CN105566162B - The preparation technology of rilpivirine intermediate - Google Patents
The preparation technology of rilpivirine intermediate Download PDFInfo
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- CN105566162B CN105566162B CN201610097412.0A CN201610097412A CN105566162B CN 105566162 B CN105566162 B CN 105566162B CN 201610097412 A CN201610097412 A CN 201610097412A CN 105566162 B CN105566162 B CN 105566162B
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- acrylonitrile
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
The invention belongs to medicinal chemistry art, and in particular to a kind of preparation technology of rilpivirine intermediate, comprise the following steps：The dimethylaniline of (1) 4 bromine 2,6 and acrylonitrile reaction 3 (3,5-dimethylphenyl of 4 amino 3,5) acrylonitrile of generation under palladium and Phosphine ligands catalysis（It is trans：Cis=5:1）；(2) cis-trans mixture crystallization purifying in hydrochloric acid isopropanol obtains (E) 3 (3,5-dimethylphenyl of 4 amino 3,5) acrylonitrile salt；On the basis of existing technology, raw material is easy to get the present invention, and cost is low simple to operate, the requirement that suitable industry is produced greatly.
Description
Technical field：
The invention belongs to medicinal chemistry art, and in particular to a kind of to be synthesized with bromo- 2, the 6- dimethylanilines of 4- for initiation material
The preparation technology of rilpivirine intermediate.
Background technology：
Rilpivirine, English name is Rilpivirine, chemical entitled 4- [[4- [[4- [(E) -2-
Cyanoethenyl] -2,6-dimethyl-phenyl] amino] pyrimidin-2-yl] amino] benz onitrile, be
New non-nucleoside reverse transcriptase inhibitor (the non-nucleoside researched and developed by Tibotec drugmakers of the U.S.
Reverse tran-scriptase inhibitor, NNRTI), listed in May, 2011 in the U.S., trade name Edurant.
With being easily-synthesized, the features such as antiviral activity is strong, oral administration biaavailability is high, security is good.
On the synthesis of rilpivirine intermediate (E) -3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile hydrochloride,
Org.Process.Res.Dev 2008,530-536 synthetic method, i.e., with iodo- 2, the 6- dimethylanilines of 4- for initiation material
It is (trans in palladium carbon (5%mol) catalysis generation 3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile with acrylonitrile：Cis=4~
5:1), using DMA as solvent, 130-140 DEG C of reaction temperature；Because reaction temperature is high, process produces a large amount of burnt
Oil, recovery and post processing to palladium carbon cause many difficulties.
The content of the invention：
In order to overcome, above-mentioned process conditions are harsh, catalyst cost is high and post-process the defects such as trouble, it is contemplated that
There is provided a kind of simple to operate, good product quality, cost is low, be easy to large-scale production rilpivirine intermediate preparation technology.
In order to realize goal of the invention, the technical solution adopted by the present invention is：A kind of rilpivirine intermediate (E) -3- (4- ammonia
Base -3,5- 3,5-dimethylphenyl) acrylonitrile hydrochloride preparation technology, with bromo- 2, the 6- dimethylanilines of 4- for initiation material, it is special
Levy and be, comprise the following steps：
(1) under conditions of 20~40 DEG C of temperature, bromo- 2, the 6- dimethylanilines of 4- are dissolved in molten with acrylonitrile and sodium acetate
Reacted 7~8 hours in agent and under palladium and Phosphine ligands L catalysis, obtain 3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile
Cis-trans-isomer mixture；Wherein the mol ratio of cis-isomer and transisomer is 4~5:1；
(2) 3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile cis-trans-isomer mixture, the 60- in hydrochloric acid isopropanol
After 65 DEG C are stirred 16 hours, 10-15 DEG C is cooled to, (E) -3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile salt is filtrated to get
Hydrochlorate；Reaction equation is：
Described phosphorus ligand L structural formula is
In step (1), palladium and Phosphine ligands L account for respectively bromo- 2, the 6- dimethylanilines of 4- and acrylonitrile, sodium acetate,
Palladium and Phosphine ligands L mixture are (i.e. with palladium and Phosphine ligands L divided by the total mole number of the mixture of 5 kinds of materials of the above
Obtained percentage be corresponding molar percentage) mole percent be respectively 0.1~0.5% and 0.2~1.0%.Described third
The mol ratio of alkene nitrile and the bromo- 2,6- dimethylanilines of 4- is 1.1:1.0~1.5:1.0.The bromo- 2,6- diformazans of sodium acetate and 4-
The mol ratio of base aniline is 1.2:1.0~2.0:1.0.Solvent for use is acetonitrile, THF or 1,4- dioxane.It is preferred that, step
(1) reaction temperature of acrylonitrile and the bromo- 2,6- dimethylanilines of 4- is 20~30 DEG C in.
The mol ratio of 3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile cis-trans-isomer mixtures and hydrochloric acid isopropanol is
1.5:1.0~6.0:1.0.
The present invention with palladium (0.1-0.5mol%) and Phosphine ligands L (0.2-1mol%) for catalyst system and catalyzing, in temperature 20
Under conditions of~40 DEG C, bromo- 2, the 6- dimethylanilines of 4- react 3~6 hours with acrylonitrile and sodium acetate in THF, obtain
3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile is (trans：Cis=4~5:1)；3- (4- amino -3,5- 3,5-dimethylphenyls)
Acrylonitrile cis-trans-isomer mixture, in hydrochloric acid isopropanol 60-65 DEG C stirring 16 hours after, be cooled to 10-15 DEG C, filter
To (E) -3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile hydrochloride.It is harsh that the technique solves process conditions, catalyst into
The difficulty such as this height and post processing trouble, while avoid the protection of other patents, with simple to operate, good product quality, into
This low advantage, is easy to large-scale production.
Embodiment
The present invention is further described with reference to specific embodiment.
Embodiment one：
(compound2Synthesis)
20L four-hole bottles equipped with thermometer, mechanical agitation, constant pressure funnel and device for absorbing tail gas, nitrogen displacement three
It is secondary, THF (10L), palladium (5.6g, 0.5%mol) and Phosphine ligands L (28g, 1%mol) are added, 20~30 DEG C of stirrings 1 are small
When.Sequentially add bromo- 2, the 6- dimethylanilines (1.0Kg, 5mol) of sodium acetate (1.02Kg, 7.5mol), 4- and acrylonitrile
(405g,7.5mol).20~30 DEG C are continued stirring reaction 4 hours, then add water (5.0L), and stratification separates organic phase,
Aqueous phase is extracted once with the tertiary ether of first (5L).Merge organic phase, 3- (4- amino -3,5- 3,5-dimethylphenyl) third is obtained after being concentrated under reduced pressure
Alkene nitrile crude product 870g is (trans：Cis=4.6:1), crude yield 102%.
(compound3Synthesis)
In the 20L four-hole bottles equipped with thermometer, mechanical agitation, constant pressure funnel and device for absorbing tail gas, 3- is added
(4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile crude product 870g (800g) and ethanol (6L), stirring are warming up to 50~60 DEG C, slowly
Hydrochloric acid isopropanol (600g, 30%wt) is added dropwise, controls temperature to be less than 70 DEG C during dropwise addition.After completion of dropping, continue 50~
60 DEG C are stirred 12 hours.10-20 DEG C is cooled to, filtering, isopropanol (each 1L) is washed twice, and 40-50 DEG C is dried in vacuo and must produce
Thing (880g), two step yields 85%, purity 98%.(cis-isomer content 1.0%)
API-MS(m/z):209[M+1]-。
1HNMR (solvent DMSO-d6；Internal standard TMS)：δ2.31(s,6H),δ6.30(d,1H),δ7.35(s,2H),δ7.48
(d,1H),δ9.12(br s,3H)。
Embodiment two：
(compound2Synthesis)
20L four-hole bottles equipped with thermometer, mechanical agitation, constant pressure funnel and device for absorbing tail gas, nitrogen displacement three
It is secondary, THF (10L), palladium (1.2g, 0.1%mol) and Phosphine ligands L (6g, 0.2%mol) are added, 20~30 DEG C of stirrings 1 are small
When.Sequentially add bromo- 2, the 6- dimethylanilines (1.0Kg, 5mol) of sodium acetate (1.02Kg, 7.5mol), 4- and acrylonitrile
(405g,7.5mol).20~30 DEG C are continued stirring reaction 4 hours, then add water (5.0L), and stratification separates organic phase,
Aqueous phase is extracted once with the tertiary ether of first (5L).Merge organic phase, 3- (4- amino -3,5- 3,5-dimethylphenyl) third is obtained after being concentrated under reduced pressure
Alkene nitrile crude product 870g is (trans：Cis=4.7:1), crude yield 102%.
(compound3Synthesis)
In the 20L four-hole bottles equipped with thermometer, mechanical agitation, constant pressure funnel and device for absorbing tail gas, 3- is added
(4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile crude product 870g (800g) and ethanol (6L), stirring are warming up to 65 DEG C, are slowly added dropwise
Hydrochloric acid isopropanol (600g, 30%wt), controls temperature to be less than 70 DEG C during dropwise addition.After completion of dropping, continue in 65 DEG C of stirrings
12 hours.10-20 DEG C is cooled to, filtering, isopropanol (each 1L) is washed twice, and 40-50 DEG C is dried in vacuo to obtain product (880g),
Two step yields 85%, purity 98%.(cis-isomer content 1.1%)
Embodiment three：
(compound2Synthesis)
20L four-hole bottles equipped with thermometer, mechanical agitation, constant pressure funnel and device for absorbing tail gas, nitrogen displacement three
It is secondary, THF (10L), palladium (5.6g, 0.5%mol) and Phosphine ligands L (28g, 1%mol) are added, 20~30 DEG C of stirrings 1 are small
When.Sequentially add bromo- 2, the 6- dimethylanilines (1.0Kg, 5mol) of sodium acetate (1.02Kg, 7.5mol), 4- and acrylonitrile
(405g,7.5mol).20~30 DEG C are continued stirring reaction 4 hours, then add water (5.0L), and stratification separates organic phase,
Aqueous phase is extracted once with the tertiary ether of first (5L).Merge organic phase, 3- (4- amino -3,5- 3,5-dimethylphenyl) third is obtained after being concentrated under reduced pressure
Alkene nitrile crude product 870g is (trans：Cis=4.6:1), crude yield 102%.
(compound3Synthesis)
In the 20L four-hole bottles equipped with thermometer, mechanical agitation, constant pressure funnel and device for absorbing tail gas, 3- is added
(4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile crude product 870g (800g) and ethanol (6L), stirring are warming up to 50~60 DEG C, slowly
Hydrochloric acid isopropanol (300g) is added dropwise, controls temperature to be less than 70 DEG C during dropwise addition.After completion of dropping, continue small in 60 DEG C of stirrings 12
When.10-20 DEG C is cooled to, filtering, isopropanol (each 1L) is washed twice, and 40-50 DEG C is dried in vacuo to obtain product (880g), two steps
Yield 85%, purity 98%.(cis-isomer content 0.9%)
General principle, principal character and the advantage of the present invention has been shown and described above.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes and improvements
It all fall within the protetion scope of the claimed invention.The claimed scope of the invention is by appended claims and its equivalent circle
It is fixed.
Claims (4)
1. a kind of preparation technology of rilpivirine intermediate (E) -3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile hydrochloride,
With bromo- 2, the 6- dimethylanilines of 4- for initiation material, it is characterised in that comprise the following steps：
(1) under conditions of 20~40 DEG C of temperature, bromo- 2, the 6- dimethylanilines of 4- are dissolved in solvent with acrylonitrile and sodium acetate
And reacted 7~8 hours under palladium and Phosphine ligands L catalysis, 3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile is obtained along anti-
Isomer mixture；Wherein the mol ratio of transisomer and cis-isomer is 4~5:1；
(2) 3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile cis-trans-isomer mixture, 50-65 DEG C in hydrochloric acid isopropanol
After stirring 16 hours, 10-15 DEG C is cooled to, (E) -3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile hydrochloride is filtrated to get；
Reaction equation is：
；
Described phosphorus ligand L structural formula isPalladium and Phosphine ligands in the reaction system of step (1)
L mole percent is respectively 0.1~0.5% and 0.2~1.0%；The bromo- 2,6- dimethylanilines of acrylonitrile and 4- rub
You are than being 1.1:1.0~1.5:1.0；The mol ratio of the bromo- 2,6- dimethylanilines of sodium acetate and 4- is 1.2:1.0~2.0:
1.0。
2. a kind of rilpivirine intermediate (E) -3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile salt according to claim 1
The preparation technology of hydrochlorate, it is characterised in that solvent for use is acetonitrile, THF or Isosorbide-5-Nitrae-dioxane, volume 5-15L.
3. a kind of rilpivirine intermediate (E) -3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile salt according to claim 1
The preparation technology of hydrochlorate, it is characterised in that the reaction temperature of acrylonitrile and bromo- 2, the 6- dimethylanilines of 4- is 20 in step (1)
~30 DEG C.
4. a kind of rilpivirine intermediate (E) -3- (4- amino -3,5- 3,5-dimethylphenyls) acrylonitrile salt according to claim 1
The preparation technology of hydrochlorate, it is characterised in that 3- (4- amino -3,5- 3,5-dimethylphenyl) acrylonitrile cis-trans-isomer mixtures and salt
The mol ratio of sour isopropanol is 1.5:1.0~6.0:1.0.
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| CN106008366A (en) * | 2016-05-25 | 2016-10-12 | 山东大学 | Preparation method of rilpivirine |
| CN106187916B (en) * | 2016-07-04 | 2018-08-21 | 宜昌人福药业有限责任公司 | A method of effectively removing rilpivirine isomers |
| AU2020391004A1 (en) | 2019-11-29 | 2022-04-07 | Aptorum Therapeutics Limited | Composition including rilpivirine and use thereof for treating tumors or cancer |
| CN111333543B (en) * | 2020-04-17 | 2022-09-16 | 武汉工程大学 | Synthesis method of rilpivirine intermediate |
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| "Palladium-meta-Terarylphosphine Catalyst for the Mizoroki-Heck Reaction of (Hetero)Aryl Bromides and Functional Olefins;Daniel Weiliang Tay et al.;《The Journal of Organic Chemistry》;20140313;第80卷;第4054-4063页 * |
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