CN104447554A - Preparation method for ivabradine and hydrochloride thereof - Google Patents
Preparation method for ivabradine and hydrochloride thereof Download PDFInfo
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- CN104447554A CN104447554A CN201310432986.5A CN201310432986A CN104447554A CN 104447554 A CN104447554 A CN 104447554A CN 201310432986 A CN201310432986 A CN 201310432986A CN 104447554 A CN104447554 A CN 104447554A
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- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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Abstract
The invention provides a preparation method for ivabradine and hydrochloride thereof. The preparation method for ivabradine comprises: step a1, enabling a compound shown as a formula III and a compound shown as a formula IV to have a nucleophilic substitution reaction in a polar aprotic solvent in the presence of an acid binding agent and a composite phase-transfer catalyst to generate ivabradine; and step b1, performing separation and purification on ivabradine obtained in the step a1. The composite phase-transfer catalyst is composed of a quaternary ammonium salt phase-transfer catalyst and a polyether phase-transfer catalyst with the mass ratio of 1-8:1, and X in the formula III is selected from Cl, Br, I, sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, p-methylbenzene sulfonyloxy, o-methylbenzene sulfonyloxy or m-methylbenzene sulfonyloxy. The method is capable of substantially shortening the time of nucleophilic substitution reaction, reducing reaction temperature, improving product purity and reducing production cost.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the preparation method of S 16257-2 and hydrochloride thereof.
Background technology
S 16257-2 and there is very high pharmacology and therapeutic value with the additive salt of pharmaceutically acceptable acid, the various clinical conditions for the treatment of or prevention myocardial ischemia can be widely used in, as stenocardia, myocardial infarction and adjoint rhythm disturbance etc., also can be used for treatment in heart failure, is a kind ofly treat the boundless cardiovascular drugs of new generation of prospect.
Hydrochloric acid Ivabradine, chemistry is by name: 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3,4,5-tetrahydrochysene-2H-benzazepine-2-keto hydrochloride, its structure is as follows:
Preparation method and the therepic use of Ivabradine hydrochloride is described in EP0534859.In this patent, adopt and first carry out the method (syntheti c route 1) that nucleophilic substitution reaction carries out shortening again and prepare hydrochloric acid Ivabradine, concrete preparation method is as follows:
There is following shortcoming in above-mentioned syntheti c route 1: the reaction times is longer, temperature of reaction is higher, wherein the nucleophilic substitution reaction time is more than 15.0h, temperature of reaction is 90-100 DEG C, nucleophilic substitution reaction prepares dehydrogenation S 16257-2 in addition and shortening prepares the last handling process that S 16257-2 two-step reaction all needs column chromatography, and organic solvent consumption is large, and yield low (being about 17.0%), there is heavy-metal residual, problem that process costs is higher, be difficult to realize industrialization and produce.
The patent documentations such as CN101284813, CN101544605, CN101768116 adopt and first carry out shortening, then the method (syntheti c route 2) of carrying out nucleophilic substitution reaction prepares hydrochloric acid Ivabradine, and concrete preparation method is as follows:
Compared with syntheti c route 1, catalytic hydrogenation reaction moves forward by syntheti c route 2, but in prior art and by product is many, needs to carry out column chromatography process to reaction product after nucleophilic substitution reaction completes all at more than 20h the nucleophilic substitution reaction time of syntheti c route 2.
All there is long reaction time, need column chromatography process in above-mentioned syntheti c route 1 and syntheti c route 2, organic solvent consumption is large, heavy-metal residual and the problem such as process costs is higher, is difficult to industrialization and prepares the S 16257-2 or hydrochloric acid Ivabradine that meet medicinal requirements.
Along with the development of science and technology, some novel methods preparing S 16257-2 are suggested, but these methods exist raw material or intermediate is difficult to the problems such as acquisition.
Summary of the invention
For the problems referred to above, one object of the present invention is the preparation method providing a kind of S 16257-2, the method adopts the complex phase transfer catalyst be made up of quaternary ammonium salt-type phase transfer catalyst and polyethers phase-transfer catalyst to prepare S 16257-2, can remarkable Reaction time shorten, reduce temperature of reaction, improve product purity, and raw material easily obtains.
Another object of the present invention is to the preparation method that a kind of hydrochloric acid Ivabradine is provided.
For achieving the above object, the invention provides a kind of preparation method of S 16257-2, described preparation method comprises:
Step a1: make compound shown in compound and formula IV shown in formula III that nucleophilic substitution reaction occur under the existence of acid binding agent and complex phase transfer catalyst in polar aprotic solvent and generate S 16257-2;
Step b1: the S 16257-2 obtained in step a1 to be separated, purifying;
Wherein, described complex phase transfer catalyst is that the quaternary ammonium salt-type phase transfer catalyst of 1 ~ 8:1 and polyethers phase-transfer catalyst form by mass ratio, and described X is selected from Cl, Br, I, sulfonyloxy, methanesulfonyloxy group, phenylsulfonyloxy, tolysulfonyl oxygen base, adjacent tosyloxy or a tosyloxy.
Preferably, described quaternary ammonium salt-type phase transfer catalyst is selected from benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, Morpan BB or benzyltrimethylammonium bromide, more preferably Morpan BB; Described polyethers phase-transfer catalyst is selected from polyoxyethylene glycol, polyoxyethylene fatty alcohol or polyoxyethylene alkylphenol, more preferably polyoxyethylene glycol, particularly preferably the polyoxyethylene glycol of molecular weight between 200 ~ 800;
Preferably, described acid binding agent is selected from sodium carbonate, salt of wormwood, saleratus or sodium bicarbonate;
Preferably, described polar aprotic solvent is selected from dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), dimethyl sulfoxide (DMSO) (DMSO) or acetonitrile (ACN).
Preferably, the consumption of described complex phase transfer catalyst is 2.0% ~ 6.0% of compound quality shown in formula IV, more preferably 4.0%.
Preferably, in described complex phase transfer catalyst, the mass ratio of described quaternary ammonium salt-type phase transfer catalyst and described polyethers phase-transfer catalyst is 2 ~ 6:1, more preferably 4:1.
Preferably, following methods is adopted to prepare compound shown in formula III:
Compound shown in formula II is dissolved in alcoholic solvent, adds acetic acid, compound shown in catalytic hydrogenation reaction production III occurs under palladium carbon catalyst effect; In compound shown in its Chinese style II, the definition of X is identical with the definition of X in compound shown in formula III;
Preferably, described alcoholic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol or Virahol.
Preferably, the nucleophilic substitution reaction in described step a1 carries out at 85-88 DEG C;
Preferably, described step b1 specifically comprises: after the reaction of compound shown in compound and formula IV shown in formula III, cooling, filter, collect filtrate, filtrate is added in saturated nacl aqueous solution, extract by ethyl acetate, be separated organic phase, after concentrating under reduced pressure, obtain S 16257-2.
The present invention further provides a kind of preparation method of hydrochloric acid Ivabradine, the S 16257-2 preparation that described hydrochloric acid Ivabradine is prepared by adopting aforesaid method.
Preferably, the preparation method of described hydrochloric acid Ivabradine comprises the following steps:
Step a2: adopt aforesaid method to prepare S 16257-2;
Step b2: the S 16257-2 obtained in step a2 is dissolved, and obtain S 16257-2 organic acid salt by salt-forming reaction;
Step c2: dissolve described S 16257-2 organic acid salt, obtain S 16257-2 highly finished product after adjust pH, extraction, separation, washing;
Steps d 2: dissolve described S 16257-2 highly finished product, add hydrochloric acid, obtain hydrochloric acid Ivabradine.
Preferably, the preparation method of described hydrochloric acid Ivabradine comprises the following steps:
Step a2: adopt aforesaid method to prepare S 16257-2;
Step b2: adopt acetonitrile to dissolve the S 16257-2 obtained in step a2, add organic acid, salify crystallization, filter and obtain S 16257-2 organic acid salt;
Step c2: be dissolved in water described S 16257-2 organic acid salt, adjust pH to 8 ~ 9, extract by ethyl acetate, be separated organic phase, successively with after saturated metal complex agent solution and saturated nacl aqueous solution washing, be separated organic phase, drying and decolouring after, filter, collect filtrate, after evaporated under reduced pressure solvent, obtain S 16257-2 highly finished product;
Steps d 2: adopt S 16257-2 highly finished product described in organic solvent dissolution, drips hydrochloric acid, adjust ph to 2 ~ 3, and after reaction, concentrated solvent is to dry, and crystallization filters, obtains hydrochloric acid Ivabradine.Concrete reaction scheme is as follows:
Preferably, the organic acid in described step b2 is selected from oxalic acid, tartrate, propanedioic acid, lactic acid, pyruvic acid, fumaric acid, succsinic acid, toxilic acid, citric acid, methylsulfonic acid, Phenylsulfonic acid or camphorsulfonic acid;
Preferably, the metal chelating agent in described step c2 be selected from ammonia hydroxyl complexing agent, complexone, disodium ethylene diamine tetraacetate or sulfydryl complexing agent one or more;
Preferably, the organic solvent in described steps d 2 is selected from methyl alcohol, ethanol, acetonitrile, acetone or ethyl acetate, more preferably acetonitrile.
Below technical scheme of the present invention is described in detail.
The present invention prepares S 16257-2 by making compound shown in compound and formula IV shown in formula III, under the existence of complex phase transfer catalyst, nucleophilic substitution reaction occur, and then prepares Ivabradine hydrochloride.
The catalytic hydrogenation reaction of contriver to compound shown in formula II carries out studying and finds: the ehter bond in compound shown in formula II under the condition of heating and strong acid easily fracture generate demethyl impurity, easily hydrolysis generation molecular weight is the hydroxyl impurity of 279 under strongly alkaline conditions.Contriver by adding acetic acid in alcoholic solvent, converting compounds shown in formula II is made to be that acetate is to strengthen its stability, the generation of side reaction in effective control catalytic hydrogenation reaction, decrease the generation that demethyl impurity and molecular weight are the hydroxyl impurity of 279, thus improve the purity of compound shown in formula III.
Based on compound shown in compound and formula IV shown in formula III all containing phenyl ring and diether linkage structure, contriver carries out the design of phase-transfer catalyst according to " similar mix " principle.Contriver carries out research to conventional phase-transfer catalyst and finds: when not using phase-transfer catalyst, the reaction times reaches 22.0h; When using quaternary ammonium salt-type phase transfer catalyst as single-phase transfer catalyst, the reaction times can foreshorten to 18.5 ~ 20.5h, and catalytic effect is not ideal enough; When using polyethers phase-transfer catalyst as single-phase transfer catalyst, the reaction times can foreshorten to 19.5 ~ 21.5h, and catalytic effect is not good; Crown ether-like phase transfer catalysts price is costly, and toxic, to nucleophilic substitution reaction without promoter action, without catalytic effect.
On the basis of single-phase transfer catalyst result of study, contriver's sudden caprice, polyethers phase-transfer catalyst not good for catalytic effect and the dissatisfactory quaternary ammonium salt-type phase transfer catalyst of catalytic effect are carried out compound use, result is wondrous: add by quaternary ammonium salt-type phase transfer catalyst and polyethers phase-transfer catalyst that (quaternary ammonium salt-type phase transfer catalyst is as Primary Catalysts using the complex phase transfer catalyst that the mass ratio of 1 ~ 8:1 forms, polyethers phase-transfer catalyst is as promotor), nucleophilic substitution reaction can be made to carry out in homogeneous phase, and make the nucleophilic substitution reaction time foreshorten to 5.0-11.0h by more than the 20.0h of prior art, temperature of reaction is reduced to 85 ~ 88 DEG C by 90-100 DEG C of prior art, and the purity of reaction product is improved.
Contriver carries out research to the nucleophilic substitution reaction generating S 16257-2 and finds: compound shown in formula III reacts facile hydrolysis in the basic conditions for a long time and produces hydroxyl impurity, hydroxyl impurity can produce solvation with anionic reactive reagent, and reactive behavior is reduced.Contriver utilizes complex phase transfer catalyst, and becoming inhomogeneous reaction is on the one hand homogeneous reaction, accelerates speed of reaction, reduces the hydrolysis of compound shown in formula III; Amino on the other hand in quaternary ammonium salt-type phase transfer catalyst and the hydroxyl in polyethers phase-transfer catalyst have good mutual solubility, more significantly reduce two alternate surface tension, " synergism " effect can be played, further increase the transformation efficiency of reaction.Quaternary ammonium salt-type phase transfer catalyst and polyethers phase-transfer catalyst carry out composite after complex phase transfer catalyst contain two kinds of catalytic active centers (polyether segment and quaternary ammonium salt structure), the quaternary ammonium salt-type phase transfer catalyst that exists for of polyethers phase-transfer catalyst provides the larger region of a polarity, is conducive to the transfer of quaternary ammonium salt-type phase transfer catalyst to negative ion; Meanwhile, polyethers phase-transfer catalyst itself can complex cation as phase-transfer catalyst, transfer positively charged ion, thus is conducive to the carrying out of nucleophilic substitution reaction.
After nucleophilic substitution reaction completes, the complex phase transfer catalyst used in the present invention is owing to being dissolved in polar aprotic solvent and water, after filtering, complex phase transfer catalyst is transferred in filtrate reaction mother liquor, is removed by proceeding to aqueous phase after aqueous phase and organic extractant phase layering.
The present invention makes converting compounds shown in formula II be that acetate is to strengthen its stability by adopting acetic acid, thus improve the purity of compound shown in III, and further by adopting the complex phase transfer catalyst catalysis nucleophilic substitution reaction be made up of quaternary ammonium salt-type phase transfer catalyst and polyethers phase-transfer catalyst, the purity of the S 16257-2 making reaction generate is improved.And can not be directly used in by the S 16257-2 that nucleophilic substitution reaction generates and prepare hydrochloric acid Ivabradine, need to carry out purification process to it, after prior art carries out column chromatography process to the S 16257-2 that reaction generates for this reason, ability is for the preparation of hydrochloric acid Ivabradine.Though column chromatography process effectively can remove impurity, cost is high, and organic solvent usage quantity is large, and the difficulty of producing for industrialization is larger.And in the method for the invention, S 16257-2 organic acid salt is formed by adding organic acid in acetonitrile, the chiral isomer of hydroxyl impurity and S 16257-2 just can be removed through simple salify crystallization in acetonitrile, make the purity of S 16257-2 organic acid salt reach more than 99.0%, optical purity reaches more than 99.5%.Then adopt in sig water and organic acid dissociates S 16257-2 make it be dissolved in ethyl acetate, by saturated metal chelating agent solution washing removing metal ion, and adopt charcoal absorption coloring matter (decolouring), obtain highly purified S 16257-2, thus avoid column chromatography procedure, greatly reduce the use of organic solvent, reduce production cost, industrialization prospect is good.Due to the S 16257-2 highly finished product good product quality obtained, purity is high, S 16257-2 is formed after hydrochloride, and only need to use acetonitrile making beating just can realize natural crystallization under room temperature, the hydrochloric acid Ivabradine obtained after filtration is without the need to again refining the related request that just can meet bulk drug.
Use saturated nacl aqueous solution can suppress the formation of emulsion layer in step b1 and step c2, be conducive to improving extraction efficiency.The solubleness of organic acid salt in acetonitrile due to S 16257-2 chiral isomer is greater than the solubleness of S 16257-2 chiral isomer hydrochloride in acetonitrile, by first generating organic acid salt in acetonitrile, regeneration hydrochloride, after simple salify crystallization, by filtering that just to remove molecular weight be 279.0 content and be hydroxyl impurity and the S 16257-2 chiral isomer of 0.5% ~ 5.0%.Metal chelating agent can form stable water soluble complex with complexing of metal ion, thus by making the metal ion of organic phase be extracted into aqueous phase, makes organic phase and aqueous phase layering and removes metal ion.Contriver by experiment comparative study finds: if the method first generating organic acid salt, regeneration hydrochloride in acetonitrile not adopting the present invention to propose, then in the hydrochloric acid Ivabradine finally obtained, the content of chiral isomer is difficult to meet medicinal requirements; If the method for the employing or not the present invention to propose in addition saturated metal chelating agent solution washing organic phase, then the heavy metal in the hydrochloric acid Ivabradine product finally obtained and residue on ignition are difficult to meet medicinal requirements.
Compared with prior art, the preparation method of S 16257-2 of the present invention and hydrochloride thereof at least has following beneficial effect:
One, the present invention by using the complex phase transfer catalyst be made up of with the mass ratio of 1 ~ 8:1 quaternary ammonium salt-type phase transfer catalyst and polyethers phase-transfer catalyst in nucleophilic substitution reaction, significantly shorten the reaction times, and make temperature of reaction be reduced to 85 ~ 88 DEG C, decrease the generation of side reaction, improve the purity of S 16257-2;
Two, the present invention forms the organic acid salt of S 16257-2 by adding organic acid and adds the process of saturated metal chelating agent washing, effectively can remove the impurity such as metal ion, hydroxyl impurity and chiral isomer, thus minimizing metal residual, avoid column chromatography procedure, greatly reduce the use of organic solvent, improve purity and the yield of S 16257-2, reduce production cost, the industrialization being conducive to realizing S 16257-2 is produced, and the hydrochloric acid Ivabradine adopting the inventive method to obtain meets the related request of bulk drug;
Three, the present invention makes converting compounds shown in formula II be that acetate is to strengthen its stability by adding acetic acid, effectively control the generation of side reaction in catalytic hydrogenation reaction, decrease the generation that demethyl impurity and molecular weight are the hydroxyl impurity of 279, improve the purity of compound shown in formula III, and then improve the purity of S 16257-2 and hydrochloride thereof;
Four, the present invention more easily obtains for the preparation of the raw material of S 16257-2.
Accompanying drawing explanation
Fig. 1 is the HPLC figure of the embodiment of the present invention 2 Chinese style III compound related substance;
Fig. 2 is the HPLC figure of S 16257-2 related substance in the embodiment of the present invention 2;
Fig. 3 is the HPLC figure of comparative example's Chinese style III compound as its free base related substance;
Fig. 4 is the HPLC figure of S 16257-2 highly finished product related substance in the embodiment of the present invention 4;
Fig. 5 is the HPLC figure of hydrochloric acid Ivabradine related substance in the embodiment of the present invention 4;
Fig. 6 is the HPLC figure of hydrochloric acid Ivabradine chiral isomer in the embodiment of the present invention 4;
Fig. 7 is the infrared spectrogram of hydrochloric acid Ivabradine in the embodiment of the present invention 4.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Reagent material used in following embodiment, if no special instructions, is commercially available purchase product.
embodiment 1the research of phase-transfer catalyst
Contriver studies conventional phase-transfer catalyst (as shown in table 1).Adopt HPLC(high performance liquid chromatography) terminal of method monitoring nucleophilic substitution reaction, be considered as reacting completely when the residual content of compound shown in formula III (wherein substituent X is Cl) is less than 0.5%.Experimental result is as shown in table 1, and as seen from Table 1, when not using phase-transfer catalyst, nucleophilic substitution reaction is for up to 22.0h; When using the quaternary ammonium salt-type phase transfer catalyst of catalytic amount (for 2% ~ 10% of compound quality shown in formula IV) as single-phase transfer catalyst, serve certain katalysis, the reaction times foreshortens to 18.5 ~ 20.5h, but catalytic effect is still not ideal enough; When using the polyethers phase-transfer catalyst of catalytic amount (for 2% ~ 10% of compound quality shown in formula IV) as single-phase transfer catalyst, the reaction times foreshortens to 19.5 ~ 21.5h, and catalytic effect is not good; Crown ether-like phase transfer catalysts price costly, and has toxicity, adopts the crown ether-like phase transfer catalysts of catalytic amount (for 2% ~ 10% of compound quality shown in formula IV) to nucleophilic substitution reaction without promoter action, without catalytic effect.
The different phase-transfer catalyst of table 1 is on the impact of the preparation of S 16257-2
| Phase-transfer catalyst | Reaction times | Purity | Molar yield (in formula IV compound) |
| Benzyltriethylammoinium chloride | 19.0h | 88.07% | 98.6% |
| Benzyl triethyl ammonium bromide | 19.0h | 87.89% | 97.1% |
| Morpan BB | 18.5h | 88.71% | 98.2% |
| Benzyltrimethylammonium bromide | 19.5h | 88.27% | 97.8% |
| Tetrabutyl amonium bromide | 20.0h | 86.45% | 98.5% |
| Tetrabutylammonium chloride | 20.5h | 87.13% | 98.3% |
| Polyoxyethylene glycol-200 | 19.5h | 88.09% | 97.6% |
| PEG-8 00 | 19.5h | 87.55% | 98.3% |
| Polyoxyethylene fatty alcohol | 21.0h | 85.40% | 98.2% |
| Polyoxyethylene alkylphenol | 21.5h | 86.23% | 99.1% |
| Hexaoxacyclooctadecane-6-6 | 22.5h | 84.56% | 98.4% |
| Nothing | 22.0h | 85.63% | 98.8% |
Contriver using quaternary ammonium salt-type phase transfer catalyst as Primary Catalysts, polyethers phase-transfer catalyst forms complex phase transfer catalyst as promotor and tests, the mass ratio arranging Primary Catalysts and promotor is 5:1, the consumption of complex phase transfer catalyst is 3% of formula IV compound quality, and experimental result is as shown in table 2.As known from Table 2, by the compound use of Primary Catalysts and promotor, catalytic effect is better than single-phase transfer catalyst greatly; Wherein, the compound use effect of Morpan BB and polyoxyethylene glycol-200 is best, and the reaction times foreshortens to 5.5h, the high purity 94.04% of S 16257-2, and molar yield reaches 97.8%; Morpan BB and PEG-8 00 compound use the reaction time also foreshorten to 6.0h, and the purity of S 16257-2 reaches 93.28%, and molar yield reaches 98.2%.In addition, when Primary Catalysts (quaternary ammonium salt-type phase transfer catalyst) be benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, Morpan BB or benzyltrimethylammonium bromide time, it combines from different polyethers phase-transfer catalyst (PEG-8 00, polyoxyethylene glycol-200, polyoxyethylene fatty alcohol and polyoxyethylene alkylphenol) complex phase transfer catalyst formed and obtains preferably catalytic effect, reaction times foreshortens to 5.5-11.0h, the purity of S 16257-2 reaches more than 89.85%, and molar yield reaches more than 96.3%.
The different complex phase transfer catalyst of table 2 is on the impact of the preparation of S 16257-2
Contriver investigates the mass ratio of the Primary Catalysts Morpan BB in complex phase transfer catalyst and promotor polyoxyethylene glycol-200 further, the consumption arranging complex phase transfer catalyst in experiment is 3% of formula IV compound quality, and experimental result is as shown in table 3.As known from Table 3, when the mass ratio of Morpan BB and polyoxyethylene glycol-200 is 1:1, reaction times just starts remarkable shortening, the quality of Morpan BB is that 4 times of the reaction times of the quality of polyoxyethylene glycol-200 foreshorten to 5.5h, the high purity 93.88% of S 16257-2, molar yield reaches 99.0%, and catalytic effect is best.When the quality of Morpan BB is 2 ~ 6 times of the quality of polyoxyethylene glycol-200, the reaction times foreshortens to 5.5 ~ 7.5h, and the purity of S 16257-2 reaches 92.63% ~ 93.88%, and molar yield reaches 97.9% ~ 99.0%, and catalytic effect is better.Along with the further increase of Morpan BB consumption, suppress acid binding agent effect, the reaction times can not be shortened further because it is attached on acid binding agent, the purity of S 16257-2 then starts to decline; When the quality of Morpan BB is 8 times of the quality of polyoxyethylene glycol-200, the reaction times is increased to 11.0h, and the purity drop to 87.55% of S 16257-2.Thus, the present invention arranges in complex phase transfer catalyst, and the mass ratio of Primary Catalysts and promotor is 1 ~ 8:1, preferably 2 ~ 6:1.
The mass ratio of table 3 Morpan BB and polyoxyethylene glycol-200 is on the impact of the preparation of S 16257-2
| Mass ratio | Reaction times | Purity | Molar yield (in formula IV compound) |
| 1：2 | 16.0h | 86.07% | 97.5% |
| 1：1 | 13.5h | 88.10% | 98.3% |
| 2：1 | 7.5h | 92.63% | 98.4% |
| 3：1 | 6.0h | 93.15% | 97.9% |
| 4：1 | 5.5h | 93.88% | 99.0% |
| 6：1 | 6.5h | 92.64% | 98.3% |
| 8：1 | 11.0h | 87.55% | 97.6% |
Contriver is determining that the mass ratio of Morpan BB and polyoxyethylene glycol-200 is on the basis of 4:1, and investigate the consumption of complex phase transfer catalyst further, result is as shown in table 4.As known from Table 4, the quality that the quality of complex phase transfer catalyst is compound shown in formula IV 4.0% time, the reaction times foreshortens to 5.0h, the high purity 96.47% of S 16257-2, and molar yield reaches 99.1%, and catalytic effect is best.As the 2.0%-6.0% that the quality of complex phase transfer catalyst is the quality of compound shown in formula IV, the reaction times foreshortens to below 6.5h, and the purity of S 16257-2 reaches more than 92.13%, and molar yield reaches more than 97.8%, and catalytic effect is better.Thus, the quality of the preferred complex phase transfer catalyst of the present invention 2.0%-6.0% that is compound quality shown in formula IV.
Table 4 complex phase transfer catalyst consumption is on the impact of the preparation of S 16257-2
embodiment 2the preparation of S 16257-2
1, the preparation of formula III compound
By 40.0g7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepine-2-ketone (formula II compound) is dissolved in 200mL Virahol, add 9g acetic acid, be transferred in high-pressure hydrogenation reactor, add 2g10% palladium carbon catalyst in 35 ~ 40 DEG C, hydrogenation reaction 18h under 1 ~ 4atm pressure.Filter, with a small amount of washed with isopropyl alcohol filter cake, Recover palladium Pd/carbon catalyst, obtains 7,8-dimethoxy-3-(3-chloropropyl)-1 by filtrate in 40 ~ 45 DEG C of evaporated under reduced pressure solvents, 3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone acetate (formula III compound) oily matter, slowly adds methyl alcohol crystallization under room temperature, 5 ~ 10 DEG C of growing the grain 2h, filter, dry, obtain 42.2g7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone acetate (formula III compound), purity is 98.12%, and molar yield is 87.2%.As shown in Figure 1, the peak-data in Fig. 1 is as shown in table 5 for the HPLC figure of formula III compound related substance.
The HPLC figure peak-data of table 5 formula III compound related substance
2, the preparation of S 16257-2
In 500mL tri-mouthfuls of reaction flasks, by 20.0g formula IV compound dissolution in 200mL DMF, add 40.0g anhydrous K
2cO
3stir 30 minutes, then formula III compound, 0.8g complex phase transfer catalyst (being obtained by mixing with the mass ratio of 4:1 by Morpan BB and polyoxyethylene glycol-200) prepared by 32.0g the present embodiment is added, reaction system is warming up to 85-88 DEG C, adopt HPLC method monitoring reaction end, react completely after reaction 5.0h.After completion of the reaction, cooling, collecting by filtration filtrate, is added to filtrate in 500mL saturated nacl aqueous solution, uses 250mL and 200mL extraction into ethyl acetate twice respectively, merges organic phase, adds 20g anhydrous Na
2sO
4drying, filter, by filtrate concentrating under reduced pressure at 50 DEG C, obtain 38.1g S 16257-2, purity is 96.62%, and the molar yield calculated with formula IV compound is for 98.9%.As shown in Figure 2, the peak-data in Fig. 2 is as shown in table 6 for the HPLC figure of S 16257-2 related substance.
The HPLC figure peak-data of table 6 S 16257-2 related substance
comparative examplethe preparation of 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone
The present embodiment is except not adding except acetic acid, and each material consumption and operation steps are all identical with the method for preparation formula III compound in embodiment 2.
By 40.0g7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepine-2-ketone (formula II compound) is dissolved in 200mL Virahol, be transferred in high-pressure hydrogenation reactor, add 2g10% palladium carbon catalyst in 35 ~ 40 DEG C, hydrogenation reaction 18h under 1 ~ 4atm pressure.Filter, with a small amount of washed with isopropyl alcohol filter cake, Recover palladium Pd/carbon catalyst, obtains 7,8-dimethoxy-3-(3-chloropropyl)-1 by filtrate in 40 ~ 45 DEG C of evaporated under reduced pressure solvents, 3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone oily matter, slowly adds methyl alcohol crystallization under room temperature, 5 ~ 10 DEG C of growing the grain 2h, filter, dry, obtain 35.6g7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone (free alkali of formula III compound), purity is 92.38%, and molar yield is 88.4%.As shown in Figure 3, the peak-data in Fig. 3 is as shown in table 7 for the HPLC figure of formula III compound as its free base related substance.
The HPLC figure peak-data of table 7 formula III compound as its free base related substance
Known by the method comparing the embodiment of the present invention 2 and comparative example, when not adding the free alkali of acetic acid preparation formula III compound, purity is 92.38%, and the embodiment of the present invention 2 adopts the purity adding formula III compound that acetic acid prepares to be 98.12%, thus, the present invention adopts method preparation formula III compound advantageous adding acetic acid in the purity of raising formula III compound, thus is conducive to improving the final S 16257-2 of preparation and the purity of hydrochloric acid Ivabradine.
embodiment 3the preparation of S 16257-2
1, the preparation of formula III compound
By 40.0g7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepine-2-ketone (formula II compound) is dissolved in 180mL ethanol, add 9g acetic acid, be transferred in high-pressure hydrogenation reactor, add 2g10% palladium carbon catalyst in 35 ~ 40 DEG C, hydrogenation reaction 18h under 1 ~ 4atm pressure.Filter, with a small amount of washing with alcohol filter cake, Recover palladium Pd/carbon catalyst, obtains 7,8-dimethoxy-3-(3-chloropropyl)-1 by filtrate in 40 ~ 45 DEG C of evaporated under reduced pressure solvents, 3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone acetate (formula III compound) oily matter, slowly adds methyl alcohol crystallization under room temperature, 5 ~ 10 DEG C of growing the grain 2h, filter, dry, obtain 42.4g7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone acetate (formula III compound), purity is 98.10%, and molar yield is 87.6%.
2, the preparation of S 16257-2
In 500mL tri-mouthfuls of reaction flasks, by 20.0g formula IV compound dissolution in 200mL DMF, add 30.7g anhydrous Na
2cO
3stir 30 minutes, then formula III compound, 1.2g complex phase transfer catalyst (being obtained by mixing with the mass ratio of 6:1 by Morpan BB and polyoxyethylene alkylphenol) prepared by 32.0g the present embodiment is added, reaction system is warming up to 85-88 DEG C, adopt HPLC method monitoring reaction end, react completely after reaction 8.0h.After completion of the reaction, cooling, collecting by filtration filtrate, is added to filtrate in 500mL saturated nacl aqueous solution, uses 250mL and 200mL extraction into ethyl acetate twice respectively, merges organic phase, adds 20g anhydrous Na
2sO
4drying, filter, by filtrate concentrating under reduced pressure at 50 DEG C, obtain 38.2g S 16257-2, purity is 96.55%, and the molar yield calculated with formula IV compound is for 99.1%.
embodiment 4the preparation of Ivabradine hydrochloride
1, the preparation of S 16257-2 highly finished product
Get S 16257-2 38.0g prepared by above-described embodiment 2, add 250mL acetonitrile, stir, slowly add 10.5g bis-oxalic acid hydrate, salify 30min under room temperature, crystallization 2h, filter, collect S 16257-2 oxalate.Adding 400mL water makes S 16257-2 oxalate dissolve completely, with the NaOH solution adjust pH to 8.5 of 10% massfraction, add 400mL extraction into ethyl acetate again, stratification after stirring, organic phase is successively with the saturated EDTA-2Na solution of 200mL and the washing of 200mL saturated nacl aqueous solution, layering, collect organic phase, add 20g anhydrous sodium sulfate drying, and add 0.4g activated carbon decolorizing 30min, filter, filtrate is evaporated to dry at 50 DEG C, obtain 28.7g S 16257-2 highly finished product, purity is 99.88%, and molar yield is 75.5%.As shown in Figure 4, the peak-data in Fig. 4 is as shown in table 8 for the HPLC figure of S 16257-2 highly finished product related substance.
The HPLC figure peak-data of table 8 S 16257-2 highly finished product related substance
2, the preparation of hydrochloric acid Ivabradine
Get S 16257-2 highly finished product 28.5g prepared by the present embodiment, add 180mL acetonitrile, stir, drip salt acid for adjusting pH value to 2 ~ 3, stir salify 30min, concentrated solvent, to dry, adds 500mL acetonitrile crystallization, filter, 24.8g hydrochloric acid Ivabradine is obtained, purity >=99.95%, optical purity >=99.95% in 60 DEG C of vacuum-dryings, single impurity≤0.05%, molar yield is 80.7%.As shown in Figure 5, the peak-data in Fig. 5 is as shown in table 9 for the HPLC figure of hydrochloric acid Ivabradine related substance; HPLC figure (volume injected: 10 μ l, post: AD-H(4.6mm × 250mm, 5 μm) of hydrochloric acid Ivabradine chiral isomer, flow rate: 0.5ml/min, determined wavelength: UV286nm) as shown in Figure 6, the peak-data in Fig. 6 is as shown in table 10; The infrared spectrogram of hydrochloric acid Ivabradine as shown in Figure 7.
The HPLC figure peak-data of table 9 hydrochloric acid Ivabradine related substance
The HPLC figure peak-data of table 10 hydrochloric acid Ivabradine chiral isomer
embodiment 5the preparation of Ivabradine hydrochloride
1, the preparation of S 16257-2 highly finished product
Get S 16257-2 38.0g prepared by above-described embodiment 3, add 250mL acetonitrile, stir, slowly add 9.7g mono-hydration DL-tartrate, salify 30min under room temperature, crystallization 5h, filter, collect S 16257-2 tartrate.Adding 400mL water makes S 16257-2 tartrate dissolve completely, with the NaOH solution adjust pH to 8.5 of 10% massfraction, add 400mL extraction into ethyl acetate again, stratification after stirring, organic phase is successively with the saturated EDTA-2Na solution of 200mL and the washing of 200mL saturated nacl aqueous solution, layering, collect organic phase, add 20g anhydrous sodium sulfate drying, and add 0.4g activated carbon decolorizing 30min, filter, filtrate is evaporated to dry at 50 DEG C, obtain 27.6g S 16257-2 highly finished product, purity is 99.79%, and molar yield is 72.6%.
2, the preparation of hydrochloric acid Ivabradine
Get S 16257-2 highly finished product 27.5g prepared by the present embodiment, add 180mL acetonitrile, stir, drip salt acid for adjusting pH value to 2 ~ 3, stir salify 30min, concentrated solvent, to dry, adds 500mL acetonitrile crystallization, filter, 24.0 hydrochloric acid Ivabradines are obtained, purity >=99.95%, optical purity >=99.95% in 60 DEG C of vacuum-dryings, single impurity≤0.05%, molar yield is 80.1%.
Specific description of embodiments of the present invention does not above limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (10)
1. a preparation method for S 16257-2, is characterized in that, described preparation method comprises:
Step a1: make compound shown in compound and formula IV shown in formula III that nucleophilic substitution reaction occur under the existence of acid binding agent and complex phase transfer catalyst in polar aprotic solvent and generate S 16257-2;
Step b1: the S 16257-2 obtained in step a1 to be separated, purifying;
Wherein, described complex phase transfer catalyst is that the quaternary ammonium salt-type phase transfer catalyst of 1 ~ 8:1 and polyethers phase-transfer catalyst form by mass ratio, and described X is selected from Cl, Br, I, sulfonyloxy, methanesulfonyloxy group, phenylsulfonyloxy, tolysulfonyl oxygen base, adjacent tosyloxy or a tosyloxy.
2. preparation method according to claim 1, is characterized in that, described quaternary ammonium salt-type phase transfer catalyst is selected from benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, Morpan BB or benzyltrimethylammonium bromide, preferred Morpan BB; Described polyethers phase-transfer catalyst is selected from polyoxyethylene glycol, polyoxyethylene fatty alcohol or polyoxyethylene alkylphenol, preferred polyoxyethylene glycol, more preferably the polyoxyethylene glycol of molecular weight between 200 ~ 800;
Preferably, described acid binding agent is selected from sodium carbonate, salt of wormwood, saleratus or sodium bicarbonate;
Preferably, described polar aprotic solvent is selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) or acetonitrile.
3. preparation method according to claim 1 and 2, is characterized in that, the consumption of described complex phase transfer catalyst is 2.0% ~ 6.0% of compound quality shown in formula IV, preferably 4.0%.
4. preparation method according to any one of claim 1 to 3, is characterized in that, in described complex phase transfer catalyst, the mass ratio of described quaternary ammonium salt-type phase transfer catalyst and described polyethers phase-transfer catalyst is 2 ~ 6:1, preferred 4:1.
5. preparation method according to any one of claim 1 to 4, is characterized in that, adopts following methods to prepare compound shown in formula III:
Compound shown in formula II is dissolved in alcoholic solvent, adds acetic acid, compound shown in catalytic hydrogenation reaction production III occurs under palladium carbon catalyst effect; In compound shown in its Chinese style II, the definition of X is identical with the definition of X in compound shown in formula III;
Preferably, described alcoholic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol or Virahol.
6. preparation method according to any one of claim 1 to 5, is characterized in that, the nucleophilic substitution reaction in described step a1 carries out at 85-88 DEG C;
Preferably, described step b1 specifically comprises: after the reaction of compound shown in compound and formula IV shown in formula III, cooling, filter, collect filtrate, filtrate is added in saturated nacl aqueous solution, extract by ethyl acetate, be separated organic phase, after concentrating under reduced pressure, obtain S 16257-2.
7. a preparation method for hydrochloric acid Ivabradine, is characterized in that, the S 16257-2 preparation that described hydrochloric acid Ivabradine is prepared by the preparation method adopted according to any one of claim 1-6.
8. preparation method according to claim 7, is characterized in that, the preparation method of described hydrochloric acid Ivabradine comprises the following steps:
Step a2: adopt the preparation method according to any one of claim 1-6 to prepare S 16257-2;
Step b2: the S 16257-2 obtained in step a2 is dissolved, and obtain S 16257-2 organic acid salt by salt-forming reaction;
Step c2: dissolve described S 16257-2 organic acid salt, obtain S 16257-2 highly finished product after adjust pH, extraction, separation, washing;
Steps d 2: dissolve described S 16257-2 highly finished product, add hydrochloric acid, obtain hydrochloric acid Ivabradine.
9. preparation method according to claim 8, is characterized in that, the preparation method of described hydrochloric acid Ivabradine comprises the following steps:
Step a2: adopt the preparation method according to any one of claim 1-6 to prepare S 16257-2;
Step b2: adopt acetonitrile to dissolve the S 16257-2 obtained in step a2, add organic acid, salify crystallization, filter and obtain S 16257-2 organic acid salt;
Step c2: be dissolved in water described S 16257-2 organic acid salt, adjust pH to 8 ~ 9, extract by ethyl acetate, be separated organic phase, successively with after saturated metal complex agent solution and saturated nacl aqueous solution washing, be separated organic phase, drying and decolouring after, filter, collect filtrate, after evaporated under reduced pressure solvent, obtain S 16257-2 highly finished product;
Steps d 2: adopt S 16257-2 highly finished product described in organic solvent dissolution, drips hydrochloric acid, adjust ph to 2 ~ 3, and after reaction, concentrated solvent is to dry, and crystallization filters, obtains hydrochloric acid Ivabradine.
10. preparation method according to claim 9, it is characterized in that, the organic acid in described step b2 is selected from oxalic acid, tartrate, propanedioic acid, lactic acid, pyruvic acid, fumaric acid, succsinic acid, toxilic acid, citric acid, methylsulfonic acid, Phenylsulfonic acid or camphorsulfonic acid;
Preferably, the metal chelating agent in described step c2 be selected from ammonia hydroxyl complexing agent, complexone, disodium ethylene diamine tetraacetate or sulfydryl complexing agent one or more;
Preferably, the organic solvent in described steps d 2 is selected from methyl alcohol, ethanol, acetonitrile, acetone or ethyl acetate, more preferably acetonitrile.
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