CN104447573A - Preparation method for etravirine - Google Patents
Preparation method for etravirine Download PDFInfo
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- CN104447573A CN104447573A CN201410699294.1A CN201410699294A CN104447573A CN 104447573 A CN104447573 A CN 104447573A CN 201410699294 A CN201410699294 A CN 201410699294A CN 104447573 A CN104447573 A CN 104447573A
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- FKLWVQBVVYUQGJ-UHFFFAOYSA-N Cc1cc(C#N)cc(C)c1OC(N=C(NC(C=C1)=CCC1C#N)N1)=CC1Cl Chemical compound Cc1cc(C#N)cc(C)c1OC(N=C(NC(C=C1)=CCC1C#N)N1)=CC1Cl FKLWVQBVVYUQGJ-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1cc(C#N)cc(C)c1OC1=CC(*)NC(Nc(cc2)ccc2C#N)=N1 Chemical compound Cc1cc(C#N)cc(C)c1OC1=CC(*)NC(Nc(cc2)ccc2C#N)=N1 0.000 description 1
- CMORVDDKOVDMDP-UHFFFAOYSA-N Cc1cc(C#N)cc(C)c1Oc1nc(Nc(cc2)ccc2C#N)nc(Cl)c1 Chemical compound Cc1cc(C#N)cc(C)c1Oc1nc(Nc(cc2)ccc2C#N)nc(Cl)c1 CMORVDDKOVDMDP-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
Abstract
The invention discloses a preparation method for etravirine. The method comprises the following steps: performing nucleophilic substitution on a pyrimidine ring to generate an intermediate IV under the action of an alkali by taking a compound II and a compound III as initial raw materials; performing the nucleophilic substitution on the intermediate IV and aminobenzonitrile under an alkaline condition to generate a key intermediate V; performing ammoniation on the key intermediate V in a microwave reactor to generate an intermediate VI; performing bromination on the intermediate VI to generate a target product, namely the etravirine I. The preparation method disclosed by the invention is high in reaction selectivity and easy to operate; compared with the original synthetic method, the reaction time is greatly shortened; the energy consumption is reduced; the reaction yield is improved; the overall yield reaches 38.5 percent; the preparation method is suitable for industrial large-scale production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method of etravirine.
Background technology
Etravirine (Etravirine, R-165335, TMC-125), chemistry 4-by name [amino-5 bromo-2-(the 4-cyanogen phenol ammonia) pyrimidine-4-oxygen of 6-]-3,5-xylylic acid nitrile, that the one of Tibotec company of the subsidiary/member companies exploitation of Johson & Johnson belongs to the non-nucleoside reverse transcriptase (NNRTI) of I type human immunodeficiency virus (HIV-1), by destroying the catalytic site of reversed transcriptive enzyme with the specific binding of HIV1-RT and then blocking RNA dependency and the dependent DNA polymerase activity of DNA, thus play anti HIV-1 virus effect.Clinical study shows, in the patient using NNRTI class medicine first, etravirine demonstrates very strong antiviral activity, and the patient that HIV-1 infects has good drug metabolism to distribute after oral etravirine, and tolerance is good.Etravirine obtains FDA approval on January 18th, 2008 by preferential examination and approval procedures, and the treatment of other inverases of coupling has produced the HIV-positive of resistance, for the pharmacological agent of ten hundreds of HIV persons and AIDS patient provides new selection.
Synthetic method at present about etravirine is mainly divided into following two kinds:
One, take halogenated pyrimidine as the synthetic route of starting raw material:
This compound is first public in international monopoly WO0027825A1, and be prepared by starting raw material with the chloro-5-bromo pyrimi piperidine of 2,4,6-tri-, wherein synthetic route is:
The chloro-5-bromo pyrimi piperidine of starting raw material 2,4,6-tri-used by this route is not easy to obtain, and final step ammonifying process needs reaction under high pressure 4 days under the condition of 150 DEG C, yield is only 41%, there is the defect of long reaction time, low conversion rate, is not suitable for suitability for industrialized production.
Be then the synthesis that initial feed reports this compound with 2,4,6-trichloropyrimidine in document (Organic Process Research & Development 2010,14,657 – 660), synthetic route is as follows:
This route for initial feed, obtains target product etravirine through two step nucleophilic substitution, ammonification and bromination with 2,4,6-trichloropyrimidine.Each step raw material of this route is simple and easy to get, and the reaction yield of each step is also all greatly improved, and total reaction yield can reach 30.4%.But the 3rd step aminating reaction needs to react 12h under the condition of High Temperature High Pressure, there is very large danger and potential safety hazard, and serious waste time and the energy in suitability for industrialized production, urgently improve.
Two, with the synthetic route that is raw material or intermediate to cyano group benzene guanidine:
Make public for the first time with the synthetic route that is starting raw material to cyano group benzene guanidine in document (Bioorg.Med.Chem.Lett., 2011,11 (17), 2235-9):
This route with to cyano group benzene guanidine for initial feed, then obtain target product etravirine through cyclization, chlorination, bromination, nucleophilic substitution and ammonification.But the initial feed used by this route is expensive and should not obtain, and there is the low problem of reaction yield in the nucleophilic substitution reaction of route the 4th step and the aminating reaction of the 5th step, thus the total recovery that result in whole piece synthetic route is less than 10%, is not suitable for suitability for industrialized production.
Similarly, patent WO2012001695A1 discloses with the synthetic route that is intermediate to cyano group benzene guanidine:
This route, with being obtained by reacting cyano group benzene guanidine to cyano-aniline and cyanamide, then obtains target product etravirine through cyclization, chloro, nucleophilic substitution, ammonification, bromination reaction.But wherein the first step generates and is only 24% to the reaction yield of cyano group benzene guanidine, the reaction yield of last nucleophilic substitution, ammonification and bromination is all less than 50%, and total reaction yield, also less than 10%, is not suitable for suitability for industrialized production.
In the method for above-mentioned synthesis etravirine, not easily low with the total recovery of the reaction problem of starting raw material is all there is with the synthetic route being raw material or intermediate to cyano group benzene guanidine, and take halogenated pyrimidine as the problem that the synthetic route of starting raw material also exists the low and aminating reaction overlong time of aminating reaction yield, therefore need to find a kind of more efficient, there is the method for industrial production value to synthesize etravirine and intermediate thereof.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of easy and simple to handle, total recovery is high, has the preparation method of the etravirine of industrial production value.
Technical scheme of the present invention is as follows:
A preparation method of etravirine I,
The method is with Compound II per and compound III for initial feed, and the nucleophilic substitution reaction occurred under the effect of alkali on pyrimidine ring generates intermediate compound IV;
Then, intermediate compound IV generates key intermediate V in the basic conditions with to cyano-aniline generation nucleophilic substitution;
Key intermediate V carries out ammonification and generates intermediate VI in microwave reactor;
Finally, intermediate VI generates target product etravirine I through bromination.
In the step of described preparation intermediate compound IV, described alkali is DIPEA.
Described prepares in the step of intermediate V, and described alkaline condition is potassium tert.-butoxide.
The present invention specifically, a kind of preparation method of etravirine, step is as follows:
(1) starting material compound II and compound III are dissolved in non-protonic solvent, and the N-4 position nucleophilic substitution reaction issuing raw compounds II in the effect of alkali DIPEA generates intermediate compound IV; Wherein, Compound II per: compound III: the mol ratio of DIPEA three is 1.0:1.0-1.8:1.3-2.2, and reaction solvent is Isosorbide-5-Nitrae-dioxane, N-Methyl pyrrolidone or DMF, and temperature of reaction is 65-85 DEG C;
(2) intermediate compound IV and to cyano-aniline under the effect of alkali potassium tert.-butoxide, generate intermediate V with the N-1 position nucleophilic substitution reaction that intermediate compound IV occurs in dipole solvent; 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, and reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), and temperature of reaction is 0-10 DEG C;
(3) intermediate V and ammoniacal liquor join in dipole solvent, are obtained by reacting intermediate VI; Wherein, reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), temperature of reaction 100-150 DEG C, reaction pressure 100-135psi, reaction times 5-35min.
(4) intermediate VI and bromine join the bromination of carrying out intermediate in non-protonic solvent and obtain final product etravirine I; Wherein the ratio of compound VI and bromizating agent is 1:1.2-2, and reaction solvent is methylene dichloride, tetrahydrofuran (THF) or acetonitrile, and temperature of reaction is 0-10 DEG C.
The present invention is with Compound II per and compound III for initial feed, and the nucleophilic substitution reaction occurred under the effect of alkali on pyrimidine ring generates intermediate compound IV; Then intermediate compound IV generates key intermediate V in the basic conditions with to cyano-aniline generation nucleophilic substitution; Key intermediate V carries out ammonification and generates intermediate VI in microwave reactor; Intermediate VI generates target product etravirine I through bromination.
Synthetic route of the present invention is as follows:
According to the present invention, preferably,
Compound II per described in step (1): compound III: alkali DIPEA three preferred molar ratio 1.0:1.2-1.4:1.6-1.8; The preferred 70-80 DEG C of temperature of reaction; Preferred Isosorbide-5-Nitrae-the dioxane of reaction solvent.
In step (2), compound IV: to cyano-aniline: the preferred 1.0:1.0:2.0 of mol ratio of alkali potassium tert.-butoxide; The preferred 0-5 DEG C of temperature of reaction; The preferred N-Methyl pyrrolidone of reaction solvent.
In step (3), react and carry out in microwave reactor; Wherein said microwave reaction preferred solvent N-Methyl pyrrolidone; The preferred 120-150 DEG C of temperature; The preferred 120-135psi of pressure; Reaction times preferred 15-30min.
In step (4), the preferred 1:1.4-1.6 of molar ratio of compound VI and bromizating agent; The preferred methylene dichloride of reaction solvent; The preferred 0-5 DEG C of temperature of reaction.
The invention provides a kind of novel method of synthesizing etravirine and synthesizing its intermediate with microwave reactor, present method reaction preference is high, simple to operate, and shorten the reaction times widely compared to original synthetic method, reduce energy consumption, overall yield of reaction has brought up to 38.5% by original 30.4%, is applicable to suitability for industrialized production.
Below in conjunction with the case study on implementation of embodiment, the present invention will be further described.
Embodiment
The synthesis of embodiment 1 (1) compound IV
By 2,4,6-trimethylpyrimidine II (110mmol, 20.0g) with 3,5-dimethyl-4-4-hydroxy-benzonitrile III (110mmol, 16.2g) and N, N-diisopropylethylamine (DIEA) (132mmol, 17.0g) join in 70 DEG C of reaction 2h in 100mL Isosorbide-5-Nitrae-dioxane, when question response liquid is cooled to about 10 DEG C, in reaction solution, add the aqueous solution of 200mL at leisure and stir 30min, filter, vacuum-drying obtains 29.8g intermediate compound IV, yield 92.5%.
1H NMR(400MHz,DMSO-d6,ppm)δ:7.76(2H,s,C
3,C
5-Ph-H),7.64(1H,s,pyrimidine-H),2.12(6H,s,CH
3).ESI-MS：m/z 294.28(M+1).C
13H
9Cl
2N
3O(293.01),mp:207-209℃。
(2) synthesis of compound V
Intermediate compound IV (68mmol prepared by upper step, 20.0g), join in 100mL N-Methyl pyrrolidone to cyano-aniline (68mmol, 8.0g), then in 30min, in reaction solution, add potassium tert.-butoxide under condition of ice bath and holding temperature 0-5 DEG C of continuation stirring 2h.Then slowly reaction solution is joined in 500mL water and stir 10min, filter.Then join in 200mL water by gained filter cake, being adjusted to pH with the hydrochloric acid soln of 3M is 6-7, filters, dry.Then dried filter cake is joined in ethyl acetate, 70 DEG C of stirring and refluxing 30min, are cooled to 10 DEG C, filter, and then repeat single job, with the ethyl acetate solution washing leaching cake that 20mL is cold by same step, at 50 DEG C of temperature, vacuum-drying obtains 15.5g intermediate V, yield 60.6%.
1H NMR(400MHz,DMSO-d6,ppm)δ:10.56(1H,s,NH),7.79(2H,s,C
3,C
5-Ph’-H),7.45-7.51(4H,m,Ph-H),6.93(1H,s,pyrimidine-H),2.13(6H,s,CH
3).ESI-MS：m/z:376.5(M+1),393.3(M+18),398.4(M+23),C
20H
14ClN
5O(375.09),277-279℃。
(3) synthesis of compound VI:
Be that the ammoniacal liquor of 25% and the N-Methyl pyrrolidone solvent of 20mL join in microwave reaction pipe by intermediate V (5.3mmol, 2.0g), 15mL massfraction, then put in microwave reactor.Temperature of reaction 130 DEG C is set, reaction times 30min, high-speed stirring, in reaction process, produces pressure 130psi.React complete and be cooled to 5-10 DEG C later, in reaction solution, then add 5mL water at this temperature and maintain and continue at this temperature to stir 30min, generation precipitates in a large number, filter, filter cake washes with water, and then at the temperature of 45-50 DEG C, vacuum-drying obtains 1.63g intermediate VI, yield 85.6%.
1H NMR(400MHz,DMSO-d6,ppm)δ:9.57(1H,s,NH),7.73(2H,s,C
3,C
5-Ph’-H),7.65(2H,d,J＝8.0Hz,C
3,C
5-Ph-H),7.46(2H,d,J＝8.0Hz,C
2,C
6-Ph-H),6.80(2H,s,NH
2),5.47(1H,s,pyrimidine-H),2.12(6H,s,CH
3).ESI-MS：m/z 357.4(M+1),379.5(M+23).C
20H
16N
6O(356.14),mp：283-286℃。
(4) synthesis of Compound I
Intermediate VI (8.4mmol, 3.0g) is dissolved in 30mL methylene dichloride, under the condition of 0-5 DEG C, in this solution, then drips the dichloromethane solution 6mL of bromine (9.4mmol, 1.5g) and maintain this temperature continuation stirring 5h.Then in reaction solution, add 50mL water and adjust pH=9-10 with the diluted sodium hydroxide solution of 4mol/L.Then maintain pH=8-9 with metabisulfite solution and diluted sodium hydroxide solution, and stir 1h, then vacuum-drying obtains etravirine crude product by the washing of the solid filtering of precipitation and at the temperature of 55-60 DEG C.Dried crude product etravirine is dissolved in the methanol solution of 40mL, and add gac decolorization filtering at the temperature of 55-60 DEG C wherein, evaporated under reduced pressure solvent, then recrystallization in ethyl acetate, filtration drying obtains 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,C
3,C
5-Ph’-H),7.54(2H,d,J＝8.0Hz,C
3,C
5-Ph-H),7.43(2H,d,J＝8.0Hz,C
2,C
6-Ph-H),7.13(2H,s,NH
2),2.12(6H,s,CH
3).ESI-MS：m/z:435.4(M+1),427.4(M+3),457.4(M+23)，C
20H
15BrN
6O(434.05)，mp:254-256℃。
Claims (8)
1. a preparation method of etravirine I, is characterized in that,
The method is with Compound II per and compound III for initial feed, and the nucleophilic substitution reaction occurred under the effect of alkali on pyrimidine ring generates intermediate compound IV;
Then, intermediate compound IV generates key intermediate V in the basic conditions with to cyano-aniline generation nucleophilic substitution;
Key intermediate V carries out ammonification and generates intermediate VI in microwave reactor;
Finally, intermediate VI generates target product etravirine I through bromination.
2. according to the preparation method of claim 1, it is characterized in that, in the step of described preparation intermediate compound IV, described alkali is DIPEA.
3. according to the preparation method of claim 1, it is characterized in that, described prepares in the step of intermediate V, and described alkaline condition is potassium tert.-butoxide.
4., according to the arbitrary described preparation method of claim 1-3, it is characterized in that, step is as follows:
(1) starting material compound II and compound III are dissolved in non-protonic solvent, and the N-4 position nucleophilic substitution reaction issuing raw compounds II in the effect of alkali DIPEA generates intermediate compound IV; Wherein, Compound II per: compound III: the mol ratio of DIPEA three is 1.0:1.0-1.8:1.3-2.2, and reaction solvent is Isosorbide-5-Nitrae-dioxane, N-Methyl pyrrolidone or DMF, and temperature of reaction is 65-85 DEG C;
(2) intermediate compound IV and to cyano-aniline under the effect of alkali potassium tert.-butoxide, generate intermediate V with the N-1 position nucleophilic substitution reaction that intermediate compound IV occurs in dipole solvent; 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, and reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), and temperature of reaction is 0-10 DEG C;
(3) intermediate V and ammoniacal liquor join in dipole solvent, are obtained by reacting intermediate VI; Wherein, reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), temperature of reaction 100-150 DEG C, reaction pressure 100-135psi, reaction times 5-35min;
(4) intermediate VI and bromine join the bromination of carrying out intermediate in non-protonic solvent and obtain final product etravirine I; Wherein the ratio of compound VI and bromizating agent is 1:1.2-2, and reaction solvent is methylene dichloride, tetrahydrofuran (THF) or acetonitrile, and temperature of reaction is 0-10 DEG C.
5. according to the preparation method of claim 4, it is characterized in that, the Compound II per described in step (1): compound III: alkali DIPEA three mol ratio is 1.0:1.2-1.4:1.6-1.8; Temperature of reaction is 70-80 DEG C; Reaction solvent is Isosorbide-5-Nitrae-dioxane.
6., according to the preparation method of claim 4, it is characterized in that, in step (2), compound IV: to cyano-aniline: the mol ratio of alkali potassium tert.-butoxide is 1.0:1.0:2.0; Temperature of reaction is 0-5 DEG C; Reaction solvent is N-Methyl pyrrolidone.
7. according to the preparation method of claim 4, it is characterized in that, in step (3), react and carry out in microwave reactor; Wherein said reaction solvent N-Methyl pyrrolidone; Temperature of reaction is 120-150 DEG C; Pressure is 120-135psi; Reaction times is 15-30min.
8. according to the preparation method of claim 4, it is characterized in that, in step (4), the molar ratio of compound VI and bromizating agent is 1:1.4-1.6; Reaction solvent is methylene dichloride; Temperature of reaction is 0-5 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108218795A (en) * | 2016-12-21 | 2018-06-29 | 上海医药工业研究院 | A kind of 2,4- di-amino-pyrimidines analog derivative, preparation method, intermediate and application |
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| CN108218795A (en) * | 2016-12-21 | 2018-06-29 | 上海医药工业研究院 | A kind of 2,4- di-amino-pyrimidines analog derivative, preparation method, intermediate and application |
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