CN102285910B - Method for preparing (S)-carvedilol - Google Patents
Method for preparing (S)-carvedilol Download PDFInfo
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- CN102285910B CN102285910B CN201110184231.9A CN201110184231A CN102285910B CN 102285910 B CN102285910 B CN 102285910B CN 201110184231 A CN201110184231 A CN 201110184231A CN 102285910 B CN102285910 B CN 102285910B
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- carvedilol
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- carbazole
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- 238000000034 method Methods 0.000 title claims abstract description 30
- OGHNVEJMJSYVRP-KRWDZBQOSA-N (2s)-1-(9h-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol Chemical compound COC1=CC=CC=C1OCCNC[C@H](O)COC1=CC=CC2=C1C1=CC=CC=C1N2 OGHNVEJMJSYVRP-KRWDZBQOSA-N 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- UEOHATPGKDSULR-UHFFFAOYSA-N 9h-carbazol-4-ol Chemical compound N1C2=CC=CC=C2C2=C1C=CC=C2O UEOHATPGKDSULR-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 229960004195 carvedilol Drugs 0.000 claims description 36
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 238000011049 filling Methods 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 230000002000 scavenging effect Effects 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- CKJRKLKVCHMWLV-UHFFFAOYSA-N 2-(2-methoxyphenoxy)ethanamine Chemical compound COC1=CC=CC=C1OCCN CKJRKLKVCHMWLV-UHFFFAOYSA-N 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 17
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 2
- LRWZZZWJMFNZIK-NFJMKROFSA-N (2R)-2-chloro-3-methyloxirane Chemical compound CC1O[C@@H]1Cl LRWZZZWJMFNZIK-NFJMKROFSA-N 0.000 abstract 1
- SZDYRZVWNVIYGO-UHFFFAOYSA-N n-benzyl-2-(2-methoxyphenoxy)ethanamine Chemical compound COC1=CC=CC=C1OCCNCC1=CC=CC=C1 SZDYRZVWNVIYGO-UHFFFAOYSA-N 0.000 abstract 1
- 238000005086 pumping Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 22
- OGHNVEJMJSYVRP-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1C1=CC=CC=C1N2 OGHNVEJMJSYVRP-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- 206010019280 Heart failures Diseases 0.000 description 4
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 4
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FFZGDNBZNMTOCK-UHFFFAOYSA-N 1-[benzyl-[2-(2-methoxyphenoxy)ethyl]amino]-3-(9h-carbazol-4-yloxy)propan-2-ol Chemical compound COC1=CC=CC=C1OCCN(CC=1C=CC=CC=1)CC(O)COC1=CC=CC2=C1C1=CC=CC=C1N2 FFZGDNBZNMTOCK-UHFFFAOYSA-N 0.000 description 3
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005815 base catalysis Methods 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- OGHNVEJMJSYVRP-QGZVFWFLSA-N (2r)-1-(9h-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol Chemical compound COC1=CC=CC=C1OCCNC[C@@H](O)COC1=CC=CC2=C1C1=CC=CC=C1N2 OGHNVEJMJSYVRP-QGZVFWFLSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- -1 chloro-2 propyl Chemical group 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007033 dehydrochlorination reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
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- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
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- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000000712 neurohormone Substances 0.000 description 1
- 102000008434 neuropeptide hormone activity proteins Human genes 0.000 description 1
- 108040002669 neuropeptide hormone activity proteins Proteins 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
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- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
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- 230000000304 vasodilatating effect Effects 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry and particularly relates to a method for preparing (S)-carvedilol. The method comprises: pumping 4-hydroxy carbazole and (R)-epoxy chloropropane into a reaction kettle, wherein in a reaction process, reaction feed liquid is pumped into an external circulation water removing system filled with a water remover; and reacting prepared (S)-4-(2,3-epoxyropoxy)-9H-carbazole with N-benzyl-2-(2-methoxy phenoxy)ethyl amine to obtain (S)-carvedilol. In the reaction process of the first step, water generated in the reaction process is effectively removed by an external circulation water removing device, so that the loss of (S)-4-(2,3-epoxyropoxy)-9H-carbazole is reduced; low-energy-consumption simple and quick production is realized; the conversion rate of the product of the first step, namely (S)-4-(2,3-epoxyropoxy)-9H-carbazole, is over 90 percent; the final (S)-carvedilol yield is over 85 percent; and the utilization rate of the reaction substrate is improved obviously.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the method for a kind of preparation the (S)-carvedilol, particularly a kind of utilize the 4-hydroxycarbazole produce (
SThe method of)-carvedilol.
Background technology
The chemical name of carvedilol (Carvedilol) is 1-(9
H-carbazole-4-oxygen base)-3-[2-(2-methoxyphenoxy) ethylamino]-the 2-propyl alcohol.Its chemical structural formula is as follows:
Carvedilol has very strong beta-receptor retardation, has simultaneously blocking-up α concurrently
1-acceptor and vasodilatory pharmacological mechanism have calcium antagonism during high density, renin-angiotensin-aldosterone system capable of blocking is mainly used in essential hypertension and anginal treatment.Clinical study is also found; this medical instrument has the multiple effect of neurohormone antagonism, can protect strongly vascular endothelial cell, suppresses migration and the propagation of vascular smooth muscle cell; can reduce simultaneously peripheral vascular resistance and delay apoptosis, reducing myocardial infarction and heart failure risk with cardiac insufficiency.
This medicine is researched and developed successfully by Luo Shi Bao Ling Man, is Novel alpha, beta-blocker, is the antiadrenergic drug medicine with treatment hypertension and chronic heart failure dual function.Initial Public Offering in 1991, commodity are called " Dilatrend ".Nineteen ninety-five, after the application of Britain SmithKline Beecham, this medicine of drugs approved by FDA is used for the treatment congestive heart failure, and this is the beta adrenergic blocker that first approval is used for this disease, trade(brand)name " Corge ".1996, successively in the listing of the states such as Mexico, Israel, Denmark, Spain, Sweden, Canada, present many national approveds were used for the treatment of heart failure to this medicine, and find also that in clinical it has indication widely.
At home and abroad only with the racemic modification listing, the single chiral carvedilol has no listing as new drug to carvedilol at present.Modern pharmacological research shows, (
R)-carvedilol has the alpha-receptor retardation, and (
S)-carvedilol has the beta-receptor retardation.The people such as Kurt carried out (
R)-and (
SThe stereoselectivity in vivo effect study of)-carvedilol, find to only have (
S)-carvedilol can make the beta-receptor retardance, and (
RAs if)-carvedilol can increase sympathetic tone, as a kind of physiological response, by blocked blood pressure drops (Chirality, 2001,13 (7): 342-346) of causing of alpha-receptor.This explanation (
R)-and (
S)-carvedilol has different pharmacological actions, existing research discovery simultaneously (
SThe beta-receptor retardation of)-carvedilol than (
R)-enantiomorph strong 200 times (Archives of Pharmacal Research, 2004,27 (9): 973-977; Cardiovascular Drugs and Therapy, 2002,16 (2): 133-140.).Take the racemic modification medicine that gone on the market as the basis, the single enantiomer chiral drug that the exploitation drug effect is high, side effect is little has become a focus of new drug initiative.
Main six of the synthetic route about racemize carvedilol and chirality enantiomorph thereof of reporting at present is as follows respectively.
Synthetic route
1:
1999, the people such as Ratkai with
N-benzyl-2-(2-methoxyphenoxy) ethamine (compound
1) and the chiral epichlorohydrin reacting generating compound
2Enantiomorph; Again with 4-hydroxycarbazole (compound
3) reaction generation chirality
N-benzyl carvedilol (compound
4); Realize benzyl acquisition chirality carvedilol (compound by palladium catalyzed hydrogenation at last
5) (EP 918055; EP 1142873; EP 1142874).
Synthetic route
2:
Calendar year 2001, the people such as Pittelkow are with Phenyl Chloroformate 99 (compound
6) be raw material and 1,3-, two chloro-2 propyl alcohol reacting generating compounds
7Compound
7Again with 2-(2-methoxyphenoxy) ethamine (compound
8) generation substitution reaction generation compound
9Compound
9Carry out again the condensation reaction dehydrochlorination and generate chipal compounds
10Then with 4-hydroxycarbazole (compound
3) reaction generation chipal compounds
11Last open loop generates final product chirality carvedilol (compound
5) (WO 2001087837; WO 2007097504).The disorderly length of the reaction scheme of the method makes the productive rate of whole technique just descend to some extent.And, need to use hydrogenating reduction (or acidic hydrolysis) in its final step reaction, reduced to a certain extent its security that operates in industrial production.
2002, the people such as Hildesheim were with 4-(2,3-glycidoxy)-9
H-carbazole (compound
12) be raw material and 2-(2-methoxyphenoxy) ethamine (compound
8) direct reaction generation carvedilol (compound
5) (WO 2002000216).2004, the people such as Hercek were with 4-(2,3-glycidoxy)-9
H-carbazole and compound
8Hydrochloride reaction, (WO 2004041783 to have made the carvedilol hydrochloride; WO 2004113296).In the same year, the people such as Ramanjaneyulu are with 4-hydroxyl-9
H-carbazole (compound
3) be that raw material and chiral epichlorohydrin generate chirality 4-(2,3-glycidoxy)-9 under base catalysis
H-carbazole (compound
12), synthesized carvedilol base enantiomorph (compound with same method afterwards
5) (WO 2004094378).2005, the people such as Shah were with compound
12The chirality enantiomorph is that the starting raw material reaction makes chirality carvedilol base (compound
5), become again base to be further purified product after the base salify of this seminar with acquisition subsequently, make its purity reach 99.5%(WO 2005080329) report that simultaneously the patent of this operational path also has WO 2005115981; WO 2006061364; US 20060270858; EP 1741700; US 20070191456; WO 2008038301; WO 2009115902; WO 20090286991 etc., this operational path has shortened reaction scheme effectively, has reduced to a certain extent the growing amount of by product and has improved productive rate.
Synthetic route
4
2005, the people such as Kankan were with 2,3-dihydro-1
H-carbazole-4 (9
H)-ketone (compound
13) be that raw material generates 4-hydroxyl-9 under alkaline condition
H-carbazole (compound
3); Generate again 4-(2,3-glycidoxy)-9 under base catalysis with chiral epichlorohydrin
H-carbazole enantiomorph (compound
12), compound
12Then with
N-benzyl-2-(2-methoxyphenoxy) ethamine (compound
1) reaction generation chirality
N-benzyl carvedilol (compound
4); Realize benzyl acquisition chirality carvedilol (compound by palladium catalyzed hydrogenation at last
5) (WO 2005113502).The shortcomings such as it is many that this operational path also exists reactions steps, and ultimate yield is low need to use hydrogenating reduction (or acidic hydrolysis) in the reaction of final step simultaneously, have brought larger hidden danger for the operational safety in industrial production.
Synthetic route
5
2009, the people such as Modi were with 1-(9
H-carbazole-4-oxygen base)-3-halo-2-propyl alcohol (compound
14) be raw material with
N-benzyl-2-(2-methoxyphenoxy) ethamine (compound
8) generation carvedilol (compound
5) (WO 2009115906).
2009, the people such as Kumar were with 4-(2,3-glycidoxy)-9
H-carbazole (compound
12) and benzylamine (compound
15) be the raw material synthetic compound
16Compound
16Again with 1-(2-chloroethoxy)-2-anisole (compound
17) the reaction generation
N-benzyl carvedilol (compound
4); Realize benzyl acquisition carvedilol (compound by palladium catalyzed hydrogenation at last
5) (WO 2009116069).
Generally speaking in prior art with operational path
3Synthesis step be minimum, cost is minimum, is conducive to industry's enlarging production most.But, can follow a large amount of water generates when the first step reaction is carried out in this technique, and then make the product compound under the catalysis of alkali
12In molecule, the ring opening hydrolysis reaction easily occurs in epoxy bond, has finally reduced compound
12Yield.Therefore, how effectively to remove the water that produces in reaction process, become further raising reaction yield, the necessary means that reduces production costs.
Summary of the invention
Technical purpose of the present invention be to provide a kind of by the 4-hydroxycarbazole and (
R)-epoxy chloropropane be raw material production (
SThe method of)-carvedilol, reaction scheme is as follows.Make the water that produces in reaction process effectively to be removed, reduce (
S)-4-(2,3-glycidoxy)-9
HThe loss of-carbazole realizes less energy-consumption, produces simply, quickly, obtain the first step product (
S)-4-(2,3-glycidoxy)-9
HThe transformation efficiency of-carbazole is greater than 90%, final (
SThe yield of)-carvedilol is greater than 85%, and the reaction substrate utilization ratio obviously improves.
For realizing technical purpose of the present invention, technical scheme of the present invention is: the 4-hydroxycarbazole that will mix by mole proportioning, (
R)-epoxy chloropropane and catalyzer alkali pump enter in reactor, be heated to temperature of reaction, violent stirring reaction will react feed liquid and be pumped into certain flow rate to circulate in the outer circulation water scavenging system of filling water-removal agent and dewater in reaction process, then will pass back into and continue in reactor to react.After reaction finishes, reaction product is steamed except unnecessary (
R)-epoxy chloropropane, residuum recrystallization in ethyl acetate get (
S)-4-(2,3-glycidoxy)-9
H-carbazole.To again (
S)-4-(2,3-glycidoxy)-9
H-carbazole with
N-benzyl-2-(2-methoxyphenoxy) ethamine is fed in reactor by a mole proportioning, after adding dissolution with solvents, is heated to temperature of reaction, violent stirring reaction, reaction removes solvent under reduced pressure after finishing, re-crystallizing in ethyl acetate namely get (
S)-carvedilol.
4-hydroxycarbazole of the present invention and (
RMole proportioning of)-epoxy chloropropane is 1:1～1:6.
Mole proportioning of 4-hydroxycarbazole of the present invention and catalyzer is 1:1～1:3.
Catalyzer of the present invention comprises sodium hydroxide, potassium hydroxide or salt of wormwood.
The first step temperature of reaction of the present invention is at 30～90 ℃.
The first step reaction times of the present invention is at 1～8 h.
Water-removal agent of the present invention comprises molecular sieve, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate or anhydrous magnesium sulfate.
The external circulating system of filling water-removal agent of the present invention, external circulating system wherein be a filling water-removal agent except water column, perhaps two and above filling water-removal agent except the water column series combination, perhaps two and above filling water-removal agent except the water column parallel combination.
The flow that reaction material liquid pump of the present invention enters to load the external circulating system of water-removal agent is to add 0.2～3 times of 4-hydroxycarbazole molar weight.
Of the present invention (
S)-4-(2,3-glycidoxy)-9
H-carbazole with
NMole proportioning of-benzyl-2-(2-methoxyphenoxy) ethamine is 1:1～1:5.
Second step reaction solvent of the present invention comprises ethanol, acetone or Virahol.
Second step temperature of reaction of the present invention is at 30～90 ℃.
The second step reaction times of the present invention is at 1～6 h.
The present invention's proposition (
SThe beneficial effect of)-carvedilol production method is:
(1) external circulating system of the filling water-removal agent of the present invention design, not only water-removal agent is cheap, change, regeneration is convenient, and owing to water-removal agent can not being introduced reaction system, therefore by present method obtain (
S)-4-(2,3-glycidoxy)-9
H-carbazole through simple recrystallization purifying just can be directly with
NThe generation of-benzyl-2-(2-methoxyphenoxy) ethamine (
S)-carvedilol, the Product Green environmental protection can be widely used in the industry of fine chemicals and industrial chemicals etc.
(2) external circulating system of the filling water-removal agent of the present invention's design, can design arbitrarily according to the throughput of reactor size, quantity and array mode except water column, and select different water-removal agents, to satisfy the requirement of the water of removing continuously, efficiently the reaction system generation.
(3) the present invention has been owing in time having removed efficiently water, effectively suppressed the first step reaction product (
S)-4-(2,3-glycidoxy)-9
HThe ring opening hydrolysis reaction of-carbazole under base catalysis improved product yield.
Description of drawings
Fig. 1 is structural representation of the present invention.
Being labeled as in figure: 1-raw material storage tank; The 2-pump; The 3-reactor; The 4-mechanical stirring device; 5-outer circulation water scavenging system; 6-product discharging control valve.
Embodiment
Embodiment 1
The outer circulation water scavenging system of the present embodiment is the water column that removes of single filling water-removal agent, and except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection are: Alltech Prevail C
18(250 mm * 0.46 mm * 5 μ m) chromatographic column; Moving phase: methyl alcohol: water=75:25; Column temperature: 30 ℃; Flow velocity: 1 mL/min; Sample size: 20 μ L; UV detects wavelength: 243 nm.
With the 4-hydroxycarbazole and (
R)-epoxy chloropropane is with the mol ratio of 1:1, and it is standby that 4-hydroxycarbazole and catalyzer sodium hydroxide are hybridly prepared into reaction substrate with the mol ratio three of 1:1.5.2.45 kg hybrid reaction substrates are pumped in the reactor of 3 L, be heated to 90 ℃ of violent stirring reactions, to react feed liquid in reaction process passes into the flow of 5.84 mol/h the outer circulation water scavenging system that is filled with Calcium Chloride Powder Anhydrous and returns in reactor, stop after reacting 2 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure reclaim unnecessary (
R)-epoxy chloropropane, residuum is measured through HPLC, (
S)-4-(2,3-glycidoxy)-9
H-carbazole yield is 91.4%.
Embodiment 2
The outer circulation water scavenging system of the present embodiment be two filling water-removal agents except the water column parallel combination, except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 1, and the implementation step that changes catalyzer water-removal agent and each operating parameters is as follows:
With the 4-hydroxycarbazole and (
R)-epoxy chloropropane is with the mol ratio of 1:2, and it is standby that 4-hydroxycarbazole and catalyzer potassium hydroxide are hybridly prepared into reaction substrate with the mol ratio three of 1:2.2.45 kg hybrid reaction substrates are pumped in the reactor of 3 L, be heated to 60 ℃ of violent stirring reactions, to react feed liquid in reaction process passes into the flow of 1.02 mol/h the outer circulation water scavenging system that is filled with anhydrous sodium sulphate and returns in reactor, stop after reacting 1 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure reclaim unnecessary (
R)-epoxy chloropropane, residuum is measured through HPLC, (
S)-4-(2,3-glycidoxy)-9
H-carbazole yield is 94.7%.
The outer circulation water scavenging system of the present embodiment be three filling water-removal agents except the water column series combination, except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 1, and the implementation step that changes catalyzer water-removal agent and each operating parameters is as follows:
With the 4-hydroxycarbazole and (
R)-epoxy chloropropane is with the mol ratio of 1:4.5, and it is standby that 4-hydroxycarbazole and catalyzer carbonic acid potassium are hybridly prepared into reaction substrate with the mol ratio three of 1:1.2.45 kg hybrid reaction substrates are pumped in the reactor of 3 L, be heated to 45 ℃ of violent stirring reactions, to react feed liquid in reaction process passes into the flow of 4.98 mol/h the outer circulation water scavenging system that is filled with molecular sieve and returns in reactor, stop after reacting 8 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure reclaim unnecessary (
R)-epoxy chloropropane, residuum is measured through HPLC, (
S)-4-(2,3-glycidoxy)-9
H-carbazole yield is 90.2%.
Embodiment 4
The outer circulation water scavenging system of the present embodiment be three filling water-removal agents except the water column parallel combination, except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 1, and the implementation step that changes catalyzer water-removal agent and each operating parameters is as follows:
With the 4-hydroxycarbazole and (
R)-epoxy chloropropane is with the mol ratio of 1:6, and it is standby that 4-hydroxycarbazole and catalyzer sodium hydroxide are hybridly prepared into reaction substrate with the mol ratio three of 1:3.2.45 kg hybrid reaction substrates are pumped in the reactor of 3 L, be heated to 30 ℃ of violent stirring reactions, to react feed liquid in reaction process passes into the flow of 8.65 mol/h the outer circulation water scavenging system that is filled with anhydrous magnesium sulfate and returns in reactor, stop after reacting 5 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure reclaim unnecessary (
R)-epoxy chloropropane, residuum is measured through HPLC, (
S)-4-(2,3-glycidoxy)-9
H-carbazole yield is 92.2%.
Embodiment 5
Will (
S)-4-(2,3-glycidoxy)-9
H-carbazole with
N-benzyl-2-(2-methoxyphenoxy) ethamine drops in reactor with mole proportioning mixture 1.67 kg of 1:3, adds 1 L dissolve with ethanol, is heated to 50 ℃ of violent stirring reactions, stops after reaction 3 h.Remove solvent under reduced pressure, the sherwood oil recrystallization namely get (
S)-carvedilol base is measured through HPLC, (
SThe yield of)-carvedilol is 87.4%,
e.
e.% be 97.3%.
Reaction substrate and product HPLC method for qualitative and quantitative detection are: Daicel AD-H(250 mm * 0.46 mm * 5 μ m) chromatographic column; Moving phase: normal hexane: Virahol: diethylamine=70:30:0.05; Column temperature: 30 ℃; Flow velocity: 1 mL/min; Sample size: 20 μ L; UV detects wavelength: 243 nm.
Will (
S)-4-(2,3-glycidoxy)-9
H-carbazole with
N-benzyl-2-(2-methoxyphenoxy) ethamine drops in reactor with mole proportioning mixture 1.15 kg of 1:1, adds 1 L acetone solution, is heated to 30 ℃ of violent stirring reactions, stops after reaction 6 h.Remove solvent under reduced pressure, the sherwood oil recrystallization namely get (
S)-carvedilol base is measured through HPLC, (
SThe yield of)-carvedilol is 88.4%,
e.
e.% be 96.1%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 5.
Embodiment 7
Will (
S)-4-(2,3-glycidoxy)-9
H-carbazole with
N-benzyl-2-(2-methoxyphenoxy) ethamine drops in reactor with mole proportioning mixture 2.38 kg of 1:5, adds 1 L Virahol dissolving, is heated to 90 ℃ of violent stirring reactions, stops after reaction 1 h.Remove solvent under reduced pressure, the sherwood oil recrystallization namely get (
S)-carvedilol base is measured through HPLC, (
SThe yield of)-carvedilol is 89.9%,
e.
e.% be 98.6%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 5.
Claims (11)
- One kind prepare ( SThe method of)-carvedilol is characterized in that comprising the following steps:The first step reaction: with the 4-hydroxycarbazole, ( R)-epoxy chloropropane and catalyzer alkali pump enter in reactor, be heated to temperature of reaction, the violent stirring reaction, to react feed liquid in reaction process pumps into certain flow rate in the outer circulation water scavenging system of filling water-removal agent and circulates and dewater, pass back into again in reactor and to continue reaction, after reaction finishes, reaction product is steamed except unnecessary ( R)-epoxy chloropropane, residuum recrystallization in ethyl acetate get ( S)-4-(2,3-glycidoxy)-9 H-carbazole; The temperature of the first step reaction is at 30～90 ℃; The described the first step reaction times is at 1～8 h;The second step reaction: will ( S)-4-(2,3-glycidoxy)-9 H-carbazole and 2-(2-methoxyphenoxy) ethamine is fed in reactor, after adding dissolution with solvents, is heated to temperature of reaction, violent stirring reaction, reaction removes solvent under reduced pressure after finishing, re-crystallizing in ethyl acetate namely get ( S)-carvedilol.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: described 4-hydroxycarbazole and ( RThe mol ratio of)-epoxy chloropropane is 1:1～1:6.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: the mol ratio of described 4-hydroxycarbazole and catalyzer is 1:1～1:3.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: the catalyzer of described the first step reaction is sodium hydroxide, potassium hydroxide or salt of wormwood.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol, it is characterized in that: the external circulating system of described the first step reaction is the water column that removes by a filling water-removal agent, perhaps more than two the filling water-removal agent except the water column series combination, perhaps the forming except the water column parallel combination of filling water-removal agent more than two.
- According to the described preparation of claim 1 or 5 ( SThe method of)-carvedilol is characterized in that: the water-removal agent of described the first step reaction comprises molecular sieve, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate or anhydrous magnesium sulfate.
- According to the described preparation of claim 1 or 5 ( SThe method of)-carvedilol is characterized in that: in the reaction of the described the first step, to enter to load the flow of the external circulating system of water-removal agent be to add 0.2～3 times of 4-hydroxycarbazole molar weight to the reaction material liquid pump.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: described ( S)-4-(2,3-glycidoxy)-9 HThe mol ratio of-carbazole and 2-(2-methoxyphenoxy) ethamine is 1:1～1:5.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: the solvent of described second step reaction comprises ethanol, acetone or Virahol.
- According to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: the temperature of described second step reaction is at 30～90 ℃.
- 11. according to preparation claimed in claim 1 ( SThe method of)-carvedilol is characterized in that: the time of described second step reaction is at 1～6 h.
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| WO2019019049A1 (en) * | 2017-07-26 | 2019-01-31 | 华南农业大学 | Anti-candida albicans piperazine derivative, preparation method therefor and application thereof |
| CN109336965A (en) * | 2018-10-30 | 2019-02-15 | 江南大学 | A kind of synthetic method of carazolol artificial antigen |
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