WO2022134316A1 - 一种托吡卡胺的制备方法 - Google Patents
一种托吡卡胺的制备方法 Download PDFInfo
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- WO2022134316A1 WO2022134316A1 PCT/CN2021/079470 CN2021079470W WO2022134316A1 WO 2022134316 A1 WO2022134316 A1 WO 2022134316A1 CN 2021079470 W CN2021079470 W CN 2021079470W WO 2022134316 A1 WO2022134316 A1 WO 2022134316A1
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- Prior art keywords
- tropicamide
- toluene
- ethyl acetate
- reaction
- triethylamine
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- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960004791 tropicamide Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 81
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 59
- JACRWUWPXAESPB-UHFFFAOYSA-N tropic acid Chemical compound OCC(C(O)=O)C1=CC=CC=C1 JACRWUWPXAESPB-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 2-chlorocarbonyl-2-phenylethyl Chemical group 0.000 claims abstract description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000926 separation method Methods 0.000 claims abstract description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZBAMQLFFVBPAOX-UHFFFAOYSA-N n-(pyridin-4-ylmethyl)ethanamine Chemical compound CCNCC1=CC=NC=C1 ZBAMQLFFVBPAOX-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 238000000967 suction filtration Methods 0.000 claims abstract description 4
- 238000000605 extraction Methods 0.000 claims abstract description 3
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-methyl-PhOH Natural products CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012267 brine Substances 0.000 claims description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 2
- NWCHELUCVWSRRS-UHFFFAOYSA-N atrolactic acid Chemical compound OC(=O)C(O)(C)C1=CC=CC=C1 NWCHELUCVWSRRS-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 abstract description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 238000005352 clarification Methods 0.000 abstract 1
- 239000012043 crude product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 239000011780 sodium chloride Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 abstract 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 230000004438 eyesight Effects 0.000 description 4
- 230000004436 pseudomyopia Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- 210000001508 eye Anatomy 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 230000004379 myopia Effects 0.000 description 2
- 208000001491 myopia Diseases 0.000 description 2
- VGFZORUFTNLGLI-UHFFFAOYSA-N 1-pyridin-4-ylpropan-1-amine Chemical compound CCC(N)C1=CC=NC=C1 VGFZORUFTNLGLI-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 238000005285 chemical preparation method Methods 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
Definitions
- the invention relates to a medicinal chemical preparation method, in particular to a method for synthesizing tropicamide with 3-hydroxy-2-phenylpropionic acid.
- Pseudo-myopia is a temporary short-sightedness, which is a common eye disease and is more common in adolescents. Due to overuse of the eye, the patient's ciliary muscle will continue to contract and spasm. At this time, the thickness of the lens will increase, and the observed object will be blurred. After the spasm disappears, the vision will recover, but the eyeball will not produce qualitative pathological changes. , and no major changes in physiological functions. Pseudo-myopia usually lasts from a few days to several months in adolescents. This stage is the best period for clinical treatment. If it is not treated in time, it will gradually develop into true myopia, which seriously affects vision and is not conducive to daily life. At present, drugs are mainly used. Treatment helps patients improve their condition.
- Tropicamide the structural formula is as follows:
- Tropicamide is the main component of tropicamide eye drops, which is mainly used to treat juvenile pseudomyopia, and to adjust uncorrected vision and eye adjustment of patients. It can effectively relieve the pseudo-myopia of adolescents, restore the eyesight of patients, and has fewer adverse reactions and high medication safety.
- the present invention has higher requirements on the purity of the raw material drug for the tropicamide eye drops. Therefore, it is very important to develop the synthesis and purification process of tropicamide, and to improve the purity of the drug is of great significance to improve the safety of clinical medication.
- the purpose of the present invention is to provide a preparation method of tropicamide.
- An object of the present invention is to provide a preparation method of tropicamide, the method comprising the following steps:
- the preparation method of the present invention further comprises the following steps:
- the preparation method of the present invention further comprises the following steps:
- the synthetic route of tropicamide of the present invention is as follows:
- the mol ratio of 3-hydroxy-2-phenylpropionic acid and triethylamine in step (1) is 30:1 ⁇ 50:1; the mol ratio of 3-hydroxy-2-phenylpropionic acid and acetyl chloride is 1 : 1 ⁇ 1:3.5, the molar ratio of 3-hydroxy-2-phenylpropionic acid and dimethyl sulfoxide is 1:1 ⁇ 1:2, the heating temperature is at 40 ⁇ 100°C, and the reflux is 2 ⁇ 5h.
- the molar ratio of 3-hydroxy-2-phenylpropionic acid and triethylamine in step (1) is 20:1; the molar ratio of 3-hydroxy-2-phenylpropionic acid and acetyl chloride is 1:2, The molar ratio of 3-hydroxy-2-phenylpropionic acid to dimethyl sulfoxide was 1:1.4, the heating temperature was 50°C, and the mixture was refluxed for 3h.
- the molar ratio of ethylpyridin-4-ylmethylamine and triethylamine in step (2) is 1:1 ⁇ 1:3, ethylpyridin-4-ylmethylamine and 2-chlorocarbonyl-2-benzene
- the molar ratio of ethyl ethyl ester is 1:1 ⁇ 1:2, and it is cooled to -5 ⁇ 5°C.
- the molar ratio of ethylpyridin-4-ylmethylamine and triethylamine in step (2) is 1:1 to 1:1.1, ethylpyridin-4-ylmethylamine and 2-chlorocarbonyl-2-
- the molar ratio of phenylethyl ester is 1:1 ⁇ 1:1.1, and it is cooled to 0°C.
- step (3) 5-15 mL of 3N hydrochloric acid solution is added for hydrolysis at 40-70° C. for 3-8 h.
- step (3) add 10 mL of 3N hydrochloric acid solution to hydrolyze at 50 to 55 °C for 5 h
- step (4) the temperature is lowered to 0 ⁇ 15° C., and saturated aqueous sodium bicarbonate solution is added dropwise to adjust the pH to 5 ⁇ 10.
- step (4) the temperature is lowered to 0 ⁇ 10° C., and saturated aqueous sodium bicarbonate solution is added dropwise to adjust the pH to 7 ⁇ 8.
- the separation in step (5) is to first obtain high-purity tropicamide through recrystallization.
- the preparation method of the present invention comprises the following steps:
- the preparation method of the present invention with respect to the existing technology, has the following beneficial effects:
- the crude oily product was dissolved in ethyl acetate, slowly added dropwise with heptane at 0°C, crystallized, and washed with suction to obtain the target product tropicamide.
- the detected purity was 100% and the yield was 95%.
Abstract
本发明涉及一种托吡卡胺的制备方法，所述方法步骤如下： (1)将3-羟基-2-苯基丙酸、甲苯投入到烧杯中搅拌均匀氮气置换后保护，加热回流，不溶；反应分别加入三乙胺和乙酰氯，加热回流至溶清，降至室温，滴加氯化亚砜，继续反应，减压浓缩干得到2-氯羰基-2-苯基乙酯； (2)准备另一夹套瓶，加入乙基吡啶-4-基甲胺，三乙胺和甲苯，氮气置换后保护，冷却，缓慢滴加2-氯羰基-2-苯基乙酯溶于甲苯的溶液。滴毕，继续反应； (3)上述反应完全后滴加水，分液萃取，盐水洗涤，甲苯层加入3N盐酸溶液水解，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤； (4)降温，滴加饱和碳酸氢钠水溶液调节PH，乙酸乙酯萃取，有机相浓缩得淡黄色油状物； (5)油状物粗品用乙酸乙酯溶解，缓慢滴加庚烷，析晶，抽滤洗涤得到目标产物托吡卡胺。
Description
本发明涉及一种药物化学制备方法，具体地说是一种以3-羟基-2-苯基丙酸合成托吡卡胺的方法。
假性近视是一种暂时性近视，属于常见眼科疾病，多见于青少年。由于用眼过度，患者睫状肌会出现持续收缩痉挛现象，此时晶状体厚度会增加，观察物体模糊不清，待痉挛现象消失后，视力便会恢复，但眼球不会发生器质性病理改变，且生理功能也无较大改变。青少年发生假性近视时间普遍持续几天至几个月，这一阶段是临床治疗的最佳时期，若不及时治疗会逐渐发展为真性近视，严重影响视力，不利于日常生活，目前主要通过药物治疗帮助患者改善病情。
托吡卡胺，结构式如下：
托吡卡胺是托吡卡胺滴眼液的主要成分，主要用于治疗青少年假性近视，对患者裸眼视力及眼调节。有效缓解青少年假性近视状况，恢复患者眼睛视力，且不良反应较少，用药安全性较高。
目前无相关文献关于托吡卡胺合成方法的报道。本发明针对托吡卡胺滴眼液对原料药的纯度要求较高。因此，开发托吡卡胺合成及纯化工艺十分重要，提高药品纯度，对提高临床用药的安全性具有重大的意义。
发明内容
本发明的目的在于提供一种托吡卡胺的制备方法。
本发明的一个目的是提供托吡卡胺的的制备方法，所述方法，包括以下步骤：
本发明所述的制备方法，进一步包括以下步骤：
本发明所述的制备方法，进一步包括以下步骤：
优选的，本发明所述的托吡卡胺的合成路线，如下所示：
本发明所述的制备方法，具体操作步骤如下：
(1)将3-羟基-2-苯基丙酸、甲苯投入到烧杯中搅拌均匀氮气置换后保护，加热回流，不溶；反应分别加入三乙胺和乙酰氯，加热回流至溶清，降至室温，滴加氯化亚砜，继续反应，减压浓缩干得到2-氯羰基-2-苯基乙酯；
(2)准备另一夹套瓶，加入乙基吡啶-4-基甲胺，三乙胺和甲苯，氮气置换后保护，冷却。缓慢滴加2-氯羰基-2-苯基乙酯溶于甲苯的溶液。滴毕，继续反应。
(3)上述反应完全后滴加水，分液萃取，盐水洗涤，甲苯层加入3N盐酸溶液水解，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤；
(4)降温，滴加饱和碳酸氢钠水溶液调节PH，乙酸乙酯萃取，有机相浓缩得淡黄色油状物。
(5)油状物粗品用乙酸乙酯溶解，缓慢滴加庚烷，析晶，抽滤洗涤得到目标产物托吡卡胺。
其中，步骤(1)中的3-羟基-2-苯基丙酸与三乙胺的摩尔比30:1～50:1；3-羟基-2-苯基丙酸与乙酰氯的摩尔比1:1～1:3.5，3-羟基-2-苯基丙酸与二甲亚砜的摩尔比1:1～1:2，加热温度在在40～100℃，回流2～5h。
优选的，步骤(1)中的3-羟基-2-苯基丙酸与三乙胺的摩尔比20:1；3-羟基-2-苯基丙酸与乙酰氯的摩尔比1:2，3-羟基-2-苯基丙酸与二甲亚砜的摩尔比1:1.4，加热温度在50℃，回流3h。
其中，步骤(2)中的乙基吡啶-4-基甲胺与三乙胺的摩尔比1:1～1:3，乙基吡啶-4-基甲胺与2-氯羰基-2-苯基乙酯的摩尔比1:1～1:2，冷却至-5～5℃。
优选的，步骤(2)中的乙基吡啶-4-基甲胺与三乙胺的摩尔比1:1～1:1.1，乙基吡啶-4-基甲胺与2-氯羰基-2-苯基乙酯的摩尔比1:1～1:1.1，冷却至0℃。
其中，步骤(3)中加入5～15mL 3N盐酸溶液40～70℃水解3-8h。
优选的，步骤(3)中加入10mL 3N盐酸溶液50～55℃水解5h
其中，步骤(4)中降温至0～15℃，滴加饱和碳酸氢钠水溶液调节PH至5～10。
优选的，步骤(4)中降温至0～10℃，滴加饱和碳酸氢钠水溶液调节PH至7～8。
其中，步骤(5)中分离是先通过重结晶得到高纯度托吡卡胺。
进一步优选的，本发明的制备方法，包括以下步骤：
(1)50mL夹套瓶加入2.5g 3-羟基-2-苯基丙酸，10mL甲苯，氮气置换后保护，加热至50℃。分别加入37mg三乙胺和2.33g乙酰氯，反应3h，溶清；降至室温，滴加2.5g氯化亚砜，继续反应3h，减压浓缩干得到2-氯羰基-2-苯基乙酯。
(2)准备另一50mL夹套瓶，加入0.55g乙基吡啶-4-基甲胺，0.46g三乙胺和10mL甲苯，氮气置换后保护，冷却至0-5℃。缓慢1g滴加2-氯羰基-2-苯基乙酯溶于3mL甲苯的溶液，控温5℃以下。滴毕，维持0-5℃反应1-2h。
(3)反应完全，滴加10mL水，分液萃取，盐水洗涤，甲苯层加入10mL 3N盐酸溶液50-55℃水解3-5h，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤2次。
(4)降温至0-10℃，滴加饱和碳酸氢钠水溶液调节PH至7-8，乙酸乙酯萃取，有机相浓缩得淡黄色油状物。
(5)油状物粗品用乙酸乙酯溶解，0-10℃缓慢滴加庚烷，析晶，抽滤洗涤得到目标产物托吡卡胺。
上述合成路线中出现的化合物1-5的中文名称：
化合物1：3-羟基-2-苯基丙酸
化合物2：2-氯羰基-2-苯基乙酯
化合物3：乙基吡啶-4-基甲胺
化合物4：N-乙基-N-(4-吡啶甲基)-α-甲基乙酯-苯乙酰胺
化合物5：N-乙基-N-(4-吡啶甲基)-α-羟甲基-苯乙酰胺(托吡卡胺)
上述化合物1-5，1,2,3,,5是已知化合物，4是未知化合物。
本发明的制备方法，相对于现有的工艺而言，具有以下有益效果：
目前并没有托吡卡胺相关合成工艺的报道，本发明作为唯一托吡卡胺的合成工艺，其合成路线简单，操作便利，用时短，成本低，通过本发明的方法制备得到的托吡卡胺具有纯度高(100％)和收率高(95％)等特点，对于提高药品质量，提高临床用药的安全性具有重大的意义。
图1托吡卡胺成品纯度100％LC-MS检测图谱
通过以下具体实施例对本发明作进一步的说明，但不作为本发明的限制
实施例1、托吡卡胺
50mL夹套瓶加入2.5g 3-羟基-2-苯基丙酸，10mL甲苯，加热至50℃。分别加入三乙胺和乙酸酐，反应3h，溶清；浓缩反应体系，降至室温，滴加5g氯化亚砜，继续反应4h，减压浓缩干得到2-氯羰基-2-苯基乙酯。
准备另一50mL夹套瓶，加入0.55g乙基吡啶-4-基甲胺，三乙胺和10mL甲苯，冷却至0℃。缓慢1g滴加2-氯羰基-2-苯基乙酯溶于3mL甲苯的溶液，控温5℃以下。滴毕，维持0℃反应2h，反应完全，滴加10mL水，分液萃取，盐水洗涤，甲苯层加入10mL 3N盐酸溶液55℃水解5h，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤2次，降温至0℃，滴加饱和碳酸氢钠水溶液调节PH至7，乙醚对其进行重结晶，实验失败，未能得到目标产物。
实施例2、托吡卡胺
50mL夹套瓶加入2.5g 3-羟基-2-苯基丙酸，10mL甲苯，加热至50℃。分别加入三乙胺和乙酸酐，反应3h，溶清；浓缩反应体系，降至室温，滴加5g氯化亚砜，继续反应4h，减压浓缩干得到2-氯羰基-2-苯基乙酯。
准备另一50mL夹套瓶，加入0.55g乙基吡啶-4-基甲胺，三乙胺和10mL甲苯，冷却至0℃。缓慢1g滴加2-氯羰基-2-苯基乙酯溶于3mL甲苯的溶液，控温5℃以下。滴毕，维持0℃反应2h，反应完全，滴加10mL水，分液萃取，盐水洗涤，甲苯层加入10mL 3N盐酸溶液55℃水解5h，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤2次，降温至0℃，滴加饱和碳酸氢钠水溶液调节PH至7，乙酸乙酯萃取，有机相浓缩得淡黄色油状物。油状物粗品用乙酸乙酯溶解，0℃缓慢滴加庚烷，析晶，抽滤洗涤得到目标产物托吡卡胺，收率为65％。
实施例3、托吡卡胺
50mL夹套瓶加入2.5g 3-羟基-2-苯基丙酸，10mL甲苯，氮气置换后保护，加热至50℃。分别加入三乙胺和乙酰氯，反应3h，溶清；降至室温，滴加2.5g氯化亚砜，继续反应3h，减压浓缩干得到2-氯羰基-2-苯基乙酯。
准备另一50mL夹套瓶，加入0.55g乙基吡啶-4-基甲胺，三乙胺和10mL甲苯，氮气置换后保护，冷却至0℃。缓慢1g滴加2-氯羰基-2-苯基乙酯溶于3mL 甲苯的溶液，控温5℃以下。滴毕，维持0℃反应2h，反应完全，滴加10mL水，分液萃取，盐水洗涤，甲苯层加入10mL 3N盐酸溶液55℃水解3-5h，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤2次，降温至0℃，滴加饱和碳酸氢钠水溶液调节PH至7，乙酸乙酯萃取，有机相浓缩得淡黄色油状物。油状物粗品用乙酸乙酯溶解，0℃缓慢滴加庚烷，析晶，抽滤洗涤得到目标产物托吡卡胺，检测纯度为100％，收率为95％。
Claims (9)
- 一种托吡卡胺的制备方法，包括以下步骤：
- 根据权利要求1所述的制备方法，进一步包括以下步骤：
- 根据权利要求1所述的制备方法，进一步包括以下步骤：
- 根据权利要求1所述的制备方法，进一步包括以下步骤：
- 根据权利要求1所述的制备方法，步骤如下：(1)将3-羟基-2-苯基丙酸、甲苯投入到烧杯中搅拌均匀氮气置换后保护，加热回流，不溶；反应分别加入三乙胺和乙酰氯，加热回流至溶清，降至室温，滴加氯化亚砜，继续反应，减压浓缩干得到2-氯羰基-2-苯基乙酯；(2)准备另一夹套瓶，加入乙基吡啶-4-基甲胺，三乙胺和甲苯，氮气置换后保护，冷却，缓慢滴加2-氯羰基-2-苯基乙酯溶于甲苯的溶液。滴毕，继续反应；(3)上述反应完全后滴加水，分液萃取，盐水洗涤，甲苯层加入3N盐酸溶液水解，冷至室温，分液，分离得到水相，水相乙酸乙酯洗涤；(4)降温，滴加饱和碳酸氢钠水溶液调节PH，乙酸乙酯萃取，有机相浓缩得淡黄色油状物；(5)油状物粗品用乙酸乙酯溶解，缓慢滴加庚烷，析晶，抽滤洗涤得到目标产物托吡卡胺。
- 根据权利要求1所述的托吡卡胺的合成方法，其特征在于：步骤a中的3-羟基-2-苯基丙酸与三乙胺的摩尔比30:1～50:1；3-羟基-2-苯基丙酸与乙酰氯的摩尔比1:1～1:3.5，3-羟基-2-苯基丙酸与二甲亚砜的摩尔比1:1～1:2；步骤a中加热温度在在40～100℃，回流2h。
- 根据权利要求1所述的托吡卡胺合成方法，其特征在于：步骤b中的乙基吡啶-4-基甲胺与三乙胺的摩尔比1:1～1:3，乙基吡啶-4-基甲胺与2-氯羰基-2-苯基乙酯的摩尔比1:1～1:2；步骤b中的反应温度为-5～5℃。
- 根据权利要求1所述的托吡卡胺合成方法，其特征在于：步骤c中加入5～15mL 3N盐酸溶液40～70℃水解3-8h。
- 根据权利要求1所述的托吡卡胺合成方法，其特征在于：步骤d中降温至0～15℃，滴加饱和碳酸氢钠水溶液调节PH至5～10；步骤d中使用乙酸乙酯与庚烷进行重结晶提纯。
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