CN104059009A - 一种依折麦布重要中间体的合成方法 - Google Patents
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- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title claims abstract description 12
- 229960000815 ezetimibe Drugs 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 13
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- XXSSRSVXDNUAQX-QGZVFWFLSA-N 1-(4-fluorophenyl)-5-[(4s)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentane-1,5-dione Chemical compound C1=CC(F)=CC=C1C(=O)CCCC(=O)N1C(=O)OC[C@@H]1C1=CC=CC=C1 XXSSRSVXDNUAQX-QGZVFWFLSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- -1 (S)-2-(3,5-dimethylphenyl methylol)-Pyrrolidine hydrochloride Chemical compound 0.000 claims description 3
- OKEWPICUMQBHIM-UHFFFAOYSA-N NC1C(C(=O)O)(C=CC=C1C(=O)O)C Chemical compound NC1C(C(=O)O)(C=CC=C1C(=O)O)C OKEWPICUMQBHIM-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-Butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 4
- 238000010531 catalytic reduction reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 description 1
- 125000000352 p-cymenyl group Chemical group C1(=C(C=C(C=C1)C)*)C(C)C 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- BPEVHDGLPIIAGH-UHFFFAOYSA-N ruthenium(3+) Chemical compound [Ru+3] BPEVHDGLPIIAGH-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种式Ⅰ所示的依折麦布重要中间体的合成方法，采用不对称钌催化剂催化还原方法得到，本发明提供的合成方法收率高，非对应异构体可控、成本有明显优势，易于实现工业化大生产。
Description
技术领域
本发明属于药物化学领域，具体涉及一种依折麦布重要中间体的合成。
背景技术
依折麦布（Ezetimibe）是由先灵葆雅（Schering-Plough）制药公司和默克（Merck）公司联合开发的新型胆固醇吸收抑制剂。2002年11月首次在德国上市，同期在美国上市，商品名为“益适纯”（EZETROL），是目前上市的唯一的选择性胆固醇吸收抑制剂，主要阻断胆固醇的外源性吸收途径，通过作用于胆固醇转运蛋白抑制肠道内胆固醇的吸收，可适用于各型高脂血症，尤其适用于对他汀类药物效果不佳或不能耐受的病人，以及一些遗传性和药源性高脂血症患者。
2005年市场销售额达7.9亿美元，目前已成为降血脂药市场上的重磅炸弹药物，市场前景广阔。所以开发生产该药物将有重要的社会效益和巨大的经济效益。
先灵公司于1999年12月6日申请的专利CN1130342C公开了一种改进的手性合成依折麦布的方法，其中重要中间体（ ）（3R，4S）-1-（4-氟苯基）-3-[(3S)-3-(4-氟苯基)-3-羟丙基]-4-（4-苄氧苯基）-2-氮杂环丁酮的合成是通过（R）-Me-CBS催化下使用硼烷手性还原所得；CN102746249A专利中采用二甲硫醚硼烷化物、（-）-DIP-Cl还原剂还原所得式（）化合物；合成依折麦布的重要中间体常采用手性还原剂手性恶唑烷酮和硼烷二甲硫醚（CBS/BMS）进行不对称还原，但存在缺点，硼烷二甲硫醚为易燃易爆试剂，不易实现工业化；手性恶唑硼烷辅助试剂国内无稳定，价廉的供货商；导致成本很高。传统专利的方法如下：
。
发明内容
本发明针对现有技术的上述缺陷，提供一种收率高，非对应异构体可控的、成本有明显优势，易于实现工业化大生产的依折麦布的重要中间体（）的合成方法。
式1结构式：
经过对不对称还原进行了深入研究，本发明采用的合成方法如下：
。
上述合成路线中：
手性催化剂为式（Ⅲ）所示结构化合物，由含钌的配合物与手性配体经过配体交换反应所得。
进一步，含钌的配合物选自[氯化钌（对-异丙基苯甲烷）] 2 或（Cp*RuCl2）2，优选[氯化钌（对-异丙基苯甲烷）] 2 ，其结构如下所示：
注：上述[Cp*RuCl2]2为二氯(五甲基环戊二烯基)合钌(III)聚合物
手性配体选自 (1R,2S)-顺式-1-氨基-2-茚醇、（-）-1,3-二苯基-2-氨基-1-丙醇、（-）-2-氨基-3-甲基-1,1-二苯基-1-丁醇、（S）-2-（二甲基苯基羟甲基）-四氢吡咯盐酸盐，优选为(1R,2S)-顺式-1-氨基-2-茚醇。
如上所述，式（Ⅲ）所示手性催化剂的合成如下所示：
注：上述反应式中Cym为对-异丙基苯甲烷
本发明中，原料与手性催化剂的摩尔比例为20:1~10:1。
本发明所用高沸点极性溶剂为甲醇、乙醇、异丙醇、乙二醇、异丁醇、叔丁醇、乙腈、丙腈、乙酸乙酯、乙酸丁酯其中的一种或它们的组合，优选异丙醇。
具体合成操作如下：
（1）手性钌催化剂（式Ⅲ所式化合物）的预备
先将[氯化钌（对-异丙基苯甲烷）] 2 加入到异丙醇中，然后将(1R,2S)-顺式-1-氨基-2-茚醇加入作为配体，在氮气保护下，常温搅拌2h，与[氯化钌（对-异丙基苯甲烷）] 2 配合物结合生成不对称手性催化剂式Ⅲ所示化合物；
（2）依折麦布中间体的制备
反应完成后，将反应液加入到高压反应釜中，然后向反应液中加入式Ⅱ原料，充入氢气，0.2MPa下反应3h，浓缩反应液，精制得目标化合物式Ⅰ所示化合物。
本发明中，该手性钌催化剂催化的氢化还原反应，收率达到95%，非对映异构体含量可控，成本具有明显优势。
具体实施方式
实施例1 依折麦布中间体（式Ⅰ所示化合物）的合成
手性钌催化剂（式Ⅲ所式化合物）的预备：
在100mL单口瓶中加入 [氯化钌（对-异丙基苯甲烷）] 2 （0.1g，0.16mmol），异丙醇40mL, (1R,2S)-顺式-1-氨基-2-茚醇(0.0245g,1.6mmol)，反应瓶抽真空后进行氮气保护，常温搅拌2h；
依折麦布中间体的制备：
将上述手性钌催化剂的反应液倒入500mL高压反应釜内，加入20mL的异丙醇，加入式Ⅱ所示化合物原料(0.815g,1.64mmol),反应釜抽真空后，充入氢气，使压力达到0.2MPa，室温反应3h，制备薄层检测（TLC;展开剂为PE:EA=3:1）反应全部完成；浓缩反应液后用PE：EA（4:1~3:1）洗脱得到白色固体粉末0.774g产物，收率95.5%。MS 500.5[M+H]+。
化合物的核磁数据如下:
1H-NMR（600MHZ，CDCl3）δ：
d=1.85-2.05(m,4H,CH2CH2),3.07-3.17(m,1H,CHCO),4.55(d,J=2.4Hz,1H,CHN),4.17-4.76(m,1H.ArCH),5.10(s,2H,OCH2Ph),6.90-7.07(m,6H,ArH),7.20-7.44(m,11H,ArH)。
实施例2 依折麦布中间体（式Ⅰ所示化合物）的合成
手性钌催化剂（式Ⅲ所式化合物）的预备：
在1000mL圆底烧瓶中加入 [氯化钌（对-异丙基苯甲烷）] 2 （244g，0.402mol），异丙醇500mL, (1R,2S)-顺式-1-氨基-2-茚醇(59.9g,0.402mol)，反应瓶抽真空后进行氮气保护，常温搅拌2h；
依折麦布中间体的制备：
将上述手性钌催化剂的反应液倒入100L高压反应釜内，加入20L的异丙醇，加入式Ⅱ所示化合物原料(2000g，4.02mmol),反应釜抽真空后，充入氢气，使压力达到0.2MPa，室温反应3h，反应HPLC中控，反应完成后旋干溶剂加入20L水和20L乙酸乙酯搅拌后萃取，合并有机相，用水洗涤，旋干溶液，加入甲醇18L升温至65℃，搅拌30min后趁热过滤，加入9L H2O，升温至65℃溶清后，自然冷却至20~25℃，析出白色固体；搅拌4~6小时候抽滤，45℃真空干燥4h，得到1905g，收率为95.2%，MS 500.5[M+H]+。化合物的核磁数据如下:
1H-NMR（600MHZ，CDCl3）δ：
d=1.85-2.05(m,4H,CH2CH2),3.07-3.17(m,1H,CHCO),4.55(d,J=2.4Hz,1H,CHN),4.17-4.76(m,1H.ArCH),5.10(s,2H,OCH2Ph),6.90-7.07(m,6H,ArH),7.20-7.44(m,11H,ArH)。
Claims (5)
1.一种式Ⅰ所示的依折麦布重要中间体的合成方法，合成路线如下：
。
2.根据权利要求1所述的合成方法，其中式所示的手性催化剂的合成是由含钌的配合物和手性配体进行配体交换反应制得，其中：
含钌配合物选自[氯化钌（对-异丙基苯甲烷）] 2 或（Cp*RuCl2）2；
手性配体选自 (1R,2S)-顺式-1-氨基-2-茚醇、（-）-1,3-二苯基-2-氨基-1-丙醇、（-）-2-氨基-3-甲基-1,1-二苯基-1-丁醇、（S）-2-（二甲基苯基羟甲基）-四氢吡咯盐酸盐。
3.权利要求2所述的含钌配合物为[氯化钌（对-异丙基苯甲烷）] 2 ，手性配体为(1R,2S)-顺式-1-氨基-2-茚醇。
4.根据权利要求2所述，其中式所示的手性催化剂的合成如下：
。
5.根据权利要求1所述合成方法，其具体制备过程如下：
（1）手性钌催化剂（式所式化合物）的预备
先将[氯化钌（对-异丙基苯甲烷）] 2 加入到异丙醇中，然后将(1R,2S)-顺式-1-氨基-2-茚醇加入作为交换配体，在氮气保护下，常温搅拌2h，与[氯化钌（对-异丙基苯甲烷）] 2 配合物结合生成不对称手性催化剂式所示化合物；
（2）依折麦布中间体的制备
反应完成后，将反应液加入到高压反应釜中，然后向反应液中加入式Ⅱ原料，抽真空，充入氢气，0.2MPa下室温反应3h，精制得目标化合物式Ⅰ所示化合物。
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