CN1315823C - New method for synthesizing Ramosetron Hydrochloride - Google Patents
New method for synthesizing Ramosetron Hydrochloride Download PDFInfo
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- CN1315823C CN1315823C CNB2004100725958A CN200410072595A CN1315823C CN 1315823 C CN1315823 C CN 1315823C CN B2004100725958 A CNB2004100725958 A CN B2004100725958A CN 200410072595 A CN200410072595 A CN 200410072595A CN 1315823 C CN1315823 C CN 1315823C
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- 238000000034 method Methods 0.000 title claims abstract description 21
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 title claims abstract description 12
- 229950001588 ramosetron Drugs 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- -1 alkane acyl chloride Chemical class 0.000 claims description 8
- 229940074386 skatole Drugs 0.000 claims description 7
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 claims description 5
- 229960002185 ranimustine Drugs 0.000 claims description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 238000005194 fractionation Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 2
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 abstract description 2
- 125000002883 imidazolyl group Chemical group 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- OJHWPOJTJKJBLA-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-benzimidazole Chemical compound C1C=CC=C2NCNC21 OJHWPOJTJKJBLA-UHFFFAOYSA-N 0.000 abstract 2
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 238000010960 commercial process Methods 0.000 abstract 1
- 238000011017 operating method Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- OQIQSTLJSLGHID-WNWIJWBNSA-N aflatoxin B1 Chemical compound C=1([C@@H]2C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O OQIQSTLJSLGHID-WNWIJWBNSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- BKJXEZGPZLLYHX-UHFFFAOYSA-N 3,4-dihydro-2h-pyrrole-5-carbaldehyde Chemical compound O=CC1=NCCC1 BKJXEZGPZLLYHX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention discloses a new method for synthesizing ramosetron hydrochloride, which uses tetrahydro benzimidazole as initial raw materials and adopts imidazole ring acyl group protection to prepare and obtain acidylable tetrahydrobenzimidazole derivatives, fragrant carbon acylation is carried out to the derivatives to obtain a compound (I), and acid hydrolysis is carried out to the compound (I) to prepare mixed ramosetron. The total yield is about 76 % and is higher than the synthesis yield (about 70%) reported by the existing literature. Thereby, the present invention is completed by the new method for synthesizing. Compared with the prior art, the present invention has the advantages of simple preparation method, and moderate reaction condition, exples partial solvent of which the use is restricted, simplifies operating methods, and saves raw material and reduces production cost simultaneously and is suitable for commercial processes.
Description
Technical field
The present invention relates to a kind of preparation method of Tetrahydrobenzimidazderivative derivative of acidylate, the novel method of a kind of synthetic hydrochloric acid ranimustine of saying so more specifically.
Background technology
Ramosetron hydrochloride (Ramosetron hydrochloride) chemical name is (-)-5-(R)-[(3-(1-skatole base)) carbonyl]-4,5,6, and 7-Tetrahydrobenzimidazderivative hydrochloride is a kind of novel highly selective 5-HT
3Receptor antagonist, it is to be present in the 5-HT that imports the vagus nerve tip in the gastrointestinal mucosal into by blocking-up
3Acceptor, suppress that chemotherapeutics, operation etc. cause feel sick, gastrointestinal side effect such as vomiting.Be mainly used in clinically that prevention or treatment chemotherapeutics cause feel sick, symptom of digestive tract such as vomiting.
Chinese patent ZL90100544.4 has authorized the preparation method of Tetrahydrobenzimidazderivative derivative; it is to be starting raw material with 5-carboxylic acid benzoglyoxaline methyl sulfate, by hydrogenation, hydrolysis, amidation, aromatic nucleus phosphinylidyneization, fractionation, salify altogether six-step process prepare ramosetron hydrochloride.In this patent system Preparation Method, part intermediate such as N-(4,5,6,7-Tetrahydrobenzimidazderivative-5-yl) carbonyl pyrrolidine and hydrochloride thereof, all soluble in water, be difficult to reach the purpose of separation, purifying in the experimental implementation by technology such as extraction commonly used, recrystallizations, and yield lower (about about 30%).In addition, in the reaction of aromatic nucleus phosphinylidyne, adopt 1,2 ethylene dichloride as reaction solvent, this reagent belongs to national class control reagent, and toxicity is stronger, is unfavorable for suitability for industrialized production, should avoid using.
Summary of the invention
For solving above technological difficulties, the inventor adopts the method for imidazole ring acyl group protection first through experimental study repeatedly, prepares the Tetrahydrobenzimidazderivative derivative of acidylate, is reaction solvent with the acetonitrile subsequently, through the aromatic carbon acidylate, prepares compound (I).This intermediate is a solid, can carry out purifying by the method for recrystallization.(I) acid hydrolysis deprotection base is prepared the DL ranimustine, and total recovery is 76%.The synthesis yield that is higher than former patent, thus with a kind of new synthetic method, finished this invention.By retrieval, synthetic method of the present invention is not seen any bibliographical information at present.
The objective of the invention is to, a kind of novel method of synthetic hydrochloric acid ranimustine of suitable suitability for industrialized production is provided, concrete steps are as follows:
(1). with compound (I) and 1-12N (preferred 3-6N) hydrochloric acid, Hybrid Heating is returned slide, cooling, mixture is added drop-wise in the aqueous sodium hydroxide solution of 5-50% (preferred 5-25%), makes 5-[(1-skatole-3-yl) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative (compound IV).
Wherein, R is C
1～C
4The alkane of straight or branched; As preferable methyl, ethyls such as methyl, ethyl, propyl group, sec.-propyls.
(2). compound (IV) makes ramosetron hydrochloride (V) through the chirality resolving agent.Described chiral separation agent comprises tartrate, dibenzoyl tartaric acid, and preferred dibenzoyl tartaric acid is pressed currently known methods and split, make (-)-(R)-5-[(1-skatole-3-yl) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative hydrochloride (V) is a ramosetron hydrochloride.
Above-mentioned compound (I) can be prepared as follows:
(A). compound under alkaline condition (II) prepares compound (III) with the alkane acyl chloride reaction.
Described alkaline condition is known mineral alkali, organic bases for example NaOH, Na
2CO
3, methylamine, diethylamine or triethylamine etc.Compound (II) is 1 with the mole ratio of alkane acyl chlorides: 0.5-5, preferred 1: 1-3.
The described reaction times is 2-10 hour; Temperature of reaction is 20-160 ℃, and preferred 2-4 hour, temperature was 50-130 ℃.
(B). compound (III) makes 1-alkyloyl-5-[(1-skatole-3-yl with Pyrrolidine, the reaction of N-skatole in acetonitrile or chloroform) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative compound (I).
Described compound III: Pyrrolidine: the mole ratio of N-skatole is 1: 0.1-3: 1-5, preferred 1: 0.5-3: 1-3.Reaction times is 1-10 hour; Temperature of reaction is 0-160 ℃, and preferred temperature is 2-140 ℃.
Alkane acyl chlorides described in the reaction mainly comprises preferred Acetyl Chloride 98Min. such as Acetyl Chloride 98Min., propionyl chloride or butyryl chloride, isobutyryl chloride etc. or propionyl chloride.
Be the new synthetic route of ramosetron hydrochloride of the present invention below.
The present invention is with 4,5,6, and 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol is starting raw material, and by aromatic nucleus phosphinylidyneization, hydrolysis, fractionation, salify is totally 4 step prepared in reaction target compounds.The intermediate 1-alkyl acyl-5-carboxylic acid-4 that makes in the novel method; 5; 6; 7-benzoglyoxaline (III), 1-alkyloyl-5-[(1-skatole-3-yl) carbonyl]-4; 5; 6,7-Tetrahydrobenzimidazderivative (I) etc. is new compound, passes through prepared in reaction ramosetron hydrochloride (V) such as acidylate, hydrolysis, fractionation in the preparation process.
The present invention compares with prior art, and the preparation method is simple, and the reaction conditions gentleness has been got rid of 1,2 stronger ethylene dichloride of toxicity, and intermediate can adopt the method purifying of recrystallization, and is easy and simple to handle, and total recovery is higher than the preparation method of patent, and has reduced production cost.This operational path studies confirm that through lab scale exploration, pilot scale amplification, the ramosetron hydrochloride that makes, and it is simple, accurate that each goes on foot the intermediate control method, and product yield is higher, and synthesis technique is stable, and is quality controllable, is suitable for suitability for industrialized production.
Embodiment
The present invention is further illustrated below in conjunction with embodiment, but the scope of protection of present invention is not limited in the following specific embodiment operation that provides.
The preparation of raw material 5-carboxylate methyl ester benzoglyoxaline vitriol of the present invention makes with reference to benzimidazoles derivative synthesis preparation method in meticulous organic chemical industry's handbook (P482-496).
4,5,6, the preparation of 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol (II) is to adopt the method for Chinese patent ZL90100544.4 to obtain (embodiment 1-2 specifically sees reference).
Reference example 1
The preparation of 5-carboxylate methyl ester benzoglyoxaline vitriol
Add 3200ml methyl alcohol in the reaction flask of 5L, the 5-carboxylic acid benzoglyoxaline vitriol of 304g stirs the vitriol oil of Dropwise 35 2ml down, reflux 7 hours, cooling, the activated carbon of adding 20g, reflux 0.5 hour, heat filtering, filtrate concentrates, cooling, get white crystals, filtration, dry 240g, fusing point: 169-171 ℃, the yield 74% of getting.
Reference example 2
4,5,6, the preparation (II) of 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol
In the autoclave of 2L, add the acetate of 1200ml, the 5-carboxylic acid benzoglyoxaline methyl esters vitriol of 80g, the 10%Pd/C of 40g (dry weight), 80 ℃, 60kg/cm
2Pressure condition under about 16 hours of hydrogenation (no longer change to pressure till), cooling, discharging, filtering catalyst, concentrating under reduced pressure gets light yellow oil, the 6N hydrochloric acid that adds 300ml, reflux 4 hours is evaporated to driedly, adds the acetone of 30ml, filter, dry, as to get 53.6g white crystals, fusing point 145-148 ℃, yield 70%.
Embodiment 1
1-ethanoyl-5-carboxylic acid-4,5,6, the preparation of 7-benzoglyoxaline (III)
With 4,5,6 of 66g, 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol, the triethylamine of 62.0g, the acetonitrile of 300ml add in the reaction flask, drip the 36.2g Acetyl Chloride 98Min., reflux stirred 4 hours, acetonitrile layer was evaporated to dried, cooling, the water of dropping 300ml is used ethyl acetate extraction, drying is filtered, and filtrate decompression is concentrated into dried, get brown oil 70g, can directly drop into next step and react.
Embodiment 2
1-ethanoyl-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the preparation of 7-Tetrahydrobenzimidazderivative (I)
With acetyl Tetrahydrobenzimidazderivative 70g, the acetonitrile of 200ml, the sulfur oxychloride of 40ml adds in the reaction flask, is heated to backflow, stirs 2 hours, and underpressure distillation goes out partial solvent and takes excessive sulfur oxychloride out of.Cool off, the Pyrrolidine of slow Dropwise 5 3g and the acetonitrile solution of 100ml under 2 ℃ condition drip and finish, and are warming up to room temperature, stir 2 hours, and 40 ℃ were stirred 1 hour, and concentrating under reduced pressure gets brown oil 132g.
With the brown oil of 132g, the N-skatole of 100g adds in the acetonitrile of 300ml, adds the phosphoryl chloride of 132g, stirs 7 hours under heating, vigorous reflux, is chilled to room temperature.Under the cooling conditions, slowly drip the water of 660ml, the ethyl acetate of 500ml stirs, layering, organic layer is used anhydrous magnesium sulfate drying after washing 2 times with water, filters, and is evaporated to dried light brown solid 87.7g, fusing point: 176-178 ℃, yield 81.2%, the HPLC detection level is greater than 98%.
Carry out structural identification by nuclear-magnetism, concrete test result as follows:
1H?NMR(400MHz，CDCl
3)δ：2.03-2.04(1H，d)，2.21(1H，s)，2.66(3H，s)，2.79-3.23(4H，m)，3.47(1H，s)，3.855(3H，s)，7.258-7.34(3H，m)，7.79(1H，s)，8.36-8.51(2H，q).
Embodiment 3
5-[(1-skatole-3-yl) carbonyl]-4,5,6, the preparation of 7-Tetrahydrobenzimidazderivative (IV)
With 20g 1-ethanoyl-5-[(1-skatole-3-yl) carbonyl]-4,5,6; the 7-Tetrahydrobenzimidazderivative adds 100ml; in the aqueous hydrochloric acid of 6N, heated and stirred refluxed 4 hours; cooling; be added drop-wise in 25% the aqueous sodium hydroxide solution, separate out light yellow solid, filtration drying gets faint yellow solid 16.5g; fusing point 118-120 ℃, yield 95%.
The nuclear-magnetism determination data:
1H?NMR(400MHz，DMSO)δ：1.81-1.91(1H，m)，2.14-2.17(1H，d)，2.67-2.90(4H，m)，3.62-3.69(1H，t)，3.86(3H，s)，7.21-7.30(2H，m)，7.53-7.55(1H，d)，8.19-8.21(1H，d)，8.54(1H，s)，8.91(1H，s)。
Embodiment 4
(-)-(R)-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the preparation (V) of 7-Tetrahydrobenzimidazderivative hydrochloride
5-[(1-skatole-3-yl with 22.5g) carbonyl]-4,5,6, the single water thing of (+) DIBTA of 7-Tetrahydrobenzimidazderivative and 30.7g adds among the DMF of 200ml, be stirred to moltenly entirely, slowly drip the water of 100ml, stirring at room 2 hours, filter, drying gets light yellow solid 22g.With DMF/ water (2: 1) recrystallization three times of this solid, get (-)-(R)-[(1-skatole-3-yl) carbonyl]-4,5,6 of 18g, the 7-Tetrahydrobenzimidazderivative. (+) DIBTA salt, fusing point 169-170 ℃, yield 35%.
The above-mentioned salt of 1gg is added in the water of 100ml, add the chloroform of 100ml, stir the ammoniacal liquor that drips 20ml down, layering, water layer extracts 2 times, merges organic layer, underpressure distillation gets light yellow solid, adds the Virahol of 80ml, stirring and dissolving, the concentrated hydrochloric acid of adding 4ml stirs, separate out white solid gradually, filter, drying, the product of 7.5g.
The product of 7.5g is added in 75ml Virahol and water (10: the 1) solution, add the gac of 1g, reflux 15 minutes, heat filtering, white crystals is separated out in cooling, filters, and drying gets 6g, and fusing point 240-245 ℃, recrystallization yield 80%.
Specific rotation :-42.9 (c1.12, methyl alcohol)
The HPLC:C8 post, content is greater than 99.5% (normalization method)
(post of 4.6mm * 25cm), content (R) is greater than 99% for nuclear magnetic data: YMCA-K03.
1H?NMR(400MHz，DMSO)δ：1.81-1.91(1H，m)，2.14-2.17(1H，d)，2.67-2.90(4H，m)，3.62-3.69(1H，t)，3.86(3H，s)，7.21-7.30(2H，m)，7.53-7.55(1H，d)，8.19-8.21(1H，d)，8.54(1H，s)，8.91(1H，s)。
Claims (6)
1, a kind of novel method of synthetic hydrochloric acid ranimustine, it comprises the steps:
(1). with 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol (II) is starting raw material, prepares compound (III) through the alkane acyl chloride reaction under alkaline condition; Compound (III) makes compound (I) with Pyrrolidine, the reaction of N-skatole;
Wherein, R is C
1～C
4The alkyl of straight or branched;
(2). compound (I) and 1-12N mixed in hydrochloric acid are heated back slide, and cooling is added drop-wise to mixture in the aqueous sodium hydroxide solution of 5-50%, makes compound (IV);
(3). compound (IV) makes ramosetron hydrochloride (V) through tartrate or dibenzoyl tartaric acid chiral separation agent fractionation.
2, novel method as claimed in claim 1 is characterized in that, described alkane acyl chlorides is Acetyl Chloride 98Min., propionyl chloride or butyryl chloride.
3, novel method as claimed in claim 1 is characterized in that, described alkali is methylamine, diethylamine or triethylamine.
4, novel method as claimed in claim 1 is characterized in that, compound (II) with the mol ratio of alkane acyl chlorides is: 1: 0.5-5.
5, novel method as claimed in claim 1 is characterized in that, compound (III): Pyrrolidine: the mol ratio of N-skatole is 1: 0.1-3: 1-5.
6, novel method as claimed in claim 1 is characterized in that, compound (II) is 2-10 hour with the reaction times that the alkane acyl chloride reaction prepares compound (III), and temperature of reaction is 20-160 ℃; Compound (III) is 1-10 hour with the reaction times of Pyrrolidine, N-skatole prepared in reaction compound (I), and temperature of reaction is 0-160 ℃.
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| CNB2004100725958A CN1315823C (en) | 2004-11-02 | 2004-11-02 | New method for synthesizing Ramosetron Hydrochloride |
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| CNB2004100725958A CN1315823C (en) | 2004-11-02 | 2004-11-02 | New method for synthesizing Ramosetron Hydrochloride |
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| CN1315823C true CN1315823C (en) | 2007-05-16 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100390165C (en) * | 2005-06-24 | 2008-05-28 | 天津康鸿医药科技发展有限公司 | Medicinal composition containing alkyl acyl ramosqiong and its application |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100436451C (en) | 2005-04-11 | 2008-11-26 | 安斯泰来制药株式会社 | Novel process for producing ramosetron or its salt |
| CN101585831B (en) * | 2008-05-23 | 2012-11-07 | 北京成宇化工有限公司 | Synthetic method of ramosetron |
| CN102038637B (en) * | 2009-10-23 | 2012-02-15 | 华北制药股份有限公司 | Method for preparing hydrochloric acid ramosetron injection |
| CN102212059B (en) * | 2011-04-15 | 2013-04-03 | 南京优科制药有限公司 | Method for cyclically preparing ramosetron hydrochloride by racemization |
| CN105669655A (en) * | 2016-03-01 | 2016-06-15 | 苏州艾缇克药物化学有限公司 | Synthesis method of Ramosetron |
| CN105646456A (en) * | 2016-03-01 | 2016-06-08 | 苏州艾缇克药物化学有限公司 | High-yield production method of ramosetron |
| CN109115914B (en) * | 2018-10-03 | 2021-06-04 | 四川中科微纳科技有限公司 | High performance liquid chromatography method for separating ramosetron hydrochloride and S-type enantiomer thereof |
| CN109115913B (en) * | 2018-10-03 | 2021-08-06 | 济南迪安医学检验中心有限公司 | HPLC method for separating ramosetron hydrochloride and S-type enantiomer thereof based on conventional phenyl chromatographic column |
| CN117229266B (en) * | 2023-11-13 | 2024-03-01 | 成都通德药业有限公司 | Method for synthesizing ramosetron racemate and salt thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045583A (en) * | 1989-02-02 | 1990-09-26 | 山之内制药株式会社 | Tetrahydrobenzimidazderivative derivative |
-
2004
- 2004-11-02 CN CNB2004100725958A patent/CN1315823C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045583A (en) * | 1989-02-02 | 1990-09-26 | 山之内制药株式会社 | Tetrahydrobenzimidazderivative derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100390165C (en) * | 2005-06-24 | 2008-05-28 | 天津康鸿医药科技发展有限公司 | Medicinal composition containing alkyl acyl ramosqiong and its application |
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