CN115536577B - 一种氨氯地平碱的制备方法 - Google Patents
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- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000003513 alkali Substances 0.000 title claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 125000006239 protecting group Chemical group 0.000 claims abstract description 11
- -1 Ethyl-4- (2-phthalimidoethoxy) acetoacetic acid Chemical compound 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 7
- 230000009615 deamination Effects 0.000 claims description 7
- 238000006481 deamination reaction Methods 0.000 claims description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 6
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical group O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- BJZJDEOGMBZSLE-UHFFFAOYSA-N cyclohexane;hydrate Chemical group O.C1CCCCC1 BJZJDEOGMBZSLE-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
- RIGKLAOKQFKWNN-UHFFFAOYSA-N ethyl 4-[2-(1,3-dioxoisoindol-2-yl)ethoxy]-3-oxobutanoate Chemical compound C1=CC=C2C(=O)N(CCOCC(=O)CC(=O)OCC)C(=O)C2=C1 RIGKLAOKQFKWNN-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000376 reactant Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- XKORCTIIRYKLLG-UHFFFAOYSA-N methyl 3-aminobut-2-enoate Chemical compound COC(=O)C=C(C)N XKORCTIIRYKLLG-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 239000007809 chemical reaction catalyst Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- GGBJHURWWWLEQH-UHFFFAOYSA-N Butyl-cyclohexane Natural products CCCCC1CCCCC1 GGBJHURWWWLEQH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- RVPCEXXEUXIPEO-UHFFFAOYSA-N OC(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl Chemical compound OC(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl RVPCEXXEUXIPEO-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229950008554 levamlodipine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本申请提供一种氨氯地平碱的制备方法，属于二氢吡啶类钙拮抗剂合成技术领域。以乙基‑4‑（2‑邻苯二甲酰亚胺基乙氧基）乙酰乙酸为起始原料，催化剂作用下，与邻氯苯甲醛、3‑氨基丁烯酸甲酯进行成环反应，环合产物水解脱氨基保护基制得氨氯地平游离碱。将本申请应用于氨氯地平及其中间体制备，具有原料和反应试剂廉价易得、操作简便安全、收率高成本低等优点，反应总收率可达到72%以上，纯度可达到99.0%以上。
Description
技术领域
本申请涉及一种氨氯地平碱的制备方法，属于二氢吡啶类钙拮抗剂合成技术领域。
背景技术
氨氯地平，又称阿洛地平、苯甲酸氨氯地平、二氢吡啶磺酸盐、苯磺酸氨氯地平，化学名为3-乙基-5-甲基-2-〔(2-氨基乙氧基)甲基〕-4-(2-氯苯基)-6-甲基-1,4-二氢--3,5-吡啶二羧酸酯，是美国辉瑞公司开发的第三代二氢吡啶类钙拮抗剂，具有舒张血管的作用，可用于高血压、心绞痛的治疗。而作为氨氯地平系列的关键中间体，氨氯地平碱可以进一步拆分制备左氨氯地平，进而制备临床使用广泛的苯磺酸盐和马来酸盐等。
氨氯地平文献报道的制备工艺较多，大多存在操作繁琐、收率偏低、成本较高、污染大等缺陷。因此，开发一种原料易得且便宜的氨氯地平碱显得尤为重要。
发明内容
有鉴于此，本申请提供一种氨氯地平碱的制备方法，原料和试剂价廉易得，整个工艺安全性和可操作性俱佳，收率高，成本低。
具体地，本申请是通过以下方案实现的：
一种氨氯地平碱的制备方法，以乙基-4-(2-邻苯二甲酰亚胺基乙氧基)乙酰乙酸(II)为起始原料，催化剂作用下，与邻氯苯甲醛、3-氨基丁烯酸甲酯进行环合反应，环合产物(III)在脱氨基保护基作用下水解得氨氯地平游离碱(I)。
上述过程的反应式表述如下：
该方案以乙基-4-(2-邻苯二甲酰亚胺基乙氧基)乙酰乙酸为起始原料，工序经成环、水解反应即可制得目标产物氨氯地平游离碱。操作简便工艺安全。
进一步的，作为优选：
所述环合反应催化剂：碳酸钾(K2CO3)、碳酸氢钾(KHCO3)、碳酸钠(Na2CO3)、碳酸氢钠(NaHCO3)、十六烷基三甲基溴化胺(CTAB)、苄基三乙基氯化铵(TEBA)中的任一种或其组合，以碳酸钾为优选。
所述环合反应中乙基-4-(2-邻苯二甲酰亚胺基乙氧基)乙酰乙酸乙酯、邻氯苯甲醛和3-氨基丁烯酸甲酯的摩尔比为：1:1:1～1:1.3:1.3，以1:1.1:1.1为优选。
所述环合反应中添加有溶剂，溶剂为甲苯、二甲苯、二甲基甲酰胺(DMF)、环己烷中的任一种，以甲苯为优选。在环合反应回流过程中，同时蒸去部分共沸物，带走水分，更利于反应的顺利进行。
所述脱氨基保护基为甲胺、三甲胺、三乙胺、水合肼、盐酸羟胺中的任一种或其组合，以三乙胺/水合肼为优选。
所述环合反应经重结晶形成环合产物，所述其重结晶溶剂为环己烷-水的混合物，环己烷与水的体积比1:1～8:1，优选4:1。
所述水解反应中添加有溶剂，溶剂为环己烷、正己烷、乙醇、异丙醇、异丁醇、乙酸乙酯、乙酸丁酯中的任一种或其组合，以环己烷为优选。
所述水解反应产物经重结晶得到氨氯地平游离碱，所述重结晶溶剂为丙酮-水，丙酮-水的体积比为1:1～5:1，以3:1为优选。
上述过程还可以表述如下：
(1)乙基-4-(2-邻苯二甲酰亚胺基乙氧基)乙酰乙酸乙酯(II)，与邻氯苯甲醛、3-氨基丁烯酸甲酯在碳酸钾催化下，进行环合反应，反应产物经环己烷-水重结晶，制得4-(2-氯苯基)-3-乙氧羧酸-5-甲氧羧酸-6-甲基-2-〔(2-邻苯二甲酰亚胺)乙氧基〕-1,4-二氢吡啶(III)；
(2)在环己烷/水作溶剂，4-(2-氯苯基)-3-乙氧羧酸-5-甲氧羧酸-6-甲基-2-〔(2-邻苯二甲酰亚胺)乙氧基〕-1,4-二氢吡啶(III)与三乙胺/水合肼回流反应脱保护基，粗品经丙酮-水重结晶，制得氨氯地平碱(I)。
上述过程中，原料和反应试剂廉价易得，操作简便安全，收率高，成本低等。两步反应总收率可达到72％以上，纯度可达到99.0％以上。
具体实施方式
实施例1
本实施例所制备的产物为氨氯地平中间体(III)：4-(2-氯苯基)-3-乙氧羧酸-5-甲氧羧酸-6-甲基-2-〔(2-邻苯二甲酰亚胺)乙氧基〕-1,4-二氢吡啶。
本实施例中，上述化合物的制备具体步骤如下：
将化合物(II)31.9g(0.1mol)、邻氯苯甲醛15.5g(0.11mol)、3-氨基丁烯酸甲酯12.7g(0.11mol)、碳酸钾1g、甲苯200ml，加热于回流状态下反应5h，回流反应期间蒸去少量溶剂。反应毕，冷却。加水200ml，盐酸调pH3～4，分层，水层再用甲苯100ml×3提取，合并油层，水洗。回收溶剂，加入环己烷-水(4:1)重结晶，得到淡黄色固体即化合物(III)的质量为45.4g。
上述过程反应式表达如下：
化合物(III)的收率84.3％，取淡黄色固体以HPLC法测定，含量>98.5％。
实施例1-1
本实施例与实施例1的设置相同，区别在于：环合反应中各物料比采用表1(表1中，II指代乙基-4-(2-邻苯二甲酰亚胺基乙氧基)乙酰乙酸乙酯，C7H5ClO指代邻氯苯甲醛，C5H9NO2指代3-氨基丁烯酸甲酯，III指代氨氯地平中间体)所示，论证物料比对反应及化合物(III)的影响。
表1：物料比对环合反应的影响
对比表1结果可以看出：化合物(II)和邻氯苯甲醛/3-氨基丁烯酸甲酯的投料比，随着邻氯苯甲醛/3-氨基丁烯酸甲酯添加量的递增，反应收率及纯度也逐渐提高。但达到1:1.1:1.1之后，投料比例进一步增大，收率和纯度略有降低。
实施例1-2
本实施例与实施例1的设置相同，区别在于：化合物(II)：邻氯苯甲醛：3-氨基丁烯酸甲酯＝1:1.1:1.1，环合反应催化剂采用表2(表2中，“-”指代不添加催化剂，III指代氨氯地平中间体)所示，论证催化剂对反应效果及化合物(III)的影响。
表2：催化剂对环合反应的影响
在环合反应中，基于大量试验验证，从收率、质量及用量方面进行综合考察，本案中加入K2CO3作为催化剂，效果最好，收率达到84.3％，含量稳定在98.5％以上。CTAB、TEBA等相转移催化剂次之，碳酸氢钾、碳酸钠和碳酸氢钠等碳酸盐催化效果较差，不用催化剂收率更低。
实施例1-3
本实施例与实施例1的设置相同，区别在于：环合反应中采用的溶剂如表3所示(用量均为200ml)，论证溶剂对反应过程的影响。
表3：溶剂对环合反应的影响
在本案环合反应中，溶剂选择以苯、甲苯、二甲苯、DMF、环己烷及二氧六环为溶剂，试验表明甲苯、二甲苯及二氧六环效果较好，考虑毒性及成本因素优选甲苯。
申请人同时还对溶剂的添加量进行了实验，结果表明：当溶剂添加量满足200ml时，即可促进反应的平稳、高效进行，再增加溶剂量对收率和质量影响不明显。
实施例2
本实施例与实施例1的设置相同，区别在于：环合反应过程中未蒸除少量水分，具体过程如下：
将化合物(II)31.9g(0.1mol)、邻氯苯甲醛15.5g(0.11mol)、3-氨基丁烯酸甲酯12.7g(0.11mol)、中间体(3)31.9g(0.1mol)、碳酸钾1g、甲苯200ml，加热于回流状态下反应5h。反应毕，冷却。加水200ml，盐酸调pH3～4，分层，水层再用甲苯100ml×3提取，合并油层。回收溶剂，加入环己烷-水(4:1)重结晶，得到淡黄色固体40.8g，收率75.7％。HPLC法测定含量>98.5％。
对比实施例1和实施例2可以看出，环合反应中，水分的存在抑制正反应的进程，进而降低了反应收率。而蒸除水分，移去反应产物水，有利于反应的进行，并表现为收率上，实施例1的收率比实施例2高出将近10％。在采用其他催化剂、其他投料比时，该影响也表现一致。
实施例3
本实施例制备的是化合物(I)，即氨氯地平碱，6-甲基-2-(2-氨基乙氧基)甲基-4-(2-氯苯基)-1,4-二氢-3,5-吡啶二甲酸甲乙酯，其制备具体步骤如下：
将化合物(III)53.9g(0.1mol)，三乙胺14ml(0.1mol)，60％水合肼8.5g(0.1mol)，环己烷400ml，水200ml加热回流反应3h，反应结束后，冷却至室温。静置分层，水层用环己烷100ml×2提取，合并油层，水洗，调pH8～9，分去水层，减压浓缩。蒸干后，取样测试未经重结晶提纯的该阶段粗品的纯度，纯度为90.1％；然后用丙酮-水(3:1)进行重结晶，活性炭脱色，趁热抽滤，滤液自然冷却结晶12h，再冷冻(≤5℃)。抽滤，干燥。得浅黄色固体36.9g，收率91.2％。m.p.(熔点)177～179℃(文献178-179℃)，对淡黄色固体采用HPLC法测定含量≥99.0％。
前后纯度对比可以看出，粗品经丙酮-水(3:1)重结晶后，纯度提高5％以上。更换丙酮--水的配比，该趋势依然保持一致，根据收率确定丙酮-水(3:1)为宜。其他试验乙酸乙酯-水、乙醇-水、水-正庚烷也可以，考虑到收率、成本及回收处理问题，故采用丙酮-水为优选。
实施例3-1
本实施例与实施例3的设置相同，区别在于：溶剂选择如表4所示，以论证不同溶剂对脱氨基保护基反应的影响。
表4：溶剂对水解反应的影响
在水解反应中，溶剂主要起到提高各物料接触速度的作用，试验结果显示：
水解反应采用异丙醇为溶剂时，收率偏低；以环己烷、正己烷、正庚烷、乙酸丁酯、乙酸异丙酯等为溶剂收率和质量较好，同时环己烷回收纯化方便，便于套用。
申请人同时还对溶剂的添加量进行了实验，结果表明：当溶剂添加量满足充分溶解时，即可促进反应的平稳、高效进行，再增加使用量，对收率和质量没有显著影响。
实施例3-2
本实施例与实施例3的设置相同，区别在于：脱氨基保护基采用表5所示，以论证不同脱氨基保护基对反应收率及质量的影响。
表5：不同脱氨基保护基对反应的影响
脱保护基试剂在水解反应中主要起到促进氨基保护基脱去的作用，单独采用甲胺、三甲胺、三乙胺收率偏低，胺类与水合肼、盐酸羟胺合用时均可达到比较好的效果。
上述案例以1:1的方式进行混合使用，申请人同时还对氨基保护基的添加量和混合比进行了实验，结果表明：在脱保护基试剂使用量满足1:1时，即可促进脱氨基保护的平稳进行，增加使用量对收率和质量没有显著影响，大幅度增加水合肼使用量(三乙胺用量不变)，质量没有显著变化，收率略有下降。混合使用时，混合比以1:1为优。
同时，申请人还就本案与现有技术进行比对，具体如表6所示。
表6：本案与现有技术的比对结果
Claims (1)
1.一种氨氯地平碱的制备方法，其特征在于：以乙基-4-（2-邻苯二甲酰亚胺基乙氧基）乙酰乙酸为起始原料，催化剂作用下，与邻氯苯甲醛、3-氨基丁烯酸甲酯进行环合反应，环合产物水解脱氨基保护基，两步反应制得氨氯地平游离碱，
所述催化剂为碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、十六烷基三甲基溴化胺、苄基三乙基氯化铵中的任一种或其组合，
所述环合反应中乙基-4-（2-邻苯二甲酰亚胺基乙氧基）乙酰乙酸乙酯、邻氯苯甲醛和3-氨基丁烯酸甲酯的摩尔比为：1:1:1~1:1.3:1.3，
所述环合反应中添加有溶剂，溶剂为甲苯、二甲苯、二甲基甲酰胺、环己烷、四氢呋喃、二氧六环中的任一种或其组合，在环合反应中进行回流，蒸去共沸物，
所述脱氨基保护基为三乙胺、三甲胺、甲胺、水合肼、盐酸羟胺中的任一种或其组合，
所述水解反应中添加有溶剂，溶剂为环己烷、正己烷、正庚烷、乙醇、异丙醇、异丁醇、乙酸乙酯、乙酸丁酯、乙酸异丙酯中的任一种或其组合，
所述环合反应产物经重结晶精制，重结晶溶剂为环己烷-水的混合物，环己烷与水的体积比1:1~8:1，
所述水解反应产物经重结晶得到氨氯地平游离碱，重结晶溶剂为丙酮-水，丙酮-水的体积比为1:1~5:1。
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