WO2015096071A1 - Method for preparing aliphatic phosphate ester having protected hydroxyl with optical activity - Google Patents

Method for preparing aliphatic phosphate ester having protected hydroxyl with optical activity Download PDF

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Publication number
WO2015096071A1
WO2015096071A1 PCT/CN2013/090454 CN2013090454W WO2015096071A1 WO 2015096071 A1 WO2015096071 A1 WO 2015096071A1 CN 2013090454 W CN2013090454 W CN 2013090454W WO 2015096071 A1 WO2015096071 A1 WO 2015096071A1
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phosphate ester
hydroxyl
optically active
double bond
reaction
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PCT/CN2013/090454
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French (fr)
Chinese (zh)
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王鹏
李丕旭
谷向永
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苏州鹏旭医药科技有限公司
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Priority to PCT/CN2013/090454 priority Critical patent/WO2015096071A1/en
Publication of WO2015096071A1 publication Critical patent/WO2015096071A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring

Definitions

  • the present invention relates to the synthesis of a hydroxyl-protected phosphate ester of the new drug 'fteprostinii' for the treatment of pulmonary hypertension.
  • Prostacyclin analogue Treprostijiil is effective in the treatment of brachial hypertension, including primary and secondary brachial hypertension. Its efficacy is similar to that of epoprostenol, and it can be used as an alternative to prostacyclin for intravenous injection, and it has little effect on the pharmacokinetics and pharmacodynamics of warfarin in combination with warfarin.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art, and to provide a synthesis of an optically active, rhomboprotective phosphate ester which is particularly suitable for the preparation of a novel drug for the treatment of pulmonary hypertension, Treprostiml.
  • an aspect of the present invention provides a method for preparing an optically active hydroxy-protected aliphatic phosphoric acid, which in turn includes the steps -
  • Another aspect of the invention provides a method of preparing an optically active hydroxy-protected aliphatic phosphate, which in turn comprises the steps of:
  • the starting material for the above preparation method is a chiral alcohol having a configuration with a double bond at the end.
  • the compound 2 or the compound 4 contains an unsaturated bond which is a double bond
  • the catalyst used for the addition reaction of the 3 ⁇ 4 acid ester to the double bond includes benzoyl peroxide, dodecanoyl peroxide, di-tert-butyl peroxide. Or dicumyl peroxide, in an amount of 0.05 to 0.3 equivalents of the reaction substrate.
  • the phosphate used in the addition reaction of the phosphate to the double bond is dimethyl phosphite, diethyl phosphate or diphenyl fluorene or the like.
  • the addition reaction of the phosphate to the double bond is carried out using a solvent 1,4-dioxane, DMF or n-heptane, preferably a solvent, 4-dioxane.
  • reaction conditions for the addition reaction of the phosphate to the double bond include heating to 10 (TC).
  • the protection strategy employed for the protection of the hydroxy group includes protection by silyl ether, ether, ester or carbonate.
  • the protective reaction to a hydroxyl group when the protecting group is TESCi, the reaction conditions are imidazole as a base, and DMF is a solvent; when the protecting group is THP, the catalyst is 1 2 , dichloroformamidine is a solvent, and the amount of DHP is 1-10;
  • the protecting group is Cbz
  • the preferred base is an alkali metal carbonate.
  • the protective reaction to a hydroxy group, the protecting group is Cbz, and is reacted with a benzyl halide in the presence of a base.
  • the present invention has the following advantages over the prior art:
  • the present invention provides a method for preparing an optically active long-chain aliphatic phosphate, by using a chiral alcohol having a terminal ethylenic bond, in an initiator Under the action of the phosphate ester, the double bond is selectively added to obtain an optically active phosphate compound, and then the hydroxyl group is protected to obtain a phosphate compound which is protected by a plurality of different kinds of Baohu; or Protection, and then reacting with the phosphate to obtain an optically active phosphate compound.
  • the preparation method is fast, efficient and low-cost, and is especially suitable for the preparation of a new drug Treprostiml side chain for pulmonary hypertension.
  • the invention relates to a method for preparing an optically active hydroxy-protected aliphatic phosphate, which can be carried out in two ways, namely: First, after the phosphate ester and the double bond are added, the hydroxyl group is protected, and finally the mesh is obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a method for preparing an aliphatic phosphate ester having protected hydroxyl with optical activity, which can efficiently synthesize the side chains or precursors of the drug, Treprostinil, for treating pulmonary arterial hypertension. It is a completely new synthetic route and synthetic strategy. The product precursor is obtained by the radical addition reaction of optical active alcohol with a double bond at its terminal, catalyzed by benzoyl peroxide, and the hydroxyl can further be protected by different strategies so as to prepare the target compound; the compound can also be obtained as follows: protecting the hydroxyl at first, and then an addition reaction on the double bond is carried out using a phosphate ester. The aliphatic phosphate ester ester having protected hydroxyl prepared by the present invention can be used for preparing the new drug, Treprostinil, for treating pulmonary arterial hypertension.

Description

基保护的脂肪族磷酸酯的制备方法 技术领域  Method for preparing base-protected aliphatic phosphates
本发明涉及- 备肺动脉高压治疗新药 'fteprostinii 性的羟基被 保护的磷酸酯的合成。 The present invention relates to the synthesis of a hydroxyl-protected phosphate ester of the new drug 'fteprostinii' for the treatment of pulmonary hypertension.
背景技术  Background technique
前列环素（依前列醇）连续静脉注射是目前临床肺动脉高压的标准治疗方案。 但静脉注射可能引起的严重不良反应促使人们迸行新药以及新制剂的研究 幵发。 前列环素类似物 Treprostijiil可有效治疗踔动脉高压 包括原发性和继 发性姉动脉高压的治疗。其疗效与依前列醇类似，可作为静餘注射用前列环素 的替代 药,且与华法林联合使 对华法林药动学和药效学几无影响。 Continuous intravenous injection of prostacyclin (eprostol) is currently the standard treatment for clinical pulmonary hypertension. However, the serious adverse reactions that may be caused by intravenous injection have prompted people to carry out research on new drugs and new preparations. Prostacyclin analogue Treprostijiil is effective in the treatment of brachial hypertension, including primary and secondary brachial hypertension. Its efficacy is similar to that of epoprostenol, and it can be used as an alternative to prostacyclin for intravenous injection, and it has little effect on the pharmacokinetics and pharmacodynamics of warfarin in combination with warfarin.
Figure imgf000002_0001
Figure imgf000002_0001
Ttreprostinil  Ttreprostinil
在 Ttreprostinil的合成过程中， 涉及到一种长链手性醇侧链的合成， 具体 的合成方法仅有少数文献报道文献报道 （EP0159784, IP 1985208936, US4668814A , US 4683330. ) , 其合成路线长、 原料试剂不易得、 中间还 涉及一歩贵重金属催化的不对称环氧化反应， 总体成本高昂， 具体路线 如下-
Figure imgf000003_0001
In the synthesis of Ttreprostinil, a synthesis of a long-chain chiral alcohol side chain is involved. The specific synthesis method has only been reported in a few literatures (EP0159784, IP 1985208936, US4668814A, US 4683330.), and its synthetic route is long. Raw material reagents are not easy to obtain, and there is also an asymmetric epoxidation reaction catalyzed by precious metals. The overall cost is high, and the specific route is as follows -
Figure imgf000003_0001
OH OH OH OH
(RO)2P (RO) 2 P
OH OPG OPG  OH OPG OPG
因此发明一种快速、 高效的合成该类侧链的方法意义十分重大。 Therefore, inventing a fast and efficient method for synthesizing such side chains is of great significance.
发明内容  Summary of the invention
本发明所要解决的技术问题是克服现有技术的不足， 提供一种特别适用 于肺动脉高压治疗新药 Treprostiml侧链制备的光学活性的径基保护的磷酸酯的 合成 yi。 The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art, and to provide a synthesis of an optically active, rhomboprotective phosphate ester which is particularly suitable for the preparation of a novel drug for the treatment of pulmonary hypertension, Treprostiml.
为解决以上技术问题，本发明一方面提供一种光学活性的羟基保护的脂肪族磷 酸酯的制备方法， 依次包括步骤-In order to solve the above technical problems, an aspect of the present invention provides a method for preparing an optically active hydroxy-protected aliphatic phosphoric acid, which in turn includes the steps -
(a) 磷酸酯不饱和键的加成： 磷酸酯在催化剂的伤用下对化合物 2的不饱和键 进行加成， 得到产物 3 , (a) Addition of a phosphate ester unsaturated bond: The phosphate ester is added to the unsaturated bond of the compound 2 under the action of a catalyst to obtain a product 3
HOP(OMe)2 0 HOP(OMe) 2 0
MeO-P  MeO-P
OH (PhC02)20 OH (PhC0 2 ) 2 0
OMe OH  OMe OH
2 3 .  twenty three .
(b) 对产物 3的羟基采取多种不同的保护策略进行保护， 得到与产物 3骨架相同 的目标化合物 L (b) The hydroxy group of product 3 is protected by a number of different protection strategies to obtain the same target compound L as the product 3 skeleton.
0  0
MeO~P MeO— P  MeO~P MeO- P
OMe OH OMe 0、  OMe OH OMe 0,
PG  PG
3 本发明另一方面提供另外一种光学活性的羟基保护的脂肪族磷酸酯的制备方法，依次 包括如下步骤：  3 Another aspect of the invention provides a method of preparing an optically active hydroxy-protected aliphatic phosphate, which in turn comprises the steps of:
(a)对化合物 2的羟基进行保护， 得到化合物 4, (b) 羟基保护的含不饱和键的化合物 4进一歩和 ϋ酸酯进行加成反应得到目标化 合物 1 ,
Figure imgf000004_0001
(a) protecting the hydroxyl group of compound 2 to obtain compound 4, (b) a hydroxyl-protected unsaturated bond-containing compound 4 is further subjected to an addition reaction with a phthalic acid ester to obtain a target compound 1,
Figure imgf000004_0001
在一特定实例中， 上述制备方法的起始原料为末端带有双键的 构型的手性醇。 In a specific example, the starting material for the above preparation method is a chiral alcohol having a configuration with a double bond at the end.
优选地， 前述化合物 2或化合物 4所含不饱和键为双键， ¾酸酯对双键的加成反 应所用的催化剂包括过氧化苯甲酰， 过氧化十二酰， 过氧化二特丁基或过氧化二异丙 苯， 用量为反应底物的 0.05- 0.3当量。 Preferably, the compound 2 or the compound 4 contains an unsaturated bond which is a double bond, and the catalyst used for the addition reaction of the 3⁄4 acid ester to the double bond includes benzoyl peroxide, dodecanoyl peroxide, di-tert-butyl peroxide. Or dicumyl peroxide, in an amount of 0.05 to 0.3 equivalents of the reaction substrate.
优选地， 磷酸酯对双键的加成反应所用的磷酸酯为亚磷酸二甲酯， 磷酸二乙酯或二苯 基礴氧或类似物。 Preferably, the phosphate used in the addition reaction of the phosphate to the double bond is dimethyl phosphite, diethyl phosphate or diphenyl fluorene or the like.
优选地， 磷酸酯对双键的加成反应采用溶剂 1,4 -二氧六环、 DMF或正庚烷， 优选溶剂 为〗，4-二氧六环。 Preferably, the addition reaction of the phosphate to the double bond is carried out using a solvent 1,4-dioxane, DMF or n-heptane, preferably a solvent, 4-dioxane.
优选地， 磷酸酯对双键的加成反应的反应条件包括加热至 10(TC。 Preferably, the reaction conditions for the addition reaction of the phosphate to the double bond include heating to 10 (TC).
优选地， 对羟基的保护采用的保护策略， 包括通过硅醚， 醚， 酯或碳酸脂进行保护。 具体地， 对羟基的保护反应， 当保护基为 TESCi , 反应的条件以咪唑为碱， DMF 为溶剂； 当保护基团为 THP时， 催化剂为 12, 二氯甲垸为溶剂， DHP 量在 1-10; 当保护基为 Cbz时， 优选的碱为碱金属碳酸盐。 Preferably, the protection strategy employed for the protection of the hydroxy group includes protection by silyl ether, ether, ester or carbonate. Specifically, the protective reaction to a hydroxyl group, when the protecting group is TESCi, the reaction conditions are imidazole as a base, and DMF is a solvent; when the protecting group is THP, the catalyst is 1 2 , dichloroformamidine is a solvent, and the amount of DHP is 1-10; When the protecting group is Cbz, the preferred base is an alkali metal carbonate.
在一特定实^中， 对羟基的保护反应， 保护基为 Cbz, 在碱存在下与苄基卤化物反应。 于上述技术方案的实施， 本发明与现有技术相比具有如下优点： 本发明提供光学活性 的长链的脂肪族磷酸酯的制备方法， 通过带有末端烯键的手性醇， 在引发剂的作用下， 磷酸酯选择性的对双键进行加成， 得到光学活性的磷酸酯化合物， 接着对羟基进行保护， 得到由多种不同保沪基保沪的磷酸酯化合物； 或者先对羟基进行保护， 然后再与磷酸酯 反应， 得到光学活性的磷酸酯化合物。 制备方法快速、 高效、 成本低， 特别适用于肺动 脉高压治疗新药 Treprostiml侧链的制备。 In a specific embodiment, the protective reaction to a hydroxy group, the protecting group is Cbz, and is reacted with a benzyl halide in the presence of a base. In the practice of the above technical solution, the present invention has the following advantages over the prior art: The present invention provides a method for preparing an optically active long-chain aliphatic phosphate, by using a chiral alcohol having a terminal ethylenic bond, in an initiator Under the action of the phosphate ester, the double bond is selectively added to obtain an optically active phosphate compound, and then the hydroxyl group is protected to obtain a phosphate compound which is protected by a plurality of different kinds of Baohu; or Protection, and then reacting with the phosphate to obtain an optically active phosphate compound. The preparation method is fast, efficient and low-cost, and is especially suitable for the preparation of a new drug Treprostiml side chain for pulmonary hypertension.
具体实施方式  detailed description
本发明涉及一种光学活性的羟基保护的脂肪族磷酸酯的制备方法， 该制备方 法可以通过以下两种方式进行， 即： 首先磷酸酯和双键进行加成后再进行羟基的保护， 最终得到目 The invention relates to a method for preparing an optically active hydroxy-protected aliphatic phosphate, which can be carried out in two ways, namely: First, after the phosphate ester and the double bond are added, the hydroxyl group is protected, and finally the mesh is obtained.
如下： as follows:
Figure imgf000005_0001
Figure imgf000005_0001
也可以首先对羟基进行保护后再和磷酸酯反应最终得到目标化合物 1,如 下：
Figure imgf000005_0002
下面结合具体的实施例对本发 步的说明， 但本发明不限于以下 实施例。 It is also possible to first protect the hydroxyl group and then react with the phosphate to finally obtain the target compound 1, as follows:
Figure imgf000005_0002
The present invention will be described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.
实施例 1
Figure imgf000005_0003
Example 1
Figure imgf000005_0003
向化合物 2 ( 1 eq)的 1,4-二氧六环 ( 10 vol)溶液中加入亚磷酸二甲酯（3 eq) 和过氧化苯甲酰 （0.3 eq)。 将体系加热至 80Ό条件下反应 1- 2h, 气相监测反 应完成。 向反应中加入水 （ 100 m:L)， EA ( 100mL*4) 萃取。 有机相分别用 饱和 NH4C1 ( 100 mL)、 饱和 NaHCO3(100 mL)、 Brine( 100 mL)洗涤一次。 硫 酸镁干燥， 过滤旋千， 得到的产物 3直接用于下一步反应。 To a solution of compound 2 (1 eq) in 1,4-dioxane (10 vol) was added dimethyl phosphite (3 eq) and benzoyl peroxide (0.3 eq). The system was heated to 80 Torr for 1 - 2 h, and the gas phase monitoring reaction was completed. Water (100 m: L) and EA (100 mL * 4) were added to the reaction. The organic phase respectively, Brine (100 mL) and washed once with saturated NH 4 C1 (100 mL), saturated NaHCO 3 (100 mL). The magnesium sulfate was dried, filtered, and the obtained product 3 was directly used for the next reaction.
对所得产物进行核磁测试的数据如下: 1H NMR (400 Hz, CDC13) δ 3.57 (d， J --- ---】0,8 Hz, 6H), 3.40 (m, 1 H), 3.24 (m, 1 H), 1.70 . 1,44 (m, 4H)， 1.43 - 1.21 (m,The data of the nuclear magnetic test of the obtained product are as follows: 1H NMR (400 Hz, CDC1 3 ) δ 3.57 (d, J --- ---) 0,8 Hz, 6H), 3.40 (m, 1 H), 3.24 ( m, 1 H), 1.70 . 1,44 (m, 4H), 1.43 - 1.21 (m,
5H), 1.13 (m, 5H), 0.72 (ηι, 3H). 5H), 1.13 (m, 5H), 0.72 (ηι, 3H).
实施例 2  Example 2
MeO-P MeO-P MeO-P MeO-P
OMe OH OMe O.  OMe OH OMe O.
、TES  TES
3 5 将化合物 3 ( 1 eq)的 DMF( 10 vol)溶液冷却至（)°C ,依次加入眯¾和 TESC1, 室温下反应 2-3 h。 气相监测反应结束， 加入 30 mL水将反应淬灭。 加入 ： i:L 水， EA ( 1 L*3) 萃取。 有机相分别用饱和 NH4C〖 （ 1 L)、 饱和 NaHC03(iL)、 Brine(l L)洗涤一次。 硫酸镁干燥， 过滤旋干， 过柱， 得到目标化合物 4。 产 率 88%。 3 5 Cool down the compound 3 (1 eq) in DMF (10 vol) to () °C, add 眯3⁄4 and TESC1 in sequence, and react at room temperature for 2-3 h. The gas phase monitoring reaction was completed, and the reaction was quenched by the addition of 30 mL of water. Join: i:L Water, EA (1 L*3) extraction. The organic phase was washed once with saturated NH 4 C (1 L), saturated NaHC0 3 (iL), Bri ne (l L), respectively. The residue was dried over magnesium sulfate, filtered and dried, and then filtered to afford the title compound 4. The yield was 88%.
对所得产物进行核磁测试的数据如下： fHNM:R(40() MHz, CDC13) δ 3.73 (d， J 10,7 Hz, 6H), 3.64 (dd, J ::: 11,3, 5.8 Hz, IH), 1,83― 1.58 (m, 4H), 1.57― 1,46 (m, 2H), 1.45 - 1.36 (m, 2H), 1.36 - 1.20 (m, 6H), 0.96 (t, J = 7.9 Hz, 9H), 0.89 (t, J == 7.0 Hz, 3H), 0.59 (q, J：:: 8.0 Hz, 6H). The data of the nuclear magnetic test of the obtained product are as follows: f HNM: R (40 () MHz, CDC1 3 ) δ 3.73 (d, J 10, 7 Hz, 6H), 3.64 (dd, J ::: 11,3, 5.8 Hz, IH), 1,83― 1.58 (m, 4H), 1.57― 1,46 (m, 2H), 1.45 - 1.36 (m, 2H), 1.36 - 1.20 (m, 6H), 0.96 (t, J = 7.9 Hz, 9H), 0.89 (t, J == 7.0 Hz, 3H), 0.59 (q, J::: 8.0 Hz, 6H).
实施例 3  Example 3
Figure imgf000006_0001
将化合物 3 (50 g, 1 eq) 的 DCM (4 vol) 溶液依次加入 DHP(2 eq)和 l2, 室 温下反应。气相监测反应结束，加入 30 mL饱和硫代硫酸钠溶液将反应淬灭。 加入 500 mL水， EA ( 500 m *3) 萃取。 有机相分别用饱和 NH4C1 ( 1 L)、 饱和 NaHC03(lL)、 Brine(l L)洗涤一次。 硫酸镁千燥， 过滤旋干， 过柱， 得 到目标化合物 5。 产率 79'½。
Figure imgf000006_0001
Compound 3 (50 g, 1 eq) in DCM (4 vol) were sequentially added DHP (2 eq) and 2, the reaction at room temperature for l. The gas phase monitoring reaction was completed, and the reaction was quenched by adding 30 mL of a saturated sodium thiosulfate solution. Add 500 mL of water and extract with EA (500 m *3). The organic phase was washed once with saturated NH 4 C1 (1 L), saturated NaHC0 3 (lL), and Brine (l L). The magnesium sulfate was dried, filtered and dried, and passed through a column to give the objective compound 5. The yield is 79'1⁄2.
对所得产物进行核磁测试的数据如下: 1H NMR (400 MHz, CDC13) δ 4.62 (dd, j :: 7.7， 4.5 Hz, IH), 3.94―.3.84 (ni, IH), 3.75 (s, 3H), 3.72 fs, 3H)， 3.61 (dd, j = 7.3, 4.1 Hz, IH), 3.49 (dd, j = 10.8, 5.7 Hz, IH), 1,90 - 1.23 (m， 20H), 0.89 (t j 6.8 Hz, 3H). The data of the nuclear magnetic test of the obtained product are as follows: 1H NMR (400 MHz, CDC13) δ 4.62 (dd, j :: 7.7, 4.5 Hz, IH), 3.94 -.3.84 (ni, IH), 3.75 (s, 3H) , 3.72 fs, 3H), 3.61 (dd, j = 7.3, 4.1 Hz, IH), 3.49 (dd, j = 10.8, 5.7 Hz, IH), 1,90 - 1.23 (m, 20H), 0.89 (tj 6.8 Hz, 3H).
实施例 4
Figure imgf000006_0002
Example 4
Figure imgf000006_0002
三口瓶中， 加入 K2C03(2 eq)， DMF(iOmL), 苄溴 ( 1.5 eq), 2 (2 g, :ieq)， N2保护， 80Ό搅拌 30h， 水洗后， 萃取后过柱， 得到 1.8 g， 产率 46%。 In a three-necked flask, add K 2 C0 3 (2 eq), DMF (iOmL), benzyl bromide (1.5 eq), 2 (2 g, :ieq), N 2 protection, stirring at 80 ° for 30 h, after washing, extraction and column , 1.8 g, yield 46%.
对所得产物进行核磁测试的数据如下； ^HNMR (400 MHz, CDC13) δ 7,38-7.14 (m, 5H), 5.80-5.58 (ra, IH), 5,13― 4,93 (m, 4H), 4,77― 4.60 (ra, IH), 2,29 (t, j - 6,4 Hz, 2H), 】.63-1,4】 （m, 2H), 1.35-1.10(m, 6H), 0.89-0.71 (m, 3H). The data of the nuclear magnetic test of the obtained product are as follows; ^HNMR (400 MHz, CDC13) δ 7,38-7.14 (m, 5H), 5.80-5.58 (ra, IH), 5,13-4,93 (m, 4H ), 4,77― 4.60 (ra, IH), 2,29 (t, j - 6,4 Hz, 2H), 】.63-1,4] (m, 2H), 1.35-1.10 (m, 6H) ), 0.89-0.71 (m, 3H).
实施例 S HOp(〇Me)2 > MeO-P' Example S HO p (〇Me) 2 >MeO-P'
OCbz (PhCOO)2 OMe OCbz OCbz (PhCOO) 2 OMe OCbz
8 室温下向反应瓶中依次加入 6 (300mg, 1eq)， 1,4-二氧六环， HOP(OMe)2( 5eq)， (PhCOO)2 (0.3eq), 油浴加热至 80 ° C反应 4h， TLC检测， 原料反应完全， 冷却后直接过柱， 得到产品 i90 mg产品 8， 产率： 45%。 8 Add 6 (300 mg, 1 eq), 1,4-dioxane, HOP(OMe )2 (5 eq), (PhCOO) 2 (0.3 eq) to the reaction flask at room temperature, and heat to 80 ° C in an oil bath. The reaction was carried out for 4 h, detected by TLC, and the reaction of the starting material was complete. After cooling, the column was directly passed to obtain the product i90 mg of product 8, yield: 45%.
对所得产物迸行核磁测试的数据如下： lH NMR (400 MHz, CDC13) δ 7.50 - 7.26 (m, 5H), 5.15 (s, 2H), 4,78 - 4.66 (m, 1H), 3.72 (d, J - 10.8 Hz, 6H), —1,85 1,46 (m, 8H), 1.28 (d, J 6.8 Hz, 6H), 0,87 (i, J 6,5 Hz, 3H). The data for the nuclear magnetic test of the obtained product are as follows: l H NMR (400 MHz, CDC13) δ 7.50 - 7.26 (m, 5H), 5.15 (s, 2H), 4,78 - 4.66 (m, 1H), 3.72 ( d, J - 10.8 Hz, 6H), —1,85 1,46 (m, 8H), 1.28 (d, J 6.8 Hz, 6H), 0,87 (i, J 6,5 Hz, 3H).
实施例 6  Example 6
TESCl  TESCl
imidazole S  Imidazole S
2 9 2 9
将化合物 2 ( 1 eq) 的 DMF (： 10 vol )溶液冷却至 0°C ' 依次加入咪唑和 TESCl, 室温下反应 2- -3 h。 气相监测反应结束， 加入 30 !nL水将反应淬灭。 加入 1L 水， EA ( 1 3,*3) 萃取。 有机相分别用饱和 NH4C1 ( 1 L) 、 饱和 NaHC03 ( 1L)、 BrineCl L)洗涤一次。 硫酸镁千燥， 过滤旋千， 过柱， 得到目标化合物 9。 产率 92%。 以上对本发明做了详尽的描述， 其目的在于让熟悉此领域技术的人士能够了 解本发明的内容并加以实施， 并不能以此限制本发明的保护范 ， 凡根据本 发明的精神实质所作的等效变化或修饰， 都应涵盖在本发明的保护范围内。 The solution of compound 2 (1 eq) in DMF (: 10 vol) was cooled to 0 ° C. The imidazole and TESCl were added in sequence, and the reaction was carried out at room temperature for 2 - 3 h. The gas phase monitoring reaction was completed, and the reaction was quenched by adding 30 ? nL of water. Add 1 L of water and extract with EA (1 3, *3). The organic phase was washed once with saturated NH 4 C1 (1 L), saturated NaHC0 3 (1 L), BrineCl L). The magnesium sulfate was dried, filtered, and passed through a column to obtain the target compound 9. The yield was 92%. The present invention has been described in detail above, and is intended to be understood by a person skilled in the art of the invention, and is not intended to limit the scope of the invention. Modifications or modifications are intended to be included within the scope of the invention.

Claims

权利要求： Rights request:
1、 一种光学活性的羟基保护的脂肪族磯酸酯的制备方法， 依次包括步骤- 1. A method for preparing optically active hydroxyl-protected aliphatic phosphate esters, which in turn includes the steps -
(a) 磷酸酯不饱和键的加成： 磷酸酯在催化剂的作用下对化合物 2 的不饱和键迸行 加成， 得到产物 3， (a) Addition of the unsaturated bond of phosphate ester: The phosphate ester adds to the unsaturated bond of compound 2 under the action of a catalyst to obtain product 3.
Figure imgf000008_0001
Figure imgf000008_0001
(b) 对产物 3的羟基进行保护， 得到骨架相同的目标化合物 1，
Figure imgf000008_0002
一种光学活性的羟基保护的脂肪族磷酸酯的制备方 依次包括步骤 : (b) Protect the hydroxyl group of product 3 to obtain target compound 1 with the same skeleton,
Figure imgf000008_0002
The preparation method of an optically active hydroxyl-protected aliphatic phosphate includes the following steps :
(a) 对化合物 2的羟基进行保护， 得到化合物 4， (a) Protect the hydroxyl group of compound 2 to obtain compound 4,
OH 0、 OH 0.
PG PG
2 4 twenty four
(b) 羟基保护的含不饱和键的化合物 4进一步和磷酸酯进行加成反应得到目标化合物 1 , (b) The hydroxyl-protected compound 4 containing an unsaturated bond is further subjected to an addition reaction with a phosphate ester to obtain the target compound 1.
0 0
HOP(OMe)2' MeO-F>' HOP ( OMe )2'MeO-F>'
ό ό
PG OMe 0、 PG OMe 0.
PG PG
4 1 4 1
3、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磯酸酯的制备方法， 其特 征在于： 起始原料为末端带有双键的 S-构型的手性醇。 3. The method for preparing optically active hydroxyl-protected aliphatic phosphate ester according to claim 1 or 2, characterized in that: the starting material is an S-configured chiral alcohol with a double bond at the end.
4、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磷酸酯的制备方法， 其特 征在于： 不饱和键为双键， 磷酸酯对双键的加成反应所用的催化剂包括过氧化苯甲酰， 过氧化十二酰， 过氧化二特丁基或过氧化二异丙苯， 用量为反应底物的 0.05-0.3当量。 4. The preparation method of optically active hydroxyl-protected aliphatic phosphate ester according to claim 1 or 2, characterized in that: the unsaturated bond is a double bond, and the catalyst used in the addition reaction of the phosphate ester to the double bond includes: The dosage of benzoyl oxide, dodecanoyl peroxide, ditert-butyl peroxide or dicumyl peroxide is 0.05-0.3 equivalents of the reaction substrate.
5、 根据权利要求〗 或 2所述的光学活性的羟基保护的脂肪族遴酸酯的制备方法， 其特 征在于： 不饱和键为双键， ¾酸酯对双键的加成反应所用的磷酸酯为亚磷酸二甲酯， 亚 磷酸二乙酯或二苯基磷氧或类似物。 5. The method for preparing optically active hydroxyl-protected aliphatic acid ester according to claim 2 or 2, characterized in that: the unsaturated bond is a double bond, and the phosphoric acid used in the addition reaction of the acid ester to the double bond The ester is dimethyl phosphite, Diethyl phosphate or diphenylphosphine oxide or similar.
6、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磯酸酯的制备方法， 其特 征在于： 不饱和键为双键， 磷酸酯对双键的加成反应采用溶剂 1，4-二氧六环、 DMF 或 正庚垸， 优选溶剂为 1 ,4-二氧六环。 6. The preparation method of optically active hydroxyl-protected aliphatic phosphate ester according to claim 1 or 2, characterized in that: the unsaturated bond is a double bond, and the addition reaction of the phosphate ester to the double bond uses solvent 1, 4-dioxane, DMF or n-heptane, the preferred solvent is 1,4-dioxane.
7、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磷酸酯的制备方法， 其特 征在于： 不饱和键为双键， 磷酸酯对双键的加成反应的反应条件包括加热至 50°C - 100C。 7. The preparation method of optically active hydroxyl-protected aliphatic phosphate ester according to claim 1 or 2, characterized in that: the unsaturated bond is a double bond, and the reaction conditions of the addition reaction of the phosphate ester to the double bond include heating. to 50°C - 100C.
8、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磷酸酯的制备方法， 其特 征在于： 羟基的保护采用的保护策略， 包括通过硅醚， 醚， 酯或碳酸脂进行保护。 8. The preparation method of optically active hydroxyl-protected aliphatic phosphate esters according to claim 1 or 2, characterized in that: the protection strategy adopted for the protection of hydroxyl groups includes protection by silicon ether, ether, ester or carbonate. .
9、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磷酸酯的制备方法， 其特 征在于： 对羟基的保护反应， 保护基为 TESCi, 反应的条件以咪唑为碱， DMF为溶剂。 9. The preparation method of optically active hydroxyl-protected aliphatic phosphate ester according to claim 1 or 2, characterized in that: the protection reaction of hydroxyl group is TESCi, the reaction conditions are imidazole as base, and DMF is Solvent.
10、 根据权利要求〗或 2所述的光学活性的羟基保护的脂肪族磷酸酯的制备方法， 其特 征在于； 对羟基的保护反应， 保护基团为 THP, 催化剂为 】2, 二氯甲烷为溶剂， DHP 用量在 j„io。 10. The method for preparing optically active hydroxyl-protected aliphatic phosphates according to claim 〗 or 2, characterized in that: in the protection reaction of hydroxyl groups, the protecting group is THP, the catalyst is 】 2 , and dichloromethane is Solvent, DHP dosage is j„io.
1 1、 根据权利要求 1或 2所述的光学活性的羟基保护的脂肪族磷酸酯的制备方法， 其特 征在于： 对羟基的保护反应， 保护基为 Cbz， 在碱存在下与苄基卤化物反应。 1 1. The preparation method of optically active hydroxyl-protected aliphatic phosphate ester according to claim 1 or 2, characterized in that: protection reaction of hydroxyl group, the protecting group is Cbz, and benzyl halide in the presence of a base reaction.
PCT/CN2013/090454 2013-12-25 2013-12-25 Method for preparing aliphatic phosphate ester having protected hydroxyl with optical activity WO2015096071A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668814A (en) * 1984-03-08 1987-05-26 The Upjohn Company Interphenylene carbacyclin derivatives
WO2013040068A2 (en) * 2011-09-12 2013-03-21 Irix Pharmaceuticals, Inc. Process for preparing synthetic prostacyclins
CN103073582A (en) * 2013-02-05 2013-05-01 中国科学院上海有机化学研究所 Synthesis method of monoalkyl hydrocarbyl phosphonate
US20130331593A1 (en) * 2010-07-22 2013-12-12 Alphora Research Inc. Synthesis Of Treprostinil And Intermediates Useful Therein

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668814A (en) * 1984-03-08 1987-05-26 The Upjohn Company Interphenylene carbacyclin derivatives
US20130331593A1 (en) * 2010-07-22 2013-12-12 Alphora Research Inc. Synthesis Of Treprostinil And Intermediates Useful Therein
WO2013040068A2 (en) * 2011-09-12 2013-03-21 Irix Pharmaceuticals, Inc. Process for preparing synthetic prostacyclins
CN103073582A (en) * 2013-02-05 2013-05-01 中国科学院上海有机化学研究所 Synthesis method of monoalkyl hydrocarbyl phosphonate

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