ７．５に調整し、抽出した。有機層を４．８％塩化ナトリウム水溶液（１１．０ｋｇ）で洗浄した。ＤＭＳＯ（１６．５ｋｇ）を加え、減圧濃縮した。ＤＭＳＯ（５．８ｋｇ）を加え、４０℃で３０分間かけて水（０．９ｋｇ）を滴下し、１時間撹拌した。３０分間かけて２５℃に冷却し、３０分間撹拌した。２５℃で３０分間かけて水（１．４ｋｇ）を滴下し、析出した結晶を濾取した。９０％ＤＭＳＯ水溶液（１０．０ｋｇ）及び水（２７．０ｋｇ）で洗浄後、乾燥して化合物（ＶＩＩＩ’）のＤＭＳＯ付加物（２．９８ｋｇ、収率９５．２％）の結晶を得た。
1H-NMR（CDCl₃）δ：0.87 (t, J = 6.8Hz, 3H), 1.20-1.34 (m, 6H), 1.37 (t, J = 7.1Hz, 3H), 1.44 (d, J = 6.5Hz, 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 (q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H).
粉末Ｘ線回折の結果を図９および表７に示す。

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．２°±０．２°、７．０°±０．２°、８．７°±０．２°、１０．５°±０．２°、１２．３°±０．２°、１４．０°±０．２°、１５．８°±０．２°、１９．３°±０．２°、２２．５°±０．２°および２４．１°±０．２°にピークが認められた。
ＴＧ／ＤＴＡ分析結果を図１０に示す。
次に、下記参考例１に記載の濃縮乾固物および上記ＤＭＳＯ付加物結晶のＨＰＬＣの結果を各々、図１１および図１２、図１３および図１４、ならびに表８に示す。

（単位は、ピーク面積（％）を示す。ＨＰＬＣは上記メソッドＣにて測定した。）
上記表の結果に示す通り、抽出液と比較すると、化合物（ＶＩＩＩ’）のＤＭＳＯ付加物の結晶中には、有機不純物Ｄの残存が少なく、約５６％除去できることがわかる。
（工程８）
窒素雰囲気下、化合物（ＶＩＩＩ’）のＤＭＳＯ付加物（２．５０ｋｇ）をエタノール（１５．８ｋｇ）に溶解した。溶液に２４％水酸化ナトリウム水溶液（１．９７ｋｇ）を４５℃で３０分間かけて滴下し、３時間撹拌した。反応液を２５℃に冷却し、水（２０．０ｋｇ）及びエタノール（７．８ｋｇ）を加えた。１８％塩酸（２．６１ｋｇ）を２５℃で３０分間かけて滴下し、特許文献２３に記載の方法に従って製造した種晶を加えた。３時間撹拌した後、一晩静置した。その後、析出した結晶を濾取し、５０％エタノール水溶液（１４．２ｋｇ）で洗浄後、乾燥して化合物（ＸＩ’）（１．９９ｋｇ、収率９３．９％）を得た。
NMR（CDCl₃）δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 - 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 - 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz) , 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
粉末Ｘ線回折の結果を図１５に示す。(Synthesis of Compound (XI ′))

(Step 2) Synthesis of Compound 4 Under a nitrogen atmosphere, Compound 3 (3.00 kg) was added dropwise to a 1 mol / L isopropylmagnesium chloride tetrahydrofuran solution (11.40 kg) at 25 ° C. over 1 hour and stirred for 2 hours. A 1 mol / L isopropyl magnesium chloride tetrahydrofuran solution (0.56 kg) was added at 25 ° C., and the mixture was stirred for 2 hours. N-methoxy-N-methylacetamide (1.45 kg) was added dropwise to the reaction solution at 25 ° C. over 40 minutes, and the mixture was stirred for 80 minutes. 7% hydrochloric acid (9.7 kg) was added to the reaction mixture, and the mixture was extracted with toluene (11.0 kg). The obtained organic layer was washed twice with water (7.5 kg each), and the solvent was distilled off under reduced pressure to obtain Compound 4 (2.63 kg).
NMR (CDCl ₃ ) δ ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H)
ppm:

(Step 3) Synthesis of Compound 5 Under nitrogen atmosphere, Compound 4 (2.63 kg) was mixed with chloro [(1S, 2S) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (p-cymene). Ruthenium (II) (28.6 g), tetrahydrofuran (1.3 kg) and triethylamine (880.0 g) were added. Formic acid (570.0 g) was added dropwise at 40 ° C. over 6 hours and stirred for 1 hour. To the reaction solution, 3.5% hydrochloric acid (14.4 kg) was added and extracted with toluene (13.0 kg). The organic layer was washed with 3.5% hydrochloric acid (14.4 kg) and water (7.5 kg), and the solvent was concentrated under reduced pressure to obtain a toluene solution of compound 5 (4.44 kg).

(Step 4) Synthesis of Compound 6 Under a nitrogen atmosphere, potassium hydroxide (6.03 kg) was dissolved in water (6.0 kg). Tetrabutylammonium bromide (182.0 g) and a toluene solution of compound 5 (4.44 kg) were added to the solution. 1-Bromohexane (2.79 kg) was added dropwise at 60 ° C. over 1 hour and stirred for 4 hours. Water (4.4 kg) was added to the reaction solution for extraction. The obtained organic layer was filtered through powdered cellulose, and toluene (3.0 kg) and water (7.6 kg) were added to the filtrate for extraction. The solvent was distilled off from the organic layer under reduced pressure. The operation of adding toluene (7.8 kg) and distilling off the solvent under reduced pressure was repeated 5 times to obtain a toluene solution of compound 6 (10.0 kg).

(Step 5) Synthesis of Compound 7 In a nitrogen atmosphere, compound 6 was added to magnesium powder (301.0 g), tetrahydrofuran (1.3 kg), toluene (6.4 kg), and 1 mol / L isopropyl magnesium chloride tetrahydrofuran solution (432.0 g). Toluene solution (0.50 kg) was added at 30 ° C. and stirred for 2 hours. A toluene solution of compound 6 (9.50 kg) was added dropwise at 50 ° C. over 3 hours, and the mixture was stirred for 2 hours. 1-Bromohexane (746.0 g) was added at 50 ° C. and stirred for 1 hour. A solution of 2-chloro-N-methoxy-N-methylacetamide (1.78 kg) in toluene (5.3 kg) was added dropwise at 5 ° C. over 1 hour and stirred for 1 hour. To the reaction solution, 3.7% hydrochloric acid (16.7 kg) was added and extracted. The obtained organic layer was washed with water (15.0 kg) and then concentrated under reduced pressure to obtain a toluene solution of compound 7 (8.25 kg).

(Step 6) Synthesis of Compound (II ′) Under a nitrogen atmosphere, a toluene solution (8.25 kg) of Compound 7 in thiourea (1.03 kg), ethanol (1.2 kg) and toluene (6.3 kg) at 65 ° C. The solution was added dropwise over 3 hours and stirred for 2 hours. The reaction solution was extracted by adding 0.7% hydrochloric acid (30.6 kg), and washed twice with water (30.0 kg). Ethanol (9.5 kg), heptane (10.0 kg) and 3.5% hydrochloric acid (5.9 kg) were added to the organic layer for extraction. The obtained aqueous layer was combined with the aqueous layer extracted from the organic layer with 4% hydrochloric acid (1.5 kg) and ethanol (3.5 kg), washed with heptane (10.0 kg), and ethanol (3.1 kg) was added. added. An 8% aqueous sodium hydroxide solution (6.0 kg) was added dropwise at 5 ° C. over 30 minutes and stirred for 20 minutes. An 8% aqueous sodium hydroxide solution (5.8 kg) was added dropwise at 5 ° C. over 15 minutes. The precipitated crystals were collected by filtration and washed with 45% aqueous ethanol (10.9 kg) and water (15.0 kg) (crude crystals of compound (II ′)). The obtained crude crystals were dissolved in ethanol (8.1 kg) at 50 ° C., cooled to 10 ° C. over 1 hour, and stirred for 30 minutes. Water (10.0 kg) was added dropwise over 2 hours and stirred for 30 minutes. The precipitated crystals were collected by filtration and washed with 50% aqueous ethanol (7.5 kg) and water (10.0 kg) (crystals of compound (II ′) after recrystallization in an ethanol / water system). The obtained crystals were dissolved in toluene (1.6 kg) and heptane (1.3 kg) at 55 ° C., cooled to 20 ° C. over 1 hour, and stirred for 30 minutes. Heptane (6.3 kg) was added dropwise over 30 minutes and stirred for 15 minutes. The precipitated crystals were collected by filtration, washed with a mixed solvent of toluene (0.3 kg) and heptane (2.3 kg), and then dried to obtain compound (II ′) (1.67 kg, yield 44.5%). (Crystal of compound (II ′) after recrystallization by toluene / heptane system).
NMR (CDCl ₃ ) δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2-1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 ( 2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 12.5 ± 0.2 °, 13.0 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0.2 °, 23 Peaks were observed at 0.0 ± 0.2 ° and 24.3 ± 0.2 °.
The optical purity results of the crude crystal of compound (II ′), the crystal of compound (II ′) after recrystallization with ethanol / water system, and the crystal of compound (II ′) after recrystallization with toluene / heptane system are shown respectively. 3, FIG. 4 and FIG. 5 and Table 5.

(HPLC was measured by method A above.)
As shown in the results of the above table, compared with recrystallization by ethanol / water system, recrystallization by toluene / heptane system can produce crystals of compound (II ′) having high optical purity.
Next, HPLC results of the above-mentioned crude crystals of compound (II ′), crystals of compound (II ′) after recrystallization with ethanol / water system, and crystals of compound (II ′) after recrystallization with toluene / heptane system Are shown in FIGS. 6, 7 and 8 and Table 6, respectively.

(Unit indicates peak area (%). ND indicates non-detection. HPLC was measured by the method B above.)
As shown in the results of the above table, it can be seen that recrystallization with toluene / heptane system can efficiently remove organic impurities A and B as compared with recrystallization with ethanol / water system.

(Step 7) Synthesis of DMSO adduct of compound (VIII ′) Under nitrogen atmosphere, compound (II ′) (1.50 kg) and compound (VII ′) (1.43 kg) were mixed with ethyl acetate (17.6 kg) and triethylamine. (1.09 kg) was sequentially added and dissolved. Diphenyl phosphorochloridate (1.46 kg) was added dropwise at 50 ° C. over 1 hour and stirred for 3 hours. The reaction mixture was cooled to 25 ° C., 2.6% hydrochloric acid (8.1 kg) was added, and the mixture was extracted. To the obtained organic layer, a 6.3% aqueous sodium hydroxide solution (3.2 kg) and a 14% aqueous sodium carbonate solution (5.2 kg) were added and stirred for 20 minutes. The mixture was adjusted to pH 7.5 with 8.3% hydrochloric acid and extracted. The organic layer was washed with a 4.8% aqueous sodium chloride solution (11.0 kg). DMSO (16.5 kg) was added and concentrated under reduced pressure. DMSO (5.8 kg) was added, water (0.9 kg) was added dropwise at 40 ° C. over 30 minutes, and the mixture was stirred for 1 hour. Cool to 25 ° C. over 30 minutes and stir for 30 minutes. Water (1.4 kg) was added dropwise at 25 ° C. over 30 minutes, and the precipitated crystals were collected by filtration. After washing with 90% aqueous DMSO solution (10.0 kg) and water (27.0 kg), it was dried to obtain a DMSO adduct (2.98 kg, yield 95.2%) of compound (VIII ′).
1H-NMR (CDCl ₃ ) δ: 0.87 (t, J = 6.8Hz, 3H), 1.20-1.34 (m, 6H), 1.37 (t, J = 7.1Hz, 3H), 1.44 (d, J = 6.5Hz , 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 ( q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H).
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0. 2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° ± 0. Peaks were observed at 2 ° and 24.1 ° ± 0.2 °.
The TG / DTA analysis results are shown in FIG.
Next, FIG. 11 and FIG. 12, FIG. 13 and FIG. 14, and Table 8 show the HPLC results of the concentrated dried product described in Reference Example 1 and the DMSO adduct crystal, respectively.

(The unit indicates the peak area (%). HPLC was measured by the above method C.)
As shown in the results of the above table, it can be seen that the organic impurity D remains little in the DMSO adduct crystal of the compound (VIII ′) and can be removed by about 56% as compared with the extract.
(Process 8)
Under a nitrogen atmosphere, a DMSO adduct (2.50 kg) of compound (VIII ′) was dissolved in ethanol (15.8 kg). A 24% aqueous sodium hydroxide solution (1.97 kg) was added dropwise to the solution at 45 ° C. over 30 minutes, and the mixture was stirred for 3 hours. The reaction was cooled to 25 ° C. and water (20.0 kg) and ethanol (7.8 kg) were added. 18% hydrochloric acid (2.61 kg) was added dropwise at 25 ° C. over 30 minutes, and seed crystals produced according to the method described in Patent Document 23 were added. After stirring for 3 hours, the mixture was allowed to stand overnight. Thereafter, the precipitated crystals were collected by filtration, washed with a 50% aqueous ethanol solution (14.2 kg), and dried to obtain compound (XI ′) (1.99 kg, yield 93.9%).
NMR (CDCl ₃ ) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2-1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52-1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
The result of powder X-ray diffraction is shown in FIG.

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．２°±０．２°、６．９°±０．２°、１０．４°±０．２°、１２．１°±０．２°、１３．８°±０．２°、１５．６°±０．２°、１７．３°±０．２°、１９．１°±０．２°、２０．８°±０．２°および２４．３°±０．２°にピークが認められた。
ＴＧ／ＤＴＡ分析結果を図１７に示す。Various adducts of the compound (VIII ′) shown below can be produced in the same manner as in Step 7 of Example 2.
(Reference Example 1)
(Synthesis of Acetone Adduct Crystal of Compound (VIII ′))
(Process 1)
Under a nitrogen atmosphere, toluene (43.3 g) and triethylamine (6.67 g) were sequentially added to and dissolved in compound (II ′) (10.03 g) and compound (VII ′) (9.60 g). Diphenyl phosphorochloridate (8.85 g) was added dropwise at 45 ° C. over 1 hour and stirred for 3 hours. The reaction mixture was cooled to 25 ° C., and extracted with toluene (34.6 g) and 2.4% hydrochloric acid (54.1 g). A 4.4% aqueous sodium hydroxide solution (22.3 g) and a 3.3% aqueous sodium carbonate solution (31.6 g) were added to the obtained organic layer for extraction. The obtained organic layer was washed with a 4.8% aqueous sodium chloride solution (74.6 g) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a concentrated dry product of (Compound (VIII ′) (19.53 g).
(Process 2)
(Compound (VIII ′) (300 mg) was dissolved in acetone (200 μL) at room temperature and allowed to stand at 5 ° C. for 2 days, and then the precipitated crystals were separated by filtration and washed with an ice-cooled 90% acetone aqueous solution, Crystals of an acetone adduct (163.2 mg) of compound (VIII ′) were obtained.
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 12.1 ° ± 0. 2 °, 13.8 ° ± 0.2 °, 15.6 ° ± 0.2 °, 17.3 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.8 ° ± 0. Peaks were observed at 2 ° and 24.3 ° ± 0.2 °.
The TG / DTA analysis results are shown in FIG.

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：５．６°±０．２°、１０．８°±０．２°、１４．０°±０．２°、１８．０°±０．２°、１９．７°±０．２°、２０．５°±０．２°、２２．６°±０．２°、２３．７°±０．２°、２４．８°±０．２°および２７．２°±０．２°にピークが認められた。
ＴＧ／ＤＴＡ分析結果を図１９に示す。(Reference Example 2)
(Synthesis of Hydroxyl Adduct Crystal of Compound (VIII ′))
Compound (VIII ′) (500 mg) synthesized according to Step 1 of Reference Example 1 was dissolved in a 1 mol / L hydrogen chloride-isopropanol solution (0.89 mL) at room temperature and allowed to stand at 5 ° C. for 4 days. The precipitated crystals were separated by filtration and washed with an ice-cooled 90% acetonitrile aqueous solution to obtain a hydrochloric acid adduct (373.0 mg) of compound (VIII ′).
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.6 ° ± 0.2 °, 10.8 ° ± 0.2 °, 14.0 ° ± 0.2 °, 18.0 ° ± 0. 2 °, 19.7 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.6 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.8 ° ± 0. Peaks were observed at 2 ° and 27.2 ° ± 0.2 °.
The TG / DTA analysis results are shown in FIG.

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．７°±０．２°、５．８°±０．２°、６．８°±０．２°、１１．７°±０．２°、１３．６°±０．２°、１８．３°±０．２°、２０．２°±０．２°、２４．０°±０．２°、２４．３°±０．２°および３０．１°±０．２°にピークが認められた。
ＴＧ／ＤＴＡ分析結果を図２１に示す。(Reference Example 3)
(Synthesis of benzoic acid adduct crystal of compound (VIII ′))
Compound (VIII ′) (500 mg) and benzoic acid (220.9 mg) synthesized according to Step 1 of Reference Example 1 were dissolved in acetonitrile (2.5 mL) at room temperature and allowed to stand at 5 ° C. for 4 days. The precipitated crystals were separated by filtration and washed with an ice-cooled 90% acetonitrile aqueous solution to obtain crystals of the benzoic acid adduct (521.6 mg) of compound (VIII ′).
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.7 ° ± 0.2 °, 5.8 ° ± 0.2 °, 6.8 ° ± 0.2 °, 11.7 ° ± 0. 2 °, 13.6 ° ± 0.2 °, 18.3 ° ± 0.2 °, 20.2 ° ± 0.2 °, 24.0 ° ± 0.2 °, 24.3 ° ± 0. Peaks were observed at 2 ° and 30.1 ° ± 0.2 °.
The TG / DTA analysis results are shown in FIG.

粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．５°±０．２°、５．９°±０．２°、６．８°±０．２°、１１．８°±０．２°、１３．６°±０．２°、１６．３°±０．２°、１８．０°±０．２°、１９．９°±０．２°、２１．５°±０．２°および２３．８°±０．２°にピークが認められた。
ＴＧ／ＤＴＡ分析結果を図２３に示す。
次に、実施例２の工程７記載の抽出液および上記アセトン付加物結晶、塩酸付加物結晶、安息香酸付加物結晶およびｐ−トルイル酸付加物結晶のＨＰＬＣの結果を各々、図１１および図１２、図２４および図２５、図２６および図２７、図２８および図２９、図３０および図３１、ならびに表１３に示す。

（単位は、ピーク面積（％）を示す。ＨＰＬＣは上記メソッドＣにて測定した。）
上記表の結果に示す通り、抽出液と比較すると、化合物（ＶＩＩＩ’）のアセトン付加物の結晶中および塩酸付加物の結晶中には、有機不純物Ｄの残存が少なく、各々約５５％、約２７％除去できることがわかる。また、化合物（ＶＩＩＩ’）の安息香酸付加物の結晶中には、有機不純物Ｃおよび有機不純物Ｄの残存が少なく、各々約２６％、約２３％除去できることがわかる。さらに、化合物（ＶＩＩＩ’）のｐ−トルイル酸付加物の結晶中には、有機不純物ＣおよびＤの残存が少なく、各々約１９％、約１２％除去できることがわかる。(Reference Example 4)
(Synthesis of p-toluic acid adduct crystal of compound (VIII ′))
Compound (VIII ′) (500 mg) synthesized in accordance with Step 1 of Reference Example 1 and p-toluylbenzoic acid (243.6 mg) were dissolved in acetonitrile (5.0 mL) at room temperature and allowed to stand for 4 days. The precipitated crystals were separated by filtration and washed with an ice-cooled 90% aqueous acetonitrile solution to obtain a p-toluic acid adduct (588.2 mg) crystal of compound (VIII ′).
The results of powder X-ray diffraction are shown in FIG.

In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.5 ° ± 0.2 °, 5.9 ° ± 0.2 °, 6.8 ° ± 0.2 °, 11.8 ° ± 0. 2 °, 13.6 ° ± 0.2 °, 16.3 ° ± 0.2 °, 18.0 ° ± 0.2 °, 19.9 ° ± 0.2 °, 21.5 ° ± 0. Peaks were observed at 2 ° and 23.8 ° ± 0.2 °.
The TG / DTA analysis results are shown in FIG.
Next, HPLC results of the extract described in Step 7 of Example 2 and the above-mentioned acetone adduct crystal, hydrochloric acid adduct crystal, benzoic acid adduct crystal, and p-toluic acid adduct crystal are shown in FIGS. 11 and 12, respectively. 24 and 25, FIG. 26 and FIG. 27, FIG. 28 and FIG. 29, FIG. 30 and FIG.

(The unit indicates the peak area (%). HPLC was measured by the above method C.)
As shown in the results of the above table, when compared with the extract, the residue of the organic impurity D is small in the crystals of the acetone adduct of the compound (VIII ′) and the crystals of the hydrochloric acid adduct. It can be seen that 27% can be removed. It can also be seen that organic impurities C and organic impurities D remain little in the crystal of the benzoic acid adduct of compound (VIII ′) and can be removed by about 26% and about 23%, respectively. Further, it can be seen that the organic impurities C and D remain little in the crystal of the p-toluic acid adduct of the compound (VIII ′), and can be removed by about 19% and about 12%, respectively.

  The production method of the present invention is useful for industrially producing an optically active 1,3-thiazole derivative having a thrombopoietin receptor agonist activity as a pharmaceutical product.

Claims (25)

Formula (I):

(Wherein X ¹ is a leaving group; R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl) and a compound represented by thiourea is reacted. Formula (II):

(Wherein R ¹ , R ² and R ³ are as defined above),
A method for producing a crystal of a compound represented by formula (II), wherein the obtained compound represented by formula (II) is crystallized. The method for producing a crystal according to claim 1, wherein the crystal is crystallized with a nonpolar solvent. The method for producing a crystal according to claim 1 or 2, wherein crystallization is performed with a non-polar solvent selected from the group consisting of toluene, xylene, heptane and hexane. Crystallization with a mixed solvent of 1 or 2 solvent selected from toluene or xylene and 1 or 2 solvent selected from heptane or hexane, according to any one of claims 1 to 3, A method for producing crystals. The method for producing a crystal according to any one of claims 1 to 4, wherein the crystal is crystallized with a mixed solvent of toluene and heptane. R ¹ is methyloxy;
The method for producing a crystal of a compound represented by the formula (II) according to any one of claims 1 to 5, wherein R ² is methyl; and R ³ is n-hexyl. The method for producing a crystal according to claim 6, wherein organic impurities in the crystal of the compound represented by formula (II) are removed to 1.5 wt% or less by crystallization. The optical purity of the crystal of the compound represented by formula (II) is 97% e.e. e. The method for producing a crystal according to claim 6 or 7, which is as described above. In the presence of a base, formula (V):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom)
Reacting N-formylmorpholine, N-formylpiperidine or N, N-dimethylformamide as a formylation reagent,
And the product of the above step includes formula (VI):

(Wherein R ⁶ and R ⁷ are each independently C 1 -C 3 alkyl; R ⁸ is each independently C 1 -C 3 alkyl). Formula (VII), characterized in that

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above). The method for producing a compound represented by the formula (VII) according to claim 9, wherein the base is LDA, KHMDS, LHMDS, n-butyllithium or phenyllithium. R ⁴ and R ⁵ are both chlorine atoms;
The method for producing a compound represented by the formula (VII) according to claim 9 or 10, wherein R ⁶ is methyl; and R ⁷ is ethyl. Formula (II):

(Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl)
A compound of formula (VII):

(Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl)
With a compound of formula (VIII):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above),
A method for producing a crystal of a compound represented by formula (VIII), wherein the obtained compound represented by formula (VIII) is crystallized. R ¹ is methyloxy;
R ² is methyl;
R ³ is n-hexyl;
R ⁴ and R ⁵ are both chlorine atoms;
The method for producing a crystal of a compound represented by the formula (VIII) according to claim 12, wherein R ⁶ is methyl; and R ⁷ is ethyl. 14. The method for producing a crystal according to claim 13, wherein organic impurities of the crystal of the compound represented by formula (VIII) are removed to 2.0% by weight or less by crystallization. Compound (VIII ′):

Or crystals of its adduct. The crystal according to claim 15, which is a crystal of a dimethyl sulfoxide adduct. In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0. The crystal according to claim 16, which has a peak at 2 °, 24.1 ° ± 0.2 °. In powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0. 2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° ± 0. The crystal according to claim 16, which has a peak at 2 °, 24.1 ° ± 0.2 °. According to the production method according to claim 1, formula (II):

(Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl). ):

(Wherein R ¹ , R ² and R ³ are as defined above; R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl) A method for producing a crystal of a compound. According to the production method of claim 9, formula (VII):

Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl). :

(Wherein R ¹ is C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl; R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above) The manufacturing method of the crystal | crystallization of the compound shown by these. According to the production method according to claim 1, formula (II):

(Wherein R ¹ is C1-C3 alkyloxy or a halogen atom; R ² and R ³ are each independently C1-C8 alkyl),
And according to the production method of claim 9, formula (VII):

Wherein R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ are each independently C1-C3 alkyl). :

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as described above). A method according to any one of claims 12, 19, 20 and 21 of formula (VIII):

Wherein R ¹ is a C1-C3 alkyloxy or halogen atom; R ² and R ³ are each independently C1-C8 alkyl; R ⁴ and R ⁵ are each independently a halogen atom; R ⁶ and R ⁷ is each independently a crystal of a compound represented by C1-C3 alkyl), and the resulting crystal of the compound represented by formula (VIII) is hydrolyzed, wherein formula (XI):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above). R ¹ is methyloxy;
R ² is methyl;
R ³ is n-hexyl;
R ⁴ and R ⁵ are both chlorine atoms;
The method for producing a crystal of a compound represented by the formula (XI) according to claim 22, wherein R ⁶ is methyl; and R ⁷ is ethyl. The method for producing a crystal according to claim 23, wherein the content of the organic impurity in the crystal of the compound represented by formula (XI) is 1.0% by weight or less. The optical purity of the crystal of the compound represented by formula (XI) is 95% e.e. e. The method for producing a crystal according to claim 23 or 24, which is as described above.

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