CN105906486B - 沙格雷酯中间体2‑[2‑(3‑甲氧基苯基)乙基]苯酚的合成方法 - Google Patents
沙格雷酯中间体2‑[2‑(3‑甲氧基苯基)乙基]苯酚的合成方法 Download PDFInfo
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- CN105906486B CN105906486B CN201610251703.0A CN201610251703A CN105906486B CN 105906486 B CN105906486 B CN 105906486B CN 201610251703 A CN201610251703 A CN 201610251703A CN 105906486 B CN105906486 B CN 105906486B
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- FFYNAVGJSYHHFO-UHFFFAOYSA-N sarpogrelate Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 FFYNAVGJSYHHFO-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229950005789 sarpogrelate Drugs 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- HGQQRAXOBYWKDV-UHFFFAOYSA-N 2-[2-(3-methoxyphenyl)ethyl]phenol Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)O)=C1 HGQQRAXOBYWKDV-UHFFFAOYSA-N 0.000 title abstract 3
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims abstract description 7
- PBEJTRAJWCNHRS-UHFFFAOYSA-N 2-phenylmethoxybenzaldehyde Chemical group O=CC1=CC=CC=C1OCC1=CC=CC=C1 PBEJTRAJWCNHRS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003208 petroleum Substances 0.000 claims abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- 239000004519 grease Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 3
- 240000000203 Salix gracilistyla Species 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 235000021419 vinegar Nutrition 0.000 abstract description 2
- 239000000052 vinegar Substances 0.000 abstract description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/141—Esters of phosphorous acids
- C07F9/1414—Esters of phosphorous acids with arylalkanols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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Abstract
本发明公开了一种沙格雷酯中间体2‑[2‑(3‑甲氧基苯基)乙基]苯酚的合成方法，涉及有机合成技术领域，本发明采用易得价廉的间甲氧基氯苯为原料，与亚磷酸三乙酯缩合，然后与邻苯甲氧基苯甲醛(由水杨醋与氯苯制得)缩合，再加氢使双键烷基化，并用石油醚结晶，得到白色结晶性的目标产物，简化处理步骤，降低损失率，产物纯度达99.5％，用该品质2‑[2‑(3‑甲氧基苯基)乙基]苯酚制备盐酸沙格雷酯，单个杂质都小于0.1％，产品纯度达99.8％以上。
Description
技术领域：
本发明涉及有机合成技术领域，具体涉及一种沙格雷酯中间体2-[2-(3-甲氧基苯基)乙基]苯酚的合成方法。
背景技术：
2-[2-(3-甲氧基苯基)乙基]苯酚是抗血栓药盐酸沙格雷酯的关键中间体，由于该中间体熔点较低，现行技术是用该中间体的油状物用于下步合成沙格雷酯，造成最终产品杂质高、颜色差，纯化困难，成本居高不下。而已报道的合成路线存在步骤繁多、反应条件苛刻、三废生成量大和收率低的缺点，不利于工业化生产。
发明内容：
本发明所要解决的技术问题在于提供一种工艺简单、成本低且收率高的沙格雷酯中间体2-[2-(3-甲氧基苯基)乙基]苯酚的合成方法。
本发明所要解决的技术问题采用以下的技术方案来实现：
沙格雷酯中间体2-[2-(3-甲氧基苯基)乙基]苯酚的合成方法，包括如下步骤：
(1)1-苄氧基-2-[2-(3-甲氧基苯基)乙烯基]苯的合成：向100g间甲氧基氯苯中加入300ml亚磷酸三乙酯，混合物升温至回流反应1.5h，反应结束后减压回收亚磷酸三乙酯，再向残液中加入136g邻苯甲氧基苯甲醛和400ml无水乙醇，回流反应8h，经回收溶剂后加入冰水，搅拌，过滤得到390g 1-苄氧基-2-[2-(3-甲氧基苯基)乙烯基]苯湿品；
(2)2-[2-(3-甲氧基苯基)乙基]苯酚的合成：将上步所得的产物湿品加入500ml80％甲醇中，并加入6g 5％钯碳作催化剂，再通入氢气15atm，氢化至体系不吸氢为止，过滤除去钯碳，减压回收甲醇，然后冷却、分层，得到下层产物油层，向油状物中加入200ml石油醚，于-2～0℃搅拌2h，过滤得到结晶产品，再于20～25℃真空烘干得115g产品，HPLC检测纯度为99.6％。
本发明的有益效果是：本发明采用易得价廉的间甲氧基氯苯为原料，与亚磷酸三乙酯缩合，然后与邻苯甲氧基苯甲醛(由水杨醋与氯苯制得)缩合，再加氢使双键烷基化，并用石油醚结晶，得到白色结晶性的目标产物，简化处理步骤，降低损失率，产物纯度达99.5％，用该品质2-[2-(3-甲氧基苯基)乙基]苯酚制备盐酸沙格雷酯，单个杂质都小于0.1％，产品纯度达99.8％以上。
具体实施方式：
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例，进一步阐述本发明。
实施例1
(1)1-苄氧基-2-[2-(3-甲氧基苯基)乙烯基]苯的合成：向100g间甲氧基氯苯中加入300ml亚磷酸三乙酯，混合物升温至回流反应1.5h，反应结束后减压回收亚磷酸三乙酯，再向残液中加入136g邻苯甲氧基苯甲醛和400ml无水乙醇，回流反应8h，经回收溶剂后加入冰水，搅拌，过滤得到390g 1-苄氧基-2-[2-(3-甲氧基苯基)乙烯基]苯湿品；
(2)2-[2-(3-甲氧基苯基)乙基]苯酚的合成：将上步所得的产物湿品加入500ml80％甲醇中，并加入6g 5％钯碳作催化剂，再通入氢气15atm，氢化至体系不吸氢为止，过滤除去钯碳，减压回收甲醇，然后冷却、分层，得到下层产物油层，向油状物中加入200ml石油醚，于-2～0℃搅拌2h，过滤得到结晶产品，再于20～25℃真空烘干得115g产品，HPLC检测纯度为99.6％。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (1)
1.沙格雷酯中间体2-[2-(3-甲氧基苯基)乙基]苯酚的合成方法，其特征在于，包括如下步骤：
(1)1-苄氧基-2-[2-(3-甲氧基苯基)乙烯基]苯的合成：向100g间甲氧基氯苄中加入300ml亚磷酸三乙酯，混合物升温至回流反应1.5h，反应结束后减压回收亚磷酸三乙酯，再向残液中加入136g邻苯甲氧基苯甲醛和400ml无水乙醇，回流反应8h，经回收溶剂后加入冰水，搅拌，过滤得到390g 1-苄氧基-2-[2-(3-甲氧基苯基)乙烯基]苯湿品；
(2)2-[2-(3-甲氧基苯基)乙基]苯酚的合成：将上步所得的产物湿品加入500ml 80％甲醇中，并加入6g 5％钯碳作催化剂，再通入氢气15atm，氢化至体系不吸氢为止，过滤除去钯碳，减压回收甲醇，然后冷却、分层，得到下层产物油层，向油状物中加入200ml石油醚，于-2～0℃搅拌2h，过滤得到结晶产品，再于20～25℃真空烘干得115g产品，HPLC检测纯度为99.6％。
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| CN107324979A (zh) * | 2017-08-16 | 2017-11-07 | 北京奥得赛化学股份有限公司 | 一种盐酸沙格雷酯中间体的制备方法 |
| CN114394905A (zh) * | 2019-03-18 | 2022-04-26 | 安徽峆一药业股份有限公司 | 盐酸沙格雷酯中间体2-(3-二甲氨基-2-羟基)丙氧基苯甲醛的合成方法 |
| CN109824527A (zh) * | 2019-03-18 | 2019-05-31 | 安徽峆一药业股份有限公司 | 一种盐酸沙格雷酯的合成方法 |
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| A practical synthesis of sarpogrelate hydrochloride and in vitro platelet aggregation inhibitory activities of its analogues;Guo Hua Chen等;《Chinese Chemical Letters》;20100106;第21卷(第3期);第288页Scheme 1 * |
| 白藜芦醇的化学合成研究;王世盛等;《中国药物化学杂质》;20040430;第14卷(第2期);第91页右栏，Fig 1；第92页右栏1.4-1.5部分 * |
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