CN109761911A - A kind of preparation method of the polysubstituted pyrimidine derivative as Elagolix intermediate - Google Patents
A kind of preparation method of the polysubstituted pyrimidine derivative as Elagolix intermediate Download PDFInfo
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- CN109761911A CN109761911A CN201910118479.1A CN201910118479A CN109761911A CN 109761911 A CN109761911 A CN 109761911A CN 201910118479 A CN201910118479 A CN 201910118479A CN 109761911 A CN109761911 A CN 109761911A
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- pyrimidine derivative
- polysubstituted pyrimidine
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Abstract
The invention discloses a kind of preparation methods of polysubstituted pyrimidine derivative as Elagolix intermediate, it is characterized in that, alkylated reaction occurs under alkaline condition for the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) benzene and 6- methyluracil shown as a formula V, obtains polysubstituted pyrimidine derivative shown in formula I:
Description
Technical field
The invention belongs to organic syntheses and medicine intermediate technical field, and in particular to one kind is used as Elagolix intermediate
Polysubstituted pyrimidine derivative preparation method
Background technique
A kind of women that endometriosis (EMs) refers to that endo cell is planted in abnormal position and is formed is common
Gynecological disease.The disease incidence of the disease reaches 10.0%, and is in obvious ascendant trend.It is mainly with dysmenorrhea, pelvic pain and infertile
Infertility is main feature.According to statistics, in the world, puzzlement of much 1.76 hundred million women by endometriosis.
Elagolix is a kind of oral GnRH antagonist, the approval of food and drug administration is obtained, to control
Pain caused by treating because of endometriosis.Its in the synthesis process using to a kind of intermediate be shown in formula I more
Substituted pyrimidines derivative:
According to the record of United States Patent (USP) WO2009062087, polysubstituted pyrimidine derivative shown in formula I can be by following roads
Line synthesis:
However, the raw material ketene dimer that the synthetic route uses is more toxic, so that having certain danger in production process
It is dangerous.
Summary of the invention
Technical problem to be solved by the present invention lies in: regular course synthesizes polysubstituted pyrimidine substituent shown in formula I
When need using ketene dimer, lead to that there is risk in production process.
The present invention solves above-mentioned technical problem using following technical scheme:
A kind of preparation method of the polysubstituted pyrimidine derivative as Elagolix intermediate, the 2- (bromine as shown in formula IV
Methyl) alkylated reaction occurs under alkaline condition for the fluoro- 3- of -1- (trifluoromethyl) benzene and 6- methyluracil shown as a formula V,
Obtain polysubstituted pyrimidine derivative shown in formula I；
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, the concrete operations for producing polysubstituted pyrimidine derivative shown in formula I are as follows: the 2- as shown in formula IV (bromomethyl) -1-
Fluoro- 3- (trifluoromethyl) benzene is dissolved in solvent, and alkali and catalyst are added thereto, alkylated reaction then occurs；Reaction terminates
Afterwards, mixture is concentrated to dryness, concentrate is washed, dry, purifying obtains polysubstituted pyrimidine derivative shown in formula I.
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, the solvent are selected from DMF, DMAc, THF, diethylene glycol dimethyl ether, 2- methyltetrahydrofuran, isopropyl acetate, 1,2- dichloro
Any one of ethane.
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, any of the alkali in potassium carbonate, potassium dihydrogen phosphate, cesium carbonate, saleratus, triethylamine, DIPEA, pyridine, DBU
Kind.
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, the catalyst are selected from TBAI, TBAOTf or TBAB.
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
The concrete operations of method, the washing are as follows: it first uses and is washed in the cleaning composition being made of methylene chloride and aqueous hydrochloric acid solution,
Divide and takes organic phase；Saturated sodium bicarbonate, saturated common salt water washing organic phase are successively used again.
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) benzene and 1.0-2.4equiv. of every 1.0g, 10equiv.
6- methyluracil reaction shown as a formula V.
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, when the 2- as shown in formula IV (bromomethyl) -1- fluoro- 3- (trifluoromethyl) benzene of every 1.0g, 10equiv. participate in reaction, alkali
Dosage is 1.2-3.0equiv., and the dosage of catalyst is 0.1-0.2equiv..
Preferably, the preparation side of a kind of polysubstituted pyrimidine derivative as Elagolix intermediate of the present invention
Method, the process of the alkylated reaction are to be heated to 25-100 DEG C of reaction 6-32h；Or it is heated to back flow reaction 18h.
The technology of the present invention the utility model has the advantages that
Technical solution of the present invention is achieved with target product merely through single step reaction, also, the synthetic route without using
Have virose raw material, improves the safety in production process.
Specific embodiment
For convenient for those skilled in the art understand that technical solution of the present invention, now in conjunction with specification specific embodiment to the present invention
Technical solution is described further.
The embodiment of the present invention synthesizes polysubstituted pyrimidine derivative shown in formula I by following routes:
Synthesis process is described in detail below by way of specific embodiment.
Embodiment 1
In the reactor, by 1.0g, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) of 1.0equiv.
Benzene is dissolved in the DMF of 10mL, and the carbon of 1.2equiv. 6- methyluracil shown as a formula V, 1.8equiv. are added thereto
System is heated to 70 DEG C of reaction 18h by the TBAI of sour potassium, 0.1equiv.；After reaction, reaction mixture is concentrated to dryness,
Using the mixed liquor washing concentrate of methylene chloride and 1N aqueous hydrochloric acid solution, divides and take organic phase；Unsaturated carbonate hydrogen is successively used again
Sodium water solution, saturated common salt water washing organic phase, it is then dry with sodium sulphate and be spin-dried for, it chromatographs to obtain 0.89equiv.'s through column
Polysubstituted pyrimidine derivative shown in formula I, yield 89%.It is detected using high resolution mass spectrum (ESI+), detected value is
303.0758；M+H+High resolution mass spectrum calculating value be 303.0751, through compare can confirm product structure.
Embodiment 2
In the reactor, by 1.0g, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) of 1.0equiv.
Benzene is dissolved in the 2- methyltetrahydrofuran of 15mL, be added thereto 1.0equiv. 6- methyluracil shown as a formula V,
The TBAI of the triethylamine of 1.8equiv., 0.2equiv., is heated to back flow reaction 18h for system；After reaction, reaction is mixed
It closes object to be concentrated to dryness, using the mixed liquor washing concentrate of methylene chloride and 1N aqueous hydrochloric acid solution, divides and take organic phase；It successively adopts again
It is then dry with sodium sulphate and be spin-dried for saturated sodium bicarbonate aqueous solution, saturated common salt water washing organic phase, it chromatographs to obtain through column
The polysubstituted pyrimidine derivative shown in formula I of 0.62equiv., yield 62%.It is examined using high resolution mass spectrum (ESI+)
It surveys, detected value 303.0755.
Embodiment 3
In the reactor, by 1.0g, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) of 1.0equiv.
Benzene is dissolved in the DMAc of 12mL, and the carbon of 2.4equiv. 6- methyluracil shown as a formula V, 1.2equiv. are added thereto
System is heated to 100 DEG C of reaction 32h by the TBAB of potassium hydrogen phthalate, 0.1equiv.；After reaction, reaction mixture is concentrated into
It is dry, using the mixed liquor washing concentrate of methylene chloride and 1N aqueous hydrochloric acid solution, divides and take organic phase；Unsaturated carbonate is successively used again
Hydrogen sodium water solution, saturated common salt water washing organic phase, it is then dry with sodium sulphate and be spin-dried for, it chromatographs to obtain 0.88equiv. through column
Polysubstituted pyrimidine derivative shown in formula I, yield 88%.It is detected using high resolution mass spectrum (ESI+), detected value is
303.0759。
Embodiment 4
In the reactor, by 1.0g, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) of 1.0equiv.
Benzene is dissolved in the isopropyl acetate of 10mL, be added thereto 1.2equiv. 6- methyluracil shown as a formula V,
The TBAOTf of the sodium carbonate of 3.0equiv., 0.2equiv., is heated to 70 DEG C of reaction 18h for system；After reaction, it will react
Mixture is concentrated to dryness, and using the mixed liquor washing concentrate of methylene chloride and 1N aqueous hydrochloric acid solution, is divided and is taken organic phase；Again successively
It is then dry with sodium sulphate and be spin-dried for using saturated sodium bicarbonate aqueous solution, saturated common salt water washing organic phase, it is chromatographed through column
To the polysubstituted pyrimidine derivative shown in formula I of 0.89equiv., yield 89%.It is examined using high resolution mass spectrum (ESI+)
It surveys, detected value 303.0754.
Embodiment 5
In the reactor, by 1.0g, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) of 1.0equiv.
Benzene is dissolved in 1, the 2- dichloroethanes of 15mL, be added thereto 1.2equiv. 6- methyluracil shown as a formula V,
2.0equiv. pyridine, 0.1equiv. TBAI, system is heated to 25 DEG C of reaction 18h；After reaction, reaction is mixed
Object is concentrated to dryness, and using the mixed liquor washing concentrate of methylene chloride and 1N aqueous hydrochloric acid solution, is divided and is taken organic phase；It successively uses again
Saturated sodium bicarbonate aqueous solution, saturated common salt water washing organic phase, it is then dry with sodium sulphate and be spin-dried for, it chromatographs to obtain through column
The polysubstituted pyrimidine derivative shown in formula I of 0.41equiv., yield 41%.It is examined using high resolution mass spectrum (ESI+)
It surveys, detected value 303.0758.
Embodiment 6
In the reactor, by 1.0g, the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) of 1.0equiv.
Benzene is dissolved in the diethylene glycol dimethyl ether of 13mL, be added thereto 1.5equiv. 6- methyluracil shown as a formula V,
System is heated to 70 DEG C of reaction 6h by the TBAI of DBU, 0.1equiv. of 1.8equiv.；After reaction, by reaction mixture
It is concentrated to dryness, using the mixed liquor washing concentrate of methylene chloride and 1N aqueous hydrochloric acid solution, divides and take organic phase；Again successively using full
It is then dry with sodium sulphate and be spin-dried for sodium bicarbonate aqueous solution, saturated common salt water washing organic phase, it chromatographs to obtain through column
The polysubstituted pyrimidine derivative shown in formula I of 0.35equiv., yield 35%.It is examined using high resolution mass spectrum (ESI+)
It surveys, detected value 303.0760.
Technical solution of the present invention is exemplarily described invention above in conjunction with specific embodiment, it is clear that present invention tool
Body realization is not subject to the restrictions described above, as long as using the various non-realities that the inventive concept and technical scheme of the present invention carry out
Matter improve, or it is not improved the conception and technical scheme of invention are directly applied into other occasions, in guarantor of the invention
Within the scope of shield.
Claims (9)
1. a kind of preparation method of the polysubstituted pyrimidine derivative as Elagolix intermediate, which is characterized in that such as formula IV institute
Alkane occurs under alkaline condition for the fluoro- 3- of 2- (bromomethyl) -1- (trifluoromethyl) benzene and 6- methyluracil shown as a formula V shown
Glycosylation reaction obtains polysubstituted pyrimidine derivative shown in formula I；
2. a kind of preparation method of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 1,
It is characterized in that, the concrete operations for producing polysubstituted pyrimidine derivative shown in formula I are as follows: the 2- (bromine as shown in formula IV
Methyl) -1- fluoro- 3- (trifluoromethyl) benzene is dissolved in solvent, and alkali and catalyst are added thereto, alkylated reaction then occurs；
After reaction, mixture is concentrated to dryness, concentrate is washed, dry, purifying obtains polysubstituted pyrimidine shown in formula I and spreads out
Biology.
3. a kind of preparation method of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 2,
It is characterized in that, the solvent be selected from DMF, DMAc, THF, diethylene glycol dimethyl ether, 2- methyltetrahydrofuran, isopropyl acetate,
Any one of 1,2- dichloroethanes.
4. a kind of preparation method of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 2,
It is characterized in that, the alkali is selected from potassium carbonate, potassium dihydrogen phosphate, cesium carbonate, saleratus, triethylamine, DIPEA, pyridine, DBU
Any one of.
5. a kind of preparation method of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 2,
It is characterized in that, the catalyst is selected from TBAI, TBAOTf or TBAB.
6. a kind of preparation method of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 2,
It is characterized in that, the concrete operations of the washing are as follows: first using the mixing, washing being made of methylene chloride and aqueous hydrochloric acid solution
It is washed in agent, divides and take organic phase；Saturated sodium bicarbonate, saturated common salt water washing organic phase are successively used again.
7. a kind of preparation side of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 1 or 2
Method, which is characterized in that the fluoro- 3- of the 2- as shown in formula IV (bromomethyl) -1- (trifluoromethyl) benzene of every 1.0g, 10equiv. with
The 6- methyluracil reaction shown as a formula V of 1.0-2.4equiv..
8. a kind of preparation method of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 2,
It is characterized in that, the 2- as shown in formula IV (bromomethyl) -1- fluoro- 3- (trifluoromethyl) benzene of every 1.0g, 10equiv. participate in instead
At once, the dosage of alkali is 1.2-3.0equiv., and the dosage of catalyst is 0.1-0.2equiv..
9. a kind of preparation side of polysubstituted pyrimidine derivative as Elagolix intermediate according to claim 1 or 2
Method, which is characterized in that the process of the alkylated reaction is to be heated to 25-100 DEG C of reaction 6-32h；Or it is heated to back flow reaction
18h。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204498A (en) * | 2019-06-14 | 2019-09-06 | 奥锐特药业股份有限公司 | A method of it efficiently synthesizes and dislikes La Geli intermediate |
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| CN1313854A (en) * | 1999-04-10 | 2001-09-19 | 三进制药株式会社 | Antiviral pyrimidinedione derivatives and process for the preparation thereof |
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| CN105968091A (en) * | 2016-05-05 | 2016-09-28 | 青岛辰达生物科技有限公司 | Method for preparing drug Alogliptin for treating diabetes type II |
| CN108586359A (en) * | 2018-06-26 | 2018-09-28 | 杭州科巢生物科技有限公司 | A kind of synthetic method for disliking La Geli |
| WO2018198086A1 (en) * | 2017-04-28 | 2018-11-01 | Lupin Limited | Process for the preparation of elagolix and pharmaceutically acceptable salts thereof |
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2019
- 2019-02-16 CN CN201910118479.1A patent/CN109761911A/en active Pending
Patent Citations (5)
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| CN1313854A (en) * | 1999-04-10 | 2001-09-19 | 三进制药株式会社 | Antiviral pyrimidinedione derivatives and process for the preparation thereof |
| CN104402832A (en) * | 2014-11-04 | 2015-03-11 | 广东东阳光药业有限公司 | Preparation method for dihydropyrimidine derivative |
| CN105968091A (en) * | 2016-05-05 | 2016-09-28 | 青岛辰达生物科技有限公司 | Method for preparing drug Alogliptin for treating diabetes type II |
| WO2018198086A1 (en) * | 2017-04-28 | 2018-11-01 | Lupin Limited | Process for the preparation of elagolix and pharmaceutically acceptable salts thereof |
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| MOHAMMAD NAVID SOLTANI RAD ET AL.: "‘Click Synthesis’ of 1H-1，2，3-Triazolyl-Based Oxiconazole （=（1Z）-1-（2，4-Dichlorophenyl）-2-（1H-imidazol-1-yl）ethanone O-[（2，4-Dichlorophenyl）methyl]oxime） Analogs", 《HELVETICA CHIMICA ACTA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110204498A (en) * | 2019-06-14 | 2019-09-06 | 奥锐特药业股份有限公司 | A method of it efficiently synthesizes and dislikes La Geli intermediate |
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Application publication date: 20190517 |