CN107602583A - A kind of synthetic method of jak kinase inhibitor intermediate - Google Patents

Abstract

The present invention relates to a kind of preparation method of iodothiophen of 2 chlorine 7 simultaneously [3,2 D] pyrimidine, using the thiophenecarboxylate of 3 amino 2 as initiation material, through urea cyclization, chloro, reduction, iodo is prepared.The present invention is easy to operate, reaction condition is gentle, N N-iodosuccinimides are produced especially with reaction in-situ carries out iodo, it is not only environment-friendly, and the yield of iodide reaction is substantially increased, while reduce production cost, have compared with prior art and be obviously improved, be adapted to industrial-scale production.

Description

A kind of synthetic method of jak kinase inhibitor intermediate

Technical field

The invention belongs to medicinal chemistry art, and in particular to a kind of chloro- 7- iodothiophens of jak kinase inhibitor intermediate 2- are simultaneously The synthetic method of [3,2-D] pyrimidine.

Background technology

JAK (non-receptor type is intracellular kinases) plays a significant role in cell function regulation, activity to protein, Positioning and function effect are huge.JAK and gene mutation or regulation are disorderly related with a variety of diseases, such as：Autoimmune disease, Tumour, leukaemia and diabetes etc..World patent WO2009/062258A1, which discloses one kind, has thieno [3,2-D] pyrimidine The JAK inhibitor of class formation, there is good oncotherapy effect, but the synthesis of such compound is related to key intermediate 2- Simultaneously [3,2-D] pyrimidine, the patent carry out iodide reaction to chloro- 7- iodothiophens using periodic acid and ICl, and reaction effect is poor, and not Purifying is can be easily separated, yield is only 37%.Chinese patent CN2012104339097 discloses one kind with N- N-iodosuccinimides For the synthetic method of iodo reagent, although improving the yield of reaction to a certain extent, directly with N- N-iodosuccinimides For iodo reagent, its yield is extremely unstable, and from 37.5%-75%, and N- N-iodosuccinimide prices are very expensive, It is still not suitable for industrialized production.

Because above-mentioned intermediate is the key intermediate of the synthesizing thiofuran simultaneously JAK inhibitor of [3,2-D] pyrimidine class formation, because This, more efficiently synthetic method is still the demand in industry.

Present inventor has carried out experimental study to its synthetic method, it is found that using N- chlorosuccinimides and iodine Change potassium or sodium iodide reaction in-situ produces N- N-iodosuccinimides and carries out iodo, can not only improve the yield of the step (more than 88%), and stable yield, are advantageous to industrial-scale production.

The content of the invention

The technical problem to be solved in the present invention is to provide a kind of synthesis side of the chloro- 7- iodothiophens of 2- simultaneously [3,2-D] pyrimidine Method, this method has gentle easy to operate, reaction condition, high income and that stable yield, purity are high, production cost is low etc. is excellent Point, it is adapted to industrial-scale production.

To achieve the above object, technical solution of the invention：

A kind of preparation method of chloro- 7- iodothiophens of 2- simultaneously [3,2-D] pyrimidine, comprises the following steps：

1) the 3- amino -2- thiophenecarboxylates and urea of Formula V, under solvent-free, the heating response at 140-220 DEG C, instead It should terminate, the post-treated intermediate obtained shown in formula IV；

2) intermediate shown in formula IV obtains intermediate shown in formula III through chlorination；

3) intermediate shown in formula III, palladium carbon catalysis under, with hydrogen reducing react Formula II intermediate；

4) heating is added portionwise into the solution containing iodide and N- chlorosuccinimides instead in Formula II intermediate Should, it is post-treated to obtain compound shown in Formulas I；

Reaction equation is as follows：

Further, as preferable scheme, the mol ratio of step 1) compound of formula V and urea is 1: 2-6；Further Ground,

As preferable scheme, preferred 180-200 DEG C of step 1) reaction temperature.

In a preferred embodiment, chlorination uses thionyl chloride or POCl3 to be tried for chloro in step 2) Agent.

As the preferable scheme of invention, the dosage of palladium-carbon catalyst is 5-15wt%, preferably 10wt% in step 3).

Further, the solvent of solution described in step 4) is DMF, dimethyl acetamide, DMSO, ethanol, methanol, acetone In one or more.

It is highly preferred that the solvent of solution described in step 4) preferred DMF, dimethyl acetamide, DMSO.

As preferable scheme is invented, iodide described in step 4) are selected from KI or NaI.

Further, step 4) compound of formula H:N- chlorosuccinimides:Iodide=1:1.5-6:1.5-6.

As preferable scheme is invented, after step 1) reaction terminates, it is added to while hot in the sodium hydrate aqueous solution of saturation, Stirring, stand, filtering, at room temperature, mother liquor salt acid for adjusting pH to 2~4, refilter, filter cake is dried to obtain intermediate through washing Formula IV.

Further, formula IV intermediate is added in POCl3 or thionyl chloride by step 2), adds catalytic amount DMF, Heating reflux reaction, reaction terminate, and steam most POCl3, are slowly added into frozen water, are arrived with aqueous slkali regulation pH Neutrality, dichloromethane extraction, saturated sodium bicarbonate aqueous solution are washed, saturated aqueous common salt backwash, dry, be evaporated under reduced pressure to intermediate III。

Further, step 3) is in the presence of sodium acid carbonate and 10wt% palladium-carbon catalysts, with ethyl acetate and ethanol Mixed liquor is solvent, is passed through hydrogen, reacts at room temperature, filtering, removes reaction dissolvent under reduced pressure, obtains intermediate II.

Further, the operating process of step 4) is for solvent with DMF, dimethyl acetamide, DMSO etc., adds N- chloros Succimide, temperature control add iodide at 30 DEG C, when 2-3 is stirred after adding, then intermediate II are added portionwise, add Finish, be warming up to 70-100 DEG C.Reaction end is cooled to room temperature, adds water, separates out a large amount of solids, filters, and drying, obtains product I.

Beneficial effects of the present invention：

1) present invention produces N- iodo succinyl using reaction in-situ by iodide and the reaction of N- chlorosuccinimides Imines, original position are reacted, and not only increase the yield (more than 88%) of step reaction, and yield is highly stable, repeatability It is good, it is adapted to industrial-scale production, compared to prior art, is obviously improved.

2) because N- N-iodosuccinimides are expensive, N- is produced by iodide and the reaction of N- chlorosuccinimides N-iodosuccinimide substitutes and directly uses N- N-iodosuccinimides, advantageously reduces cost.

3) present invention optimizes the selection of the reaction condition of preparation technology, particularly reaction dissolvent and reactant, simplify Post processing mode, and improve yield and purity.

Embodiment

In order to further illustrate the present invention, embodiment, but protection scope of the present invention not limited to this are listed below：

Embodiment 1

1) synthesis of formula IV compound：

500g Formula V compound and 800g urea are added in dry there-necked flask, stirred, is heated to 190 DEG C, stirring is anti- 4h is answered, after the completion of reaction, in the sodium hydrate aqueous solution for the saturation for being added to 1600ml ice while hot, is stirred overnight, is filtered, filtrate With salt acid for adjusting pH to 2, filtering, filter cake is washed with water once, dries, obtains 481g formula IV compounds, HPLC：97%.

2) synthesis of formula III compound：

400g formula IV compounds are added in 1500ml thionyl chloride, and add 10mlDMF, heating reflux reaction After the completion of 10h, TLC detection reaction, remove most thionyl chloride under reduced pressure, be slowly added into frozen water, adjusted with aqueous slkali PH washes to neutrality, dichloromethane extraction, saturated sodium bicarbonate aqueous solution, and saturated aqueous common salt backwash is dry, is evaporated under reduced pressure to 450g Intermediate III, HPLC:95%.

3) synthesis of Formula II compound：

400g formula III compounds are added in 2000ml98% ethanol and 200ml ethyl acetate, added into system The palladium carbon of 200g sodium acid carbonates and 40g, hydrogen is passed through, reaction at room temperature overnight, after the completion of TLC detection reactions, is filtered, by filtrate Evaporated under reduced pressure, obtain 325g Formula II compounds, HPLC:97%.

4) synthesis of the chloro- 7- iodothiophens of compound of formula I 2- simultaneously [3,2-D] pyrimidine：

160g N- chlorosuccinimides are added in 1000ml DMF, temperature control adds 200g at 30 DEG C KI, stirred 3 hours after adding, then 100g intermediate IIs are added portionwise, finished, be warming up to 85 DEG C.Reaction end is cooled to room temperature, Water is added, separates out a large amount of solids, is filtered, drying, obtains 153g product I, yield 88%, HPLC:98%.

Embodiment 2

80g N- chlorosuccinimides are added in 600ml dimethyl acetamides, temperature control is at 25 DEG C, then adds Enter 90g KI, stirred 2.5 hours after adding, then 50g intermediate IIs are added portionwise, finish, be warming up to 100 DEG C, reaction terminates cold But to room temperature, water is added, separates out a large amount of solids, filtered, drying, obtain 82g product I, yield 95%, HPLC:99%.

Embodiment 3

150g N- chlorosuccinimides are added in 800ml DMSO, temperature control adds 180g at 30 DEG C NaI, stirred 4 hours after adding, then 100g intermediate IIs are added portionwise, finished, be warming up to 90 DEG C.Reaction end is cooled to room Temperature, water is added, separates out a large amount of solids, filtered, drying, obtain 161g product I, yield 92%, HPLC:98%.

Embodiments of the invention are its preferable embodiments, but are not limited to this.According to the spirit of the present invention, make not Same change, but as long as the spirit of the present invention is not departed from, all within protection scope of the present invention.

Claims (8)

1. a kind of preparation method of the chloro- 7- iodothiophens of 2- shown in Formulas I simultaneously [3,2-D] pyrimidine, comprises the following steps,

1) the 3- amino -2- thiophenecarboxylates and urea of Formula V, under solvent-free, the heating response at 140-220 DEG C, reaction knot Beam, the post-treated intermediate obtained shown in formula IV；

2) intermediate shown in formula IV obtains intermediate shown in formula III through chlorination；

3) intermediate shown in formula III, palladium carbon catalysis under, with hydrogen reducing react Formula II intermediate；

4) heating response into the solution containing iodide and N- chlorosuccinimides is added portionwise in Formula II intermediate, passed through Post-process to obtain compound shown in Formulas I.

Reaction equation is as follows：

2. preparation method as claimed in claim 1, it is characterised in that the mol ratio of step 1) compound of formula V and urea is 1 ∶2-6；Preferred 180-200 DEG C of reaction temperature.

3. the preparation method as described in claim any one of 1-2, it is characterised in that chlorination is sub- using dichloro in step 2) Sulfone or POCl3 are chlorinating agent.

4. the preparation method as described in claim any one of 1-3, it is characterised in that the dosage of palladium-carbon catalyst is in step 3) 5-15wt%, preferably 10wt%.

5. the preparation method as described in claim any one of 1-4, it is characterised in that the solvent of solution described in step 4) is DMF, the one or more in dimethyl acetamide, DMSO, ethanol, methanol, acetone.

6. the preparation method as described in claim any one of 1-5, it is characterised in that the solvent of solution described in step 4) is preferred DMF, dimethyl acetamide, DMSO.

7. the preparation method as described in claim any one of 1-6, it is characterised in that iodide described in step 4) be selected from KI or NaI。

8. the preparation method as described in claim any one of 1-7, it is characterised in that step 4) compound of formula H:N- chloros Succimide:Iodide=1:1.5-6:1.5-6.