JP2022546016A - 高純度エステトロールを調製するための産業的方法 - Google Patents
高純度エステトロールを調製するための産業的方法 Download PDFInfo
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- 229950009589 estetrol Drugs 0.000 title claims abstract description 28
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- -1 alkali metal hydrogen carbonate Chemical class 0.000 claims description 13
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
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- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 7
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 claims description 7
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- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 claims description 7
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- 239000001257 hydrogen Chemical group 0.000 claims description 7
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- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 claims description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
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- 229910000489 osmium tetroxide Inorganic materials 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 3
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
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Classifications
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Abstract
Description
本発明による方法の工程a)では、一般式(III)で表される3位、15α位、16α位、17β位が保護されたエステトロール誘導体が、単離されている又は単離されていない、式(II)で表される3位が保護された15,16,17-トリオール誘導体を、適切な反応物質を用いて、適切な溶媒中でアシル化することによって得られる。
本発明による方法の工程b)では、一般式(IV)で表される15α位、16α位、17β位が保護された3-ヒドロキシエステトロール誘導体が、一般式(III)で表される誘導体の3位のベンジル保護基を、移動水素化または接触水素化によって除去することによって得られる。
本発明による方法の工程c)では、アルカリ媒体中で、一般式(IV)の誘導体を、適切な溶媒中のアルカリ炭酸塩またはアルカリ水酸化物を用いて脱保護することによって式(I)のエステトロールが、調製される。
WO2013/034780A2(Crystal Pharma)に従う((15ξ,16ξ,17β)-エストラ-1,3,5(10)-トリエン-3,15,16,17-テトロール)のエステトロール異性体混合物の調製
a)シス-ヒドロキシル化
(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオールおよび(15β,16β,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオール
20.0g(55.5mmol)の3-ベンジルオキシ-エストラ-1,3,5(10),15-テトラエン-17-オール(WO2004/041839(Pantarhei)、実施例7)を、N2雰囲気下で20~25℃で、1400mLのテトラヒドロフランに溶解させ、次いで、tert-ブタノール中2w/v%の四酸化オスミウム(OsO4)(280mgのOsO4含量)14mLおよび11gのN-メチルモルホリンN-オキシドおよび150mLの水からなる溶液を、反応混合物に添加し、N2雰囲気下で20~25℃で24時間攪拌した。反応をTLC(n-ヘプタン:アセトン1:1)によってモニタリングした。
(15α,16α,17β)-エストラ-1,3,5(10)-トリエン-15,16,17-トリオールおよび(15β,16β,17β)-エストラ-1,3,5(10)-トリエン-15,16,17-トリオール
19.5gの(15ξ,16ξ,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオールを、N2雰囲気下で20~25℃で、400mLのメタノールに溶解させた。2.0gの10%Pd/C触媒を、100mLの急速冷凍されたメタノールに懸濁し、次いで、溶液に添加した。N2雰囲気をH2雰囲気に交換し、反応混合物を、大気圧下で20~25℃で6時間攪拌した。
三酢酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイル
方法A(単離あり)
a.)シス-ヒドロキシル化
(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオールおよび(15β,16β,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオール
40mgのオスミウム酸カリウム二水和物(K2OsO4.2H2O)を、N2雰囲気下で20~25℃で、100mLの2-ブタノン(メチルエチルケトン)中に懸濁し、これに7.7mLの純水および1.1gのトリメチル-アミンN-オキシド二水和物を添加した。2.0g(5.5mmol)の3-ベンジルオキシ-エストラ-1,3,5(10),15-テトラエン-17-オール(WO2004/041839(Pantarhei)、実施例7)を、40mLの2-ブタノン中に溶解させ、反応混合物に滴加した。次いで、反応混合物を、N2雰囲気下で20~25℃で28時間攪拌した。反応を、TPLC(n-ヘプタン:アセトン1:1)によってモニタリングした。
三酢酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオール
1.0g(2.53mmol)の(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオールを、N2雰囲気下で15mLのジクロロメタン中に溶解させた。1.5mLのトリエチル-アミン、6.0mLの酢酸、および72mgの4-ジメチルアミノピリジンを添加し、2時間攪拌した。反応をTLC(トルエン:アセトン4:1)によってモニタリングした。
a)シス-ヒドロキシル化
3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオールの(15α,16α,17β)、(15β,16β,17β)異性体混合物
30.03g(83.3mmol)の3-ベンジルオキシ-エストラ-1,3,5(10),15-テトラエン-17-オール(WO2004/041839(Pantarhei)、実施例7)を、N2雰囲気下で20~25℃で、480mLの2-ブタノン(メチルエチルケトン)中に溶解させ、次いで、600mgのオスミウム酸カリウム二水和物(K2OsO4.2H2O)、48.0mLの純水、および16.5gのトリメチルアミンN-オキシド二水和物を添加した。次いで、反応混合物を、N2雰囲気下で40~45℃で7時間攪拌した。反応をTLC(n-ヘプタン:アセトン1:1)によってモニタリングした。
三酢酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイル
72.0mLの無水酢酸、48mLのトリエチルアミン、および1.8gの4-ジメチルアミノピリジンを、工程a)で得られた酢酸エチル溶液に添加し、その後、N2雰囲気下で35~40℃で3時間攪拌した。反応をTLC(トルエン:アセトン4:1)によってモニタリングした。
工程b)で得られた粗生成物を、ジクロロメタン中に溶解させ、メタノールを蒸留して除き、最後に、純粋なメタノールから結晶化させた。この操作をもう一回繰り返した。こうして、30.4g(69.8%)の白色結晶が得られた。
Mp.:156.5~157.5℃。
EI-HRMS:C31H36O7[M+]についての計算値:520.24555;実測値:520.24459;デルタ=-1.86ppm。
1H NMR(499.9MHz,CDCl3) δ=5.39(1H,dd,J=8.4Hz,J=6.6Hz,H-16),5.16(1H,dd,J=10.4Hz,J=8.4Hz,H-15),5.01(1H,d,J=6.6Hz,H-17),2.08(3H,s,17-アセチル),2.06(3H,s,15-アセチル),2.04(3H,s,16-アセチル),0.94(3H,s,H-18)
13C NMR(125.7MHz,CDCl3) δ=169.8(17-アセチル CO C-20),169.0(15-アセチル CO),168.7(16-アセチル CO),83.1(C-17),72.5(C-16),69.8(C-15),51.4(C-14),39.2(C-13),19.9(17-アセチル-CH3),19.7(15-アセチル-CH3),19.6(16-アセチル-CH3),13.5(C-18)
三酢酸(15α,16α,17β)-3-ヒドロキシエストラ-1,3,5(10)-トリエン-15,16,17-トリイル
方法A
25.7g(49.36mmol)の三酢酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイル(実施例1)を、N2雰囲気下で20~25℃で、315mLの酢酸エチル中に溶解させた。770mgの10%パラジウム炭素触媒を、19mLの急速冷凍された酢酸エチル中に懸濁し、次いで、上記溶液に添加した。N2雰囲気をH2雰囲気に交換し、反応混合物を大気圧下で20~25℃で3時間攪拌した。
0.5gの三酢酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイル(実施例1)を、20~25℃で14mLのエタノール中に懸濁し、次いで、0.5mLのシクロヘキセンおよび38mgの10%Pd/C触媒を添加し、その後、還流温度で1時間攪拌した。反応をTLC(トルエン:アセトン4:1)によってモニタリングした。
Mp.:181.5~185.5℃
EI-HRMS:C24H30O7[M+]についての計算値:430.19860;実測値:430.19927;デルタ=1.55ppm。
1H NMR(499.9MHz,CDCl3) δ=5.41(1H,dd,J=8.4Hz,J=6.6Hz,H-16),5.18(1H,dd,J=10.5Hz,J=8.4Hz,H-15),5.03(1H,d,J=6.6Hz,H-17),(3H,s,17-アセチル),2.10(3H,s,15-アセチル),2.07(3H,s,16-アセチル),1.77(1H,t,J=11.1Hz,H-14),0.95(3H,s,H-18)
13C NMR(125.7MHz,CDCl3) δ=170.9(17-アセチル CO),170.1(15-アセチル CO),169.8(16-アセチル CO),84.1(C-17),73.5(C-16),70.8(C-15),52.4(C-14),40.2(C-13),20.9(17-アセチル-CH3),20.7(15-アセチル-CH3),20.6(16-アセチル-CH3),14.5(C-18)
三ギ酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイル
5.00gの(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリオール(実施例1、方法「A」、工程a))を、73mLのピリジン中に溶解させ、0℃に冷却し、次いで、0℃に冷却した49mLのギ酸および18.3mLの無水酢酸で作製した混合無水物の混合物を、添加漏斗を用いて0℃~10℃の間で約25分間添加した。1時間攪拌した後、305mLの水を反応混合物に添加し、得られた白色沈殿物を濾過して除き、水で洗浄した。乾燥粗生成物は5.65g(93.23%)の重量であった。
Mp.:153.5~154.3℃
EI HRMS:M=478.19866;デルタ=0.06ppm;C28H30O7
1H NMR(499.9MHz,CDCl3) δ=5.41(1H,dd,J=8.4Hz,J=6.6Hz,H-16),5.18(1H,dd,J=10.5Hz,J=8.4Hz,H-15),5.03(1H,d,J=6.6Hz,H-17),(3H,s,17-アセチル),2.10(3H,s,15-アセチル),2.07(3H,s,16-アセチル),1.77(1H,t,J=11.1Hz,H-14),0.95(3H,s,H-18)
13C NMR(125.7MHz,CDCl3) δ=170.9(17-アセチル CO),170.1(15-アセチル CO),169.8(16-アセチル CO),84.1(C-17),73.5(C-16),70.8(C-15),52.4(C-14),40.2(C-13),20.9(17-アセチル-CH3),20.7(15-アセチル-CH3),20.6(16-アセチル-CH3),14.5(C-18)
三ギ酸(15α,16α,17β)-3-ヒドロキシエストラ-1,3,5(10)-トリエン-15,16,17-トリイル
5.0gの三ギ酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイル(実施例3)を、N2雰囲気下で20~25℃で、150mLの酢酸エチル中に溶解させた。380mgの10%Pd/C触媒を、5mLの急速冷凍された酢酸エチル中に懸濁し、上記溶液に添加した。N2雰囲気をH2雰囲気に交換し、反応混合物を、大気圧下で20~25℃で4時間攪拌した。
Mp.:234~235℃
MS:M-H=387(ESI)
1H NMR(499.9MHz,DMSO-d6) δ=8.17(1H,s,17-ホルミル-H),8.09(1H,s,15-ホルミル-H),8.04(1H,s,16-ホルミル-H),5.52(1H,t,J=7.4Hz,H-16),5.24(1H,dd,J=10.1Hz,J=8.6Hz,H-15),5.11(1H,d,J=6.5Hz,H-17),0.99(3H,s,H-18)
13C NMR(125.7MHz,DMSO-d6) δ=159.5(17-ホルミル-C),159.3(15-ホルミル-C),158.8(16-ホルミル-C),82.4(C-17),71.7(C-16),69.2(C-15),51.3(C-14),39.6(C-13),13.5(C-18)
エステトロール((15α,16α,17β)-エストラ-1,3,5(10)-トリエン-3,15,16,17-テトロール)
方法A
19.88g(46.18mmol)の三酢酸(15α,16α,17β)-3-ヒドロキシエストラ-1,3,5(10)-トリエン-15,16,17-トリイル(実施例2)を、N2雰囲気下で20~25℃で、596mLのメタノール中に懸濁し、次いで、19.88gの炭酸カリウムを一部ずつ添加し、3時間攪拌した。反応をTLC(n-ヘプタン:アセトン1:1)によってモニタリングした。
5g(12.87mmol)の三ギ酸(15α,16α,17β)-3-ヒドロキシエストラ-1,3,5(10)-トリエン-15,16,17-トリイル(実施例4)を、N2雰囲気下で20~25℃で、150mLのメタノール中に懸濁し、次いで、5.34g(38.6mmol)の炭酸カリウムを一部ずつ添加し、3時間攪拌した。反応をTLC(n-ヘプタン:アセトン1:1)によってモニタリングした。
Mp.:240~243℃
EI-HRMS:C18H24O4[M+]についての計算値:304.16691;実測値:304.16716;デルタ=0.82ppm。
1H NMR(499.9 MHz,DMSO-d6) δ=4.86(1H,d,J=4.8Hz,OH(17)),4.61(1H,br s,OH(16)),4.26(1H,br d,J=3.3Hz,OH(15)),3.55-3.78(2H,m,H-16,15),3.25(1H,dd,J=5.7,4.7Hz,H-17),1.05(1H,dd,J=10.9Hz,J=9.4Hz,H-14),0.67(3H,s,H-18)
13C NMR(125.7MHz,DMSO-d6) δ=86.3(C-17),75.0(C-16),69.2(C-15),55.5(C-14),39.5(C-13),14.0(C-18)
Claims (24)
- 工程(a)で使用される溶媒が、脂肪族および芳香族炭化水素、ハロゲン化炭化水素、エステル、ならびにエーテルからなる群から選択される、請求項1に記載の方法。
- 工程(a)で用いられる反応物質が、無水酢酸、塩化アセチルまたは臭化アセチルである、請求項1~2のいずれか一項に記載の方法。
- 工程(a)で用いれる反応物質が、酢酸-ギ酸混合無水物である、請求項1~3のいずれか一項に記載の方法。
- 工程(a)が、第3級アミン塩基の存在下で実施される、請求項1~4のいずれか一項に記載の方法。
- 工程(a)が、得られた一般式(III)の化合物を、C1~3アルコールから結晶化させることをさらに含む、請求項1~5のいずれか一項に記載の方法。
- 工程(a)が、式(II)の化合物を精製および/または単離することなく実施される、請求項1~5のいずれか一項に記載の方法。
- 工程(b)が、水素ガスを用いた接触水素化によって実施され、触媒が、パラジウムまたは支持体にパラジウムを担持させたものからなる群から選択される、請求項1~7のいずれか一項に記載の方法。
- 接触水素化のために使用される溶媒が、アルコール、エステルおよびケトンからなる群から選択される、請求項8に記載の方法。
- 工程(b)が、シクロヘキセン試薬を用いた移動水素化によって実施される、請求項1~7のいずれか一項に記載の方法。
- 移動水素化のために使用される溶媒がアルコールである、請求項10に記載の方法。
- 工程(b)が、得られた一般式(IV)の化合物を、エステル、炭化水素、アルコール、またはそれらの混合物から結晶化させることをさらに含む、請求項1~11のいずれか一項に記載の方法。
- 工程(c)で使用される溶媒が、水、アルコール性溶媒、またはそれらの混合物からなる群から選択される、請求項1~12のいずれか一項に記載の方法。
- 工程(c)が、アルカリ金属炭酸塩またはアルカリ金属炭酸水素塩の存在下で実施される、請求項1~13のいずれか一項に記載の方法。
- 工程(c)が、アルカリ金属アルコラートまたはアルカリ金属水酸化物の存在下で実施される、請求項1~13のいずれか一項に記載の方法。
- Rがメチル基である、請求項1~15のいずれか一項に記載の方法。
- Rが水素である、請求項1~15のいずれか一項に記載の方法。
- 医薬を製造するための、請求項1~17のいずれか一項に記載の方法によって得られる式(I)の生成物の使用。
- ホルモン補充療法、腟乾燥の治療、更年期障害の治療、避妊、性欲の増強、皮膚の治療、および創傷治癒の促進における使用のための医薬を製造するための、請求項1~17のいずれか一項に記載の方法によって得られる式(I)の生成物の使用。
- 避妊における使用のための、請求項19に記載の生成物。
- ドロスピレノンと組み合わせた避妊における使用のための、請求項20に記載の生成物。
- 自己免疫障害、乳房腫瘍、前立腺がん、および結腸直腸腫瘍からなる群から選択される疾患の治療もしくは予防における使用のための、または神経保護における使用のための医薬を製造するための、請求項1~17のいずれか一項に記載の方法によって得られる式(I)の生成物の使用。
- 三酢酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイルおよび三ギ酸(15α,16α,17β)-3-(ベンジルオキシ)エストラ-1,3,5(10)-トリエン-15,16,17-トリイルからなる群から選択される、一般式(III)の化合物。
- 三ギ酸(15α,16α,17β)-3-ヒドロキシエストラ-1,3,5(10)-トリエン-15,16,17-トリイルである、一般式(IV)の化合物。
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PCT/IB2020/058148 WO2021044302A1 (en) | 2019-09-03 | 2020-09-02 | Industrial process for the preparation of high purity estetrol |
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CA3232558A1 (en) * | 2021-10-01 | 2023-04-06 | Roberto Lenna | Process for preparing (15alpha,16alpha,17 eta)-estra-1,3,5(10)-triene-3,15,16,17-tetrol (estetrol) monohydrate |
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