WO2014139087A1 - Racemization method of chiral 2-[(4,6-dimethylpyrimidine-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid - Google Patents
Racemization method of chiral 2-[(4,6-dimethylpyrimidine-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid Download PDFInfo
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- WO2014139087A1 WO2014139087A1 PCT/CN2013/072460 CN2013072460W WO2014139087A1 WO 2014139087 A1 WO2014139087 A1 WO 2014139087A1 CN 2013072460 W CN2013072460 W CN 2013072460W WO 2014139087 A1 WO2014139087 A1 WO 2014139087A1
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- diphenylpropionic acid
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000006340 racemization Effects 0.000 title claims abstract description 27
- OUJTZYPIHDYQMC-UHFFFAOYSA-N 2-[(4,6-dimethyl-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OC)C(C(O)=O)OC1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-UHFFFAOYSA-N 0.000 title claims abstract 5
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 238000003756 stirring Methods 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- -1 4,6-dimethylpyrimidin-2-yl Chemical group 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 10
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 150000002825 nitriles Chemical group 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 9
- OUJTZYPIHDYQMC-IBGZPJMESA-N (2r)-2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound O([C@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-IBGZPJMESA-N 0.000 claims 1
- BZQGAPWJKAYCHR-UHFFFAOYSA-N 3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(CC(=O)O)C1=CC=CC=C1 BZQGAPWJKAYCHR-UHFFFAOYSA-N 0.000 claims 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000012805 post-processing Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229960002414 ambrisentan Drugs 0.000 description 6
- WNMVFWUPZAXTJI-UHFFFAOYSA-N CCCCCCCCCCOC(C1=CC=CC=C1)(C2=CC=CC=C2)C(C(=O)O)OC3=NC(=CC(=N3)C(=N)N)C(=N)N Chemical compound CCCCCCCCCCOC(C1=CC=CC=C1)(C2=CC=CC=C2)C(C(=O)O)OC3=NC(=CC(=N3)C(=N)N)C(=N)N WNMVFWUPZAXTJI-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JQJBQVRTSMGDJX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxy]decane Chemical compound CCCCCCCCCCOC(C)(C)C JQJBQVRTSMGDJX-UHFFFAOYSA-N 0.000 description 1
- WINREINUAPFOBV-UHFFFAOYSA-N CCCCCCCCCCOC(C1=CC=CC=C1)(C2=CC=CC=C2)C(C(=O)O)OC3=NC(=CC(=S)N3)S Chemical compound CCCCCCCCCCOC(C1=CC=CC=C1)(C2=CC=CC=C2)C(C(=O)O)OC3=NC(=CC(=S)N3)S WINREINUAPFOBV-UHFFFAOYSA-N 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Definitions
- the present invention relates to the field of chemistry, and in particular to the optically active chiral compound 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropene
- the method of racemization of acid is a simple compound of chemistry, and in particular to the optically active chiral compound 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropene
- Ambrisentan is a selective endothelin receptor antagonist developed by Myogen (Gilead's later acquisition of Myogen) and approved by the US FDA on June 19, 2007 under the trade name Letaris.
- Clinically suitable for the treatment of pulmonary hypertension (PAH) is (+)-(2S)-2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-methoxy-3, 3-diphenylpropionic acid, the structure of which is shown as I:
- the racemic form of ambrisentan can be resolved by chiral amine, and the separation of the diastereomers in the solvent can be separated by recrystallization.
- the salt formed by the (S) configuration and the chiral amine has a smaller solubility from the solution, while the mother liquor is 2-[(4,) containing a large number of (R) configurations and a small (S) configuration.
- the present invention provides a racemization method in which chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid is subjected to chiralization.
- the obtained racemic product can be further resolved to obtain the desired (S) configuration to improve the resolution efficiency of ambrisentan, which is of great significance.
- Summary of the invention provides a racemization method of chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid.
- chiral 2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid is added to the solvent, Racemization above the boiling point of the solvent, post-treatment to give 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid Racemic product.
- the solvent in the step 1 is selected from the group consisting of a nitrile solvent, an aromatic hydrocarbon solvent, and an alkane-based solvent.
- the nitrile solvent is preferably acetonitrile or benzoquinone
- the aromatic solvent is preferably benzene
- the alkane solvent is preferably dichloromethane
- the amide solvent such as DMF is partially racerated at 90 °C.
- Ester solvents such as ethyl acetate, ether solvents such as t-butyl decyl ether, tetrahydrofuran, dioxane (cycloether), ketone solvents such as acetone, alkane solvents such as n-hexane, water and alcohol solvents Neither sterol nor isopropanol can be used for racemization of the process described herein.
- the solvent may be a mixture of two or more of acetonitrile, benzoquinone, toluene or dichlorosilane or a mixed solvent of acetonitrile, benzoquinone, toluene or dichlorosilane.
- amphoteric product of ambrisentan can be precipitated from a solvent because the solubility of the amphoteric racemate is much lower than that of a single configuration of ambrisentan.
- the racemization process can be carried out at 0 ° C to 200 ° C, more preferably 20 ° C to 110 ° C.
- the chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid is (S)-2-[(4,6-Dimercaptopyryl-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, (R)-2-[(4 ,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid or (S)-2-[(4,6-dimercaptopyrimidine-2 -yl)oxy]-3-indolyl-3,3-diphenylpropionic acid and (R)-2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3- A combination of different ratios of decyloxy-3,3-diphenylpropionic acid.
- the method for racemization of a chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid provided by the present invention, Adding 2-[(4,6-dimercaptopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid with high optical rotation value to a specific solvent, specific
- the mixture is stirred at a temperature for a period of time to undergo racemization, and after treatment, a racemized product having a lower optical rotation value or an optical rotation value of zero is obtained.
- the method of the invention has high yield, less waste, and is suitable for industrial production. Moreover, it is easy to operate, and can further improve the separation efficiency, effectively improve the atomic economy, and meet the requirements of green chemistry. detailed description
- the invention discloses a racemization method of chiral 2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, in the field
- the technician can learn from the content of this article and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
- the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention.
- the technique of the present invention is applied.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Provided is a racemization method of a chiral 2-[(4,6-dimethylpyrimidine-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid, comprising the following steps: adding a 2-[(4,6-dimethylpyrimidine-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid with a high rotation value to a specific solvent; performing the racemization at a specific temperature under stirring for a period of time; and after post-processing, a racemization product with a lower rotation or zero rotation value is obtained.
Description
一种手性 2-「(4,6-二甲基嘧啶 -2-基) ΐ-3-甲 -3,3-二苯基丙酸的消旋 化方法 技术领域 A racemic method for chiral 2-(4,6-dimethylpyrimidin-2-yl)indole-3-methyl-3,3-diphenylpropionic acid
本发明涉及化学领域， 特别涉及具有旋光性的手性化合物 2-[(4,6-二 曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸的消旋化方法。 背景技术 The present invention relates to the field of chemistry, and in particular to the optically active chiral compound 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropene The method of racemization of acid. Background technique
安立生坦（ Ambrisentan )是一种选择性的内皮素受体拮抗剂， 由美 国 Myogen(Gilead公司后来收购 Myogen公司）公司开发， 于 2007年 6月 19 日获得美国 FDA批准上市， 商品名 Letairis, 临床适用于治疗肺动脉 高压 (PAH), 化学名称为 (+)-(2S)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸， 其结构如 I所示： Ambrisentan is a selective endothelin receptor antagonist developed by Myogen (Gilead's later acquisition of Myogen) and approved by the US FDA on June 19, 2007 under the trade name Letaris. Clinically suitable for the treatment of pulmonary hypertension (PAH), the chemical name is (+)-(2S)-2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-methoxy-3, 3-diphenylpropionic acid, the structure of which is shown as I:
式 I Formula I
对于安立生坦的合成， 可以通过手性胺拆分安立生坦的外消旋体， 利用非对映体在溶剂中的溶解度差别， 通过重结晶进行分离。 我们所需 要的 （S )构型与手性胺形成的盐具有较小的溶解度从溶液中析出， 而母 液为含有大量 (R)构型和少量（ S )构型的 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3- 曱氧基 -3,3-二苯基丙酸的混合物。 本发明提供一种消旋化方法， 将手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸进行消旋化处 理， 所得的消旋化产物可进一步拆分得到所需的 （S )构型从而提高安立 生坦的拆分效率， 具有十分重要的意义。 发明内容
本发明提供了一种手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3- 二苯基丙酸的消旋化方法。 For the synthesis of ambrisentan, the racemic form of ambrisentan can be resolved by chiral amine, and the separation of the diastereomers in the solvent can be separated by recrystallization. The salt formed by the (S) configuration and the chiral amine has a smaller solubility from the solution, while the mother liquor is 2-[(4,) containing a large number of (R) configurations and a small (S) configuration. Mixture of 6-diamidopyrimidin-2-yl)oxy]-3-oxooxy-3,3-diphenylpropionic acid. The present invention provides a racemization method in which chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid is subjected to chiralization. In the racemization treatment, the obtained racemic product can be further resolved to obtain the desired (S) configuration to improve the resolution efficiency of ambrisentan, which is of great significance. Summary of the invention The present invention provides a racemization method of chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid.
手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸有 R、 S 两种构型，其中 (S)- 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙 酸的结构式如式 I所示， （R)- 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸的结构式如式 II所示。 Chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid has two configurations of R and S, wherein (S - 2-[(4,6-Dimercaptopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid has the structural formula shown in formula I, (R)- 2-[(4,6-Dimercaptopyridin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid has the structural formula shown in Formula II.
式 II Formula II
根据本发明， 将手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二 苯基丙酸加入到溶剂中， 在不高于溶剂沸点温度发生消旋化， 经后处理 得到 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸的消旋化产 物。 According to the present invention, chiral 2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid is added to the solvent, Racemization above the boiling point of the solvent, post-treatment to give 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid Racemic product.
发明人经过大量试验发现， 步骤 1所述溶剂选自腈类溶剂、 芳香烃类 溶剂、 代烷烃类溶剂。 其中腈类溶剂优选为乙腈、 苯曱腈， 芳香类溶 剂优选为曱苯， 代烷烃类溶剂优选为二氯曱烷； 酰胺类溶剂如 DMF在 90°C部分消旋。 The inventors have found through extensive experiments that the solvent in the step 1 is selected from the group consisting of a nitrile solvent, an aromatic hydrocarbon solvent, and an alkane-based solvent. The nitrile solvent is preferably acetonitrile or benzoquinone, the aromatic solvent is preferably benzene, the alkane solvent is preferably dichloromethane; and the amide solvent such as DMF is partially racerated at 90 °C.
酯类溶剂如乙酸乙酯、 醚类溶剂如叔丁基曱醚、 四氢呋喃、 二氧 六环 （环醚） ， 酮类溶剂如丙酮， 烷烃类溶剂如正己烷， 水及醇类溶剂
如曱醇、 异丙醇均不能用于本发明所述方法消旋。 Ester solvents such as ethyl acetate, ether solvents such as t-butyl decyl ether, tetrahydrofuran, dioxane (cycloether), ketone solvents such as acetone, alkane solvents such as n-hexane, water and alcohol solvents Neither sterol nor isopropanol can be used for racemization of the process described herein.
另外， 所述溶剂可以为乙腈、 苯曱腈、 曱苯、 二氯曱烷中两种以上 的混合物或含有乙腈、 苯曱腈、 曱苯、 二氯曱烷的混合溶剂。 Further, the solvent may be a mixture of two or more of acetonitrile, benzoquinone, toluene or dichlorosilane or a mixed solvent of acetonitrile, benzoquinone, toluene or dichlorosilane.
发明人发现， 安立生坦消旋化产物能够从溶剂中析出来的原因是安 立生坦外消旋体的溶解度大大低于单一构型的安立生坦。 The inventors have found that the amphoteric product of ambrisentan can be precipitated from a solvent because the solubility of the amphoteric racemate is much lower than that of a single configuration of ambrisentan.
作为优选， 消旋化过程可以在 0°C~200°C下进行， 更优选为 20°C~110°C。 Preferably, the racemization process can be carried out at 0 ° C to 200 ° C, more preferably 20 ° C to 110 ° C.
在本发明的具体实施方式中， 所述手性 2-[(4,6-二曱基嘧啶 -2-基)氧 基] -3-曱氧基 -3,3-二苯基丙酸为 (S)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧 基 -3,3-二苯基丙酸、 （R)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯 基丙酸或 (S)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸与 (R)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸不同比例的 组合。 In a specific embodiment of the invention, the chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid is (S)-2-[(4,6-Dimercaptopyryl-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, (R)-2-[(4 ,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid or (S)-2-[(4,6-dimercaptopyrimidine-2 -yl)oxy]-3-indolyl-3,3-diphenylpropionic acid and (R)-2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3- A combination of different ratios of decyloxy-3,3-diphenylpropionic acid.
本发明提供的一种手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3- 二苯基丙酸的消旋化方法， 将旋光值高的 2-[(4,6-二曱基嘧啶 -2-基)氧 基] -3-曱氧基 -3,3-二苯基丙酸加入到特定的溶剂中， 于特定温度下搅拌一 段时间进行消旋化， 经后处理得到旋光值较低或旋光值为零的消旋化产 物。 本发明方法收率高， 三废少， 适合工业化生产。 且操作方便， 能够 进一步提高拆分效率， 有效的提高原子经济性， 符合绿色化学的要求。 具体实施方式 The method for racemization of a chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid provided by the present invention, Adding 2-[(4,6-dimercaptopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid with high optical rotation value to a specific solvent, specific The mixture is stirred at a temperature for a period of time to undergo racemization, and after treatment, a racemized product having a lower optical rotation value or an optical rotation value of zero is obtained. The method of the invention has high yield, less waste, and is suitable for industrial production. Moreover, it is easy to operate, and can further improve the separation efficiency, effectively improve the atomic economy, and meet the requirements of green chemistry. detailed description
本发明公开了手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯 基丙酸的消旋化方法， 本领域技术人员可以借鉴本文内容， 适当改进工 艺参数实现。 特别需要指出的是， 所有类似的替换和改动对本领域技术 人员来说是显而易见的， 它们都被视为包括在本发明。 本发明的方法及 应用已经通过较佳实施例进行了描述， 相关人员明显能在不脱离本发明 内容、 精神和范围内对本文所述的方法和应用进行改动或适当变更与组 合， 来实现和应用本发明技术。 The invention discloses a racemization method of chiral 2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, in the field The technician can learn from the content of this article and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
为了使本领域的技术人员更好地理解本发明的技术方案， 下面结合
具体实施例对本发明作进一步的详细说明。 In order to enable those skilled in the art to better understand the technical solution of the present invention, the following combination DETAILED DESCRIPTION OF THE INVENTION The present invention is further described in detail.
ifiNMR用 AM 400型核磁共振仪记录，化学位移以 5(ppm)表示。质 谱用 Shimadzu LCMS-2010质谱仪测定，旋光度用 Perkin-Elmer 341 旋光 仪测定。 实施例 1 : The ifi NMR was recorded on an AM 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed in 5 (ppm). The mass spectrum was measured by a Shimadzu LCMS-2010 mass spectrometer and the optical rotation was measured using a Perkin-Elmer 341 polarimeter. Example 1
3.78g(10.0mmol)(R)- 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二 苯基丙酸、 60ml乙腈加入 100ml单口瓶中， 回流 4小时后自然冷却至室 温， 过滤得白色固体， 干燥， 得 3.42g白色固体， 收率 90%。 3.78 g (10.0 mmol) of (R)-2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, 60 ml of acetonitrile After cooling for 4 hours in a 100 ml single-necked flask, it was allowed to cool to room temperature, filtered to give a white solid, which was dried to give 3.42 g of white solid.
ifiNMR (CDC13) δ: 2.35(s,6H), 3.40(s,3H),6.21(s,lH) ， 6.92(s,lH)ifiNMR (CDC1 3 ) δ: 2.35(s,6H), 3.40(s,3H),6.21(s,lH) , 6.92(s,lH)
7.22-7.38(m, 10H) 7.22-7.38 (m, 10H)
MS (ESI) m/z: 379.2([M+1]+) MS (ESI) m/z: 379.2 ([M+1] + )
[a]D 20=0。（C=0.5,MeOH) 实施例 2: [a] D 20 =0. (C=0.5, MeOH) Example 2:
3.78g(10.0mmol)(S)-2-[(4,6-二曱基嘧啶 -2-基）氧基] -3-曱氧基 -3,3-二 苯基丙酸、 100ml苯曱腈加入 250ml单口瓶中， 回流 6小时后自然冷却至 室温， 过滤得白色固体， 干燥， 得 2.82g白色固体， 收率 75%。 3.78 g (10.0 mmol) of (S)-2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, 100 ml of phenylhydrazine The nitrile was added to a 250 ml single-necked flask, and after refluxing for 6 hours, it was cooled to room temperature, filtered to give a white solid, which was dried to yield 2.82 g of white solid.
[a]D 20=+15。（C=0.5,MeOH) 实施例 3: [a] D 20 = +15. (C = 0.5, MeOH) Example 3:
3.78g(10.0mmol) 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基 丙酸（R构型: S构型 =5:2)、 80ml二氯曱烷加入 250ml单口瓶中， 回流 12 小时后自然冷却至室温， 过滤得白色固体， 干燥， 得 3.02g白色固体， 收 率 80%。 [a]D 2°=0° (C=0.5,MeOH) 实施例 4: 3.78 g (10.0 mmol) 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid (R configuration: S configuration = 5:2), 80 ml of dichloromethane was added to a 250 ml single-necked flask, and after refluxing for 12 hours, it was cooled to room temperature, filtered to give a white solid, which was dried to give a white solid. [a] D 2 ° = 0° (C = 0.5, MeOH) Example 4:
3.78g(10.0mmol) 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基 丙酸 (R构型: S构型 =2:5)、 120ml曱苯加入 250ml单口瓶中， 回流 24小时
后蒸除溶剂得白色固体， 干燥， 得 3.60g白色固体， 收率 95%。 3.78 g (10.0 mmol) 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid (R configuration: S configuration =2:5), 120ml of terpene is added to a 250ml single-mouth bottle, reflux for 24 hours The solvent was evaporated to give a white solid, which was dried.
[a]D 20=+10° (C=0.5,MeOH) 实施例 5: [a] D 20 = +10° (C = 0.5, MeOH) Example 5:
3.78g(10.0mmol)(R)- 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二 苯基丙酸、 50ml乙腈、 10ml水加入 100ml单口瓶中， 回流 0.5小时后自 然冷却至室温， 过滤得白色固体， 干燥， 得 3.42g白色固体， 收率 90%。 3.78 g (10.0 mmol) of (R)-2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, 50 ml of acetonitrile, 10 ml of water was added to a 100 ml single-necked flask, and after refluxing for 0.5 hour, it was naturally cooled to room temperature, filtered to give a white solid, which was dried to give 3.42 g of white solid.
[a]D 20=0。（C=0.5,MeOH) 以上所述仅是本发明的优选实施方式， 应当指出， 对于本行业的技 术人员应该了解， 上述实施例和说明书中描述的只是说明本发明的原理， 在不脱离本发明原理的前提下还可以做出若干改进和润饰， 这些改进和 润饰也应视为本发明的保护范围。
[a] D 20 =0. (C=0.5, MeOH) The above is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art should understand that the above embodiments and the description are merely illustrative of the principles of the present invention. Several modifications and refinements can be made under the premise of the inventive concept, and such improvements and modifications should also be considered as the scope of protection of the present invention.
Claims
1、一种手性 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸 的消旋化方法， 其特征在于， 将旋光值高的 2-[(4,6-二曱基嘧啶 -2-基)氧 基] -3-曱氧基 -3,3-二苯基丙酸加入到特定溶剂中， 于特定温度下搅拌一段 时间进行消旋化， 经后处理得到旋光值较低或旋光值为零的消旋化产物。 1. A racemization method for chiral 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid, its characteristics The method consists in adding 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid with high optical rotation value into a specific solvent, and Stir for a period of time at a specific temperature to perform racemization, and then obtain a racemized product with a low optical rotation value or zero optical rotation value after post-treatment.
2、 如权利要求 1所述的消旋化方法， 其特征在于， 所述溶剂选自腈 类溶剂、 芳香烃类溶剂、 代烷烃类溶剂或其混合溶剂。 2. The racemization method according to claim 1, characterized in that the solvent is selected from nitrile solvents, aromatic hydrocarbon solvents, alkanes solvents or mixed solvents thereof.
3、 如权利要求 2所述的消旋化方法， 其特征在于， 所述腈类溶剂为 乙腈或苯曱腈。 3. The racemization method according to claim 2, wherein the nitrile solvent is acetonitrile or benzonitrile.
4、 如权利要求 2所述的消旋化方法， 其特征在于， 所述芳香烃类溶 剂为曱苯。 4. The racemization method according to claim 2, wherein the aromatic hydrocarbon solvent is toluene.
5、 如权利要求 2所述的消旋化方法， 其特征在于， 所述卤代烷烃类 溶剂为二氯曱烷。 5. The racemization method according to claim 2, characterized in that the halogenated alkane solvent is dichloromethane.
6、 如权利要求 2所述的消旋化方法， 其特征在于， 所述混合溶剂为 乙腈、 苯曱腈、 曱苯、 二氯曱烷中两种以上的混合物或含有乙腈、 苯曱 腈、 曱苯、 二氯曱烷的混合溶剂。 6. The racemization method according to claim 2, wherein the mixed solvent is a mixture of two or more of acetonitrile, benzonitrile, toluene and dichloromethane or contains acetonitrile, benzonitrile, Mixed solvent of toluene and dichloromethane.
7、 如权利要求 1所述的消旋化方法， 其特征在于， 特定的温度是指 0°C到溶剂的沸点温度。 7. The racemization method according to claim 1, wherein the specific temperature refers to a temperature ranging from 0°C to the boiling point of the solvent.
8、如权利要求 7所述的消旋化方法，其特征在于，温度为 20°C~200°C。 8. The racemization method according to claim 7, characterized in that the temperature is 20°C~200°C.
9、 如权利要求 1-8任一项所述的消旋化方法， 其特征在于， 所述手 性 2-[(4,6-二曱基嘧啶 -2-基)氧基]-曱氧基 -3,3-二苯基丙酸为 (S)-2-[(4,6-二 曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸、（R)-2-[(4,6-二曱基嘧啶 -2- 基)氧基] -3-曱氧基 -3,3-二苯基丙酸或 (S)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3- 曱氧基 -3,3-二苯基丙酸与 (R)-2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸不同比例的组合。 9. The racemization method according to any one of claims 1 to 8, characterized in that, the chiral 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-methoxy Base-3,3-diphenylpropionic acid is (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl Propionic acid, (R)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid or (S)-2- [(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid and (R)-2-[(4,6-dimethyl Combinations of different proportions of pyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid.
10、 如权利要求 1 所述的消旋化方法， 其特征在于， 冷却后析出固 体， 过滤得到 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱氧基 -3,3-二苯基丙酸的 消旋化产物， 或者直接蒸除溶剂得到 2-[(4,6-二曱基嘧啶 -2-基)氧基] -3-曱 氧基 -3,3-二苯基丙酸的消旋化产物。
10. The racemization method according to claim 1, characterized in that, after cooling, a solid is precipitated and filtered to obtain 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy The racemization product of base-3,3-diphenylpropionic acid, or the solvent can be evaporated directly to obtain 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy- Racemization product of 3,3-diphenylpropionic acid.
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| WO2011004402A2 (en) * | 2009-07-10 | 2011-01-13 | Cadila Healthcare Limited | Improved process for the preparation of ambrisentan and novel intermediates thereof |
| CN103012281A (en) * | 2011-09-22 | 2013-04-03 | 江苏康缘药业股份有限公司 | Racemization method of chiral 2-[(4, 6-sulfamethzaine-2-yl) oxygroup]-3-methoxy-3,3-diphenyl propionic acid |
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| WO2011004402A2 (en) * | 2009-07-10 | 2011-01-13 | Cadila Healthcare Limited | Improved process for the preparation of ambrisentan and novel intermediates thereof |
| CN103012281A (en) * | 2011-09-22 | 2013-04-03 | 江苏康缘药业股份有限公司 | Racemization method of chiral 2-[(4, 6-sulfamethzaine-2-yl) oxygroup]-3-methoxy-3,3-diphenyl propionic acid |
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