CN104447573B - A kind of preparation method of etravirine - Google Patents

A kind of preparation method of etravirine Download PDF

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CN104447573B
CN104447573B CN201410699294.1A CN201410699294A CN104447573B CN 104447573 B CN104447573 B CN 104447573B CN 201410699294 A CN201410699294 A CN 201410699294A CN 104447573 B CN104447573 B CN 104447573B
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solvent
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etravirine
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CN104447573A (en
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刘新泳
康东伟
展鹏
方增军
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Shandong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the preparation method of a kind of etravirine.The method, with compound II and compound III as initial feed, occurs the nucleophilic substitution on pyrimidine ring to generate intermediate compound IV under the effect of alkali；Then intermediate compound IV generates key intermediate V with to cyano-aniline generation nucleophilic displacement of fluorine in the basic conditions；Key intermediate V carries out ammonification in microwave reactor and generates intermediate VI；Intermediate VI generates target product etravirine I through bromination again.Preparation method reaction selectivity of the present invention is high, simple to operate, and significantly shortens the response time compared to original synthetic method, reduces energy resource consumption, improves reaction yield, and total recovery is up to 38.5%, is suitable for industrialized great production.

Description

A kind of preparation method of etravirine
Technical field
The invention belongs to medicinal chemistry art, be specifically related to the preparation method of a kind of etravirine.
Background technology
Etravirine (Etravirine, R-165335, TMC-125), chemical entitled 4-[the bromo-2-of 6-amino-5 (4-cyanogen phenol Ammonia) pyrimidine-4-oxygen]-3,5-xylylic acid nitrile, is that the one of Tibotec company of the subsidiary/member companies exploitation of Johson & Johnson belongs to I type The non-nucleoside reverse transcriptase (NNRTI) of HIV (human immunodeficiency virus) (HIV-1), by the specificity with HIV1-RT In conjunction with destroying the catalytic site of reverse transcriptase and then blocking RNA dependency and the dependent DNA polymerase activity of DNA, thus Play anti HIV-1 virus effect.Clinical research shows, in the patient using NNRTI class medicine first, etravirine demonstrates very Strong antiviral activity, and HIV-1 infect patient have good drug metabolism to be distributed after oral etravirine, toleration is good Good.Etravirine obtains FDA on January 18th, 2008 by preferential examination and approval procedures to be ratified, and is combined other inverases and has treated Producing the AIDSinfected patient of drug resistance, the Drug therapy for ten hundreds of HIV persons and HIV sufferers provides newly Selection.
At present the synthetic method about etravirine is broadly divided into following two:
One, the synthetic route with halogenated pyrimidine as initiation material:
This compound is first public in international monopoly WO0027825A1, is with 2, and 4,6-tri-chloro-5-Bromopyrimidines are for initial former Material preparation, wherein synthetic route is:
The chloro-5-Bromopyrimidine of initiation material 2,4,6-tri-used in this route is not easy to obtain, and final step ammonifying process needs Will under conditions of 150 DEG C reaction under high pressure 4 days, yield is only 41%, there is response time length, defect that conversion ratio is low, no It is suitable for industrialized production.
Then with 2,4 in document (Organic Process Research&Development 2010,14,657 660), 6-trichloropyrimidine is the synthesis that initial feed reports this compound, and synthetic route is as follows:
This route is with 2, and 4,6-trichloropyrimidines are initial feed, obtains target through two step nucleophilic displacement of fluorine, ammonification with bromination Product etravirine.Each step raw material of this route is simple and easy to get, and the reaction yield of each step is the most all greatly improved, overall reaction Yield is up to 30.4%.But the 3rd step aminating reaction needs to react 12h under conditions of High Temperature High Pressure, there is the biggest danger Serious waste time and the energy in dangerous and potential safety hazard, and industrialized production, it would be highly desirable to improve.
Two, with to cyano group benzene guanidine as raw material or the synthetic route of intermediate:
Document (Bioorg.Med.Chem.Lett., 2011,11 (17), 2235-9) makes public for the first time with to cyano group benzene Guanidine is the synthetic route of initiation material:
This route with to cyano group benzene guanidine as initial feed, then obtain with ammonification through cyclization, chlorination, bromination, nucleophilic displacement of fluorine Target product etravirine.But the initial feed used in this route is expensive and should not obtain, and the parent of route the 4th step There is, with the aminating reaction of the 5th step, the problem that reaction yield is low in core substitution reaction, thus result in total receipts of whole piece synthetic route Rate, less than 10%, is not suitable for industrialized production.
Similarly, patent WO2012001695A1 discloses with to the cyano group benzene guanidine synthetic route as intermediate:
This route obtains cyano group benzene guanidine with reacting cyano-aniline and cyanamide, then through cyclization, chloro, nucleophilic displacement of fluorine, Ammonification, bromination reaction obtain target product etravirine.But wherein the first step generates the reaction yield to cyano group benzene guanidine only 24%, the reaction yield of last nucleophilic displacement of fluorine, ammonification and bromination is all less than 50%, and overall reaction yield also less than 10%, is not suitable for Industrialized production.
In the method for above-mentioned synthesis etravirine, to cyano group benzene guanidine, as raw material or the synthetic route of intermediate has all existed Beginning raw material is difficult to the problem low with the total recovery reacted, and the synthetic route with halogenated pyrimidine as initiation material to there is ammonification anti- Answer yield low and the problem of aminating reaction overlong time, it is therefore desirable to searching one is more efficient, have industrial production value Method synthesize etravirine and intermediate thereof.
Summary of the invention
For the deficiencies in the prior art, the present invention provides a kind of easy and simple to handle, and total recovery is high, has industrial production value The preparation method of etravirine.
Technical scheme is as follows:
A kind of preparation method of etravirine I,
With compound II and compound III as initial feed, under the effect of alkali, there is the nucleophilic on pyrimidine ring in the method Substitution reaction generates intermediate compound IV；
Then, intermediate compound IV generates key intermediate V with to cyano-aniline generation nucleophilic displacement of fluorine in the basic conditions；
Key intermediate V carries out ammonification in microwave reactor and generates intermediate VI；
Finally, intermediate VI generates target product etravirine I through bromination.
In the step of described preparation intermediate compound IV, described alkali is DIPEA.
In the described step preparing intermediate V, described alkaline condition is potassium tert-butoxide.
The present invention is more detailed, the preparation method of a kind of etravirine, and step is as follows:
(1) starting material compound II and compound III is dissolved in non-protonic solvent, in alkali N, N-diisopropyl second The effect of amine issues the N-4 position nucleophilic substitution of raw compounds II and generates intermediate compound IV；Wherein, compound II: compound The mol ratio of III:N, N-diisopropylethylamine three is 1.0:1.0-1.8:1.3-2.2, reaction dissolvent be Isosorbide-5-Nitrae-dioxane, N-Methyl pyrrolidone or DMF, reaction temperature is 65-85 DEG C；
(2) intermediate compound IV and to cyano-aniline under the effect of alkali potassium tert-butoxide, with dipole solvent in occur intermediate compound IV N-1 position nucleophilic substitution generate intermediate V；Wherein, compound IV: to cyano-aniline: the mol ratio of alkali potassium tert-butoxide is 1.0:0.9-1.2:1.5-2.5, reaction dissolvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide, Reaction temperature is 0-10 DEG C；
(3) intermediate V and ammonia join in dipole solvent, and reaction obtains intermediate VI；Wherein, reaction dissolvent is N-first Base ketopyrrolidine, DMF or dimethyl sulfoxide, reaction temperature 100-150 DEG C, reaction pressure 100- 135psi, response time 5-35min.
(4) intermediate VI and bromine join and carry out the bromination of intermediate in non-protonic solvent and obtain end product according to song Wei Lin I；Wherein compound VI is 1:1.2-2 with the ratio of bromating agent, and reaction dissolvent is dichloromethane, oxolane or second Nitrile, reaction temperature is 0-10 DEG C.
With compound II and compound III as initial feed, under the effect of alkali, there is the nucleophilic on pyrimidine ring in the present invention Substitution reaction generates intermediate compound IV；Then intermediate compound IV generates key with to cyano-aniline generation nucleophilic displacement of fluorine in the basic conditions Intermediate V；Key intermediate V carries out ammonification in microwave reactor and generates intermediate VI；Intermediate VI generates target through bromination Product etravirine I.
Synthetic route of the present invention is as follows:
According to the invention it is preferred to,
Compound II described in step (1): compound III: alkali N, N-diisopropylethylamine three's preferred molar ratio 1.0:1.2-1.4:1.6-1.8；Preferred 70-80 DEG C of reaction temperature；Reaction dissolvent preferred 1,4-dioxane.
In step (2), the preferred 1.0:1.0:2.0 of mol ratio of compound IV: to cyano-aniline: alkali potassium tert-butoxide；Reaction Preferred 0-5 DEG C of temperature；The preferred N-Methyl pyrrolidone of reaction dissolvent.
In step (3), reaction is carried out in microwave reactor；Wherein said microwave reaction preferred solvent N-methylpyrrole Alkanone；Preferred 120-150 DEG C of temperature；The preferred 120-135psi of pressure；Response time preferred 15-30min.
In step (4), compound VI and the preferred 1:1.4-1.6 of molar ratio of bromating agent；The preferred dichloromethane of reaction dissolvent Alkane；Preferred 0-5 DEG C of reaction temperature.
The invention provides a kind of new method synthesizing etravirine and synthesizing its intermediate with microwave reactor, this method Reaction selectivity is high, simple to operate, and significantly shortens the response time compared to original synthetic method, reduces the energy and disappears Consumption, overall yield of reaction has been brought up to 38.5% by original 30.4%, is suitable for industrialized production.
Below in conjunction with the case study on implementation of detailed description of the invention, the present invention will be further described.
Detailed description of the invention
The synthesis of embodiment 1 (1) compound IV
By 2,4,6-trimethylpyrimidine II (110mmol, 20.0g) and 3,5-dimethyl-4-4-hydroxy-benzonitrile III (110mmol, 16.2g) and N, N-diisopropylethylamine (DIEA) (132mmol, 17.0g) joins 100mL 1,4-dioxy six Ring reacts 2h in 70 DEG C, when question response liquid is cooled to about 10 DEG C, in reactant liquor, is slowly added the aqueous solution of 200mL and stirs Mix 30min, filter, be vacuum dried to obtain 29.8g intermediate compound IV, yield 92.5%.1H NMR(400MHz,DMSO-d6,ppm)δ: 7.76(2H,s,C3,C5-Ph-H),7.64(1H,s,pyrimidine-H),2.12(6H,s,CH3) .ESI-MS:m/z 294.28 (M+1).C13H9Cl2N3O(293.01),mp:207-209℃。
(2) synthesis of compound V
The intermediate compound IV (68mmol, 20.0g) upper step prepared, joins 100mL to cyano-aniline (68mmol, 8.0g) In N-Methyl pyrrolidone, in 30min, in reactant liquor, then add potassium tert-butoxide under condition of ice bath and maintain temperature 0-5 DEG C Continue stirring 2h.The most slowly reactant liquor is joined stirring 10min in 500mL water, filters.Then gained filter cake is added In 200mL water, being adjusted to pH with the hydrochloric acid solution of 3M is 6-7, filters, and is dried.Then dried filter cake is joined acetic acid In ethyl ester, 70 DEG C are stirred at reflux 30min, are cooled to 10 DEG C, filter, are repeated once operation by same step the most again, use Ethyl acetate solution washing filter cake cold for 20mL, is vacuum dried to obtain 15.5g intermediate V, yield 60.6% at a temperature of 50 DEG C.1H NMR(400MHz,DMSO-d6,ppm)δ:10.56(1H,s,NH),7.79(2H,s,C3,C5-Ph’-H),7.45-7.51(4H,m, Ph-H),6.93(1H,s,pyrimidine-H),2.13(6H,s,CH3) .ESI-MS:m/z:376.5 (M+1), 393.3 (M+ 18),398.4(M+23),C20H14ClN5O(375.09),277-279℃。
(3) synthesis of compound VI:
By intermediate V (5.3mmol, 2.0g), 15mL mass fraction is ammonia and the N-crassitude of 20mL of 25% Ketone solvent joins in microwave reaction pipe, is then placed in microwave reactor.Reaction temperature 130 DEG C, response time are set 30min, high-speed stirred, course of reaction produces pressure 130psi.React complete and be cooled to 5-10 DEG C, then in this temperature later Downhill reaction liquid add 5mL water and maintains continuation stirring 30min at this temperature, producing a large amount of precipitation, filtration, filter cake water Washing, then vacuum drying obtains 1.63g intermediate VI, yield 85.6% at a temperature of 45-50 DEG C.1H NMR(400MHz, DMSO-d6,ppm)δ:9.57(1H,s,NH),7.73(2H,s,C3,C5-Ph '-H), 7.65 (2H, d, J=8.0Hz, C3,C5- Ph-H), 7.46 (2H, d, J=8.0Hz, C2,C6-Ph-H),6.80(2H,s,NH2),5.47(1H,s,pyrimidine-H), 2.12(6H,s,CH3) .ESI-MS:m/z 357.4 (M+1), 379.5 (M+23) .C20H16N6O (356.14), mp:283-286 ℃。
(4) synthesis of compound I
Intermediate VI (8.4mmol, 3.0g) is dissolved in 30mL dichloromethane, then molten to this under conditions of 0-5 DEG C Liquid drips the dichloromethane solution 6mL of bromine (9.4mmol, 1.5g) and maintains this temperature continuation stirring 5h.Then to instead Answer and liquid adds 50mL water and adjusts pH=9-10 with the diluted sodium hydroxide solution of 4mol/L.Then with metabisulfite solution and Diluted sodium hydroxide solution maintains pH=8-9, and stirs 1h, then the solid separated out is filtered washing and in the temperature of 55-60 DEG C Under be vacuum dried to obtain etravirine crude product.Dried crude product etravirine is dissolved in the methanol solution of 40mL, and wherein Add activated carbon decolorization filtering at a temperature of 55-60 DEG C, evaporated under reduced pressure solvent, then recrystallization in ethyl acetate, filter It is dried to obtain sterling etravirine 2.9g, yield 80.2%.The total recovery of this synthetic route is 92.5% × 60.6% × 85.6% × 80.2%=38.5%.
1H NMR(400MHz,DMSO-d6,ppm)δ:9.60(1H,s,NH),7.75(2H,s,C3,C5-Ph’-H),7.54 (2H, d, J=8.0Hz, C3,C5-Ph-H), 7.43 (2H, d, J=8.0Hz, C2,C6-Ph-H),7.13(2H,s,NH2),2.12 (6H,s,CH3) .ESI-MS:m/z:435.4 (M+1), 427.4 (M+3), 457.4 (M+23), C20H15BrN6O (434.05), mp: 254-256℃。

Claims (6)

1. the preparation method of an etravirine I, it is characterised in that
With compound II and compound III as initial feed, under the effect of DIPEA, there is pyrimidine in the method Nucleophilic substitution on ring generates intermediate compound IV；
Then, intermediate compound IV generates key intermediate V with to cyano-aniline generation nucleophilic displacement of fluorine under the conditions of potassium tert-butoxide；
Key intermediate V carries out ammonification in the dipole solvent of microwave reactor and generates intermediate VI；Described dipole solvent is N-Methyl pyrrolidone, N,N-dimethylformamide or dimethyl sulfoxide；
Finally, intermediate VI generates target product etravirine I through bromination.
2. according to the preparation method described in claim 1, it is characterised in that step is as follows:
(1) starting material compound II and compound III is dissolved in non-protonic solvent, at the work of DIPEA Intermediate compound IV is generated with the N-4 position nucleophilic substitution issuing raw compounds II；Wherein, compound II: compound III:N, N- The mol ratio of diisopropylethylamine three is 1.0:1.0-1.8:1.3-2.2, and described non-protonic solvent is Isosorbide-5-Nitrae-dioxy six Ring, N-Methyl pyrrolidone or DMF, reaction temperature is 65-85 DEG C；
(2) intermediate compound IV and to cyano-aniline under the effect of potassium tert-butoxide, in dipole solvent, there is the N-1 position of intermediate compound IV Nucleophilic substitution generates intermediate V；Wherein, the mol ratio of compound IV: to cyano-aniline: potassium tert-butoxide is 1.0:0.9- 1.2:1.5-2.5, described dipole solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide, instead Temperature is answered to be 0-10 DEG C；
(3) intermediate V and ammonia join in dipole solvent, and reaction obtains intermediate VI；Wherein, described dipole solvent is N- Methyl pyrrolidone, DMF or dimethyl sulfoxide, reaction temperature 100-150 DEG C, reaction pressure 100- 135psi, response time 5-35min；
(4) intermediate VI and bromine join and carry out the bromination of intermediate in non-protonic solvent and obtain end product etravirine I；Wherein compound VI is 1:1.2-2 with the molar ratio of bromine, and described non-protonic solvent is dichloromethane, oxolane Or acetonitrile, reaction temperature is 0-10 DEG C.
3. according to the preparation method of claim 2, it is characterised in that the compound II described in step (1): compound III:N, N-diisopropylethylamine three's mol ratio is 1.0:1.2-1.4:1.6-1.8；Reaction temperature is 70-80 DEG C；Non-protonic solvent For 1,4-dioxane.
4. according to the preparation method of claim 2, it is characterised in that in step (2), compound IV: to cyano-aniline: the tert-butyl alcohol The mol ratio of potassium is 1.0:1.0:2.0；Reaction temperature is 0-5 DEG C；Dipole solvent is N-Methyl pyrrolidone.
5., according to the preparation method of claim 2, it is characterised in that in step (3), reaction is carried out in microwave reactor；Its Described in dipole solvent be N-Methyl pyrrolidone；Reaction temperature is 120-150 DEG C；Pressure is 120-135psi；During reaction Between be 15-30min.
6., according to the preparation method of claim 2, it is characterised in that in step (4), compound VI with the molar ratio of bromine is 1:1.4-1.6；Non-protonic solvent is dichloromethane；Reaction temperature is 0-5 DEG C.
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US8153790B2 (en) * 2009-07-27 2012-04-10 Krizmanic Irena Process for the preparation and purification of etravirine and intermediates thereof
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