CN109651265A - A kind of preparation method of Elagolix - Google Patents
A kind of preparation method of Elagolix Download PDFInfo
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- CN109651265A CN109651265A CN201910118879.2A CN201910118879A CN109651265A CN 109651265 A CN109651265 A CN 109651265A CN 201910118879 A CN201910118879 A CN 201910118879A CN 109651265 A CN109651265 A CN 109651265A
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- elagolix
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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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the preparation methods of Elagolix a kind of, it is characterized in that, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- (the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone and 4- ketobutyric acid shown as a formula V obtain Elagolix shown in formula I through reductive amination process；
Description
Technical field
The invention belongs to organic syntheses and medicine intermediate technical field, and in particular to a kind of preparation side of Elagolix
Method.
Background technique
The structure of Elagolix is shown in formula I, is a kind of oral GnRH antagonist, is released by inhibiting pituitary to promote sexual gland
Hormone receptor is put, it is final to reduce the Sex Hormones Levers in blood circulation to treat endometriosis to treat because of intrauterine
Pain caused by endometriosis.
According to the record of United States Patent (USP) WO2009062087, following route synthesis is can be used in Elagolix:
It is learnt by said synthesis route, when synthesizing Elagolix, there are the long deficiency of route, multi-step closes the prior art
At causing to introduce the impurity for being difficult to remove in the synthesis process and technological parameter is not easily controlled, and then influence target product
Purity.
Summary of the invention
Technical problem to be solved by the present invention lies in: the route that conventional method synthesizes Elagolix is longer, and is not easy pure
Change.
The present invention solves above-mentioned technical problem using following technical scheme:
A kind of preparation method of Elagolix, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- (fluoro- 3- of 2-
Methoxyphenyl) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone and shown as a formula V
4- ketobutyric acid obtains Elagolix shown in formula I through reductive amination process；
Preferably, the preparation method of Elagolix of the present invention a kind of, the concrete operations for producing Elagolix are as follows:
In the reactor, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- (the fluoro- 3- methoxyphenyl of 2-) -1- (2-
Fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in organic solvent, such as Formula V is added thereto
Shown in 4- ketobutyric acid, acid and reducing agent, reductive amination process then occurs；After reaction, reaction mixture is washed,
Dry, purifying obtains Elagolix shown in formula I.
Preferably, the preparation method of a kind of Elagolix of the present invention, the reducing agent are triacetoxy borohydride
Sodium hydride or sodium cyanoborohydride.
Preferably, the preparation method of a kind of Elagolix of the present invention, the organic solvent are selected from methylene chloride, 1,
Any one of 2- dichloroethanes, chloroform, acetonitrile, methyl tertiary butyl ether(MTBE), THF, methanol, ethyl alcohol；Or THF and water by volume 1:
The mixture of 1 composition.
Preferably, the preparation method of a kind of Elagolix of the present invention, the acid are acetic acid, hydrochloric acid, formic acid, trifluoro
Any one of acetic acid.
Preferably, the process of the preparation method of a kind of Elagolix of the present invention, the washing reaction mixture is:
Aqueous hydrochloric acid solution washing reaction mixed liquor is first used, is divided after taking organic phase, then uses saturated common salt water washing organic phase.
Preferably, the preparation method of a kind of Elagolix of the present invention, the process of the reductive amination process be
6-32h is stirred to react at 0-25 DEG C；Or it is heated to back flow reaction 18h.
Preferably, the preparation method of a kind of Elagolix of the present invention, every 1.0g, 1.0equiv. such as Formula II institute
(R) -3- (2- amino -2- phenethyl) -5- (the fluoro- 3- methoxyphenyl of the 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl)-shown
6- methylpyrimidine -2,4 (1H, 3H)-diketone is reacted with the 4- ketobutyric acid shown as a formula V of 1-1.5equiv..
Preferably, the preparation method of a kind of Elagolix of the present invention, every 1.0g, 1.0equiv. such as Formula II institute
(R) -3- (2- amino -2- phenethyl) -5- (the fluoro- 3- methoxyphenyl of the 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl)-shown
When 6- methylpyrimidine -2,4 (1H, 3H)-diketone participates in reaction, the dosage of the reducing agent is 1-6equiv.；The dosage of the acid
For 1-2equiv..
The technology of the present invention the utility model has the advantages that
Technical solution of the present invention is achieved with target product by single step reaction, substantially reduces synthetic route, simplifies system
Standby process；The side reaction of the route is few, reduces the introducing of impurity, so that subsequent purification processing is simple and convenient, effectively increases
The purity of target product.
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 prepares Elagolix by following routes:
Lead to below
It crosses and preparation process is described in detail in conjunction with specific embodiments.
Embodiment 1
In the reactor, by 1.0g, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- of 1.0equiv.
(the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in
10mL methylene chloride, be added thereto the 4- ketobutyric acid shown as a formula V of 1.2equiv., 1.0equiv. acetic acid and
The sodium triacetoxy borohydride of 3.0equiv. is stirred to react 18h at 25 DEG C；After reaction, successively water-soluble with 1M hydrochloric acid
Liquid, saturated salt solution washing reaction liquid, it is then dry with sodium sulphate and be spin-dried for solvent, it most chromatographs to obtain 0.65equiv. through column afterwards
Elagolix shown in formula I, yield 65%.It is detected using high resolution mass spectrum (ESI-), detected value 630.2039；M-
H+High resolution mass spectrum calculating value be 630.2033, through comparing, can confirm product structure.
Embodiment 2
In the reactor, by 1.0g, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- of 1.0equiv.
(the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in
15mL methylene chloride, be added thereto the 4- ketobutyric acid shown as a formula V of 1.5equiv., 2.0equiv. acetic acid and
The sodium cyanoborohydride of 3.0equiv. is stirred to react 18h at 25 DEG C；After reaction, it successively uses 1M aqueous hydrochloric acid solution, satisfy
It is then dry with sodium sulphate and be spin-dried for solvent with brine It reaction solution, it most chromatographs to obtain 0.62equiv. such as Formulas I through column afterwards
Shown in Elagolix, yield 62%.It is detected using high resolution mass spectrum (ESI-), detected value 630.2036.
Embodiment 3
In the reactor, by 1.0g, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- of 1.0equiv.
(the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in
12mL1,2- dichloroethanes, be added thereto the 4- ketobutyric acid shown as a formula V of 1.0equiv., 1.0equiv. hydrochloric acid and
The triacetoxyl group base sodium borohydride of 1.0equiv., is stirred to react 6h at 0 DEG C；After reaction, successively water-soluble with 1M hydrochloric acid
Liquid, saturated salt solution washing reaction liquid, it is then dry with sodium sulphate and be spin-dried for solvent, it most chromatographs to obtain 0.41equiv. through column afterwards
Elagolix shown in formula I, yield 41%.It is detected using high resolution mass spectrum (ESI-), detected value 630.2036.
Embodiment 4
In the reactor, by 1.0g, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- of 1.0equiv.
(the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in
4- ketobutyric acid shown as a formula V, 2.0equiv. formic acid and the 6.0equiv. of 1.2equiv. is added in 15mL acetonitrile thereto
Sodium triacetoxy borohydride, be stirred to react 18h at 25 DEG C；After reaction, successively with 1M aqueous hydrochloric acid solution, saturation food
Salt water washing reaction liquid, it is then dry with sodium sulphate and be spin-dried for solvent, it most through column chromatographs to obtain 0.60equiv. afterwards shown in formula I
Elagolix, yield 60%.It is detected using high resolution mass spectrum (ESI-), detected value 630.2038.
Embodiment 5
In the reactor, by 1.0g, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- of 1.0equiv.
(the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in
4- ketobutyric acid shown as a formula V, the 1.0equiv. trifluoroacetic acid of 1.2equiv. is added in 10mL methyl tertiary butyl ether(MTBE) thereto
And the sodium triacetoxy borohydride of 3.0equiv., 32h is stirred to react at 25 DEG C；After reaction, 1M hydrochloric acid water is successively used
Solution, saturated salt solution washing reaction liquid, it is then dry with sodium sulphate and be spin-dried for solvent, most chromatograph to obtain through column afterwards
Elagolix 0.62equiv. shown in formula I, yield 62%.It is detected using high resolution mass spectrum (ESI-), detected value is
630.2038。
Embodiment 6
In the reactor, by 1.0g, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- of 1.0equiv.
(the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in
The 4- oxo fourth shown as a formula V of 1.0equiv. is added in the mixed solvent being made of the water of the THF and 5mLd of 5mL thereto
The sodium cyanoborohydride of acid, 1.0equiv. acetic acid and 4.0equiv., is heated to back flow reaction 18h；After reaction, it successively uses
1M aqueous hydrochloric acid solution, saturated salt solution washing reaction liquid, it is then dry with sodium sulphate and be spin-dried for solvent, most chromatograph to obtain through column afterwards
Elagolix 0.62equiv. shown in formula I, yield 57%.It is detected using high resolution mass spectrum (ESI-), detected value is
630.2034。
Various reaction raw materials and reagent used in above-described embodiment are commercial product.Certainly, in actual production
In the process, can also be obtained by corresponding synthetic method relating to organic compounds, such as 4- ketobutyric acid shown as a formula V with
According to Organic Letters, 19 (1), 254-257；The method preparation reported in 2017.
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 Elagolix, which is characterized in that (R) -3- as shown in Formula II (2- amino -2- phenethyl) -
5- (the fluoro- 3- methoxyphenyl of 2-) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone with
4- ketobutyric acid shown as a formula V obtains Elagolix shown in formula I through reductive amination process；
2. the preparation method of Elagolix according to claim 1 a kind of, which is characterized in that produce the specific of Elagolix
It operates as follows: in the reactor, (R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- (fluoro- 3- methoxybenzene of 2-
Base) -1- (2- fluoro- 6- (trifluoromethyl) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone is dissolved in organic solvent, thereto
4- ketobutyric acid, acid and reducing agent shown as a formula V is added, reductive amination process then occurs；After reaction, reaction is mixed
Close object washing, dry, purifying obtains Elagolix shown in formula I.
3. the preparation method of Elagolix according to claim 2 a kind of, which is characterized in that the reducing agent is three second
Triacetoxyborohydride or sodium cyanoborohydride.
4. the preparation method of Elagolix according to claim 2 a kind of, which is characterized in that the organic solvent is selected from two
Any one of chloromethanes, 1,2- dichloroethanes, chloroform, acetonitrile, methyl tertiary butyl ether(MTBE), THF, methanol, ethyl alcohol；Or THF and water
The mixture of 1:1 composition by volume.
5. the preparation method of Elagolix according to claim 2 a kind of, which is characterized in that it is described acid be acetic acid, hydrochloric acid,
Any one of formic acid, trifluoroacetic acid.
6. the preparation method of Elagolix according to claim 2 a kind of, which is characterized in that the washing reaction mixture
Process be: first using aqueous hydrochloric acid solution washing reaction mixed liquor, after point taking organic phase, then organic using saturated common salt water washing
Phase.
7. the preparation method of Elagolix according to claim 1 or 2 a kind of, which is characterized in that the reduction amination is anti-
The process answered is to be stirred to react 6-32h at 0-25 DEG C；Or it is heated to back flow reaction 18h.
8. the preparation method of Elagolix according to claim 1 a kind of, which is characterized in that every 1.0g, 1.0equiv.'s
(R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- (the fluoro- 3- methoxyphenyl of 2-) -1- (fluoro- 6- (fluoroform of 2-
Base) benzyl) -6- methylpyrimidine -2,4 (1H, 3H)-diketone reacts with the 4- ketobutyric acid shown as a formula V of 1-1.5equiv..
9. the preparation method of Elagolix according to claim 2 a kind of, which is characterized in that every 1.0g, 1.0equiv.'s
(R) -3- as shown in Formula II (2- amino -2- phenethyl) -5- (the fluoro- 3- methoxyphenyl of 2-) -1- (fluoro- 6- (fluoroform of 2-
Base) benzyl) when participating in reaction, the dosage of the reducing agent is 1-6equiv. for -6- methylpyrimidine -2,4 (1H, 3H)-diketone；Institute
The dosage for stating acid is 1-2equiv..
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110615768A (en) * | 2019-09-12 | 2019-12-27 | 丽珠集团新北江制药股份有限公司 | A crystal form of GnRHR medicine and preparation method thereof |
| CN114641468A (en) * | 2019-09-03 | 2022-06-17 | 工业化学有限公司 | Process for the synthesis of the sodium salt of 4- [ [ (1R) -2- [5- (2-fluoro-3-methoxyphenyl) -3- [ [ 2-fluoro-6- (trifluoromethyl) -phenyl ] methyl ] -3, 6-dihydro-4-methyl-2, 6-dioxo-1 (2H) -pyrimidinyl ] -1-phenylethyl ] amino ] -butyric acid (ELAGOLIX sodium salt) and intermediates of said process |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1819829A (en) * | 2003-07-07 | 2006-08-16 | 纽罗克里生物科学有限公司 | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| CN104136441A (en) * | 2012-02-28 | 2014-11-05 | Sk化学公司 | Gonadotropin releasing hormone receptor antagonists, method for the preparation thereof and pharmaceutical composition comprising the same |
-
2019
- 2019-02-16 CN CN201910118879.2A patent/CN109651265A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1819829A (en) * | 2003-07-07 | 2006-08-16 | 纽罗克里生物科学有限公司 | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| CN104136441A (en) * | 2012-02-28 | 2014-11-05 | Sk化学公司 | Gonadotropin releasing hormone receptor antagonists, method for the preparation thereof and pharmaceutical composition comprising the same |
Non-Patent Citations (2)
| Title |
|---|
| AHMED F. ABDEL-MAGID ET AL.: "Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures", 《J. ORG. CHEM.》 * |
| CHEN CHEN ET AL.: "Discovery of Elagolix, a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin Releasing Hormone Receptor", 《J. MED. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114641468A (en) * | 2019-09-03 | 2022-06-17 | 工业化学有限公司 | Process for the synthesis of the sodium salt of 4- [ [ (1R) -2- [5- (2-fluoro-3-methoxyphenyl) -3- [ [ 2-fluoro-6- (trifluoromethyl) -phenyl ] methyl ] -3, 6-dihydro-4-methyl-2, 6-dioxo-1 (2H) -pyrimidinyl ] -1-phenylethyl ] amino ] -butyric acid (ELAGOLIX sodium salt) and intermediates of said process |
| CN110615768A (en) * | 2019-09-12 | 2019-12-27 | 丽珠集团新北江制药股份有限公司 | A crystal form of GnRHR medicine and preparation method thereof |
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Application publication date: 20190419 |