CN109280045A - The synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- - Google Patents
The synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- Download PDFInfo
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- CN109280045A CN109280045A CN201811546031.1A CN201811546031A CN109280045A CN 109280045 A CN109280045 A CN 109280045A CN 201811546031 A CN201811546031 A CN 201811546031A CN 109280045 A CN109280045 A CN 109280045A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/06—Halogens; Compounds thereof
- B01J27/135—Halogens; Compounds thereof with titanium, zirconium, hafnium, germanium, tin or lead
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Abstract
The invention discloses a kind of synthetic methods of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5-, belong to pharmaceutical field, which is characterized in that react 2- chlorothiophene and haloacetyl chloride under the effect of the catalyst and obtain the chloro- 2- thiophene chloride of 5-.The reaction process are as follows: 1) mix haloacetyl chloride, catalysts and solvents A; it is passed through protection gas; control pressure is 3~5 atmospheric pressure; temperature is controlled to 80~115 DEG C, the solution of 2- chlorothiophene and solvent B is added dropwise, and controls and the time is added as 20~30min; it finishes; reaction temperature is increased to 145~155 DEG C, increases pressure to 7~9 atmospheric pressure, then proceeding to 20~35h of reaction reaction terminates；2) system cooled and filtered is removed into solid, filtrate is added in the water of 2~4 times of volumes, is then extracted with solvent C, and after extracting solution desiccant dryness, concentration is evaporated off solvent and obtains product.Synthetic method of the present invention is safe and reliable, production cost is low, and basic no three wastes generates, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to a kind of synthesis of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5-
Method.
Background technique
Razaxaban (Rivaroxaban) is by Bayer Bitterfeld GmbH medicine and the success of Johnson Co.'s cooperative research and development. 2008
It gets the Green Light listing in Canada and European Union in year October, trade name Xarelto.Razaxaban is that first, the whole world is oral
Direct Xa factor inhibitor, can highly selective, Reverse transcriptase is free and the Xa factor and prothrombin activity that combine, with agent
Amount-dependence mode extends activated partial thromboplastin time plate (PT) and prothrombin time (aPTT), thus when extending blood coagulation
Between, it reduces fibrin ferment and is formed.Essential distinction with traditional antithrombotic reagent heparin is that it does not need antithrombin Ⅲ participation, can
The Xa factor that direct antagonism dissociates and combines.And heparin then needs the effect of antithrombin Ⅲ competence exertion, and factor is multiple
The Xa factor closed in object is invalid.This new oral anticoagulant is described as anticoagulant therapy and potential lethal thrombus by medical field
One major progress of prevention area will become milestone new in cardio-cerebralvascular drug development history.It is with biological utilisation
Degree is high, and treatment spectrum of disease is wide, and dose-effect relationship is stablized, convenient oral, the low feature of bleeding risk.Razaxaban can be used for preventing non-
Valvular Patients With Atrial Fibrillation cerebral apoplexy and non-central nervous system embolism reduce the risk of coronary syndrome recurrence
Deng；Be also prevention and treatment phlebothrombosis drug, for prevent hip joint and knee prosthesis postoperative patient person deep vein thrombosis (DVT) and
The formation of pulmonary embolism (PE).
For the synthesis of razaxaban, researcher develops a variety of methods and route, and the chloro- 2- thiophene chloride of 5- is
Wherein important intermediate, as follows:
Having more documents to disclose using 5- chlorothiophene -2- carboxylic acid in the prior art is that starting material prepares the chloro- 2- of 5-
Thiophene chloride, as follows.
There are also thionyl chlorides, oxalyl in addition to triphosgene for the chloride reagent of the synthesis chloro- 2- thiophene chloride of 5- at present
Chlorine etc., since heat release is very violent when with carboxylic acid reaction for such chlorinating agent, when dosing operation, inevitably requires to control
System is gradually added dropwise in certain range of reaction temperature, the major defect that energy consumption is high, period length is the current technology.In addition, chlorine
Change sulfoxide to the serious corrosion of equipment, the sulfur dioxide of a large amount of asphyxiatings is contained in industrial tail gas, it is tight to belong to national environmental protection
One of the gas of lattice control, three-protection design are difficult.And the transport and use of thionyl chloride set reaction by stringent control
Standby sealing requirements are very high, and production operation safety is poor；Not only to air-sensitive, encountering moisture can decompose releasing oxalyl chloride
Poisonous gas CO, CO2And HCl, and oxalyl chloride has high toxicity and corrosivity, can seriously stimulate eyes, skin and breathing
Road, the reagent bottle for holding oxalyl chloride must save under shady and cool, dry environment, and strictly seal, such chloride reagent exists
Daily transport, storage or metering are extremely inconvenient when using.
Summary of the invention
The purpose of the present invention is to the deficiencies in the prior art, provide it is a kind of it is safe and reliable, production cost is low,
Basic no three wastes generates, is suitable for the preparation method of the chloro- 2- thiophene chloride of 5- of industrialized production.
To achieve the above object, the present invention adopts the following technical scheme:
The synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5-, which is characterized in that by 2- chlorothiophene and halogenated
Chloroacetic chloride reacts under the effect of the catalyst obtains the chloro- 2- thiophene chloride of 5-.
The reaction process are as follows:
1) haloacetyl chloride, catalysts and solvents A being mixed, is passed through protection gas, control pressure is 3~5 atmospheric pressure,
Temperature is controlled to 80~115 DEG C, the solution of 2- chlorothiophene and solvent B is added dropwise, and controls and the time is added as 20~30min, is finished,
Reaction temperature is increased to 145~155 DEG C, increases pressure to 7~9 atmospheric pressure, then proceeding to 20~35h of reaction reaction terminates；
2) system cooled and filtered is removed into solid, filtrate is added in the water of 2~4 times of volumes, is then mentioned with solvent C
It takes, after extracting solution desiccant dryness, concentration is evaporated off solvent and obtains product.
The haloacetyl chloride is trichloro-acetic chloride, tribromo-acetyl chloride or chlorine difluoroacetic acid chloride.
The method for preparing catalyst are as follows: zirconium fluoride is uniform with alumina lap, it crosses 300~600 meshes and obtains；It is described
The weight ratio of zirconium oxide and aluminium oxide is 1:(8.5~12.6)；The aluminium oxide is Alpha-alumina.
In step 1), the solvent A is THF or DMF；The solvent B is toluene or dimethylbenzene；The protection gas is
Nitrogen or argon gas.
The weight ratio of the 2- chlorothiophene and catalyst is 1:(0.05~0.075), the haloacetyl chloride and solvent A
Amount ratio is 1g:(7.1~8.5) mL, the molar ratio of the 2- chlorothiophene and haloacetyl chloride is 1:(1.06~1.12), institute
The amount ratio for stating 2- chlorothiophene and solvent B is 1g:(5.2~7.5) mL.
In step 2), the solvent C is chloroform or toluene；The desiccant is anhydrous magnesium sulfate or anhydrous chlorination
Calcium.
The present invention synthesizes the chloro- 2- thiophene first of 5- using 2- chlorothiophene and haloacetyl chloride as raw material under the effect of the catalyst
Acyl chlorides, possible reaction mechanism are as follows:
The catalyst that the present invention uses provides reaction interface for two kinds of main reactant, so that they are anti-under a surface
It answers；And catalyst has more unoccupied orbital, and the carbonylic oxygen atom in haloacetyl chloride has lone pair electrons, the two is tangible
At the trend of complex coordination, so that haloacetyl chloride Central Plains acyl chlorides carbon atom forms the intensifying trend of carbonium ion；And R base
There are electron-withdrawing groups in group, also increase trend to form above-mentioned carbonium ion.In this way, allowing for the nucleophilic of former acyl chlorides carbon atom
Property greatly reinforce, in thiphene ring sulphur atom ortho position carbon atom occur necleophilic reaction, to obtain product.Therefore, reactant
Have and have an effect on the surface of catalyst, could react and generate target product.The present invention uses the condition of higher temperature and pressurization,
Reactant can be increased in " collision " probability of catalyst surface, improve yield.
Compared with the existing technology, advantages of the present invention has:
1, reaction raw materials are easy to get and operate comparatively safe, and cost is relatively low；
2, side reaction is few, and reaction yield is higher, and product purity is higher, and process costs are lower；
3, post-processing operation is simple, pollution-free no discharge.
Specific embodiment
Combined with specific embodiments below, the present invention is further illustrated.
Embodiment 1
The synthetic method of the chloro- 2- thiophene chloride of 5-, comprising the following steps:
1) trichloro-acetic chloride, catalyst and DMF are mixed, is passed through argon gas, control pressure is 4.5 atmospheric pressure, control temperature
The solution of 2- chlorothiophene and toluene is added dropwise to 100 DEG C in degree, and controls and the time is added as 26min, finishes, increases reaction temperature extremely
152 DEG C, pressure is increased to 8.5 atmospheric pressure, then proceeding to reaction 31h reaction terminates；
Method for preparing catalyst are as follows: zirconium fluoride and Alpha-alumina are ground uniformly, 550 meshes is crossed and obtains；Zirconium oxide and α-
The weight ratio of aluminium oxide is 1:10.5.
The weight ratio of 2- chlorothiophene and catalyst is 1:0.07, and the amount ratio of the trichloro-acetic chloride and DMF are 1g:
The molar ratio of 8mL, the 2- chlorothiophene and trichloro-acetic chloride is 1:1.10, and the amount ratio of the 2- chlorothiophene and toluene is 1g:
6.8mL。
2) system cooled and filtered is removed into solid, filtrate is added in the water of 3 times of volumes, then uses chloroform recovery, mentions
After taking liquid anhydrous magnesium sulfate dry, concentration is evaporated off solvent and obtains product, molar yield 98.2%, GC purity 98.5%.
Embodiment 2
The synthetic method of the chloro- 2- thiophene chloride of 5-, comprising the following steps:
1) tribromo-acetyl chloride, catalyst and THF are mixed, is passed through nitrogen, control pressure is 3 atmospheric pressure, controls temperature
To 80 DEG C, the solution of 2- chlorothiophene and dimethylbenzene is added dropwise, and controls and the time is added as 20min, finishes, increases reaction temperature extremely
145 DEG C, pressure is increased to 7 atmospheric pressure, then proceeding to reaction 20h reaction terminates；
Method for preparing catalyst are as follows: zirconium fluoride and Alpha-alumina are ground uniformly, 300 meshes is crossed and obtains；Zirconium oxide and α-
The weight ratio of aluminium oxide is 1:8.5.
The weight ratio of 2- chlorothiophene and catalyst is 1:0.05, and the amount ratio of the tribromo-acetyl chloride and THF are 1g:
The molar ratio of 7.1mL, the 2- chlorothiophene and tribromo-acetyl chloride is 1:1.06, and the amount ratio of the 2- chlorothiophene and dimethylbenzene is
1g:5.2mL。
2) system cooled and filtered is removed into solid, filtrate is added in the water of 2 times of volumes, then uses toluene, extracting solution
After anhydrous calcium chloride drying, concentration is evaporated off solvent and obtains product, molar yield 97.1%, GC purity 98.1%.
Embodiment 3
The synthetic method of the chloro- 2- thiophene chloride of 5-, comprising the following steps:
1) chlorine difluoroacetic acid chloride, catalyst and DMF are mixed, is passed through argon gas, control pressure is 5 atmospheric pressure, control temperature
The solution of 2- chlorothiophene and toluene is added dropwise to 115 DEG C in degree, and controls and the time is added as 30min, finishes, increases reaction temperature extremely
155 DEG C, pressure is increased to 9 atmospheric pressure, then proceeding to reaction 35h reaction terminates；
Method for preparing catalyst are as follows: zirconium fluoride and Alpha-alumina are ground uniformly, 600 meshes is crossed and obtains；Zirconium oxide and α-
The weight ratio of aluminium oxide is 1 :~12.6.
The weight ratio of 2- chlorothiophene and catalyst is 1:0.075, and the amount ratio of the chlorine difluoroacetic acid chloride and DMF are 1g:
8.5mL, the molar ratio of the 2- chlorothiophene and chlorine difluoroacetic acid chloride are 1:1.12, and the amount ratio of the 2- chlorothiophene and toluene is
1g:7.5mL。
2) system cooled and filtered is removed into solid, filtrate is added in the water of 4 times of volumes, then uses chloroform recovery, mentions
After taking liquid anhydrous calcium chloride dry, concentration is evaporated off solvent and obtains product, molar yield 97.9%, GC purity 98.9%.
Embodiment 4
Reaction pressure before addition 2- chlorothiophene is set as 8 atmospheric pressure, reaction temperature is set as 130 DEG C, other reaction items
Part and material are with than same embodiment 1, molar yield 65.3%, GC purity 85.1%.
Embodiment 5
Reaction pressure before addition 2- chlorothiophene is set as 2 atmospheric pressure, reaction temperature is set as 60 DEG C, other reaction conditions
With material with than same embodiment 1, molar yield 55.2%, GC purity 61.2%.
Embodiment 6
Reaction pressure after addition 2- chlorothiophene is set as 12 atmospheric pressure, reaction temperature is set as 185 DEG C, other reaction items
Part and material are with than same embodiment 1, molar yield 70.6%, GC purity 76.5%.
Embodiment 7
Reaction pressure after addition 2- chlorothiophene is set as 5 atmospheric pressure, reaction temperature is set as 110 DEG C, other reaction items
Part and material are with than same embodiment 1, molar yield 43.1%, GC purity 50.2%.
The analysis of 8 product nucleus magnetic hydrogen spectrum of embodiment
1H-NMR (DMSO): δ 7.99 (1H), δ 6.75 (1H).Ownership of the various hydrogen on product structure is as follows:
Nmr analysis, product structure meet object, the i.e. chloro- 2- thiophene chloride of 5-.
Claims (6)
1. the synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5-, which is characterized in that by 2- chlorothiophene and halogenated second
Acyl chlorides reacts under the effect of the catalyst obtains the chloro- 2- thiophene chloride of 5-；The reaction process are as follows: 1) by haloacetyl chloride,
Catalysts and solvents A is mixed, and is passed through protection gas, and control pressure is 3~5 atmospheric pressure, is controlled temperature to 80~115 DEG C, is added dropwise
The solution of 2- chlorothiophene and solvent B, and control and the time is added as 20~30min, it finishes, increases reaction temperature to 145~155
DEG C, pressure is increased to 7~9 atmospheric pressure, and then proceeding to 20~35h of reaction reaction terminates；2) system cooled and filtered is removed
Solid, filtrate are added in the water of 2~4 times of volumes, are then extracted with solvent C, and after extracting solution desiccant dryness, concentration is evaporated off
Solvent obtains product.
2. the synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- as described in claim 1, which is characterized in that
The haloacetyl chloride is trichloro-acetic chloride, tribromo-acetyl chloride or chlorine difluoroacetic acid chloride.
3. the synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- as described in claim 1, which is characterized in that
The method for preparing catalyst are as follows: zirconium fluoride is uniform with alumina lap, it crosses 300~600 meshes and obtains；The zirconium oxide with
The weight ratio of aluminium oxide is 1:(8.5~12.6)；The aluminium oxide is Alpha-alumina.
4. the synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- as claimed in claim 2, which is characterized in that
In step 1), the solvent A is THF or DMF；The solvent B is toluene or dimethylbenzene；The protection gas be nitrogen or
Argon gas.
5. the synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- as claimed in claim 2, which is characterized in that
In step 1), the weight ratio of the 2- chlorothiophene and catalyst is 1:(0.05~0.075), the haloacetyl chloride and solvent A
Amount ratio be 1g:(7.1~8.5) mL, the molar ratio of the 2- chlorothiophene and haloacetyl chloride is 1:(1.06~1.12), institute
The amount ratio for stating 2- chlorothiophene and solvent B is 1g:(5.2~7.5) mL.
6. the synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- as claimed in claim 2, which is characterized in that
In step 2), the solvent C is chloroform or toluene；The desiccant is anhydrous magnesium sulfate or anhydrous calcium chloride.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146457A (en) * | 2015-04-22 | 2016-11-23 | 联化科技（台州）有限公司 | A kind of 5-chloro-2-acyl chlorides thiophene intermediate and preparation method thereof |
| CN106831702A (en) * | 2016-12-05 | 2017-06-13 | 浙江燎原药业股份有限公司 | A kind of preparation method of the thiophenic acid of 5 substitution 2 |
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- 2018-12-18 CN CN201811546031.1A patent/CN109280045A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146457A (en) * | 2015-04-22 | 2016-11-23 | 联化科技（台州）有限公司 | A kind of 5-chloro-2-acyl chlorides thiophene intermediate and preparation method thereof |
| CN106831702A (en) * | 2016-12-05 | 2017-06-13 | 浙江燎原药业股份有限公司 | A kind of preparation method of the thiophenic acid of 5 substitution 2 |
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