CN105601645A - Method for synthesizing ticlopidine hydrochloride - Google Patents
Method for synthesizing ticlopidine hydrochloride Download PDFInfo
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- CN105601645A CN105601645A CN201511013857.8A CN201511013857A CN105601645A CN 105601645 A CN105601645 A CN 105601645A CN 201511013857 A CN201511013857 A CN 201511013857A CN 105601645 A CN105601645 A CN 105601645A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
The invention provides a method for synthesizing ticlopidine hydrochloride. The method comprises the following steps of taking thiopheneethanol as a raw material, and protecting and activating hydroxyl by means of reacting the thiopheneethanol with paratoluensulfonyl chloride under the action of an acid-binding agent; then performing a condensation reaction with o-chlorobenzylamine; performing a ring closing reaction with 1,3-dioxolane under an acidic condition so as to obtain the ticlopidine hydrochloride. The method provided by the invention has the advantages of mild reaction condition, low production cost, high product yield, good quality and convenience for industrialized production.
Description
Technical field
The invention belongs to organic compound synthesis technical field, particularly, relate to a kind of synthetic method of ticlopidine hydrochloride.
Background technology
Ticlopidine hydrochloride is a kind of platelet aggregation inhibitor, and the active component of antithrombotic Ticlopidine, for preventing and treat the dyshaemia illness of the heart, brain and other artery that cause because of the high coherent condition of blood platelet. Cardiovascular and cerebrovascular disease is exactly that cardiovascular and cerebrovascular disease are referred to as, general reference because hyperlipidemia, blood are sticky, there is ischemic or hemorrhagic disease in the heart, brain and the body tissue that cause such as atherosclerotic, hypertension. A kind of serious threat mankind, the particularly healthy common disease of more than 50 years old the elderly, along with the raising of world population average life span, aging population is day by day serious, and three high crowds have been problems can not be ignored. The incidence of disease of the annual cardiovascular disease of China is all improving, cardiovascular diseases clinical application increases thereupon, although ticlopidine hydrochloride is a listing old medicine for a long time, but because of its good effect, side effect is little, cheap, belong to country's medicine category at a low price, no matter be to be still widely used at home or in the world.
But the synthetic route of prior art ticlopidine hydrochloride, as shown in Figure 1, taking thiophene ethamine as raw material, through imidization, cyclization, condensation, last salify makes ticlopidine hydrochloride. Because the original production technology of ticlopidine hydrochloride is outmoded, thiophene ethamine is as initiation material, and cost of material is high, causes production cost higher. Ticlopidine hydrochloride is as an old product, low price medicine, and expensive synthetic route has obviously been not suitable for carrying out suitability for industrialized production. In addition, in synthetic route, ring closure reaction has all used formaldehyde or paraformaldehyde as closing cyclization reagent, the toxicity of formaldehyde own is larger, and easy polymerization reaction take place, cause closing ring byproduct in process thing more, purification ratio is more difficult, has not only affected the yield of product, also causes end product quality not high. Therefore, in order to improve yield and the quality of product, reduce product cost, meet the need of market and ensure enterprise self economic interests, imperative to the improvement of ticlopidine hydrochloride production Technology.
Summary of the invention
Goal of the invention: for the deficiencies in the prior art, the invention provides a kind of synthetic method of ticlopidine hydrochloride, reaction condition gentleness, production cost is low, and product yield is high, quality good, is convenient to the advantages such as suitability for industrialized production.
Technical scheme: the invention provides a kind of synthetic method of ticlopidine hydrochloride, using thiophene ethanol as raw material, under the effect of acid binding agent, first and paratoluensulfonyl chloride reaction is protected activation hydroxyl to hydroxyl; Carry out condensation reaction with o-chlorine benzylamine again; Then under acid condition, and 1,3-dioxolane carries out ring closure reaction and obtains ticlopidine hydrochloride, concrete, comprises the following steps:
(1) thiophene ethanol and the paratoluensulfonyl chloride that are 1:1.05-1.15 by solvent, mol ratio join reaction unit, control temperature at 0-5 DEG C, under stirring condition, drip acid binding agent;
(2) be warming up to 20-25 DEG C of insulation reaction 1-3 hour;
(3) in the reactant liquor of step (2), add water washing 2-3 time;
(4) get solvent layer, then add wherein o-chlorine benzylamine, be heated to 80-95 DEG C of reaction 2-4 hour;
(5) be cooled to 20-25 DEG C and stir filtration after 1-3 hour;
(6) in filtrate, add water, under stirring condition, regulate system pH to arrive 8.5-9; Stratification;
(7) upper strata solvent layer continues to regulate pH to 5-5.5;
(8) be cooled to 0-5 DEG C of stirring and crystallizing 2-6 hour after filter;
(9) filter cake obtains condensation product hydrochlorate after 50-60 DEG C of vacuum drying;
(10) condensation product hydrochlorate step (9) Suo Shu and 1,3-dioxolane and hydrochloric acid are joined to reaction unit, under stirring, be warming up to 80-95 DEG C of reaction 4-8 hour;
(11) be cooled to 5-10 DEG C of stirring and crystallizing 1-3 hour after filter;
(12) filter cake, with after the washing of 1,3-dioxolane, obtains ticlopidine hydrochloride after 50-60 DEG C of vacuum drying.
The synthetic method of ticlopidine hydrochloride of the present invention, method is succinct, reaction condition gentleness, production cost is low, and it is high to react overall yield. Wherein, selecting cheap thiophene ethanol is initiation material, after p-toluenesulfonyl protection, with o-chlorine benzylamine condensation, then closes ring salify and obtains ticlopidine hydrochloride. Condensation reaction is used excessive o-chlorine benzylamine self also to can be used as acid binding agent, promotes reaction to carry out to positive direction. In addition, the tosilate producing in its reaction filters out rear alkalization can recycled after free, has greatly reduced the discharge of refuse, and the less pollution to environment, has also reduced product cost. In addition, use formaldehyde as closing cyclization reagent in original synthesis technique, byproduct of reaction is more, and yield is on the low side, steady quality. The present invention uses 1,3-dioxolane as closing cyclization reagent, and 1,3-dioxolane is both as solvent, again as reaction reagent. Under acid condition, close ring, reaction temperature and, steady quality. Not only abandon this highly toxic chemical reagent of formaldehyde, and reaction basal ration, closing ring yield reaches more than 95%, greatly reduce product cost, and due to substantially without side reaction, its reaction after generate ethylene glycol can recycle, also reduced the discharge of pollutant, reduced the pollution to environment, and post processing is easy, there is very large promotional value.
Further, the synthetic method of above-mentioned ticlopidine hydrochloride, described step also comprises ticlopidine hydrochloride subtractive process after (12), described subtractive process comprises the following steps:
(1) by after vacuum drying ticlopidine hydrochloride and absolute ethyl alcohol join reaction unit, under stirring condition, be heated to 70-75 DEG C;
(2) ticlopidine hydrochloride adds active carbon after dissolving completely;
(3) insulation decolouring is filtered after 20-40 minute while hot;
(4) filtrate is cooled to 0-5 DEG C of stirring and crystallizing 2-6 hour gradually;
(5) filter cake, with after absolute ethanol washing, must be refined ticlopidine hydrochloride after 50-60 DEG C of vacuum drying.
Product purity after refining is high, and good product quality.
Further, the synthetic method of above-mentioned ticlopidine hydrochloride, described acid binding agent drips and continues 25-35 minute. Continuing to drip acid binding agent can make reaction constantly continue to carry out to positive reaction direction.
Further, the synthetic method of above-mentioned ticlopidine hydrochloride, described acid binding agent is triethylamine. Triethylamine, as acid binding agent, promotes reaction to carry out, effective, and is easy to remove.
Preferred as one of the present invention, the synthetic method of above-mentioned ticlopidine hydrochloride, the mol ratio of described thiophene ethanol and o-chlorine benzylamine is 1:2-2.2. Ratio is reasonable, and condensation reaction is used excessive o-chlorine benzylamine self also as acid binding agent.
Further, the synthetic method of above-mentioned ticlopidine hydrochloride, described step (6) and step (7) are used salt acid for adjusting pH. Application cost is low, and can not introduce new impurity, can not affect product.
Further, the synthetic method of above-mentioned ticlopidine hydrochloride, described solvent is toluene. Raw material is easy to get, and application cost is low.
Further, the synthetic method of above-mentioned ticlopidine hydrochloride, described water is pure water. Raw material is easy to get, and application cost is low.
Beneficial effect: compared with prior art, the present invention has the following advantages: the synthetic method of ticlopidine hydrochloride of the present invention, method is succinct, cost of material is low, source is wide, reaction condition gentleness, and production cost is low, and it is high to react overall yield, and product quality is also relatively stable. The discharge of pollutant is few, has reduced the pollution to environment, and post processing is easy, has very high promotional value.
Brief description of the drawings
Fig. 1 is the synthetic route chart of ticlopidine hydrochloride described in prior art;
Fig. 2 is the synthetic route chart of ticlopidine hydrochloride of the present invention.
Detailed description of the invention
To, by several specific embodiments, further illustrate the present invention below, these embodiment, just in order to describe the problem, are not a kind of restriction.
Embodiment 1
The synthetic method of ticlopidine hydrochloride as shown in Figure 2, comprises the following steps:
1. p-toluenesulfonyl protection:
In 1000ml reaction bulb, add 500ml toluene, 50g thiophene ethanol and 80g paratoluensulfonyl chloride, open and stir, control temperature and drip 47g triethylamine under 0 DEG C of condition, drip and continue about 30min, drip off and be warming up to 20 DEG C of reactions 3 hours, in reactant liquor, add 400ml water, washing at twice, the toluene layer of having washed directly spends the next step.
2. condensation reaction
In 1000ml reaction bulb, add the toluene solution of step reaction, then add 114g o-chlorine benzylamine, be heated to 85 DEG C of reactions 3 hours, after having reacted, be cooled to 20 DEG C and stir 1 hour, filter, in filtrate, add 200ml water, stir lower drip hydrochloric acid regulation system pH value to 8.5, layering, upper toluene layer continues to drip salt acid for adjusting pH to 5, then system is cooled to 2 DEG C of stirring and crystallizing 4 hours, filters, filter cake obtains 96g condensation product hydrochloride after 50 DEG C of vacuum drying.
3. ring closure reaction
In 1000ml reaction bulb, add 96g condensation product hydrochloride, 400ml1,3-dioxolane and 5ml hydrochloric acid, under stirring, be warming up to 90 DEG C of reactions 6 hours, after having reacted, be cooled to 7 DEG C of stirring and crystallizing 3 hours, filter, filter cake is with a small amount of 1, after the washing of 3-dioxolane after 50 DEG C of vacuum drying 95g ticlopidine hydrochloride crude product.
4. refining
In 1000ml reaction bulb, add 95g ticlopidine hydrochloride crude product and 500ml absolute ethyl alcohol, under stirring, be heated to 72 DEG C, after approximately 10 minutes, after all dissolving, solid adds 2g active carbon, insulation decolouring is filtered after 20 minutes while hot, filtrate is cooled to 4 DEG C of stirring and crystallizing 4 hours gradually, filter, filter cake is with obtain 91g ticlopidine hydrochloride highly finished product after a small amount of absolute ethanol washing after 50 DEG C of vacuum drying. Total recovery 82%, purity 99.9%
Embodiment 2
The synthetic method of ticlopidine hydrochloride as shown in Figure 2, comprises the following steps:
1. p-toluenesulfonyl protection:
In 500ml reaction bulb, add 250ml toluene, 25g thiophene ethanol and 44g paratoluensulfonyl chloride, open and stir, control temperature and drip 24g triethylamine under 5 DEG C of conditions, drip and continue about 25min, drip off and be warming up to 25 DEG C of reactions 1 hour, in reactant liquor, add 200ml water, divide three washings, the toluene layer of having washed directly spends the next step.
2. condensation reaction
In 500ml reaction bulb, add the toluene solution of step reaction, then add 70g o-chlorine benzylamine, be heated to 80 DEG C of reactions 4 hours, after having reacted, be cooled to 25 DEG C and stir 3 hours, filter, in filtrate, add 200ml water, stir lower drip hydrochloric acid regulation system pH value to 9, layering, upper toluene layer continues to drip salt acid for adjusting pH to 5.5, then system is cooled to 5 DEG C of stirring and crystallizing 2 hours, filters, filter cake obtains 48g condensation product hydrochloride after 55 DEG C of vacuum drying.
3. ring closure reaction
In 500ml reaction bulb, add 48g condensation product hydrochloride, 250ml1,3-dioxolane and 5ml hydrochloric acid, under stirring, be warming up to 80 DEG C of reactions 8 hours, after having reacted, be cooled to 10 DEG C of stirring and crystallizing 1 hour, filter, filter cake is with a small amount of 1, after the washing of 3-dioxolane after 60 DEG C of vacuum drying 48g ticlopidine hydrochloride crude product.
4. refining
In 500ml reaction bulb, add 48g ticlopidine hydrochloride crude product and 300ml absolute ethyl alcohol, under stirring, be heated to 70 DEG C, after approximately 10 minutes, after all dissolving, solid adds 2g active carbon, insulation decolouring is filtered after 40 minutes while hot, filtrate is cooled to 0 DEG C of stirring and crystallizing 6 hours gradually, filter, filter cake is with obtain 45g ticlopidine hydrochloride highly finished product after a small amount of absolute ethanol washing after 55 DEG C of vacuum drying. Total recovery 77%, purity 99.8%.
Embodiment 3
The synthetic method of ticlopidine hydrochloride as shown in Figure 2, comprises the following steps:
1. p-toluenesulfonyl protection:
In 1000ml reaction bulb, add 500ml toluene, 50g thiophene ethanol and 84g paratoluensulfonyl chloride, open and stir, control temperature and drip 50g triethylamine under 4 DEG C of conditions, drip and continue about 35min, drip off and be warming up to 22 DEG C of reactions 2 hours, in reactant liquor, add 400ml water, washing at twice, the toluene layer of having washed directly spends the next step.
2. condensation reaction
In 1000ml reaction bulb, add the toluene solution of step reaction, then add 126g o-chlorine benzylamine, be heated to 95 DEG C of reactions 2 hours, after having reacted, be cooled to 22 DEG C and stir 2 hours, filter, in filtrate, add 200ml water, stir lower drip hydrochloric acid regulation system pH value to 8.5, layering, upper toluene layer continues to drip salt acid for adjusting pH to 5.5, then system is cooled to 0 DEG C of stirring and crystallizing 6 hours, filters, filter cake obtains 95g condensation product hydrochloride after 60 DEG C of vacuum drying.
3. ring closure reaction
In 1000ml reaction bulb, add 95g condensation product hydrochloride, 300ml1,3-dioxolane and 10ml hydrochloric acid, under stirring, be warming up to 95 DEG C of reactions 4 hours, after having reacted, be cooled to 5 DEG C of stirring and crystallizing 2 hours, filter, filter cake is with a small amount of 1, after the washing of 3-dioxolane after 55 DEG C of vacuum drying 93g ticlopidine hydrochloride crude product.
4. refining
In 1000ml reaction bulb, add 93g ticlopidine hydrochloride crude product and 500ml absolute ethyl alcohol, under stirring, be heated to 75 DEG C, after approximately 10 minutes, after all dissolving, solid adds 2g active carbon, insulation decolouring is filtered after 30 minutes while hot, filtrate is cooled to 5 DEG C of stirring and crystallizing 2 hours gradually, filter, filter cake is with obtain 89g ticlopidine hydrochloride highly finished product after a small amount of absolute ethanol washing after 60 DEG C of vacuum drying. Total recovery 76%, purity 99.8%.
The above is only several embodiments of invention, it should be pointed out that for those skilled in the art, not departing under the prerequisite of inventive principle, can also make some improvement, and these improve and also should be considered as protection scope of the present invention.
Claims (8)
1. a synthetic method for ticlopidine hydrochloride, is characterized in that: comprise the following steps:
(1) thiophene ethanol and the paratoluensulfonyl chloride that are 1:1.05-1.15 by solvent, mol ratio join reaction unit, control temperature at 0-5 DEG C, under stirring condition, drip acid binding agent;
(2) be warming up to 20-25 DEG C of insulation reaction 1-3 hour;
(3) in the reactant liquor of step (2), add water washing 2-3 time;
(4) get solvent layer, then add wherein o-chlorine benzylamine, be heated to 80-95 DEG C of reaction 2-4 hour;
(5) be cooled to 20-25 DEG C and stir filtration after 1-3 hour;
(6) in filtrate, add water, under stirring condition, regulate system pH to arrive 8.5-9; Stratification;
(7) upper strata solvent layer continues to regulate pH to 5-5.5;
(8) be cooled to 0-5 DEG C of stirring and crystallizing 2-6 hour after filter;
(9) filter cake obtains condensation product hydrochlorate after 50-60 DEG C of vacuum drying;
(10) condensation product hydrochlorate step (9) Suo Shu and 1,3-dioxolane and hydrochloric acid are joined to reaction unit, under stirring, be warming up to 80-95 DEG C of reaction 4-8 hour;
(11) be cooled to 5-10 DEG C of stirring and crystallizing 1-3 hour after filter;
(12) filter cake, with after the washing of 1,3-dioxolane, obtains ticlopidine hydrochloride after 50-60 DEG C of vacuum drying.
2. the synthetic method of ticlopidine hydrochloride according to claim 1, is characterized in that: described step also comprises ticlopidine hydrochloride subtractive process after (12), and described subtractive process comprises the following steps:
(1) by after vacuum drying ticlopidine hydrochloride and absolute ethyl alcohol join reaction unit, under stirring condition, be heated to 70-75 DEG C;
(2) ticlopidine hydrochloride adds active carbon after dissolving completely;
(3) insulation decolouring is filtered after 20-40 minute while hot;
(4) filtrate is cooled to 0-5 DEG C of stirring and crystallizing 2-6 hour gradually;
(5) filter cake, with after absolute ethanol washing, must be refined ticlopidine hydrochloride after 50-60 DEG C of vacuum drying.
3. the synthetic method of ticlopidine hydrochloride according to claim 1, is characterized in that: described acid binding agent drips and continues 25-35 minute.
4. according to the synthetic method of the ticlopidine hydrochloride described in claim 1 or 3, it is characterized in that: described acid binding agent is triethylamine.
5. the synthetic method of ticlopidine hydrochloride according to claim 1, is characterized in that: the mol ratio of described thiophene ethanol and o-chlorine benzylamine is 1:2-2.2.
6. the synthetic method of ticlopidine hydrochloride according to claim 1, is characterized in that: described step (6) and step (7) are used salt acid for adjusting pH.
7. the synthetic method of ticlopidine hydrochloride according to claim 1, is characterized in that: described solvent is toluene.
8. the synthetic method of ticlopidine hydrochloride according to claim 1, is characterized in that: described water is pure water.
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| EP0829482A2 (en) * | 1996-09-04 | 1998-03-18 | Poli Industria Chimica S.p.A. | Method of making thieno-pyridine derivatives |
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| EP0573955A1 (en) * | 1992-06-08 | 1993-12-15 | Fuji Photo Film Co., Ltd. | 3-Amino-5-o-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine-2-carboxylic acid derivative and process for producing the same |
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Application publication date: 20160525 |