WO2013143481A1 - Method for synthesizing and separating laropiprant and analogues thereof - Google Patents
Method for synthesizing and separating laropiprant and analogues thereof Download PDFInfo
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- WO2013143481A1 WO2013143481A1 PCT/CN2013/073363 CN2013073363W WO2013143481A1 WO 2013143481 A1 WO2013143481 A1 WO 2013143481A1 CN 2013073363 W CN2013073363 W CN 2013073363W WO 2013143481 A1 WO2013143481 A1 WO 2013143481A1
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- 0 *C=C[C@](CC1)c2c1c(cc(*)cc1*)c1[n]2* Chemical compound *C=C[C@](CC1)c2c1c(cc(*)cc1*)c1[n]2* 0.000 description 1
- NXFFJDQHYLNEJK-CYBMUJFWSA-N CS(c1c2[n](Cc(cc3)ccc3Cl)c([C@@H](CC(O)=O)CC3)c3c2cc(F)c1)(=O)=O Chemical compound CS(c1c2[n](Cc(cc3)ccc3Cl)c([C@@H](CC(O)=O)CC3)c3c2cc(F)c1)(=O)=O NXFFJDQHYLNEJK-CYBMUJFWSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
Definitions
- the present invention relates to the synthesis of active pharmaceutical ingredients of lipid-lowering drugs in the field of medicinal chemistry. Background technique
- Tredaptive Naacin / Lalo Piran
- This medicine is used to treat hyperlipidemia, especially mixed hyperlipidemia.
- Niacin is a lipid regulator and loroxilan is a potent, selective prostaglandin DPI receptor antagonist. Niacin reduces very low density lipoprotein in plasma
- VLDL low-density lipoprotein
- LDL low-density lipoprotein
- apoB apolipoprotein B
- Lp(a) triglyceride
- HDL high-density lipoprotein
- apoA-I The level of apolipoprotein AI
- Lalopiram inhibits PGD2-mediated facial flushing, a common side effect of taking niacin.
- Lalopiram has no effect on lipid levels and does not affect the action of niacin on lipids.
- Lalo Piran its structural formula (Formula X//, chemical name:
- the method of US2005222428 comprises (E)-2-(4-(4-chlorobenzyl)-7-fluoro-5-(indolyl)-1,2-dihydrocyclopenta[b]indole -3(4H)-Pyridyl)acetic acid provides optically pure lopoliram by asymmetric catalysis.
- the catalysts used are chiral phosphorus ligands and metal ruthenium compounds. Although the preparation method has good atomic economy for producing no disintegrated waste, the reaction needs to be carried out under strict anhydrous anaerobic and high pressure, and the chiral ligand and the metal ruthenium compound used are relatively expensive, so Not practical. Summary of the invention
- the inventors have surprisingly discovered that the monolithic catalyst, Raney Ni, is hydrogenated, and by resolution, the recrystallization of the cartridge can be carried out to optically pure rallopram.
- the invention therefore proposes an improved process for the preparation of rallopram comprising hydrogenation of a compound of formula X Preparation of a compound of formula XI
- One embodiment of the invention is the preferred catalysis using Raney nickel as the catalytic hydrogenation step Further, another embodiment of the invention is the use of an optically active reagent to efficiently isolate the highly optically active R-enantiomer.
- this invention provides a) a catalytic hydrogenation of a compound of formula I
- X is halogen
- R1 is C1 to C4 alkyl, halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -
- R 2 H, CI to C4 alkyl, unsubstituted benzyl , or substituted benzyl (substituted
- the group may be an alkyl group of CI to C4, OH, OR 4 , (R 4 may be an alkyl group of CI to C4), halogen, 4- ⁇ 0 2 , 4-amino group, or 4-trifluorodecyl group; 3 may be hydrogen or a C1 to C4 alkyl group.
- the preferred catalyst is Raney nickel or Pd/C. From the viewpoint of reaction rate and product purity, Raney nickel is more preferable.
- the preferred ratio of catalyst to starting material is between 5% and 40%, more preferably between 10% and 20%.
- the hydrogenation step is preferably carried out in a solvent, and optional solvents include tetrahydrofuran, 2-mercaptotetrahydrofuran, decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, butyl Ketone, pentanone, 1,4-dioxane, water, dinonyl amide, and dimethyl sulfoxide.
- solvents include tetrahydrofuran, 2-mercaptotetrahydrofuran, decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, butyl Ketone, pentanone, 1,4-dioxane, water, dinonyl amide, and dimethyl sulfoxide.
- Y may be any of the following: tetradecyl hydrazine (TMG), 1,8-diazabicyclo [5.4.0] undecane-7-ene (DBU), 1,4-diaza a ring [2.2.2] octane (DABCO), potassium t-butoxide (t-BuOK), sodium t-butoxide (t-BuONa), potassium hydroxide, sodium hydroxide, etc., preferably tetradecyl hydrazine or 1, A salt of 8-diazabicyclo[5.4.0]undec-7-ene and formula I.
- TMG tetradecyl hydrazine
- DBU 1,8-diazabicyclo [5.4.0] undecane-7-ene
- DBU 1,4-diaza a ring [2.2.2] octane
- t-BuOK potassium t-butoxide
- t-BuONa sodium t-butoxide
- the temperature of the hydrogenation reaction is 5 to 189 ° C, preferably 40 to 55 ° C; the pressure is 0.1 Mpa to 10 Mpa, preferably 1.8 to 2.5 Mpa.
- X is a halogen
- R1 is a C1 to C4 alkyl group, a halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -
- R 2 H, a CI to C4 alkyl group, an unsubstituted benzyl group, Or a substituted benzyl group (the substituent may be a C1 to C4 alkyl group, OH, OR 4 (R 4 may be a C1 to C4 alkyl group), Halogen, 4-N0 2 , 4-amino group, or 4-trifluorodecyl);
- R 3 may be hydrogen or a C1 to C4 alkyl group.
- This process is a compound of formula II
- the optical resolving agent is particularly preferably S- ⁇ -phenethylamine from the viewpoints of resolution and cost.
- the molar ratio of a suitable resolving agent to the compound of formula II is between 0.3 and 3.0, preferably between 0.5 and 1.5.
- the solvent used in the resolution of the compound of formula II is one of the following: decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, toluene, Dichlorodecane, ethyl acetate, acetone, 1,4-dioxane, nonyl tert-butyl ether, DMF, DMSO, water or any mixed solvent between these solvents.
- the temperature at the time of splitting is 0 to 189 ° C, preferably 15 to 78 ° C.
- the time is from 30 minutes to 12 hours, preferably from 1 to 4 hours.
- the compound obtained according to the procedure of the invention has an optical purity of not less than 75%.
- the optically active separation may also include a recrystallization step of the compound of Formula III.
- the solvent used in the recrystallization is decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, toluene, dichlorodecane, acetic acid Ester, acetone, 1,4-dioxane, nonyl tert-butyl ether, n-hexane, n-heptane, cyclohexane, petroleum ether or a mixed solvent of these solvents.
- optically pure lorololine can be obtained without using an expensive metal ruthenium and a chiral catalyst ligand, without forming a chiral complex to complete asymmetric hydrogenation, and without harsh reaction conditions.
- EtOAc EtOAc
- EtOAc EtOAc
- the organic phase is dried and dried to give an off-white solid (2-(4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydro-5-(sulfonyl)cyclopentadiene And [b] ⁇ -3-yl) acetic acid, 2-(4-(4-chlorobenzyl)-7-f uoro-l,2,3,4-tetrahydro-5-(methylsulfonyl)cyclopen ta[b]indol -3-yl)acetic acid ) (9.3g, 92.5%).
- both Raney nickel and Pd/C can be used for catalytic hydrogenation. Since Raney nickel does not remove chlorine from the substrate during catalytic hydrogenation, the purity of the product is higher than Pd/C. In addition, Raney nickel has a faster reaction rate than Pd/C, so that Raney nickel is more preferable in practical use.
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Abstract
The present invention relates to a synthesizing and separating method, the method comprising: a) catalytically hydrogenating a compound of formula I or pharmaceutically acceptable salt thereof to synthesize a compound of formula II, b) performing optical resolution to the compound of formula II to acquire a compound of formula III. The present invention also relates to a preparation method of optically pure compound of formula III.
Description
合成分离拉洛皮兰及其类似物的方法 技术领域 Method for synthesizing and separating laropram and its analogues
本发明涉及药物化学领域中的调脂药物的活性药物成分合成。 背景技术 The present invention relates to the synthesis of active pharmaceutical ingredients of lipid-lowering drugs in the field of medicinal chemistry. Background technique
复方烟酸 /拉洛皮兰 （ laropiprant ) 控释片是默沙东（Merck Sharp & Compound niacin / laropiprant controlled release tablets are Merck Sharp &
Dohme)公司的产品,为 2008年全球批准上市的新药。 Tredaptive (烟酸 /拉洛 皮兰） 在爱尔兰上市。 该药物用于治疗高脂血症， 特别是混合型高脂血症Dohme's products are new drugs approved worldwide in 2008. Tredaptive (Niacin / Lalo Piran) is listed in Ireland. This medicine is used to treat hyperlipidemia, especially mixed hyperlipidemia.
(特征是低密度脂蛋白和甘油酸三脂增高， 高密度脂蛋白降低）以及原发 性的血胆固醇过多 （家族性和非家族性杂合） 。 当单用他汀类药物降胆固 醇效应不佳时可和合用该药物； 对于不适合用他汀类药物治疗的患者也可 用该药物加以治疗。 烟酸是一种脂质调节剂， 拉洛皮兰是一种有力的、 选 择性的***素 DPI 受体拮抗剂。 烟酸降低血浆中的极低密度脂蛋白(characterized by a decrease in low-density lipoprotein and triglyceride, a decrease in high-density lipoprotein) and a primary hypercholesterolemia (familial and non-familial heterozygosity). The drug can be used in conjunction with a statin-lowering cholesterol-lowering effect; it can also be treated in patients who are not eligible for statin therapy. Niacin is a lipid regulator and loroxilan is a potent, selective prostaglandin DPI receptor antagonist. Niacin reduces very low density lipoprotein in plasma
( VLDL ) 和低密度脂蛋白 （LDL ) 水平、 阿朴脂蛋白 B ( apoB ) 、 甘油 酸三脂、 总胆固醇和脂蛋白 a(Lp(a))， 并提高高密度脂蛋白 （HDL ) 和阿 朴脂蛋白 A-I ( apoA-I ) 的水平。 拉洛皮兰抑制 PGD2介导的面部潮红， 这是服用烟酸常见的副反应。 拉洛皮兰对脂质水平无影响， 也不会影响烟 酸对脂质的作用。 拉洛皮兰， 其结构式 （式 X// , 化学名称： (VLDL) and low-density lipoprotein (LDL) levels, apolipoprotein B (apoB), triglyceride, total cholesterol, and lipoprotein a (Lp(a)), and increase high-density lipoprotein (HDL) and The level of apolipoprotein AI (apoA-I). Lalopiram inhibits PGD2-mediated facial flushing, a common side effect of taking niacin. Lalopiram has no effect on lipid levels and does not affect the action of niacin on lipids. Lalo Piran, its structural formula (Formula X//, chemical name:
[(3R)-4-(4-氯苄基 )-7-氟 -5- (曱磺酰基) -1,2,3,4-四氢环戊二烯并 [b] 吲 咮 -3-基 ] - 乙 酸 ( [(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl) [(3R) - 4 - ( 4 - chlorobenzyl) -7-fluoro-5- (Yue-sulfonyl) -1, 2, 3, 4 - tetrahydro-cyclopenta [b] indole NEB -3- -] (-(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)
-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid ) ； 分子式为相对分 子质量为 435.90; CAS登记号为 571170-77-9。-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid ) ; The molecular weight of the molecule is 435.90; the CAS accession number is 571170-77-9.
查阅国外文献， 发现有 J.Med. Chem.2007-50-794-806
工艺方法： 通过 Heck反应， 用到价格比较贵的 Pd(OAc)2, 通过柱层 析纯化， 然后在通过拆分， 再经过几步反应得到光学纯的拉洛皮兰。 在工 业规模是不实用的。 Check out foreign literature and find J.Med. Chem.2007-50-794-806 Process method: By the Heck reaction, the relatively expensive Pd(OAc) 2 is used , purified by column chromatography, and then optically pure loricodine is obtained by resolution and several steps. It is not practical on an industrial scale.
US2005222428的方法包括将 (E)-2-(4-(4-氯苄基 )-7-氟 -5- (曱磺酰基) - 1 ,2- 二氢环戊二烯并 [b]吲哚 -3(4H)-叉基）乙酸通过不对称催化得到光学纯的拉洛 皮兰。 使用的催化剂为手性磷配体和金属铑化合物。 尽管该制备方法对不会 产生拆分废弃物， 原子经济性较好， 但是该反应需要在严格的无水无氧及高 压下进行， 而且使用的手性配体和金属铑化合物比较贵， 所以不实用。 发明内容 The method of US2005222428 comprises (E)-2-(4-(4-chlorobenzyl)-7-fluoro-5-(indolyl)-1,2-dihydrocyclopenta[b]indole -3(4H)-Pyridyl)acetic acid provides optically pure lopoliram by asymmetric catalysis. The catalysts used are chiral phosphorus ligands and metal ruthenium compounds. Although the preparation method has good atomic economy for producing no disintegrated waste, the reaction needs to be carried out under strict anhydrous anaerobic and high pressure, and the chiral ligand and the metal ruthenium compound used are relatively expensive, so Not practical. Summary of the invention
本发明人出人意料的发现， 使用筒单的催化剂兰尼镍（Raney Ni ) 氢 化， 再通过拆分， 筒单的重结晶就能到光学纯的拉洛皮兰。 The inventors have surprisingly discovered that the monolithic catalyst, Raney Ni, is hydrogenated, and by resolution, the recrystallization of the cartridge can be carried out to optically pure rallopram.
因此本发明设计一种改进的制备拉洛皮兰的方法，包括对式 X化合物 的氢化
制得式 XI的化合物 The invention therefore proposes an improved process for the preparation of rallopram comprising hydrogenation of a compound of formula X Preparation of a compound of formula XI
将式 XI化合物拆分制得式 XII化合物 Compound of formula XI is resolved to obtain compound of formula XII
本发明的目的是提供一种新的， 筒单合成光学纯的手性药物拉洛皮兰 ( Laropiprant ) 及其类似物的新方法。 SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel, novel method for the synthesis of the optically pure chiral drug Laropiprant and its analogs.
在此发明中一个非限制性的合成路线实例如下： An example of a non-limiting synthetic route in this invention is as follows:
上反应式催化氢化步骤中，优选的催化剂是兰尼镍或 Pd/C。从反应速 率和产品纯度考虑， 更优选兰尼镍。 In the upper reactive catalytic hydrogenation step, the preferred catalyst is Raney nickel or Pd/C. From the viewpoint of reaction rate and product purity, Raney nickel is more preferable.
催化剂和原料的优选比例在 5%到 40%之间， 更优选在 10%到 20%之 间。 The preferred ratio of catalyst to starting material is between 5% and 40%, more preferably between 10% and 20%.
氢化的步骤最好在溶剂中进行， 可选择的溶剂包括四氢呋喃， 2-曱基 四氢呋喃， 曱醇， 乙醇， 丙醇， 异丙醇， 正丁醇， 异丁醇， 叔丁醇， 丙酮， 丁酮， 戊酮， 1,4-二氧六环， 水， 二曱基曱酰胺， 和二曱基亚砜。 The hydrogenation step is preferably carried out in a solvent, and optional solvents include tetrahydrofuran, 2-mercaptotetrahydrofuran, decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, butyl Ketone, pentanone, 1,4-dioxane, water, dinonyl amide, and dimethyl sulfoxide.
式 I中的药学可接受的 IV所示
其中 Y可以是下列中的任何一个： 四曱基胍 (TMG), 1 , 8-二氮杂双 环 [5.4.0]十一烷 -7-烯 (DBU), 1,4-二氮杂二环 [2.2.2]辛烷 ( DABCO ) , 叔丁 醇钾 (t-BuOK), 叔丁醇钠 (t-BuONa), 氢氧化钾， 氢氧化钠等碱， 优选四曱 基胍或 1 , 8-二氮杂双环 [5.4.0]十一烷 -7-烯与式 I成的盐。 在式 IV中， Y 与式 I化合物的摩尔比为 0.8: 1-3. 优选 0.9: 1-1.8 Pharmacologically acceptable IV as shown in formula I Wherein Y may be any of the following: tetradecyl hydrazine (TMG), 1,8-diazabicyclo [5.4.0] undecane-7-ene (DBU), 1,4-diaza a ring [2.2.2] octane (DABCO), potassium t-butoxide (t-BuOK), sodium t-butoxide (t-BuONa), potassium hydroxide, sodium hydroxide, etc., preferably tetradecyl hydrazine or 1, A salt of 8-diazabicyclo[5.4.0]undec-7-ene and formula I. In formula IV, the molar ratio of Y to the compound of formula I is 0.8: 1-3. Preferably 0.9: 1-1.8
氢化反应的温度为 5~189°C , 优选 40~55 °C ; 压力为 0.1Mpa~10Mpa, 优选 1.8~2.5Mpa。 The temperature of the hydrogenation reaction is 5 to 189 ° C, preferably 40 to 55 ° C; the pressure is 0.1 Mpa to 10 Mpa, preferably 1.8 to 2.5 Mpa.
本发明的另一个实施方式在于提供了一种得到光学活性纯的式 III化 合物的方法
式 ΠΙ中， X是卤素； R1 是 C1到 C4的烷基， 卤素， CH3S02- 或 CH3CH2S02-; R2=H, CI 到 C4的烷基， 无取代苄基， 或取代苄基 （取 代基可为 C1到 C4的烷基， OH, OR4 ( R4 可以是 C1到 C4的烷基） ，
卤素， 4-N02, 4-胺基， 或 4-三氟曱基） ； R3可以是氢或 C1到 C4的烷 基。 Another embodiment of the present invention provides a method of obtaining an optically active pure compound of formula III. In the formula, X is a halogen; R1 is a C1 to C4 alkyl group, a halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -; R 2 = H, a CI to C4 alkyl group, an unsubstituted benzyl group, Or a substituted benzyl group (the substituent may be a C1 to C4 alkyl group, OH, OR 4 (R 4 may be a C1 to C4 alkyl group), Halogen, 4-N0 2 , 4-amino group, or 4-trifluorodecyl); R 3 may be hydrogen or a C1 to C4 alkyl group.
此过程是将式 II化合物
溶剂和式 VI所示的光学拆分剂混和在
式 VI 其中 R5=曱基， 乙基， 丙基， 异丙基 ， 苯基， 苄基等， R6=曱基， 乙 基， 丙基， 异丙基， 未取代的苯基， 取代苯基， 未取代的萘基， 取代萘基， 或四氢萘基， 其中取代基为曱基或乙基。 从拆分效率和成本上考虑， 所述 光学拆分剂特别优选 S-α-苯乙胺。适宜的拆分剂与式 II所示的化合物的摩 尔比在 0.3 到 3.0 之间， 优选 0.5到 1.5之间。 式 II化合物在拆分时使用 的溶剂为下列之一： 曱醇， 乙醇， 丙醇， 异丙醇， 正丁醇， 叔丁醇， 异丁 醇， 四氢呋喃， 2-曱基四氢呋喃， 曱苯， 二氯曱烷， 乙酸乙酯， 丙酮， 1,4- 二氧六环， 曱基叔丁基醚， DMF, DMSO, 水或这些溶剂之间的任何一种 混合溶剂。 This process is a compound of formula II The solvent and the optical resolving agent shown in Formula VI are mixed in Wherein R 5 = mercapto, ethyl, propyl, isopropyl, phenyl, benzyl, etc., R 6 = mercapto, ethyl, propyl, isopropyl, unsubstituted phenyl, substituted benzene A group, an unsubstituted naphthyl group, a substituted naphthyl group, or a tetrahydronaphthyl group, wherein the substituent is a fluorenyl group or an ethyl group. The optical resolving agent is particularly preferably S-α-phenethylamine from the viewpoints of resolution and cost. The molar ratio of a suitable resolving agent to the compound of formula II is between 0.3 and 3.0, preferably between 0.5 and 1.5. The solvent used in the resolution of the compound of formula II is one of the following: decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, toluene, Dichlorodecane, ethyl acetate, acetone, 1,4-dioxane, nonyl tert-butyl ether, DMF, DMSO, water or any mixed solvent between these solvents.
拆分时的温度为 0~189°C , 优选 15~78°C。 时间从 30分钟到 12小时， 优选 1-4小时。 The temperature at the time of splitting is 0 to 189 ° C, preferably 15 to 78 ° C. The time is from 30 minutes to 12 hours, preferably from 1 to 4 hours.
据此发明的步骤得到的化合物光学纯度不低于 75%。 The compound obtained according to the procedure of the invention has an optical purity of not less than 75%.
在此发明中， 光学活性分离还可以包括化合物式 III的重结晶一步。 在重结晶中使用的溶剂为曱醇， 乙醇， 丙醇， 异丙醇， 正丁醇， 叔丁醇， 异丁醇， 四氢呋喃， 2-曱基四氢呋喃， 曱苯， 二氯曱烷， 乙酸乙酯， 丙酮， 1,4-二氧六环， 曱基叔丁基醚、 正己烷、 正庚烷、 环己烷、 石油醚或这些 溶剂之间的任何一种混合溶剂。 In this invention, the optically active separation may also include a recrystallization step of the compound of Formula III. The solvent used in the recrystallization is decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, toluene, dichlorodecane, acetic acid Ester, acetone, 1,4-dioxane, nonyl tert-butyl ether, n-hexane, n-heptane, cyclohexane, petroleum ether or a mixed solvent of these solvents.
通过本发明， 无需使用昂贵的金属铑和手性催化剂配体， 无需形成手 性络合物完成不对称氢化， 无需严苛的反应条件， 便可得到光学纯的拉洛 皮兰。
具体实施方式 By the present invention, optically pure lorololine can be obtained without using an expensive metal ruthenium and a chiral catalyst ligand, without forming a chiral complex to complete asymmetric hydrogenation, and without harsh reaction conditions. detailed description
在下文的描述中，给出了大量具体的细节以便提供对本发明更为彻 底的理解。 这些实施例是以列举的方式提供， 而并不用于限制本发明。 In the following description, numerous specific details are set forth in order to provide a These examples are provided by way of illustration and are not intended to limit the invention.
化合物 1 ((E)-2-(4-(4-氯苄基 )-7-氟 -1,2-二氢 -5- (曱磺酰基)环戊二烯并 [b] 吲 哚 -3(4H)- 叉 基 ） 乙 酸 ， (E)-2-(4-(4-chlorobenzyl)-7-fluoro- 1 , 2 -dihy dro - 5 - (methyl sulfony 1) cy clopenta [ b]indol-3(4H)-ylidene)acetic acid ) ( lO.Og) , 和四曱基胍 ( 1.4eq)用乙醇 ( 80ml) 溶解。 在***中加入 RaneyNi (2.0g) 。 通入氢气， 维持压力在 2Mpa。 升温至 50°C, 搅拌 12-16h。 降至室温 （20°C) , 过滤， 滤饼用少 量乙醇洗两次。 滤液减压蒸干， 加入乙酸乙酯 （95ml), 用 0.5N HC1 调 pH=l-2, 分液， 有机相用饱和食盐水（ 15ml)洗。 有机相干燥旋干， 得灰 白色固体化合物 ( 2-(4-(4-氯苄基 )-7-氟 -1,2,3,4-四氢 -5- (曱磺酰基） 环戊 二 烯 并 [b] 吲 哚 -3- 基 ） 乙 酸 ， 2-(4-(4-chlorobenzyl)-7-f uoro-l,2,3,4-tetrahydro-5-(methylsulfonyl)cyclopen ta[b]indol-3-yl)acetic acid ) ( 9.3g, 92.5% ) 。 Compound 1 ((E)-2-(4-(4-chlorobenzyl)-7-fluoro-1,2-dihydro-5-(indolyl)cyclopenta[b]indole-3 (4H)- fork base) acetic acid, (E)-2-(4-(4-chlorobenzyl)-7-fluoro- 1 , 2 -dihy dro - 5 - (methyl sulfony 1) cy clopenta [ b]indol-3 (4H)-ylidene)acetic acid ) ( lO.Og) , and tetradecyl hydrazine ( 1.4 eq) were dissolved in ethanol (80 ml). Add RaneyNi (2.0g) to the system. Pass hydrogen gas and maintain the pressure at 2Mpa. Warm to 50 ° C and stir for 12-16 h. Decrease to room temperature (20 ° C), filter, and filter cake twice with a small amount of ethanol. The filtrate was evaporated to dryness. EtOAc (EtOAc) The organic phase is dried and dried to give an off-white solid (2-(4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydro-5-(sulfonyl)cyclopentadiene And [b] 吲哚-3-yl) acetic acid, 2-(4-(4-chlorobenzyl)-7-f uoro-l,2,3,4-tetrahydro-5-(methylsulfonyl)cyclopen ta[b]indol -3-yl)acetic acid ) (9.3g, 92.5%).
化合物 2( 30. Og),曱醇（ 280ml)加入，加热回流 。 S-α-苯乙胺（ l.Oeq ) 加入。 加热回流下搅拌 1~2小时。 降温至室温 25 °C, 滤饼用少量曱醇洗 两次， 收集滤饼， 干燥得化合物 3 (16.5g) 的 S-α-苯乙胺盐 （ee=93.5%) 。 乙酸乙酯（ 95ml)加入， 用 1NHC1调 pH=l~2, 分液， 有机相用饱和食盐 水（25ml) 洗。 有机相干燥旋干， 得白色固体化合物 3 ( 2-((S)-4-(4-氯苄 基） -7-氟 -1,2,3,4-四氢 -5- (曱磺酰基） 环戊二烯并 [b]吲哚 -3-基）乙酸，
2-((S)-4-(4-chlorobenzyl)-7-f uoro-l,2,3,4-tetrahydro-5-(methylsulfonyl)cyclo penta[b]indol-3-yl)acetic acid ) ( 12.0g ) , 乙酸乙酯 /正庚烷重结晶， 干燥 得固体 （ 10.8g, ee=99.6%, HPLC=99.7% ) 。 Compound 2 (30. Og), decyl alcohol (280 ml) was added and heated to reflux. S-α-phenethylamine (1.Oeq) was added. Stir under heating and reflux for 1 to 2 hours. The temperature was lowered to room temperature at 25 ° C, and the filter cake was washed twice with a small amount of decyl alcohol. The cake was collected and dried to give compound 3 (16.5 g) of S-α-phenethylamine salt (ee = 93.5%). Ethyl acetate (95 ml) was added, and the mixture was adjusted to pH = 1 to 2 with 1HCI1, and the organic phase was washed with saturated brine (25 ml). The organic phase was dried and dried to give a white solid compound 3 (2-((S)-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydro-5- (sulfonyl) Cyclopentadien[b]indol-3-yl)acetic acid, 2-((S)-4-(4-chlorobenzyl)-7-f uoro-l,2,3,4-tetrahydro-5-(methylsulfonyl)cyclo penta[b]indol-3-yl)acetic acid ) ( 12.0 g), ethyl acetate / n-heptane was recrystallized, dried to give a solid ( 10.8 g, ee = 99.6%, HPLC = 99.7%).
实施例 2: Example 2:
化合物 1 ( lO.Og ) , 和 DBU ( 1.2eq )用曱醇（ 80ml )溶解。 Raney Ni Compound 1 (10.Og), and DBU (1.2 eq) were dissolved in methanol (80 ml). Raney Ni
(2.0g)加入。 通入氢气， 维持压力在 2Mpa。 升温至 50°C, 搅拌 8~12h。 降至室温（20°C) , 过滤， 滤饼用少量曱醇洗两次。 滤液减压蒸干， 加入 乙酸乙酯 （90ml), 用 0.5N HC1调 pH=l-2, 分液， 有机相用饱和食盐水 ( 15ml) 洗。 有机相干燥旋干， 得灰白色固体化合物 2 ( 8.8g, 88% ) 。 (2.0g) was added. Pass hydrogen gas and maintain the pressure at 2Mpa. Warm to 50 ° C and stir for 8~12h. Decrease to room temperature (20 ° C), filter, and wash the filter cake twice with a small amount of methanol. The filtrate was evaporated to dryness. EtOAc (EtOAc)EtOAc. The organic phase was dried and dried to give compound 2 ( 8.8 g, 88%).
化合物 2( lO.Og), 乙醇（ 140ml)加入，加热回流 。 S-α-苯乙胺（ l.Oeq) 加入。 加热回流下搅拌 1~2小时。 趁热过滤， 滤饼用少量乙醇洗两次， 收 集滤饼，干燥得 5.5g化合物 3的 S-α-苯乙胺盐（ee=92%)。乙酸乙酯（ 50ml) 加入， 用 1NHC1调 pH=l~2, 分液， 有机相用饱和食盐水（ 15ml)洗。 有 机相干燥旋干， 得白色固体化合物 3 (3.8g) 。 此白色固体用乙酸乙酯 / 正己烷重结晶， 干燥得白色固体 （3.3g,ee=99.5%, HPLC=99.6%) 。 ) 。 Compound 2 (10.Og), ethanol (140 ml) was added and heated to reflux. S-α-phenethylamine (1.Oeq) was added. Stir under heating and reflux for 1 to 2 hours. After hot filtration, the filter cake was washed twice with a small amount of ethanol, and the filter cake was collected and dried to give 5.5 g of compound 3 of S-?-phenethylamine salt (ee = 92%). Ethyl acetate (50 ml) was added, and the mixture was adjusted to pH = 1 to 2 with 1HCI1, and the organic phase was washed with saturated brine (15 ml). The organic phase was dried and dried to give a white solid compound 3 (3.8 g). The white solid was recrystallized from ethyl acetate /hexanes to afford white crystals (3.3 g, ee = 99.5%, HPLC = 99.6%). ).
实施例 3: Example 3:
化合物 1 ( lO.Og ) , 和 DABCO ( 1.2eq )用乙醇（ 80ml )溶解。 Raney Ni(2.0g)力口入。 通入氢气， 维持压力在 2Mpa。 升温至 50°C, 搅拌 8-12h。 降至室温（20°C) , 过滤， 滤饼用量乙醇洗两次。 滤液减压旋蒸干， 加入 乙酸乙酯 （90ml) ，用 0.5N HC1调 pH=l~2, 分液， 有机相用饱和食盐水 ( 15ml) 洗。 有机相干燥旋干， 得灰白色固体化合物 2 ( 8.5g, 84.8%) 。 Compound 1 (10.Og), and DABCO (1.2 eq) were dissolved in ethanol (80 ml). Raney Ni (2.0g) is in the mouth. Pass hydrogen gas and maintain the pressure at 2Mpa. Warm to 50 ° C and stir for 8-12 h. Decrease to room temperature (20 ° C), filter, and filter cake twice with ethanol. The filtrate was evaporated to dryness. EtOAc (EtOAc) (EtOAc) The organic phase was dried and dried to give compound 2 ( 8.5 g, 84.8%).
化合物 2( lO.Og), 乙醇（ 140ml)加入，加热回流 。 S-α-蔡乙胺（ l.Oeq) 加入。 加热回流下搅拌 1~2小时。 趁热过滤， 滤饼用少量乙醇洗两次， 收 集滤饼，干燥得化合物 3的 S-α-萘乙胺盐（ 5.3g , ee>90% )。乙酸乙酯（ 50ml ) 加入， 用 IN HC1调 PH=1~2, 分液， 有机相用饱和食盐水（ 15ml) 洗。 有机相干燥旋干， 得白色固体化合物 3 (3.3g) 。 此白色固体经进一步乙 酸乙酯 /石油醚重结晶纯化， 干燥得白 色固体 3 ( 3.0g,ee=99.1%, HPLC=99.3% ) 。 Compound 2 (10.Og), ethanol (140 ml) was added and heated to reflux. S-α-Cetamine (1.Oeq) was added. Stir under heating and reflux for 1 to 2 hours. After hot filtration, the filter cake was washed twice with a small amount of ethanol, and the filter cake was collected and dried to give Compound 3 S-α-naphthylethylamine salt (5.3 g, ee > 90%). Ethyl acetate (50 ml) was added, and pH was adjusted to 1 to 2 with IN HC1, and the organic phase was washed with saturated brine (15 ml). The organic phase was dried and dried to give a white solid compound 3 (3.3 g). The white solid was purified by recrystallization from EtOAc EtOAc (EtOAc:EtOAc)
实施例 4: Example 4:
化合物 1 ( lO.Og) , 和四曱基胍（ 1.4eq)用乙醇（ 80ml)溶解。 Raney
Ni(2.0g)加入。通入氢气，维持压力在 2Mpa。升温至 50°C,搅拌 12~16h。 降至室温（20°C) , 过滤， 滤饼用少量乙醇洗两次。 滤液减压旋蒸干， 加 入乙酸乙酯 （90ml) ，用 0.5N HC1调 PH=1~2, 分液， 有机相用饱和食盐 水（ 15ml)洗。 有机相干燥旋干， 得灰白色固体化合物 2 (9.3g, 92.5%)。 Compound 1 (10.Og), and tetradecyl hydrazine (1.4 eq) were dissolved in ethanol (80 ml). Raney Ni (2.0 g) was added. Pass hydrogen gas and maintain the pressure at 2Mpa. Warm to 50 ° C, stir for 12 ~ 16h. Drop to room temperature (20 ° C), filter, and filter cake twice with a small amount of ethanol. The filtrate was evaporated to dryness EtOAc (EtOAc) (EtOAc) The organic phase was dried and dried to give compound 2 (9.3 g, 92.5%).
化合物 2( 20.0g), 乙醇（ 280ml)加入，加热回流 。 S-α-苯乙胺（ l.Oeq ) 加入。 加热回流下搅拌 1~2小时。 趁热过滤， 滤饼用少量乙醇洗两次， 收 集滤饼， 干燥得 11.5g化合物 3的 S-α-苯乙胺盐 （ee=92.5%) 。 乙酸乙酯 (85ml)力口入， 用 1NHC1调 PH=1~2, 分液， 有机相用饱和食盐水（ 20ml ) 洗。 有机相干燥蒸干， 得白色固体化合物 3 (7.35g) 。 此白色固体经乙酸 乙酯 /正庚烷重结晶， 干燥得固体 （ 7.0g, ee=99.6%, HPLC=99.7% ) 。 Compound 2 (20.0 g), ethanol (280 ml) was added and heated to reflux. S-α-phenethylamine (1.Oeq) was added. Stir under heating and reflux for 1 to 2 hours. After hot filtration, the filter cake was washed twice with a small amount of ethanol, and the cake was collected and dried to obtain 11.5 g of Compound 3 of S-?-phenethylamine salt (ee = 92.5%). Ethyl acetate (85 ml) was added dropwise, and pH 1 to 2 was adjusted with 1NHC1, and the organic phase was washed with saturated brine (20 ml). The organic phase was dried and evaporated to dryness crystals crystals The white solid was recrystallized from ethyl acetate / n-heptane to afford a solid (yield: EtOAc, ee = 99.
实施例 5: Example 5
化合物 1 ( lO.Og ) , 和四曱基胍（ 1.4eq,4.1ml )用乙醇（ 80ml )溶解。 Raney Ni (2.0g) 加入。 通入氢气， 维持压力在 2Mpa。 升温至 50°C, 搅 拌 12-16h。 降至室温（20°C) , 过滤， 滤饼用少量乙醇洗两次。 滤液减压 旋蒸干， 加入乙酸乙酯（90ml)，用 0.5NHC1调 pH=l~2, 分液， 有机相用 饱和食盐水（ 15ml)洗。 有机相干燥蒸干， 得灰白色固体化合物 2 (9.3g, 92.5% ) 。 Compound 1 (10.Og), and tetradecylhydrazine (1.4 eq, 4.1 ml) were dissolved in ethanol (80 ml). Raney Ni (2.0g) joined. Pass hydrogen gas and maintain the pressure at 2Mpa. Warm to 50 ° C and stir for 12-16 h. Drop to room temperature (20 ° C), filter, and filter cake twice with a small amount of ethanol. The filtrate was evaporated to dryness. EtOAc (EtOAc) (EtOAc) The organic phase was dried to dryness to give crystals (yield: 9.3 g, 92.5%).
化合物 2(20.0g),曱醇（ 280ml)加入，加热回流 。 S-α-萘乙胺（ l.Oeq, 7.8g)加入。 加热回流下搅拌 1~2小时。 降温至室温 25°C, 滤饼用少量曱 醇洗两次， 收集滤饼， 干燥得 10.5g化合物 3的 S-α-蔡乙胺盐（ ee>90% )。 乙酸乙酯（ 90ml)加入， 用 1NHC1调 pH=l~2, 分液， 有机相用饱和食盐 水（25ml) 洗。 有机相干燥蒸干， 得白色固体化合物 3 (6.1g) 。 此白色 固体经乙酸乙酯 /正庚烷重结晶， 干燥得固体 （ 5.5g, ee=99.1%, HPLC=99.3% ) 。 Compound 2 (20.0 g), decyl alcohol (280 ml) was added and heated to reflux. S-α-naphthylethylamine (1.0 eq, 7.8 g) was added. Stir under heating and reflux for 1 to 2 hours. The temperature was lowered to room temperature at 25 ° C, and the filter cake was washed twice with a small amount of decyl alcohol. The cake was collected and dried to give 10.5 g of compound 3 of S-α-Cetamine salt (ee > 90%). Ethyl acetate (90 ml) was added, and the mixture was adjusted to pH = 1 to 2 with 1HCI1, and the organic phase was washed with saturated brine (25 ml). The organic phase was dried to dryness to give crystals (3g, Compound: The white solid was recrystallized from ethyl acetate / n-heptane to afford solid (5.5 g, ee = 99.1%, HPLC = 99.3%).
实施例 6: Example 6:
化合物 1 ( 10.0g) , 和四曱基胍（ 1.4eq)用乙醇（80ml)溶解。 Pd/C ( 1.5g)加入。 通入氢气， 维持压力在 2Mpa。 升温至 50°C, 搅拌 10-16h。 降至室温（20°C) , 过滤， 滤饼用少量乙醇洗两次。 滤液减压蒸干， 加入 乙酸乙酯 （90ml) ，用 0.5N HC1调 pH=l~2, 分液， 有机相用饱和食盐水 ( 15ml) 洗。 有机相干燥旋干， 得灰白色固体化合物 2 ( 9.2g, 92% ) 。
化合物 2( 15. Og),曱醇（210ml)加入，加热回流 。 S-α-苯乙胺（ l.Oeq ) 加入。 加热回流下搅拌 1-2小时。 降温至室温 25 °C, 滤饼用少量曱醇洗两 次， 收集滤饼， 干燥得化合物 3的 S-α-苯乙胺盐 （8.3g ,ee=93.5%) 。 乙 酸乙酯（90ml)加入， 用 1NHC1调 pH=l~2, 分液， 有机相用饱和食盐水 ( 20ml) 洗。 有机相干燥蒸干， 得白色固体化合物 3 ( 6.0g) 。 此白色固 体经乙酸乙酯 /正庚烷重结晶，干燥得固体（ 5.4g, ee=99.6%,HPLC=99.7%)。 Compound 1 (10.0 g), and tetradecyl hydrazine (1.4 eq) were dissolved in ethanol (80 ml). Pd/C (1.5g) was added. Pass hydrogen gas and maintain the pressure at 2Mpa. Warm to 50 ° C and stir for 10-16 h. Drop to room temperature (20 ° C), filter, and filter cake twice with a small amount of ethanol. The filtrate was evaporated to dryness. EtOAc (EtOAc) (EtOAc) The organic phase was dried and dried to give compound 2 ( 9.2 g, 92%). Compound 2 (15 Og), decyl alcohol (210 ml) was added and heated to reflux. S-α-phenethylamine (1.Oeq) was added. Stir under heating and reflux for 1-2 hours. The temperature was lowered to room temperature at 25 ° C, and the filter cake was washed twice with a small amount of decyl alcohol. The cake was collected and dried to give compound 3 S-?-phenethylamine salt (8.3 g, ee = 93.5%). Ethyl acetate (90 ml) was added, and the mixture was adjusted to pH = 1 to 2 with 1HCI1, and the organic phase was washed with saturated brine (20 ml). The organic phase was dried to dryness to give crystals (3 g, Compound Compound The white solid was recrystallized from ethyl acetate /EtOAc (EtOAc)
由上面实施例可以看出， 兰尼镍和 Pd/C均可以用于催化氢化。 由于 兰尼镍在催化氢化时不会脱掉底物上的氯， 因而产品纯度比 Pd/C 高。 另 夕卜， 兰尼镍比 Pd/C反应速率快， 因而在实际应用中更加优选兰尼镍。 As can be seen from the above examples, both Raney nickel and Pd/C can be used for catalytic hydrogenation. Since Raney nickel does not remove chlorine from the substrate during catalytic hydrogenation, the purity of the product is higher than Pd/C. In addition, Raney nickel has a faster reaction rate than Pd/C, so that Raney nickel is more preferable in practical use.
本发明已经通过上述实施例进行了说明， 但应当理解的是， 上述实 施例只是用于举例和说明的目的， 而非意在将本发明限制于所描述的实 施例范围内。 此外本领域技术人员可以理解的是， 本发明并不局限于上 述实施例， 根据本发明的教导还可以做出更多种的变型和修改， 这些变 型和修改均落在本发明所要求保护的范围以内。本发明的保护范围由附 属的权利要求书及其等效范围所界定。 The present invention has been described by the above-described embodiments, but it should be understood that the above-described embodiments are for the purpose of illustration and description. Further, those skilled in the art can understand that the present invention is not limited to the above embodiments, and various modifications and changes can be made according to the teachings of the present invention. These modifications and modifications are all claimed in the present invention. Within the scope. The scope of the invention is defined by the appended claims and their equivalents.
-考文献 - test literature
Tredaptive Prescribing Information" (PDF). Merck & Co.. http：〃 www.merck.com/newsroom/pdf/Tredaptive— pi.pdf. Retrieved 2009-11-14. Tredaptive Prescribing Information" (PDF). Merck & Co.. http:〃 www.merck.com/newsroom/pdf/Tredaptive— pi.pdf. Retrieved 2009-11-14.
(2) Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical Publishing Division. ISBN 0071451536. http://www.medicinenet.com/niacin/article.htm. (2) Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical Publishing Division. ISBN 0071451536. http://www.medicinenet.com/niacin/article.htm.
(3) US 2005/0222428A1. Oct.6, 2005
(3) US 2005/0222428A1. Oct.6, 2005
Claims
1. 一种合成分离方法， 其特征在于， A synthetic separation method, characterized in that
a) 催化氢化式 I所 的盐
a) Catalytic hydrogenation of the salt of formula I
以合成式 II所示的化合物 Compounds of the formula II
其中在催化氢化步骤中， 所用催化剂是兰尼镍或 Pd/C; Wherein in the catalytic hydrogenation step, the catalyst used is Raney nickel or Pd/C;
b)将式 II所示的化合物的光学拆分得式 III所示的化合物
b) optical resolution of the compound of formula II to a compound of formula III
其中 X是卤素， Where X is halogen,
Ri=Cl 到 C4的烷基、 卤素、 CH3S02-或 CH3CH2S02-; Ri=Cl to C4 alkyl, halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -;
R2=H、 CI到 C4的烷基、 未取代的苄基， 或被选自以下取代基取代 的苄基： C1到 C4烷基、 OH、 OR4、 卤素、 4-硝基、 4-胺基、 或 4-三氟曱 基， 其中 R4是 C1到 C4烷基； R 2 =H, CI to C4 alkyl, unsubstituted benzyl, or benzyl substituted with a substituent selected from C1 to C4 alkyl, OH, OR 4 , halogen, 4-nitro, 4- An amine group, or a 4-trifluoromethyl group, wherein R 4 is a C1 to C4 alkyl group;
R3是氢、 或 C1到 C4烷基。 R 3 is hydrogen or a C1 to C4 alkyl group.
2. 如权利要求 1所述的方法， 其中 X是氟。 2. The method of claim 1 wherein X is fluorine.
3. 如权利要求 1 所述的方法， 其中 R2 是卤代苄基， 卤素在间位或 对位。 The method according to claim 1, wherein R 2 is halo benzyl, halogen at the meta or para position.
4. 如权利要求 1所述的方法， 其中步骤 a)是对式 I化合物的药学可 接受的盐的催化氢化。 4. The method of claim 1 wherein step a) is a catalytic hydrogenation of a pharmaceutically acceptable salt of a compound of formula I.
5. 如权利要求 1所述的方法， 其中在催化氢化步骤中， 催化剂和式 I化合物的重量比为 5%到 40%之间。
5. The method of claim 1 wherein the weight ratio of catalyst to compound of formula I is between 5% and 40% in the catalytic hydrogenation step.
6. 如权利要求 5所述的方法， 其中催化剂和式 I所示化合物的重量 比在 10%到 20%之间。 6. A process according to claim 5 wherein the weight ratio of catalyst to compound of formula I is between 10% and 20%.
7. 如权利要求 1 所述的方法， 其中氢化时使用的溶剂选自以下组成 的组： 曱醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 叔丁醇、 异丁醇、 四氢呋喃、 2-曱基四氢呋喃、 丙酮、 丁酮、 戊酮、 1,4-二氧六环、 水、 DMF和 DMSO。 7. The method according to claim 1, wherein the solvent used in the hydrogenation is selected from the group consisting of: decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, acetone, butanone, pentanone, 1,4-dioxane, water, DMF and DMSO.
8. 如权利要求 1所述的方法， 其中， 式 I所示的化合物的药学可接 受的盐为：
式 IV 其中， Y 选自下列物质组成的组： 四曱基胍、 1,8-二氮杂二环 [5.4.0] 十一碳 -7-烯、 1,4-二氮杂二环 [2.2.2]辛烷、 t-BuOK、 t-BuONa、 KOH 或 NaOH。 8. The method of claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is: Wherein Y is selected from the group consisting of tetrakisinyl, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[ 2.2.2] Octane, t-BuOK, t-BuONa, KOH or NaOH.
9. 如权利要求 8所述的方法中， 其中 Y选自四曱基胍或 1,8-二氮杂 二环 [5.4.0]十一碳 -7-烯。 9. The method of claim 8, wherein Y is selected from the group consisting of tetradecylphosphonium or 1,8-diazabicyclo [5.4.0]undec-7-ene.
10. 如权利要求 8所述的方法中， 其中式 IV所示化合物中 Y与式 I 所示化合物的摩尔比是 0.8 ： 1到 3.0 ： 1。 10. The method according to claim 8, wherein the molar ratio of Y to the compound of formula I in the compound of formula IV is from 0.8:1 to 3.0:1.
11. 如权利要求 10所述的方法， 其中式 IV所示化合物中 Y和式 I 所示化合物的摩尔比是 0.9: 1到 1.8: 1。 The method according to claim 10, wherein the compound of the formula IV has a molar ratio of Y to the compound of the formula I of from 0.9:1 to 1.8:1.
12. 如权利要求 1所述的方法，其中催化氢化反应的温度为 5~189°C。 12. The method of claim 1 wherein the temperature of the catalytic hydrogenation reaction is from 5 to 189 °C.
13. 如权利要求 12 所述的方法， 其中催化氢化反应的温度为 40~55 °C。 13. The method of claim 12, wherein the temperature of the catalytic hydrogenation reaction is 40 to 55 °C.
14. 如权利要求 1 所述的方法， 其中催化氢化反应的压力为 0.1Mpa~10Mpa。 14. The method of claim 1 wherein the catalytic hydrogenation reaction has a pressure of from 0.1 MPa to 10 MPa.
15. 如权利要求 14所述的方法，其中催化氢化反应的压力为 l~4Mpa。 15. The method of claim 14 wherein the catalytic hydrogenation reaction has a pressure of from 1 to 4 MPa.
16. 如权利要求 1 所述的方法， 其中 X=F,
CH3S02-; R2= 4-氯 苯基， 式 III的化合物为拉洛皮兰。 16. The method of claim 1 wherein X = F, CH 3 S0 2 -; R 2 = 4-chlorophenyl, the compound of formula III is lorololan.
17. 如权利要求 1 所述的方法，其中光学拆分所使用的光学活性拆分 剂为式 VI所示的光学活性拆分剂
式 VI 17. The method of claim 1 wherein the optically active resolving agent used in the optical resolution is an optically active resolving agent of formula VI Formula VI
其中 R5=曱基、 乙基、 丙基、 异丙基、 苯基、 或苄基； R6=曱基、 乙 基、 丙基、 异丙基、 未取代的苯基、 取代的苯基、 未取代的萘基、 取代的 萘基、 四氢萘基， 其中取代基为曱基或乙基。 Wherein R 5 = fluorenyl, ethyl, propyl, isopropyl, phenyl, or benzyl; R 6 = fluorenyl, ethyl, propyl, isopropyl, unsubstituted phenyl, substituted phenyl An unsubstituted naphthyl group, a substituted naphthyl group, a tetrahydronaphthyl group, wherein the substituent is a fluorenyl group or an ethyl group.
18. 一种获得光学纯的式 III所示化合物的方法 18. A method of obtaining an optically pure compound of formula III
Ri=Cl 到 C4的烷基、 卤素、 CH3S02-或 CH3CH2S02-; Ri=Cl to C4 alkyl, halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -;
R2=H、 CI到 C4的烷基、 未取代的苄基， 或被选自以下取代基取代 的苄基： C1到 C4烷基、 OH、 OR4、 卤素、 4-硝基、 4-胺基、 或 4-三氟曱 基， 其中 R4是 C1到 C4烷基； R 2 =H, CI to C4 alkyl, unsubstituted benzyl, or benzyl substituted with a substituent selected from C1 to C4 alkyl, OH, OR 4 , halogen, 4-nitro, 4- An amine group, or a 4-trifluoromethyl group, wherein R 4 is a C1 to C4 alkyl group;
R3是氢、 或 C1到 C4烷基； R 3 is hydrogen, or a C1 to C4 alkyl group;
该方法包括将式 II所示化合物在溶剂中
式 II The method comprises the compound of formula II in a solvent Formula II
与式 VI所示的光学活性拆分剂混合
式 VI 其中 R5=曱基、 乙基、 丙基、 异丙基、 苯基、 苄基， R6=曱基、 乙基、 丙基、 异丙基、 苯基、 取代的苯基、 萘基、 取代的萘基、 四氢萘基， 其中 取代基为曱基或乙基。 Mixed with the optically active resolving agent shown in Formula VI Wherein R 5 = fluorenyl, ethyl, propyl, isopropyl, phenyl, benzyl, R 6 = fluorenyl, ethyl, propyl, isopropyl, phenyl, substituted phenyl, naphthalene A substituted naphthyl group or a tetrahydronaphthyl group, wherein the substituent is a fluorenyl group or an ethyl group.
19. 如权利要求 18所述的方法，其中所用拆分剂是 S-α-苯乙胺或 S- α- 萘乙胺。 19. The method of claim 18, wherein the resolving agent used is S-?-phenethylamine or S-?-naphthylethylamine.
20. 如权利要求 18所述的方法， 其中适宜的拆分剂与式 II所示的化 合物的摩尔比在 0.3 到 3.0 之间。
20. The method of claim 18, wherein the molar ratio of a suitable resolving agent to the compound of formula II is between 0.3 and 3.0.
21. 如权利要求 18所述的方法， 其中适宜的拆分剂与式 II所示的化 合物的摩尔比在 0.5到 1.5之间。 21. The method of claim 18, wherein the molar ratio of a suitable resolving agent to the compound of formula II is between 0.5 and 1.5.
22. 如权利要求 18所述的方法， 其中， 拆分时使用的溶剂选自： 曱 醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 异丁醇、 叔丁醇、 四氢呋喃、 2-曱基 四氢呋喃、 曱苯、 二氯曱烷、 乙酸乙酯、 丙酮、 丁酮、 戊酮、 1,4-二氧六 环、 曱基叔丁基醚、 DMF、 DMSO、 水、 或其混合物。 22. The method according to claim 18, wherein the solvent used in the resolution is selected from the group consisting of: decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, 2- Mercaptotetrahydrofuran, toluene, dichlorodecane, ethyl acetate, acetone, butanone, pentanone, 1,4-dioxane, nonyl tert-butyl ether, DMF, DMSO, water, or a mixture thereof.
23. 如权利要求 18所述的方法， 其中， 反应温度在 0-189°C。 23. The method of claim 18, wherein the reaction temperature is between 0 and 189 °C.
24. 如权利要求 18所述的方法， 其中， 反应温度在 15~78°C。 24. The method of claim 18, wherein the reaction temperature is between 15 and 78 °C.
25. 如权利要求 18所述的方法， 其中， 产物的光学纯度不低于 75%。 25. The method of claim 18, wherein the product has an optical purity of not less than 75%.
26. 如权利要求 18所述的方法， 其中， 该方法还包括式 III所示化合 物的重结晶步骤。 26. The method of claim 18, wherein the method further comprises the step of recrystallizing the compound of formula III.
27. 如权利要求 26所述的方法， 其中， 重结晶使用的溶剂选自曱醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 异丁醇、 叔丁醇、 四氢呋喃、 2-曱基四氢 呋喃、 曱苯、 二氯曱烷、 乙酸乙酯、 丙酮、 丁酮、 戊酮、 1,4-二氧六环、 曱基叔丁基醚、 正己烷、 正庚烷、 庚烷、 正辛烷、 环己烷、 石油醚、 或其 混合物。 27. The method according to claim 26, wherein the solvent used for recrystallization is selected from the group consisting of decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, 2-fluorenyl Tetrahydrofuran, toluene, dichlorodecane, ethyl acetate, acetone, butanone, pentanone, 1,4-dioxane, nonyl tert-butyl ether, n-hexane, n-heptane, heptane, n-octyl Alkane, cyclohexane, petroleum ether, or a mixture thereof.
28. 如权利要求 18所述的方法，其中， RfCHsSC -; R2=4-氯代苄基， 式 III所示化合物是拉洛皮兰。
28. The method of claim 18, wherein RfCHsSC -; R 2 = 4-chlorobenzyl, the compound of formula III is lorololan.
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| Title |
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| DAVID, M.T. ET AL.: "On the Mechanism of an Asymmetric a, beta-Unsaturated Carboxylic Acid Hydrogenation: Application to the Synthesis of a PGD2 Receptor Antagonist", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 128, no. 51, 6 December 2006 (2006-12-06), pages 17063 - 17073 * |
| LIU, WENTAO ET AL.: "Improvement on Synthesis Process of Mitiglinide Calcium", FOOD AND DRUG, vol. 11, no. 11, 10 November 2009 (2009-11-10), pages 21 - 23 * |
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