CN110938037A - Preparation method of drug intermediate of Eragoli sodium salt - Google Patents
Preparation method of drug intermediate of Eragoli sodium salt Download PDFInfo
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- CN110938037A CN110938037A CN201811104129.1A CN201811104129A CN110938037A CN 110938037 A CN110938037 A CN 110938037A CN 201811104129 A CN201811104129 A CN 201811104129A CN 110938037 A CN110938037 A CN 110938037A
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- compound
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- boc
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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
Abstract
The synthesis scheme effectively controls the cost, simplifies the reaction process and the operation process, is suitable for amplification production, is beneficial to improving the product yield and the production efficiency, can reduce the residual risk of heavy metal in the bulk drug, avoids the use of potential genotoxic substances, and is more green and safe in process.
Description
Technical Field
The application relates to the field of drug synthesis, in particular to a preparation method of an elogol sodium salt drug intermediate.
Background
Endometriosis (EMS) is a common gynecological disease in women, an estrogen-related disease, formed by intimal cells planted in abnormal locations. The endometrial cells should grow in the uterine cavity, but because the uterine cavity is communicated with the ovary and the pelvic cavity through the oviduct, the endometrial cells can enter the ovary, the pelvic cavity and the adjacent area of the uterus to grow ectopically through the oviduct.
Currently, Compound Oral Contraceptives (COC) and non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line drugs for the treatment of endometriosis. For patients diagnosed with endometriosis in combination with clinical symptoms, the administration can be done empirically, without having to undergo surgical examination. If first-line administration is not effective in relieving pain symptoms, it is recommended that a second-line treatment regimen be initiated after laparoscopy. Current second-line regimens include, for example, GnRH agonists (GnRHA), GnRH antagonists (GnRant), and the like.
It is believed that the combination of first-line therapeutic Combinations of Oral Contraceptives (COCs) and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with endometriosis clearly alleviate the pain symptoms, but NSAIDs have relatively many side effects.
The iragolide sodium salt is a new drug for the treatment of endometriosis developed jointly by AbbVie (AbbVie) and Neurocrine Biosciences, and is a novel GnRH antagonist and an oral preparation. The effect of the sodium salt of israguli on estrogen levels is altered by changing the level of GnRH inhibition of the pituitary. By this means, the sodium salt of agolide will provide a therapeutic condition for certain diseases, such as endometriosis and uterine fibroids associated pain relief, without the need for active control of bone loss, enabling a reduction in the occurrence of side effects, and the existence of these advantages is also confirmed by the various clinical results. The united states Food and Drug Administration (FDA) has approved a marketed application of the gynecological drug, namely, the sodium salt of agolide, for the treatment of endometriosis-related pain in 7/25.2018.
So far, related patents at home and abroad are reported less, and the main reported patent synthetic route is the synthetic route of original grinding Airby company (US 7056927B). The specific synthetic route is as follows:
the synthesis method in the patent introduces chiral amino alcohol fragments with higher price earlier, and has higher cost. In addition, a large amount of by-products derived from triphenylphosphine oxide and azo compounds are produced in the mitsunobu reaction, and an excessive amount of unreacted triphenylphosphine and azo compounds are produced, so that separation and purification are difficult. Meanwhile, if triphenylphosphine or triphenylphosphine oxide remains in the product, the palladium catalyst of the subsequent coupling reaction is affected, and the stability of the coupling reaction is deteriorated. In addition, palladium-catalyzed coupling reactions are relatively late, and palladium is used in relatively large amounts, is costly, and is detrimental to residual control of heavy metals in the final product.
The synthesis route of the sodium elogolide disclosed in patent US8765948B is as follows, the synthesis route of the sodium elogolide is characterized in that the sodium elogolide intermediate is prepared by substitution reaction with chiral amino alcohol methyl sulfonate, the by-product methyl sulfonic acid can be esterified with alcohol used in the subsequent process or generated in the reaction to generate mesylate, and the mesylate is a compound with potential genotoxicity, so that additional and higher requirements are provided for the process route and the quality control and test of the final product, and the production of the bulk drug is not favorable.
Disclosure of Invention
The application provides a novel synthesis scheme of Eragolisodium, and the synthesis route is as follows:
firstly, the compound 1 and the compound 2 are subjected to a mitsunobu reaction to obtain a compound 3, wherein the solvent used in the mitsunobu reaction is one or more of dichloromethane, toluene, 1, 4-dioxane, tetrahydrofuran, methyltetrahydrofuran and the like, and tetrahydrofuran is preferred. And carrying out Boc protecting group removal reaction on the compound 3 under acidic conditions to prepare a compound 4. The acid used for the Boc-protecting group removal reaction is one or more of methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, preferably methanesulfonic acid, hydrochloric acid, and more preferably hydrochloric acid. In particular, the compound 3 can be directly prepared into the compound 4 by a one-pot method without separation.
Then the compound 4 and the compound 5 react in an organic solvent in the presence of an acid-binding agent to generate an intermediate compound 6 of the drug of the sodium elogolide. And (3) carrying out hydrolysis reaction on the compound 6 in the presence of alkali to prepare the sodium elogolide.
Compared with the prior art, the method for synthesizing the sodium elogolide has the following advantages:
(1) on the premise of coupling reaction, the heavy metal residue in the bulk drug can be better controlled;
(2) on the premise of coupling reaction catalyzed by transition metal, the compound 1 is prepared by coupling reaction, and the reaction route design enables the compound 4 to be prepared from the compound 1 by continuous reaction by carrying out Boc deprotection reaction immediately after Mitsunobu reaction, so that the reaction process and the operation process are simplified, the method is suitable for large-scale production, the yield and the production efficiency are improved, and the cost is reduced;
(3) the use of potential genotoxic substances is avoided in the reaction process, and the process is more green and safe.
Detailed Description
Embodiments of the present application are described below by way of examples, and it should be appreciated by those skilled in the art that these specific examples merely illustrate selected embodiments for achieving the purposes of the present application and are not intended to limit the technical solutions. Modifications of the technical solutions of the present application in combination with the prior art are obvious from the teachings of the present application and fall within the protection scope of the present application.
The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments. Among them, the chemical agents used in the following examples are all commercially available chemical agents.
Example 1
Compound 1 (1.5 g), N-dimethylformamide (9 mL) as a solvent, compound 7 (1.44 g) and potassium carbonate (1.22 g) were sequentially added to a reaction flask, and the mixture was heated to 55 ℃ for reaction overnight. After the reaction, isopropyl acetate and water are added for liquid separation and washing. The isopropyl acetate n-heptane with the volume ratio of 1:2 is subjected to column purification to obtain the product with the yield of 86% and the purity of 92%.
The nuclear magnetic data of the product are as follows:
1H NMR (400 MHz, CDCl3) δ 7.58 (d,J= 7.9 Hz, 1H), 7.43 (m, 3H), 7.34(t,J= 7.4 Hz, 2H), 7.31-7.23 (m, 2H), 7.16 (t,J= 8.0 Hz, 1H), 7.01 (t,J= 8.1 Hz, 1H), 6.86 (t,J= 6.9 Hz, 1H), 5.78 (t,J= 8.4 Hz, 1H), 5.62 (m,1H), 5.45 (m, 1H), 5.13 (m, 1H), 4.37 (m, 1H), 4.13 (m, 1H), 3.92 (s, 3H),2.10 (s, 3H), 1.37-1.17 (m, 9H).
[M+H-Boc]+546.1；
example 2
Compound 1 (10 g), tetrahydrofuran (150 mL) was added to a 250 mL three-necked flask and stirred. Compound 2 (6.97 g) and triphenylphosphine (9.23 g) were added thereto, and diisopropyl azodicarboxylate (7.12 g) was added dropwise thereto at a temperature of 20 to 30 ℃. After the addition, the reaction is carried out under the condition of heat preservation. The reaction was tested by High Performance Liquid Chromatography (HPLC). The product HPLC retention time was consistent with the product obtained in example 1.
Example 3
Compound 1 (10 g), methylene chloride (150 mL) was added to a 250 mL three-necked flask and stirred. Compound 2 (6.95 g) and triphenylphosphine (9.23 g) were added thereto, and diisopropyl azodicarboxylate (7.11 g) was added dropwise thereto at a temperature of 20 to 30 ℃. After the addition, the reaction is carried out under the condition of heat preservation. At the end of the reaction, samples were taken for HPLC. The product HPLC retention time was consistent with the product obtained in example 1.
Example 4
A5.0L three-necked flask was charged with Compound 1 (200 g), Compound 2 (139.1 g), triphenylphosphine (184 g) and tetrahydrofuran (3.0L). Diisopropyl azodicarboxylate (142 g) was added dropwise thereto, followed by reaction at room temperature. After completion of the reaction by sampling and HPLC analysis, concentrated hydrochloric acid (187.6 g) was added to the reaction system and the mixture was heated to reflux. After the reaction is finished, concentrating, and adding potassium carbonate aqueous solution and isopropyl acetate for extraction. The aqueous phosphoric acid solution was added to the isopropyl acetate phase and the aqueous phase was washed three times with isopropyl acetate. The aqueous phase was adjusted to alkali with aqueous potassium carbonate solution, and the separated solution was extracted with isopropyl acetate (3L), and the isopropyl acetate phase was collected. The isopropyl acetate phase was concentrated and n-heptane was added and filtered to give compound 4 in 82.1% yield and 99.8% purity.
The nuclear magnetic data of the product are as follows:
1H NMR (400 MHz, DMSO-d6) δ 7.67-7.65 (m, 1H), 7.59-7.53 (m, 2H), 7.29-7.25 (m, 4H), 7.20-7.14 (m, 3H), 6.76-6.61 (m, 1H), 5.35-5.33 (m, 2H), 4.12-4.10 (m, 1H), 3.96-3.89 (m, 2H), 3.86 (s, 3H), 2.10 (s, 3H).
[M+H]+546.2。
this application is intended to cover any variations, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
Claims (9)
1. A preparation method of an elogolide sodium drug intermediate comprises the step of reacting a compound 1 with a compound 2 to generate an elogolide sodium drug intermediate compound 3,
2. the method according to claim 1, wherein the compound 1 and the compound 2 are subjected to a mitsunobu reaction to prepare the compound 3.
3. The method of claim 2, wherein the solvent used in the mitsunobu reaction is one or more selected from dichloromethane, toluene, 1, 4-dioxane, tetrahydrofuran, methyltetrahydrofuran, etc.
4. The method of claim 3, wherein the solvent used in the mitsunobu reaction is tetrahydrofuran.
5. A preparation method of an elogol sodium drug intermediate comprises the step of carrying out Boc protecting group removing reaction on a compound 3 in the presence of hydrochloric acid to generate an elogol sodium drug intermediate compound 4,
6. a preparation method of an intermediate 4 of an Eagolide sodium drug, a compound 3 can be directly prepared into the compound 4 from a compound 1 by a one-pot method without separation treatment,
7. according to the method of claim 6, after the reaction for preparing the intermediate 3, hydrochloric acid is directly added without any treatment to carry out the protection reaction of the di-tert-butyloxycarbonyl (Boc).
8. The process of claim 7, wherein the temperature of the de-Boc protection reaction is from 0 ℃ to reflux.
9. The method of claim 8, wherein the temperature of the de-Boc protection reaction is 30-50 ℃.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811104129.1A CN110938037A (en) | 2018-09-21 | 2018-09-21 | Preparation method of drug intermediate of Eragoli sodium salt |
| US16/770,035 US11377426B2 (en) | 2017-12-05 | 2018-12-03 | Processes to produce elagolix |
| PCT/US2018/063682 WO2019112968A1 (en) | 2017-12-05 | 2018-12-03 | Processes to produce elagolix |
| EP18885965.6A EP3720845A4 (en) | 2017-12-05 | 2018-12-03 | Processes to produce elagolix |
| JP2020550593A JP7200261B2 (en) | 2017-12-05 | 2018-12-03 | The process of making Elagoryx |
| TW109111870A TW202030177A (en) | 2017-12-05 | 2018-12-04 | Processes to produce elagolix |
| TW107143337A TWI693208B (en) | 2017-12-05 | 2018-12-04 | Processes to produce elagolix |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811104129.1A CN110938037A (en) | 2018-09-21 | 2018-09-21 | Preparation method of drug intermediate of Eragoli sodium salt |
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| CN110938037A true CN110938037A (en) | 2020-03-31 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372609A (en) * | 2019-07-25 | 2019-10-25 | 奥锐特药业股份有限公司 | A kind of purification process for disliking La Geli sodium salt |
| CN112457258A (en) * | 2020-11-26 | 2021-03-09 | 诚达药业股份有限公司 | Preparation method of oxalaggrin sodium and intermediate thereof |
| CN114685379A (en) * | 2022-04-29 | 2022-07-01 | 河北智恒医药科技股份有限公司 | Preparation method and application of intermediate 1 and intermediate 2 of oxaagolide |
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 |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
-
2018
- 2018-09-21 CN CN201811104129.1A patent/CN110938037A/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 |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372609A (en) * | 2019-07-25 | 2019-10-25 | 奥锐特药业股份有限公司 | A kind of purification process for disliking La Geli sodium salt |
| CN112457258A (en) * | 2020-11-26 | 2021-03-09 | 诚达药业股份有限公司 | Preparation method of oxalaggrin sodium and intermediate thereof |
| CN114685379A (en) * | 2022-04-29 | 2022-07-01 | 河北智恒医药科技股份有限公司 | Preparation method and application of intermediate 1 and intermediate 2 of oxaagolide |
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