CN105461735A - Preparation method of ticlopidine hydrochloride - Google Patents
Preparation method of ticlopidine hydrochloride Download PDFInfo
- Publication number
- CN105461735A CN105461735A CN201511013844.0A CN201511013844A CN105461735A CN 105461735 A CN105461735 A CN 105461735A CN 201511013844 A CN201511013844 A CN 201511013844A CN 105461735 A CN105461735 A CN 105461735A
- Authority
- CN
- China
- Prior art keywords
- ticlopidine hydrochloride
- preparation
- reaction
- hour
- ticlopidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of ticlopidine hydrochloride. The preparation method comprises the following steps: reacting thiophene ethanol as a raw material with paratoluensulfonyl chloride at first under the action of an acid-binding agent so as to protect and activate hydroxyl radicals; then performing condensation reaction with o-chlorobenzylamine; and then under an acidic condition, performing ring-closing reaction with 1,3-dioxolane to obtain ticlopidine hydrochloride. The preparation method is mild in reaction condition, low in production cost, high in product yield and good in product quality, and can conveniently realize industrial production.
Description
Technical field
The invention belongs to organic compound synthesis technical field, particularly, relate to a kind of preparation method of ticlopidine hydrochloride.
Background technology
Ticlopidine hydrochloride is the activeconstituents of a kind of platelet aggregation inhibitor, antithrombotic Ticlopidine, for the cycle penalty illness of the heart, brain and other artery that prevention and therapy causes because of thrombocyte high state of aggregation.Cardiovascular and cerebrovascular diseases is exactly that cardiovascular and cerebrovascular disease are referred to as, and makes a general reference because ischemia or hemorrhagic diseases occur for the heart that hyperlipidaemia, blood are sticky, atherosclerosis, hypertension etc. cause, brain and body tissue.Be a kind of serious threat mankind, the common disease that particularly more than 50 years old the elderly is healthy, along with the raising of world population mean lifetime, aging population is day by day serious, and three high crowds have been problems that can not be ignored.The sickness rate of the annual cardiovascular disease of China is all in raising, 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, no matter belong to country's medicine category at a low price, be still be widely used at home or in the world.
But the synthetic route of prior art ticlopidine hydrochloride, as shown in Figure 1, take thiophene ethamine as raw material, through imidization, cyclization, condensation, last salify obtains ticlopidine hydrochloride.Because the original production technique of ticlopidine hydrochloride is outmoded, thiophene ethamine is as starting raw material, and cost of material is high, causes production cost higher.Ticlopidine hydrochloride is as an old product, at a low price medicine, and the synthetic route of high cost has obviously been not suitable for carrying out suitability for industrialized production.In addition, in synthetic route, ring closure reaction all employ formaldehyde or paraformaldehyde as pass cyclization reagent, the toxicity of formaldehyde own is larger, and easy polymerization reaction take place, cause pass ring byproduct in process thing more, purification ratio is more difficult, not only have impact on the yield of product, also causes end product quality not high.Therefore, in order to improve yield and the quality of product, reducing 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 preparation method of ticlopidine hydrochloride, and reaction conditions is gentle, and 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 preparation method that the invention provides a kind of ticlopidine hydrochloride, using thiophene ethanol as raw material, under the effect of acid binding agent, first and Tosyl chloride reaction carries out protection activated hydroxyl groups to hydroxyl; Condensation reaction is carried out again with o-chlorine benzylamine; Then in acid condition, and 1,3-dioxolane carries out ring closure reaction and obtains ticlopidine hydrochloride, concrete, comprises the following steps:
(1) be that the thiophene ethanol of 1:1.05-1.15 and Tosyl chloride join reaction unit by solvent, mol ratio, control temperature, at 0-5 DEG C, drips acid binding agent under agitation condition;
(2) 25-30 DEG C of insulation reaction 1-3 hour is warming up to;
(3) in the reaction solution of step (2), water washing 2-3 time is added;
(4) get solvent layer, then add o-chlorine benzylamine wherein, be heated to 85-90 DEG C of reaction 2-4 hour;
(5) be cooled to 25-30 DEG C and stir filtration after 1-3 hour;
(6) add water in filtrate, under agitation 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 to filter after stirring and crystallizing 2-6 hour;
(9) filter cake obtains condenses hydrochlorate after 50-60 DEG C of vacuum-drying;
(10) the condenses hydrochlorate described in step (9) and 1,3-dioxolane and hydrochloric acid are joined reaction unit, under stirring, be warming up to 85-90 DEG C of reaction 4-8 hour;
(11) be cooled to 5-10 DEG C to filter after stirring and crystallizing 1-3 hour;
(12) filter cake is with after the washing of 1,3-dioxolane, after 50-60 DEG C of vacuum-drying, obtain ticlopidine hydrochloride.
The preparation method of ticlopidine hydrochloride of the present invention, method is succinct, and reaction conditions is gentle, and production cost is low, and it is high to react overall yield.Wherein, select cheap thiophene ethanol to be starting raw material, after p-toluenesulfonyl protection, with o-chlorine benzylamine condensation, then close ring salify and obtain ticlopidine hydrochloride.Condensation reaction uses excessive o-chlorine benzylamine self also as acid binding agent, can promote that reaction is carried out to positive dirction.In addition, the tosilate produced in its reaction filter out rear alkalization free after can recycled, greatly reduce the discharge of refuse, the less pollution to environment, also reduces product cost.In addition, use formaldehyde as pass cyclization reagent in original synthesis technique, byproduct of reaction is more, and yield is on the low side, steady quality.The present invention use 1,3-dioxolane as pass cyclization reagent, 1,3-dioxolane both as solvent, again as reaction reagent.Carry out Guan Huan in acid condition, reaction temperature and, steady quality.Not only abandon this highly toxic chemical reagent of formaldehyde, and reaction basal ration, close ring yield and reach more than 95%, greatly reduce product cost, and due to substantially without side reaction, the ethylene glycol generated after its reaction can be recycled, decrease the discharge of pollutent, decrease the pollution to environment, and aftertreatment is easy, there is very large promotional value.
Further, the preparation method of above-mentioned ticlopidine hydrochloride, described step also comprises ticlopidine hydrochloride treating process after (12), and described treating process comprises the following steps:
(1) by after vacuum-drying ticlopidine hydrochloride and dehydrated alcohol join reaction unit, be heated to 70-75 DEG C under agitation condition;
(2) ticlopidine hydrochloride adds gac after dissolving completely;
(3) insulation decolouring 20-40 minute after filtered while hot;
(4) filtrate is cooled to 0-5 DEG C of stirring and crystallizing 2-6 hour gradually;
(5), after filter cake absolute ethanol washing, ticlopidine hydrochloride must be refined after 50-60 DEG C of vacuum-drying.
Product purity after refining is high, and good product quality.
Further, the preparation 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 preparation method of above-mentioned ticlopidine hydrochloride, described acid binding agent is triethylamine.Triethylamine, as acid binding agent, promotes that reaction is carried out, effective, and is easy to remove.
Preferred as one of the present invention, the preparation 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 uses excessive o-chlorine benzylamine self also as acid binding agent.
Further, the preparation method of above-mentioned ticlopidine hydrochloride, described step (6) and step (7) use salt acid for adjusting pH.Application cost is low, and can not introduce new impurity, can not affect product.
Further, the preparation method of above-mentioned ticlopidine hydrochloride, described solvent is toluene.Raw material is easy to get, and application cost is low.
Further, the preparation 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 preparation method of ticlopidine hydrochloride of the present invention, and method is succinct, raw materials cost is low, source is wide, and reaction conditions is gentle, and production cost is low, and it is high to react overall yield, and quality product is also relatively stable.The discharge of pollutent is few, decrease the pollution to environment, and aftertreatment is easy, has very high promotional value.
Accompanying drawing explanation
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.
Embodiment
By several specific embodiment, will illustrate the present invention further below, these embodiments, just in order to describe the problem, are not a kind of restriction.
Embodiment 1
The preparation method of ticlopidine hydrochloride as shown in Figure 2, comprises the following steps:
1. p-toluenesulfonyl protection:
500ml toluene is added in 1000ml reaction flask, 50g thiophene ethanol and 80g Tosyl chloride, open and stir, control temperature drips 47g triethylamine under 0 DEG C of condition, drip and continue about 30min, drip off and be warming up to 25 DEG C of reactions 3 hours, in reaction solution, add 400ml water, wash at twice, the toluene layer washed directly spends the next step.
2. condensation reaction
The toluene solution walking reaction is added in 1000ml reaction flask, then add 114g o-chlorine benzylamine, be heated to 90 DEG C of reactions 3 hours, be cooled to 25 DEG C after having reacted and stir 1 hour, filter, add 200ml water in filtrate, stir the lower hydrochloric acid regulation system pH value that drips 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 condenses hydrochloride after 50 DEG C of vacuum-drying.
3. ring closure reaction
96g condenses hydrochloride, 400ml1 is added in 1000ml reaction flask, 3-dioxolane and 5ml hydrochloric acid, 90 DEG C of reactions 6 hours are warming up under stirring, 7 DEG C of stirring and crystallizing 3 hours are cooled to after having reacted, filter, filter cake obtains 95g ticlopidine hydrochloride crude product with after a small amount of 1,3-dioxolane washing after 50 DEG C of vacuum-drying.
4. refining
95g ticlopidine hydrochloride crude product and 500ml dehydrated alcohol is added in 1000ml reaction flask, 72 DEG C are heated under stirring, after solid all dissolves, 2g gac is added after about 10 minutes, insulation decolouring filtered while hot after 20 minutes, filtrate is cooled to 4 DEG C of stirring and crystallizing 4 hours gradually, filter, filter cake obtains 91g ticlopidine hydrochloride highly finished product with after a small amount of absolute ethanol washing after 50 DEG C of vacuum-drying.Total recovery 82%, purity 99.9%
Embodiment 2
The preparation method of ticlopidine hydrochloride as shown in Figure 2, comprises the following steps:
1. p-toluenesulfonyl protection:
250ml toluene is added in 500ml reaction flask, 25g thiophene ethanol and 44g Tosyl chloride, open and stir, control temperature drips 24g triethylamine under 5 DEG C of conditions, drip and continue about 25min, drip off and be warming up to 28 DEG C of reactions 1 hour, in reaction solution, add 200ml water, divide three washings, the toluene layer washed directly spends the next step.
2. condensation reaction
The toluene solution walking reaction is added in 500ml reaction flask, then add 70g o-chlorine benzylamine, be heated to 88 DEG C of reactions 4 hours, be cooled to 28 DEG C after having reacted and stir 3 hours, filter, add 200ml water in filtrate, stir the lower hydrochloric acid regulation system pH value that drips 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 condenses hydrochloride after 55 DEG C of vacuum-drying.
3. ring closure reaction
48g condenses hydrochloride, 250ml1 is added in 500ml reaction flask, 3-dioxolane and 5ml hydrochloric acid, 88 DEG C of reactions 8 hours are warming up under stirring, 10 DEG C of stirring and crystallizing 1 hour is cooled to after having reacted, filter, filter cake obtains 48g ticlopidine hydrochloride crude product with after a small amount of 1,3-dioxolane washing after 60 DEG C of vacuum-drying.
4. refining
48g ticlopidine hydrochloride crude product and 300ml dehydrated alcohol is added in 500ml reaction flask, 70 DEG C are heated under stirring, after solid all dissolves, 2g gac is added after about 10 minutes, insulation decolouring filtered while hot after 40 minutes, filtrate is cooled to 0 DEG C of stirring and crystallizing 6 hours gradually, filter, filter cake obtains 45g ticlopidine hydrochloride highly finished product with after a small amount of absolute ethanol washing after 55 DEG C of vacuum-drying.Total recovery 77%, purity 99.8%.
Embodiment 3
The preparation method of ticlopidine hydrochloride as shown in Figure 2, comprises the following steps:
1. p-toluenesulfonyl protection:
500ml toluene is added in 1000ml reaction flask, 50g thiophene ethanol and 84g Tosyl chloride, open and stir, control temperature drips 50g triethylamine under 4 DEG C of conditions, drip and continue about 35min, drip off and be warming up to 30 DEG C of reactions 2 hours, in reaction solution, add 400ml water, wash at twice, the toluene layer washed directly spends the next step.
2. condensation reaction
The toluene solution walking reaction is added in 1000ml reaction flask, then add 126g o-chlorine benzylamine, be heated to 85 DEG C of reactions 2 hours, be cooled to 30 DEG C after having reacted and stir 2 hours, filter, add 200ml water in filtrate, stir the lower hydrochloric acid regulation system pH value that drips 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 condenses hydrochloride after 60 DEG C of vacuum-drying.
3. ring closure reaction
95g condenses hydrochloride, 300ml1 is added in 1000ml reaction flask, 3-dioxolane and 10ml hydrochloric acid, 85 DEG C of reactions 4 hours are warming up under stirring, 5 DEG C of stirring and crystallizing 2 hours are cooled to after having reacted, filter, filter cake obtains 93g ticlopidine hydrochloride crude product with after a small amount of 1,3-dioxolane washing after 55 DEG C of vacuum-drying.
4. refining
93g ticlopidine hydrochloride crude product and 500ml dehydrated alcohol is added in 1000ml reaction flask, 75 DEG C are heated under stirring, after solid all dissolves, 2g gac is added after about 10 minutes, insulation decolouring filtered while hot after 30 minutes, filtrate is cooled to 5 DEG C of stirring and crystallizing 2 hours gradually, filter, filter cake obtains 89g ticlopidine hydrochloride highly finished product with 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, and it should be pointed out that for those skilled in the art, under the prerequisite not departing from inventive principle, can also make some improvement, these improvement also should be considered as protection scope of the present invention.
Claims (8)
1. a preparation method for ticlopidine hydrochloride, is characterized in that: comprise the following steps:
(1) be that the thiophene ethanol of 1:1.05-1.15 and Tosyl chloride join reaction unit by solvent, mol ratio, control temperature, at 0-5 DEG C, drips acid binding agent under agitation condition;
(2) 25-30 DEG C of insulation reaction 1-3 hour is warming up to;
(3) in the reaction solution of step (2), water washing 2-3 time is added;
(4) get solvent layer, then add o-chlorine benzylamine wherein, be heated to 85-90 DEG C of reaction 2-4 hour;
(5) be cooled to 25-30 DEG C and stir filtration after 1-3 hour;
(6) add water in filtrate, under agitation 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 to filter after stirring and crystallizing 2-6 hour;
(9) filter cake obtains condenses hydrochlorate after 50-60 DEG C of vacuum-drying;
(10) the condenses hydrochlorate described in step (9) and 1,3-dioxolane and hydrochloric acid are joined reaction unit, under stirring, be warming up to 85-90 DEG C of reaction 4-8 hour;
(11) be cooled to 5-10 DEG C to filter after stirring and crystallizing 1-3 hour;
(12) filter cake is with after the washing of 1,3-dioxolane, after 50-60 DEG C of vacuum-drying, obtain ticlopidine hydrochloride.
2. the preparation method of ticlopidine hydrochloride according to claim 1, is characterized in that: described step also comprises ticlopidine hydrochloride treating process after (12), and described treating process comprises the following steps:
(1) by after vacuum-drying ticlopidine hydrochloride and dehydrated alcohol join reaction unit, be heated to 70-75 DEG C under agitation condition;
(2) ticlopidine hydrochloride adds gac after dissolving completely;
(3) insulation decolouring 20-40 minute after filtered while hot;
(4) filtrate is cooled to 0-5 DEG C of stirring and crystallizing 2-6 hour gradually;
(5), after filter cake absolute ethanol washing, ticlopidine hydrochloride must be refined after 50-60 DEG C of vacuum-drying.
3. the preparation method of ticlopidine hydrochloride according to claim 1, is characterized in that: described acid binding agent drips and continues 25-35 minute.
4. the preparation method of the ticlopidine hydrochloride according to claim 1 or 3, is characterized in that: described acid binding agent is triethylamine.
5. the preparation 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 preparation method of ticlopidine hydrochloride according to claim 1, is characterized in that: described step (6) and step (7) use salt acid for adjusting pH.
7. the preparation method of ticlopidine hydrochloride according to claim 1, is characterized in that: described solvent is toluene.
8. the preparation method of ticlopidine hydrochloride according to claim 1, is characterized in that: described water is pure water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511013844.0A CN105461735A (en) | 2015-12-31 | 2015-12-31 | Preparation method of ticlopidine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511013844.0A CN105461735A (en) | 2015-12-31 | 2015-12-31 | Preparation method of ticlopidine hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105461735A true CN105461735A (en) | 2016-04-06 |
Family
ID=55599948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201511013844.0A Pending CN105461735A (en) | 2015-12-31 | 2015-12-31 | Preparation method of ticlopidine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105461735A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4127580A (en) * | 1975-02-07 | 1978-11-28 | Parcor | Process for the preparation of thieno-pyridine derivatives |
| EP0377413A1 (en) * | 1989-01-04 | 1990-07-11 | ISTITUTO BIOCHIMICO NAZIONALE SAVIO S.r.l. | Pharmaceutical compositions having topical use comprising Ticlopidine |
| US6043368A (en) * | 1996-09-04 | 2000-03-28 | Poli Industria Chimica, S.P.A. | Method of making thieno-pyridine derivatives |
| CN103467440A (en) * | 2013-10-16 | 2013-12-25 | 连云港宏业化工有限公司 | Synthesis method of 2-thiopheneethamine |
-
2015
- 2015-12-31 CN CN201511013844.0A patent/CN105461735A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4127580A (en) * | 1975-02-07 | 1978-11-28 | Parcor | Process for the preparation of thieno-pyridine derivatives |
| EP0377413A1 (en) * | 1989-01-04 | 1990-07-11 | ISTITUTO BIOCHIMICO NAZIONALE SAVIO S.r.l. | Pharmaceutical compositions having topical use comprising Ticlopidine |
| US6043368A (en) * | 1996-09-04 | 2000-03-28 | Poli Industria Chimica, S.P.A. | Method of making thieno-pyridine derivatives |
| CN103467440A (en) * | 2013-10-16 | 2013-12-25 | 连云港宏业化工有限公司 | Synthesis method of 2-thiopheneethamine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103333942A (en) | A synthetic method for (R)-praziquantel | |
| CN102617542B (en) | Method for preparing and purifying olmesartan intermediate | |
| CN105418581A (en) | Preparation method of trelagliptin succinate | |
| CN105254575B (en) | A kind of synthetic method of sulphadiazine | |
| CN101426795B (en) | Process for preparing dorzolamide | |
| JPS603387B2 (en) | Novel optically active imidazolidin-2-one derivatives and their production method | |
| CN105399753A (en) | Novel preparation method for ticlopidine hydrochloride | |
| CN103044323B (en) | A kind of purification process of SASP | |
| CN105461735A (en) | Preparation method of ticlopidine hydrochloride | |
| CN105541862A (en) | Method for preparing ticlopidine hydrochloride | |
| CN105503902A (en) | Method for synthesizing ticlopidine hydrochloride | |
| CN105601645A (en) | Method for synthesizing ticlopidine hydrochloride | |
| CN100427460C (en) | Method for synthesis of L-norvaline | |
| CN105601644A (en) | Novel method for synthesizing ticlopidine hydrochloride | |
| CN107324986A (en) | The preparation method and application of 16 (S) hilo prostaglandins | |
| CN104418810A (en) | New synthetic route of levosimendan | |
| CN101492413B (en) | Fine purification method for carprofen | |
| US6545149B2 (en) | Synthesis and crystallization of piperazine ring-containing compounds | |
| CN105001200A (en) | Preparation method of anti-angiogenesis compound and intermediate thereof | |
| CN106349145A (en) | Method for preparing intelligence-improving medicine (S)-oxiracetam | |
| CN103865976A (en) | Method of biochemically separating 8-benzyl-7, 9-dioxo-2, 8-diazo bicycle [4.3.0] nonane | |
| CN105461656A (en) | Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine | |
| CN102203077B (en) | ( pyrrolidin-2 -yl) phenyl derivatives for use in the treatment of pain | |
| CN106892926A (en) | A kind of intermediate of DPP IV inhibitor, its preparation method and the method that DPP IV inhibitor is prepared by it | |
| CN115124473B (en) | Method for synthesizing cimetidine related substance B |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160406 |
|
| RJ01 | Rejection of invention patent application after publication |