JP6899413B2 - 甲状腺ホルモンアナログ及びその多形体の合成方法 - Google Patents
甲状腺ホルモンアナログ及びその多形体の合成方法 Download PDFInfo
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
(a)R1MgX又はR1Liを式(I):
(b)R1がイソプロペニルである場合には塩基の存在下、又はR1がイソプロピルである場合には酸化剤の存在下で式(II)の化合物を式(III):
(d)6−(4−アミノ−2,6−ジクロロフェノキシ)−4−イソプロピルピリダジン−3(2H)−オンを式(IV):
R3はH又はCH2Raであり、前記式中、Raはヒドロキシル基、O結合型アミノ酸、−OP(O)(OH)2又は−OC(O)−Rbであり、Rbは低級アルキル基、アルコキシ基、アルキル酸、シクロアルキル基、アリール基、ヘテロアリール基又は−(CH2)n−ヘテロアリール基であり、nは0又は1であり;
R4はHであり、R5はCH2COOH、C(O)CO2H、又はそのエステルもしくはアミドであり、あるいはR4とR5は一緒になり、−N=C(Rc)−C(O)−NH−C(O)−であり、前記式中、RcはH又はシアノ基である。]の化合物に変換する工程を含んでいてもよい。
R3はH又はCH2Raであり、前記式中、Raはヒドロキシル基、O結合型アミノ酸、−OP(O)(OH)2又は−OC(O)−Rbであり、Rbは低級アルキル基、アルコキシ基、アルキル酸、シクロアルキル基、アリール基、ヘテロアリール基又は−(CH2)n−ヘテロアリールであり、nは0又は1であり;
R4はHであり、R5はCH2COOH、C(O)CO2H、又はそのエステルもしくはアミドであり、あるいはR4はR5は一緒になって−N=C(Rc)−C(O)−NH−C(O)−であり、前記式中、RcはH又はシアノ基である。]の化合物を投与する段階を含む。
(a)対象からの試料を準備する段階と;
(b)甲状腺ホルモン受容体(「TR」)の突然変異を検出し、前記突然変異が存在するならば、前記対象は前記化合物又はその医薬として許容可能な塩に対して応答性であると判定する段階を含む。
(a)R1MgX又はR1Liを式(I):
(b)R1がイソプロペニルである場合には塩基の存在下、又はR1がイソプロピルである場合には酸化剤の存在下で式(II)の化合物を式(III):
R3はH又はCH2Raであり、前記式中、Raはヒドロキシル基、O結合型アミノ酸、−OP(O)(OH)2又は−OC(O)−Rbであり、Rbは低級アルキル基、アルコキシ基、アルキル酸、シクロアルキル基、アリール基、ヘテロアリール基又は−(CH2)n−ヘテロアリール基であり、nは0又は1であり;
R4はHであり、R5はCH2COOH、C(O)CO2H、又はそのエステルもしくはアミドであり、あるいはR4とR5は一緒になり、−N=C(Rc)−C(O)−NH−C(O)−であり、前記式中、RcはH又はシアノ基である。前記方法は、
(a)R1MgX又はR1Liを式(I):
(b)R1がイソプロペニルである場合には塩基の存在下、又はR1がイソプロピルである場合には臭素および酸の存在下で式(II)の化合物を式(III):
(c)式(III)の化合物のアミン保護基R2が存在する場合にはこれを除去し、6−(4−アミノ−2,6−ジクロロフェノキシ)−4−イソプロピルピリダジン−3(2H)−オンを形成する工程と;場合により
(d)適切な条件下で6−(4−アミノ−2,6−ジクロロフェノキシ)−4−イソプロピルピリダジン−3(2H)−オンを式(IV)の化合物に変換する工程を含む。
適切な溶媒(例えば酢酸と水の混液)中で酸(例えばHCl)の存在下に適切な反応温度(例えば10℃未満)にて反応が完了するまで6−(4−アミノ−2,6−ジクロロフェノキシ)−4−イソプロピルピリダジン−3(2H)−オンを(2−シアノアセチル)カルバミン酸エチル及び金属亜硝酸塩(例えば亜硝酸ナトリウム)と接触させることにより中間体8を製造する。
適切な溶媒(例えばDMAC)中で適切な反応温度(例えば約120℃)にて反応が完了するまで中間体8と塩基(例えば酢酸ナトリウム又は酢酸カリウム)を接触させることにより化合物Aを製造する。
本発明は更に、少なくとも1種の医薬として許容可能な賦形剤又は担体と共に式IVの化合物を含有する医薬組成物を提供する。
X線管:CuKα,45kV,40mA
検出器:X’Celerator
ASS主スリット:1°固定
発散スリット(Prog):自動−5mm照射長
ソーラースリット:0.02ラジアン
散乱スリット(PASS):自動−5mm観測長
スキャンレンジ:3.0〜45.0°
スキャンモード:連続
ステップサイズ:0.02°
ステップ毎の時間:10秒
動作長:2.54°。
固定発散スリットサイズ:1.00°,1.59mm
交差点:44.3 °ω。
オーバーヘッド撹拌機、熱電対、還流冷却器、及びN2導入管/排出管を装着した1L容三口丸底フラスコに3,6−ジクロロピリダジン(100g,0.672mol,1倍重量)、4−アミノ−2,6−ジクロロフェノール(122g,0.686mol,1.02当量)及びDMAC(500mL,5倍容量)を仕込んだ。得られた溶液に炭酸セシウム(251g,0.771mol,1.15当量)を加え、懸濁液を110℃まで加熱した。この温度で3時間後、バッチ温度を70℃まで下げ、この温度で16時間撹拌した。1H NMR分析(DMSO)によると、ほぼ全量のジクロロピリダジンが消費されていたので、反応は完了したとみなした。バッチを室温まで冷却し、EtOAc(2L,20倍容量)を使用して3L容丸底フラスコに移した。シリカゲル(100g,1倍重量)を加え、懸濁液を30分間撹拌し、濾過した。濾液が無色で溶出するまで反応容器とケーキをEtOAc(500mL,5倍容量)でリンスした。得られた濾液を10%NaCl水溶液(2L,20倍容量)で処理し、2相混合物を30分間撹拌し、下部水層を捨てた。上部有機層を減圧下に濃縮乾涸した。EtOAc(100mL,1倍容量)を残渣に加え、減圧下に濃縮乾涸し、粗生成物である化合物2(251g,128%収率)を油状物として得た。HPLC分析によると、純度は93.4%であった。1H NMR分析(DMSO)は帰属した構造に一致し、≒25%DMAC及び2%EtOAcが存在することを示した。
カラム:Waters Sunfire C18,3.5μM,4.6×150mm
流速:1.0mL/min.
移動相A:0.05%TFA水溶液
移動相B:0.05%TFA水溶液
希釈剤:50:50 MeCN/H2O
オーバーヘッド撹拌機、熱電対、N2導入管/排出管、及び還流冷却器を装着した4L容四口丸底フラスコに4(95g,0.253mol,1倍重量)、THF(665mL,7倍容量)、及びLiCl(32.3g,0.759mol,3当量)を仕込んだ。得られた懸濁液を35℃まで加熱し、バッチ温度を35〜45℃に維持しながら、イソプロペニルマグネシウムブロミド溶液(0.5M THF溶液,1.72L,0.859mol,3.4当量)を80分間かけて加えた。得られたスラリーを40℃に3時間加熱後、HPLC分析は87%の変換率を示した。イソプロペニルマグネシウムブロミド溶液(0.5M THF溶液,51mL,0.026mol,0.1当量)を加え、スラリーを40〜43℃で更に90分間撹拌した。HPLC分析は92.9%の変換率を示したので、反応は完了したとみなした。加熱を停止し、反応混合物を14℃まで冷却し、バッチ温度を26℃未満に維持しながら、3N HCl水溶液(380mL,4倍容量)を15分間かけてゆっくりと加えると、全固形分が溶解した。下部水層を捨て、THF(350mL,3.7倍容量)で抽出した。下部水層を捨てた後、有機層を合わせ、4に対して約5倍容量まで減圧下に濃縮した。得られた溶液に10%(w/w)KOH水溶液(532mL,5.6倍容量)を加え、ショートパス蒸留装置を使用してTHFを留去しながら、混合物を85℃まで加熱した。バッチを85℃に11時間維持し、加熱を停止した。バッチを便宜上、一晩かけて周囲温度まで冷却した。得られたスラリーをHPLC分析(下記A法)した処、中間体7への変換率は99%であり、反応は完了したとみなした。
カラム:Waters Sunfire C18,3.5μM,4.6×150mm
流速:1.0mL/min.
移動相A:0.05%TFA水溶液
移動相B:0.05%TFA水溶液
希釈剤:50:50 MeCN/H2O。
オーバーヘッド撹拌機、熱電対、N2導入管/排出管を装着した2L容三口丸底フラスコに中間体7(75.0g,0.239mol,1倍重量)、酢酸(600mL,8倍容量)、水(150mL,2倍容量)、及び濃HCl(71.3mL,0.95倍容量)を仕込んだ。得られた低粘度スラリーを6℃まで冷却し、バッチ温度を10℃未満に維持しながら、NaNO2(16.8g,0.243mol,1.02当量)の水(37.5mL,0.5倍容量)溶液を10分間かけて加えた。5〜10℃で更に10分間撹拌後、HPLC分析によると、中間体7はジアゾニウム中間体に完全に変換したことが判明した。バッチ温度を10℃未満に維持しながら、NaOAc(54.5g,0.664mol,2.78当量)の水(225mL,3倍容量)溶液を6分間かけて加えた。すぐにN−シアノアセチルウレタン(37.9g,0.243mol,1.02当量)を加え、冷却を停止し、35分間かけてバッチを8℃まで自然昇温させた。HPLC分析によると、ジアゾニウム中間体は完全に消費されたので、反応は完了したとみなした。バッチを21℃まで自然昇温させ、Sharkskin濾紙で濾過した。反応容器とケーキを順次2回水洗(375mL,5倍容量)した。オレンジ色の固体を採取し、35℃の真空オーブンで64時間乾燥し、粗生成物である中間体8(104.8g,91%)を得た。
オーバーヘッド撹拌機、熱電対、N2導入管/排出管、及び還流冷却器を装着した2L容三口丸底フラスコに中間体8(89.3g,0.185mol,1倍重量)、DMAC(446mL,5倍容量)、及びKOAc(20.0g,0.204mol,1.1当量)を仕込んだ。混合物を120℃まで加熱し、この温度に2時間維持した。HPLC分析は化合物Aへの完全な変換を示した。バッチ温度を1時間かけて18℃に調整し、酢酸(22.3mL,0.25倍容量)を加えた。バッチ温度を8℃に調整し、水(714mL,8倍容量)を1時間かけて加えると、オレンジ色のスラリーが形成された。バッチをSharkskin濾紙で濾過し、ケーキを便宜上、非減圧下のN2下で一晩かけてコンディショニングした。1:1アセトン/水(445mL,5倍容量)のプレミックス溶液をフラスコに加え、減圧下にリンス液としてケーキに加えた。ケーキを2時間減圧下でコンディショニング後、オーバーヘッド撹拌機、熱電対、及びN2導入管/排出管を装着した清浄な1L容三口丸底フラスコに移した。エタノール(357mL,4倍容量)とアセトン(357mL,4倍容量)を加え、得られたスラリーを60℃まで加熱すると、溶解が生じた。バッチ温度を55〜60℃に維持しながら、水(890mL,10倍容量)を90分間かけて加えた。得られたスラリーを25℃まで冷却し、Sharkskin濾紙で濾過した。反応容器とケーキを順次1:1 EtOH/水溶液(446mL,5倍容量)で洗浄した。ケーキを便宜上、非減圧下のN2下で一晩かけてコンディショニングした。ケーキの亀裂を平らにし、真空に引いた。ケーキを水洗(179mL,2倍容量)し、70.5g(87%,粗生成物である化合物A)の一定重量になるまで45℃の真空オーブンで乾燥した。HPLC分析によると、純度は94.8%であった。
下記スキームに従って化合物Aの大規模バッチを合成した。下記スキームにおける条件は上記実施例1〜4に記載した条件と同様である。
N2置換下の100L容ジャケット付ガラス容器に中間体8(3.90kg)と酢酸カリウム(875g)を仕込んだ。N,N−ジメチルアセトアミド(DMAC,18.3L)を容器に加え、撹拌機を始動した。バッチ温度を2時間かけて115℃に調整した。115℃で2時間後、バッチから試料抽出し、HPLC分析した処、0.27%の中間体8が残留していた。バッチ温度を一晩かけて25.0℃に調整した。酢酸(975mL)をバッチに加え、バッチを更に3時間撹拌した。バッチをカルボイに移し、容器をDMAC 800mLでリンスした。減圧を使用して10μmインラインフィルターを通してバッチを100L容器に戻し、DMACリンス液(1.15L)を使用した。濾過は開始時には迅速であったが、終了時には遅くなり、フィルターが詰まった。バッチ温度を11.1℃に調整し、バッチ温度を5〜15℃に維持しながら、2時間20分間かけて脱イオン水(35.1L)を加えた。バッチを1時間維持し、密織ポリプロピレン濾布を装着した18” Nutscheフィルターを使用して濾過した。濾過は15時間を要した。1:1エタノール/脱イオン水洗浄液(19.5L)を容器に加え、10℃まで冷却し、フィルターケーキに移した。ケーキをN2及び減圧下で8時間コンディショニングし、乾燥トレーに移した。バッチを45℃及び28”/Hgの真空オーブンで乾燥し、89%収率(3.77kg)で化合物AのDMAC溶媒和物をオレンジ色/黄褐色の固体として得た。1H NMRスペクトルは帰属した構造に一致し、カール・フィッシャー解析によると、0.49%H2Oであった。XRPDは予想通りの形態、即ち化合物AのDMAC溶媒和物を示した。熱重量分析(TGA)によると、重量減少は16%であった。HPLC分析によると、純度は93.67%であった。
N2置換下の100L容ジャケット付ガラス容器に化合物AのDMAC溶媒和物(3.75kg)とエタノール(15.0L)を仕込んだ。撹拌機を始動し、アセトン(15.0L)を加えた。1時間かけてバッチ温度を10.6℃から60.0℃に調整した。この時点で、バッチは溶液であった。バッチ温度を60±5℃に維持しながら、1.5時間かけて脱イオン水をバッチに加えた。バッチを60±5℃に1時間に維持し、23.5℃まで冷却した。密織(0.67CFM)ポリプロピレン濾布を装着した18”Nutscheフィルターをセットアップし、バッチを濾過した。濾過は15時間を要した。1:1エタノール/脱イオン水洗浄液(19.5L)を容器に加え、フィルターケーキに移した。ケーキをN2及び減圧下に8時間コンディショニングし、乾燥トレーに移した。バッチを45℃及び28”/Hgの真空オーブンで5日間乾燥し、94%収率(2.90kg)で化合物Aを粉末状の黄褐色固体として得た。1H NMRスペクトルは帰属した構造に一致し、カール・フィッシャー解析は6.6%H2Oを示した。XRPDは予想通りの二水和物の形態を示した。TGAによると、重量減少は6.7%であった。HPLC分析によると、純度は96.4%(AUC)であった。
N2置換下の50L容ジャケット付ガラス容器に粗生成物である化合物A(2.90kg)とメチルイソブチルケトン(14.5L)を仕込んだ。撹拌機を始動し、1.5時間かけてバッチ温度を20.2℃から50.4℃に調整した。バッチを50℃(±5℃)に1時間維持し、20〜25℃まで冷却した。バッチを20〜25℃に2.5時間維持した。密織(0.67CFM)ポリプロピレン濾布を装着した18”Nutscheフィルターをセットアップし、バッチを濾過した。濾過は20分間を要した。メチルイソブチルケトン(MIBK,1.45L)を容器に加え、フィルターケーキに移した。ケーキを手動で再懸濁し、液体を減圧吸引した。メチルイソブチルケトン(2.90L)をフィルターケーキに加え、ケーキを手動で再懸濁した。液体を減圧吸引し、ケーキを15時間減圧及び窒素下でコンディショニングした。フィルターケーキを乾燥し、黄褐色の硬い18”×1.5”ディスク状にした。これを手で砕き、コーヒー豆挽き機にかけ、76%収率(2.72kg)でMGL−3196 MIBK溶媒和物を黄褐色粉末状固体として得た。オーブン乾燥は不要であった。1H NMRスペクトルは帰属した構造に一致し、カール・フィッシャー解析は<0.1%H2Oを示した。XRPDは予想通りのMIBK溶媒和物の形態を示した。TGAによると、重量減少は17.3%であった。HPLC分析によると、純度は98.5%であった。
上記実施例5に記載したように中間体8から得られた1:1 MIBK溶媒和物としての精製化合物A(4802g)をエタノール24リットルと共に100L容ジャケット付反応容器に仕込んだ。得られたスラリーを1時間25分間かけて80±5℃(還流)まで加熱し、混合物をこの温度で4時間25分間撹拌した。濾過した固体を2時間55分の時点で分析した処、形態変換は完了し、XRPDスペクトルは形態Iに一致した。混合物を45分間かけて20±5℃まで冷却し、この温度で15分間撹拌した。スラリーを濾過し、予め濾過しておいたエタノール(2×4.8L)でフィルターケーキを2回洗浄した。湿潤ケーキ(4.28kg)を40±5℃で118時間減圧乾燥し、3390の化合物A形態Iを得た。
N2置換下の50L容ジャケット付ガラス容器に上記実施例5からの化合物AのMIBK溶媒和物(2.72kg)とエタノール(13.6L)を仕込んだ。撹拌機を始動し、バッチ温度を1.3時間かけて16.8℃から79.4℃に調整した。バッチを79.5℃に2時間維持し、XRPD分析用に試料抽出した。XRPDは形態Iを示したので、バッチを1時間10分間かけて24.9℃まで冷却した。密織(0.67CFM)ポリプロピレン濾布を装着した18”Nutscheフィルターをセットアップし、バッチを濾過した。濾過は4分間を要した。エタノール(2.8L)を容器に加え、フィルターケーキに移した。ケーキを手動で再懸濁し、液体を減圧吸引した。エタノール(2.80L)をフィルターケーキに加え、ケーキを手動で再懸濁した。液体を減圧吸引し、ケーキを減圧及び窒素下で1時間コンディショニングした。フィルターケーキを乾燥パンに移し、45℃及び28”/Hgで1日間乾燥し、89%収率(1.96kg)で化合物Aを薄黄色固体として得た。HPLC分析によると、純度は99.6%であった。XRPD解析は形態Iに一致する。この材料300gを2”ジェットミルで粉砕し、284g(95%収率)の微粉状の化合物Aを得た。XRPD解析によると、微粉状の化合物Aは形態Iのままであることが確認された。
RCSB蛋白質データバンクから結晶構造(ID番号:1N46、1NQ0、1NQ1、1NQ2及び1NUO)を入手した。Mac OS X用MacPymol(Copyright 2006 DeLano Scientific LLC.;現在はSchrodinger Inc.の製品)を使用して蛋白質共結晶構造を整列させた。リガンド−蛋白質相互作用の全分析にもMacPymolを使用し、図3〜9を得た。これらの図から総合的に判断すると、化合物AはTHRβ突然変異体における構造変異をより良好に受け入れることが可能である。例えば突然変異体Arg316Hisにおいて、Arg316はHisに突然変異しており、Arg320はリガンドから若干ずれている。その結果、Arg316His突然変異体ではArg320とT3の特異的相互作用が弱まる。これに対して、化合物Aにおける大きな負の分極性複素環はArg316His突然変異により妨害されない良好な相互作用を形成する。換言するならば、より大きく、より分極性の高い複素環をもつ化合物AはArg320及び突然変異したHis316との間に良好な相互作用を維持する。例えば図8及び9参照。結果は他の突然変異についても同様である。
発明の趣旨又は本質的特徴から逸脱しない限り、他の特定形態でも本発明を実施することができる。従って、上記実施形態は本願明細書に記載する発明を制限するものではなく、あらゆる点において例証であるとみなすべきである。 従って、本発明の範囲は上記記載ではなく、以下の特許請求の範囲により指定されるものであり、特許請求の範囲の均等物の意味と範囲に含まれるあらゆる変更も特許請求の範囲に含むものとする。
Claims (8)
- 2θ=10.5°、18.7°、22.9°、23.6°及び24.7°にピークを含む粉末X線回折パターンを特徴とする、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の形態Iの結晶の製造方法であって、
溶媒と、化合物Aを含有する試料とを含む混合物を、60℃〜80℃である第1の温度に加熱する工程;及び
前記混合物を、0℃〜60℃である第2の温度まで冷却し、前記形態Iの結晶を得る工程
を含み、
前記溶媒がエタノール、イソプロパノール又はその組合せであり、
但し、第1の温度が60℃であるときは、第2の温度は60℃ではない、
前記方法。 - 前記第2の温度が、40℃〜60℃である、請求項1に記載の方法。
- 前記溶媒が、エタノールである、請求項1に記載の方法。
- 前記溶媒が、イソプロパノールである、請求項1に記載の方法。
- 化合物Aを含有する試料が、化合物Aの溶媒和物を含む、請求項1に記載の方法。
- 化合物Aの前記溶媒和物が、エタノール溶媒和物、メチルイソブチルケトン溶媒和物、N,N−ジメチルアセトアミド溶媒和物又は水和物である、請求項5に記載の方法。
- 2θ=10.5°、18.7°、22.9°、23.6°及び24.7°にピークを含む粉末X線回折パターンを特徴とする、2−(3,5−ジクロロ−4−((5−イソプロピル−6−オキソ−1,6−ジヒドロピリダジン−3−イル)オキシ)フェニル)−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボニトリル(「化合物A」)の形態Iの結晶の製造方法であって、
エタノールと、化合物Aを含有する試料とを含む混合物を、60℃〜80℃である第1の温度に加熱する工程;
前記混合物を、40℃〜60℃である第2の温度まで冷却する工程;
前記混合物を40℃以上の温度で濾過し、フィルターケーキを得る工程;
前記フィルターケーキを40℃以上の温度にてエタノールでリンスし、リンスしたフィルターケーキを得る工程;及び
前記リンスしたフィルターケーキを40℃以上の温度で乾燥し、前記形態Iの結晶を得る工程
を含み、
但し、第1の温度が60℃であるときは、第2の温度は60℃ではない、
前記方法。 - 前記第2の温度が、15℃〜25℃である、請求項1に記載の方法。
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