JPWO2019162149A5 - - Google Patents

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JPWO2019162149A5
JPWO2019162149A5 JP2020544224A JP2020544224A JPWO2019162149A5 JP WO2019162149 A5 JPWO2019162149 A5 JP WO2019162149A5 JP 2020544224 A JP2020544224 A JP 2020544224A JP 2020544224 A JP2020544224 A JP 2020544224A JP WO2019162149 A5 JPWO2019162149 A5 JP WO2019162149A5
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Priority claimed from EP18157888.1A external-priority patent/EP3530649B1/en
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Claims (16)

式（Ｉ）：
Figure 2019162149000001
で示される６－（ニトロオキシ）－ヘキサン酸（１Ｓ，２Ｅ）－３－［（１Ｒ，２Ｒ，３Ｓ，５Ｒ）－２－［（２Ｚ）－７－（エチルアミノ）－７－オキソ－２－ヘプテン－１－イル］－３，５－ジヒドロキシシクロペンチル］－１－（２－フェニルエチル）－２－プロペン－１－イルエステルの製造方法であって、以下の工程：
ａ）式（II）：
Figure 2019162149000002
で示される化合物を式（IV）：
Figure 2019162149000003
で示される６－（ニトロオキシ）ヘキサノイルクロリドと、遊離形の４－ジメチルアミノピリジンの存在下で反応させて、式（III）：
Figure 2019162149000004
で示される化合物を得る工程、
ｂ）式（III）の化合物のボロン酸保護基を脱離して、式（Ｉ）の化合物を得る工程
を含む製造方法。 Equation (I):
Figure 2019162149000001
6- (Nitrooxy) -caproic acid (1S, 2E) -3-[(1R, 2R, 3S, 5R) -2-[(2Z) -7- (ethylamino) -7-oxo-2- Heptene-1-yl] -3,5-dihydroxycyclopentyl] -1- (2-phenylethyl) -2-propen-1-yl ester is a method for producing the following steps:
a) Equation (II):
Figure 2019162149000002
The compound represented by the formula (IV):
Figure 2019162149000003
In the presence of free 4-dimethylaminopyridine, the 6- (nitrooxy) hexanoyl chloride represented by the above is reacted with the formula (III) :.
Figure 2019162149000004
Step of obtaining the compound indicated by,
b) A production method comprising a step of removing the boronic acid protecting group of the compound of the formula (III) to obtain the compound of the formula (I). 工程ａ）が、非プロトン性有機溶媒中で行われる、請求項１記載の製造方法。 The production method according to claim 1, wherein step a) is performed in an aprotic organic solvent. 非プロトン性有機溶媒が、メチルtert－ブチルエーテル、Ｎ，Ｎ－ジメチルホルムアミド又はジクロロメタンから選択される、請求項２記載の製造方法。 The production method according to claim 2, wherein the aprotic organic solvent is selected from methyl tert-butyl ether, N, N-dimethylformamide or dichloromethane. 非プロトン性有機溶媒が、メチルtert－ブチルエーテルである、請求項３記載の製造方法。 The production method according to claim 3, wherein the aprotic organic solvent is methyl tert-butyl ether. 工程ａ）において、式（II）の化合物対式（IV）の６－（ニトロオキシ）ヘキサノイルクロリドのモル比が、１：１．４～１：１．６であり、そして式（II）の化合物対４－ジメチルアミノピリジンのモル比が、１：２．０～１：２．４である、請求項１～４のいずれか一項記載の製造方法。 In step a), the molar ratio of the compound vs. formula (IV) 6- (nitrooxy) hexanoyl chloride of formula (II) is 1: 1.4 to 1: 1.6, and of formula (II). The production method according to any one of claims 1 to 4, wherein the molar ratio of compound to 4-dimethylaminopyridine is 1: 2.0 to 1: 2.4. 工程ａ）が、０℃～室温の範囲の温度で行われる、請求項１～５のいずれか一項記載の製造方法。 The manufacturing method according to any one of claims 1 to 5, wherein step a) is performed at a temperature in the range of 0 ° C. to room temperature. 式（IV）の６－（ニトロオキシ）ヘキサノイルクロリドが、以下の工程：
ｉ）式（Ｖ）：
Figure 2019162149000005
で示される２－カプロラクトンを、ＫＯＨ、ＮａＯＨ及びＬｉＯＨから選択される無機塩基と反応させて、式（VI）：
Figure 2019162149000006
［式中、Ｍは、Ｋ、Ｎａ又はＬｉである］で示される６－ヒドロキシヘキサン酸塩を得る工程、
ii）式（VI）の化合物をＨＮＯ３とＨ２ＳＯ４との混合物でニトロ化して、式（VII）：
Figure 2019162149000007
で示される６－（ニトロオキシ）ヘキサン酸を得る工程、
iii）式（VII）の６－（ニトロオキシ）ヘキサン酸を塩素化試薬で式（IV）の６－（ニトロオキシ）ヘキサノイルクロリドに変換する工程
を含む製造方法により得られる、請求項１～６のいずれか一項記載の製造方法。 The 6- (nitrooxy) hexanoyl chloride of formula (IV) is the following step:
i) Equation (V):
Figure 2019162149000005
2-Caprolactone represented by is reacted with an inorganic base selected from KOH, NaOH and LiOH to formulate (VI) :.
Figure 2019162149000006
The step of obtaining the 6-hydroxyhexanoate represented by [where M is K, Na or Li in the formula].
ii) The compound of formula (VI) is nitrated with a mixture of HNO 3 and H 2 SO 4 , and formula (VII):
Figure 2019162149000007
The step of obtaining 6- (nitrooxy) caproic acid represented by,
iii) Claims 1 to 6 obtained by a production method comprising a step of converting 6- (nitrooxy) caproic acid of formula (VII) to 6- (nitrooxy) hexanoyl chloride of formula (IV) with a chlorinating reagent. The manufacturing method according to any one of the above. 工程iii）で得られる式（IV）の６－（ニトロオキシ）ヘキサノイルクロリドが、更に精製することなく工程ａ）に直接使用される、請求項７記載の製造方法。 The production method according to claim 7, wherein the 6- (nitrooxy) hexanoyl chloride of the formula (IV) obtained in the step iii) is directly used in the step a) without further purification. 工程ｉ）に使用される無機塩基が、水酸化カリウムである、請求項７又は８記載の製造方法。 The production method according to claim 7 or 8, wherein the inorganic base used in step i) is potassium hydroxide. 工程ｉ）が、メタノール、エタノール又はイソプロパノールから選択される溶媒中で行われる、請求項７～９のいずれか一項記載の製造方法。 The production method according to any one of claims 7 to 9, wherein step i) is carried out in a solvent selected from methanol, ethanol or isopropanol. 有機溶媒が、メタノールである、請求項１０記載の製造方法。 The production method according to claim 10, wherein the organic solvent is methanol. 工程ii）が、ジクロロメタン中で行われる、請求項７～１１のいずれか一項記載の製造方法。 The production method according to any one of claims 7 to 11, wherein step ii) is carried out in dichloromethane. 工程iii）が、塩素化試薬として塩化オキサリルを使用して行われる、請求項７～１２のいずれか一項記載の製造方法。 The production method according to any one of claims 7 to 12, wherein step iii) is performed using oxalyl chloride as a chlorination reagent. 工程iii）が、ジクロロメタン中で行われる、請求項７～１３のいずれか一項記載の製造方法。 The production method according to any one of claims 7 to 13, wherein step iii) is carried out in dichloromethane. 式（II）の化合物が、ビマトプロストをブチルボロン酸と反応させることにより得られる、請求項１～１４のいずれか一項記載の製造方法。 The production method according to any one of claims 1 to 14 , wherein the compound of the formula (II) is obtained by reacting bimatoprost with butylboronic acid. 化学純度９９％超を有し、０．１５％～０．２６％の量の（Ｓ，Ｅ）－１－（（１Ｒ，２Ｒ，３Ｓ，５Ｒ）－２－（（Ｚ）－７－（エチルアミノ）－７－オキソヘプタ－２－エニル）－３，５－ジヒドロキシシクロペンチル）－５－フェニルペンタ－１－エン－３－イル ６－クロロヘキサノエート（化合物（Ｘ））を含む、６－（ニトロオキシ）－ヘキサン酸（１Ｓ，２Ｅ）－３－［（１Ｒ，２Ｒ，３Ｓ，５Ｒ）－２－［（２Ｚ）－７－（エチルアミノ）－７－オキソ－２－ヘプテン－１－イル］－３，５－ジヒドロキシシクロペンチル］－１－（２－フェニルエチル）－２－プロペン－１－イルエステル。It has a chemical purity of more than 99% and an amount of 0.15% to 0.26% (S, E) -1-((1R, 2R, 3S, 5R) -2-((Z) -7-((Z) -7-( Ethylamino) -7-oxohept-2-enyl) -3,5-dihydroxycyclopentyl) -5-phenylpenta-1-en-3-yl 6-chlorohexanoate (compound (X)), 6- (Nitrooxy) -hexanoic acid (1S, 2E) -3-[(1R, 2R, 3S, 5R) -2-[(2Z) -7- (ethylamino) -7-oxo-2-heptene-1-yl ] -3,5-Dihydroxycyclopentyl] -1- (2-Phenylethyl) -2-propen-1-yl ester.
JP2020544224A 2018-02-21 2019-02-12 Method for producing prostaglandin analogs that donate nitric oxide Active JP7365349B2 (en)

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EP18157888.1 2018-02-21
EP18157888.1A EP3530649B1 (en) 2018-02-21 2018-02-21 Process for the preparation of a nitric oxide donating prostaglandin analogue
PCT/EP2019/053455 WO2019162149A1 (en) 2018-02-21 2019-02-12 Process for the preparation of a nitric oxide donating prostaglandin analogue

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EP (2) EP3530649B1 (en)
JP (2) JP7365349B2 (en)
KR (1) KR20200123151A (en)
CN (1) CN111757868B (en)
AR (1) AR114262A1 (en)
CA (1) CA3089530A1 (en)
ES (2) ES2836118T3 (en)
HU (1) HUE052204T2 (en)
PH (1) PH12020551320A1 (en)
PT (1) PT3530649T (en)
SG (1) SG11202007113XA (en)
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EP3772511B1 (en) * 2019-08-05 2023-11-08 Nicox S.A. Process for the preparation of a nitric oxide donating prostaglandin analogue
EP4288413A1 (en) 2021-02-03 2023-12-13 Nicox S.A. Process for the preparation of a nitric oxide donating prostaglandin analogue
CA3232002A1 (en) 2021-09-20 2023-03-23 Nicox Sa Nitric oxide releasing prostamide as neuroprotective agent
EP4303211A1 (en) 2022-07-07 2024-01-10 Nicox S.A. Industrial process for the preparation of hexanoic acid, 6(nitrooxy)-,(1s,2e)-3-[(1r,2r,3s,5r)-2-[(2z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]3,5-dihydroxycyclopentyl]-1-(2-phenyl ethyl)-2-propen-1-yl ester and high pure product

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AR076731A1 (en) 2008-05-09 2011-07-06 Pfizer GIVING PRESSURES OF NITRIC OXIDE, USE OF THE SAME AND PHARMACEUTICAL COMPOSITIONS
CN103288698A (en) * 2013-05-07 2013-09-11 北京洛斯顿精细化工有限公司 Novel method for synthetizing prostaglandin analogue
JP6279409B2 (en) 2014-06-02 2018-02-14 株式会社ダイセル Oxidation of ketones to esters using post-treated tin-substituted zeolite beta
WO2016155906A1 (en) 2015-03-31 2016-10-06 Nicox S.A. Nitric oxide donating derivatives of fluprostenol

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