CN110372609B - Purification method of oxalagogri sodium salt - Google Patents
Purification method of oxalagogri sodium salt Download PDFInfo
- Publication number
- CN110372609B CN110372609B CN201910676081.XA CN201910676081A CN110372609B CN 110372609 B CN110372609 B CN 110372609B CN 201910676081 A CN201910676081 A CN 201910676081A CN 110372609 B CN110372609 B CN 110372609B
- Authority
- CN
- China
- Prior art keywords
- solvent
- purification method
- sodium
- salt
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of pharmacy, in particular to a method for purifying oxa-rogue sodium salt, which comprises the following steps: dissolving the crude salt of the oxa-rogue sodium in water, adjusting the pH value to be acidic to precipitate a solid, filtering, dissolving a filter cake in an ether solvent, washing with water, concentrating, drying, adding an organic solvent and an alkaline substance, reacting at room temperature, hydrolyzing to form a salt, concentrating, adding water and an ester solvent, layering, adjusting the pH value to be alkaline, extracting with a ketone solvent, drying, concentrating, adding an alkane solvent, pulping, filtering, and drying under reduced pressure to obtain the high-purity oxa-rogue sodium salt. The purification method provided by the invention is simple and convenient to operate, low in production cost, high in product purity and yield, and suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a method for purifying oxa-rogue sodium salt.
Background
Elagolix is an oral gonadotropin releasing hormone (GnRH) receptor antagonist that reversibly reduces the secretion of ovarian sex hormones, estradiol, progesterone by inhibiting endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland. To date, Elagolix has been validated in over 3000 patients from over 40 clinical studies as a small molecule drug developed specifically for women with moderate to severe endometriosis pain.
In patent US8765948, 2-fluoroanisole is used as an initial raw material, reacts with diethyl oxalate, is reduced by sodium borohydride, is substituted by methanesulfonyl chloride, bromized by tetraethylammonium bromide, catalyzed alkylation by zinc powder, substituted by phenyl chloroformate and cyclized to obtain an intermediate protected by a Boc group, is subjected to aminoalkylation with 2-fluoro-6-trifluoromethyl benzyl bromide, is subjected to removal of the Boc group under an acidic condition, is subjected to aminoalkylation with ethyl 4-bromobutyrate, and is finally hydrolyzed to form salt under an alkaline condition to obtain the salt of oxarogine sodium. As shown in the following scheme, the synthetic route has long and tedious steps, wherein a plurality of intermediates are purified by column chromatography, and are not suitable for industrial production.
In patent WO2005007165, 2-fluoro-6- (trifluoromethyl) benzonitrile is used as a starting material, and is reduced to amine through borane tetrahydrofuran, urea is formed, the amine and urea form urea, a uracil intermediate is synthesized with a diketene ring, bromination is performed with bromine, alkylation and Suzuki condensation are performed, acidolysis deprotection is performed, ammonia alkylation is performed, and finally hydrolysis is performed to obtain the sodium salt of oxalagogrel. As shown in the following flow, the route uses an environment-friendly solvent, column chromatography is used for purifying the intermediate, and finally the cation exchange column is used for obtaining the oxalagogrid sodium salt, so that the cost is high, and the route is not suitable for industrial large-scale production.
From the synthetic route of the oxa-rogue sodium salt, at present, when the high-purity oxa-rogue sodium salt is to be obtained, one or more intermediates need to pass through a column so as to obtain a high-purity target product, or an ion exchange column is adopted to purify the target product, so that the process cost is inevitably too high, and the large-scale production of the product is not facilitated. Therefore, the method for purifying the oxa-rogue sodium salt is developed, the use of column chromatography and an ion exchange column is avoided, the production cost can be greatly reduced, and the synthesis process of the oxa-rogue sodium salt is more beneficial to industrial large-scale production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the purification method which has the advantages of simple process, simple and convenient operation, low production cost, high product purity and yield, capability of reaching the quality standard of the raw material medicine and suitability for industrialization.
The invention provides a method for purifying oxa-goril sodium salt, which adopts the following technical scheme and comprises the following steps:
(1) dissolving the coarse product of the oxa-gol sodium salt in water, adjusting the pH value to acidity with hydrochloric acid, separating out a solid, and filtering;
(2) dissolving the filter cake obtained in the step (1) in an ether solvent, adding water for washing and layering, and concentrating to remove the ether solvent;
(3) adding an organic solvent and an alkaline substance into the step (2), and reacting at room temperature to form a salt;
(4) concentrating to remove organic solvent, adding water and ester solvent, washing and layering;
(5) adjusting the pH of the water layer to be alkaline by using a sodium hydroxide solution, and then extracting and layering by using a ketone solvent;
(6) drying, filtering, concentrating to remove filtrate, adding alkane solvent, and pulping;
(7) filtering, and drying under reduced pressure to obtain high-purity oxa-rogue sodium salt.
Preferably, the weight ratio of the crude product of the oxalagril sodium salt to the water in the step (1) is 1: 5-9, and more preferably 1: 7;
preferably, the pH value of the hydrochloric acid in the step (1) is adjusted to 5-6, and further preferably 5.5;
preferably, the ether solvent in step (2) is diethyl ether, methyl tert-butyl ether, isopropyl ether, anisole, and more preferably methyl tert-butyl ether;
preferably, the weight ratio of the filter cake to the ether solvent in the step (2) is 1: 50-80, and more preferably 1: 70;
preferably, the organic solvent in step (3) is methanol, ethanol, tetrahydrofuran, acetonitrile, acetone, more preferably ethanol;
preferably, the weight ratio of the crude product of the oxalagril sodium salt to the organic solvent in the step (3) is 1: 3-7, and further preferably 1: 5;
preferably, the alkaline substance in step (3) is sodium hydroxide, sodium methoxide, sodium ethoxide, and further preferably sodium hydroxide;
preferably, the molar ratio of the alkaline substances in the coarse salt of oxalagril in the step (3) is 1: 1-3, and more preferably 1: 2;
preferably, the ester solvent in step (4) is ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, more preferably isopropyl acetate;
preferably, the pH of the sodium hydroxide solution in the step (5) is adjusted to 9-11, and further preferably to 10;
preferably, the ketone solvent used in step (5) is 2-butanone, methyl isopropyl ketone, 4-methyl-2-pentanone, diisobutyl ketone, and more preferably 4-methyl-2-pentanone.
Preferably, in the step (6), the alkane solvent is cyclohexane, n-hexane or n-heptane, more preferably n-heptane.
The invention has the beneficial effects that: the invention avoids the use of column chromatography and ion exchange column, has simple process, simple operation and low production cost, and is very suitable for large-scale production in workshops. The purification method can obtain high-purity oxarogue sodium salt with the purity of not less than 99.9 percent and the single impurity of less than 0.1 percent.
Drawings
The above advantages and steps of the present invention will become apparent and readily appreciated from the following description of the embodiments taken in conjunction with the accompanying drawings, in which:
fig. 1 is a detection profile of crude loracarbef sodium salt before purification according to inventive example 1;
fig. 2 is a detection spectrum of a refined salt of oxalagril purified according to example 1 of the present invention;
fig. 3 is a detection spectrum of a refined salt of oxarogeli sodium purified according to comparative example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept and the scope of the appended claims is intended to be protected by the following claims. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited.
The analytical test instrument was SHIMADZU LC-2030C, the column was Agilent ZORBAX SB-C18, 150mm X4.6 mm, 3.5 μm, the detector was a UV detector, the wavelength was 266nm, the mobile phase A was water and trifluoroacetic acid, the mobile phase B was acetonitrile and trifluoroacetic acid, the elution procedure was 70% mobile phase A and 30% mobile phase B for 0-10min, 10% mobile phase A and 90% mobile phase B for 10-30min, and 70% mobile phase A and 30% mobile phase B for 30-40 min.
Example 1:
dissolving 10g of crude salt of the oxa-gol in 70g of water, adjusting the pH value to 5.5 by using 15% diluted hydrochloric acid to precipitate a solid, stirring for 1h, filtering, dissolving a filter cake in 70g of methyl tert-butyl ether, adding 50g of water to wash the mixture for layering, concentrating under reduced pressure to remove the methyl tert-butyl ether, adding 50g of ethanol and 25g of 5% sodium hydroxide aqueous solution, reacting for 2h at room temperature, concentrating to remove the ethanol, adding 70g of water and 40g of isopropyl acetate to wash the mixture for layering, adding 20% sodium hydroxide solution to the obtained water layer to adjust the pH value to 10, adding 40g of 4-methyl-2-pentanone to extract the obtained water layer for layering, extracting the obtained water layer with 40g of 4-methyl-2-pentanone for layering, combining organic layers, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to near dryness, adding 50g of n-heptane for pulping for 15min, filtering, and drying in a vacuum, the yield was 96.5% and the purity was 99.9% (single impurity less than 0.1%).
Example 2:
in the same manner as in example 1, 10g of crude loragol sodium salt was dissolved in 70g of water instead of 10g of crude loragol sodium salt in 90g of water to obtain refined loragol sodium salt in 93.5% yield and 99.9% purity (less than 0.1% single impurity).
Example 3:
the same procedure as in example 1 was followed, except that the pH of 15% dilute hydrochloric acid was changed to 5.5 and the pH of 15% dilute hydrochloric acid was changed to 6, to obtain refined salt of oxarogine sodium in 92.7% yield and 99.9% purity (less than 0.1% single impurity).
Example 4:
in the same manner as in example 1, the cake was dissolved in 70g of methyl t-butyl ether, instead of being dissolved in 80g of methyl t-butyl ether, to obtain fine salt of oxarogine sodium in a yield of 96.2% and a purity of 99.9% (less than 0.1% of single impurity).
Example 5:
the procedure of example 1 was followed, and methyl t-butyl ether was changed to diethyl ether to obtain refined salt of oxarogli sodium in 91.9% yield and 99.9% purity (less than 0.1% single impurity).
Example 6:
the procedure of example 1 was followed, and ethanol was changed to tetrahydrofuran to obtain refined loragol sodium salt in 94.5% yield and 99.9% purity (less than 0.1% single impurity).
Example 7:
in the same manner as in example 1, sodium methoxide was used instead of 5% aqueous sodium hydroxide solution to obtain refined loracarbef sodium salt in a yield of 92.6% and a purity of 99.8% (less than 0.1% of impurities).
Example 8:
by the same operation as in example 1, 4-methyl-2-pentanone was changed to diisobutyl ketone to obtain refined salt of oxagolide in 93.9% yield and 99.9% purity (less than 0.1% single impurity).
Example 9:
the procedure of example 1 was followed, and n-heptane beating was changed to cyclohexane beating, to obtain refined salt of oxa-golide in 95.3% yield and 99.8% purity (less than 0.1% single impurity).
Comparative example 1:
the difference from example 1 is that: the procedure of example 1 was followed, and ethanol was changed to isopropanol to obtain refined loragol sodium salt in 88.5% yield and 99.4% purity (more than 0.2% single impurity).
Comparative example 2:
the difference from example 1 is that: the same procedure as in example 1 was repeated except that the pH of 15% diluted hydrochloric acid was adjusted to 5.5, instead of adjusting the pH to 3, to obtain refined salt of oxagoril in a yield of 90.2% and a purity of 99.1% (more than 0.1% of single impurity).
Comparative example 3:
the difference from example 1 is that: the procedure of example 1 was followed, except that the pH of 20% sodium hydroxide solution was changed to 10 and 8, to obtain refined salt of oxagoride in 88.4% yield and 89.6% purity (more than 0.2% single impurity).
Comparative example 4:
the difference from example 1 is that: in the same manner as in example 1, 10g of crude loragol sodium salt was dissolved in 70g of water, instead of 30g of water, to obtain refined loragol sodium salt in 88.4% yield and 98.2% purity (more than 0.1% single impurity).
Comparative example 5:
the difference from example 1 is that: in the same manner as in example 1, 10g of crude loragol sodium salt was dissolved in 70g of water instead of 120g of water to obtain refined loragol sodium salt with a yield of 95.4% and a purity of 97.8% (more than 0.1% of single impurity).
Comparative example 6:
the difference from example 1 is that: the same procedure as in example 1 was repeated except that the cake was dissolved in 70g of methyl t-butyl ether instead of 30g of methyl t-butyl ether to obtain a refined salt of oxarogine sodium in a yield of 92.3% and a purity of 95.6% (more than 0.2% of single impurity).
Comparative example 7:
the difference from example 1 is that: the same procedure as in example 1 was repeated except that the filter cake was dissolved in 70g of methyl t-butyl ether instead of 100g of methyl t-butyl ether to obtain a refined salt of oxarogine sodium in 97.6% yield and 97.8% purity (more than 0.2% single impurity).
Comparative example 8:
the difference from example 1 is that: the procedure of example 1 was followed, except that 50g of n-heptane was added and the pulping was changed to 50g of cyclopentane, to obtain refined salt of oxarogine sodium in 92.4% yield and 96.3% purity (more than 0.2% single impurity).
Claims (11)
1. The method for purifying the oxalagogrid sodium salt is characterized by comprising the following steps:
(1) dissolving the coarse product of the oxa-gol sodium salt in water, adjusting the pH value to acidity with hydrochloric acid, separating out a solid, filtering, and collecting a filter cake;
(2) dissolving the filter cake in an ether solvent, adding water, washing for layering, and concentrating to remove the ether solvent;
(3) adding an organic solvent and an alkaline substance, and reacting at room temperature to form salt;
(4) concentrating to remove the organic solvent, adding water and an ester solvent, washing and layering;
(5) adjusting the pH of the water layer to be alkaline by using a sodium hydroxide solution, and then extracting and layering by using a ketone solvent;
(6) drying, filtering, concentrating to remove filtrate, adding alkane solvent, and pulping;
(7) filtering, and drying under reduced pressure to obtain high-purity oxa-rogue sodium salt;
wherein, the pH value of hydrochloric acid is adjusted to 5-6 in the step (1), and the pH value of sodium hydroxide solution is adjusted to 9-11 in the step (5).
2. The purification method according to claim 1, wherein the weight ratio of the crude salt of oxarogue sodium to water in step (1) is 1:5 to 9.
3. The purification method according to claim 1, wherein the ethereal solvent in the step (2) is diethyl ether, methyl tert-butyl ether, isopropyl ether or anisole.
4. The purification method according to claim 1, wherein the weight ratio of the filter cake to the ether solvent in the step (2) is 1:50 to 80.
5. The purification method according to claim 1, wherein the organic solvent in step (3) is methanol, ethanol, tetrahydrofuran, acetonitrile or acetone.
6. The purification method according to claim 1, wherein the weight ratio of oxadegril to the organic solvent in the step (3) is 1:3 to 7.
7. The purification method according to claim 1, wherein the basic substance in the step (3) is sodium hydroxide, sodium methoxide or sodium ethoxide.
8. The purification method according to claim 1, wherein the molar ratio of oxalagril to the basic substance in the step (3) is 1:1 to 3.
9. The purification method according to claim 1, wherein the ester solvent in step (4) is ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate.
10. The purification method according to claim 1, wherein the ketone solvent in step (5) is 2-butanone, methyl isopropyl ketone, 4-methyl-2-pentanone, or diisobutyl ketone.
11. The purification method according to claim 1, wherein the alkane solvent in the step (6) is cyclohexane, n-hexane, or n-heptane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910676081.XA CN110372609B (en) | 2019-07-25 | 2019-07-25 | Purification method of oxalagogri sodium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910676081.XA CN110372609B (en) | 2019-07-25 | 2019-07-25 | Purification method of oxalagogri sodium salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110372609A CN110372609A (en) | 2019-10-25 |
| CN110372609B true CN110372609B (en) | 2021-04-09 |
Family
ID=68255800
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910676081.XA Active CN110372609B (en) | 2019-07-25 | 2019-07-25 | Purification method of oxalagogri sodium salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110372609B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112694445B (en) * | 2019-10-22 | 2023-07-28 | 成都倍特药业股份有限公司 | Purification method of oxaagole sodium intermediate |
| CN113125575B (en) * | 2019-12-31 | 2023-04-18 | 济南尚博生物科技有限公司 | Quantitative analysis method of 1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methylpyrimidine-diketone |
| CN112494425B (en) * | 2020-12-14 | 2023-06-23 | 珠海优润医药科技有限公司 | Oral solution of oxarogridia sodium and preparation method thereof |
| CN112679442B (en) * | 2021-01-08 | 2022-09-06 | 浙江乐普药业股份有限公司 | Preparation method of oxaagolide sodium |
| CN113121451B (en) * | 2021-03-31 | 2022-11-18 | 江苏海岸药业有限公司 | Method for purifying and preparing oxa-goril sodium |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100424078C (en) * | 2003-07-07 | 2008-10-08 | 纽罗克里生物科学有限公司 | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| US8765948B2 (en) * | 2007-11-07 | 2014-07-01 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| WO2018189212A1 (en) * | 2017-04-12 | 2018-10-18 | Sandoz Ag | Acid addition salts of an orally available gonadotropin-releasing hormone receptor antagonist |
| WO2018224063A2 (en) * | 2017-06-08 | 2018-12-13 | Zentiva, K.S. | Solid forms of elagolix |
| CN110938037A (en) * | 2018-09-21 | 2020-03-31 | 苏州鹏旭医药科技有限公司 | Preparation method of drug intermediate of Eragoli sodium salt |
| EP3724167A1 (en) * | 2017-12-11 | 2020-10-21 | Synthon B.V. | Process for preparing elagolix |
| CN109651171A (en) * | 2019-01-13 | 2019-04-19 | 苏州鹏旭医药科技有限公司 | The preparation method and application of the intermediate and its salt of Yi Lageli and its sodium salt |
| CN110501446B (en) * | 2019-08-28 | 2021-12-17 | 江苏海岸药业有限公司 | Analysis method of oxa-goril sodium raw material and synthetic intermediate thereof |
| CN110746362A (en) * | 2019-11-08 | 2020-02-04 | 安礼特（上海）医药科技有限公司 | Crystal form of eugolic acid sulfate and preparation and application thereof |
-
2019
- 2019-07-25 CN CN201910676081.XA patent/CN110372609B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110372609A (en) | 2019-10-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110372609B (en) | Purification method of oxalagogri sodium salt | |
| CN111511722B (en) | Method for preparing oxa-goril intermediate and composition thereof | |
| WO2010128518A2 (en) | Novel process for the preparation of cisatracurium besylate | |
| US10927095B2 (en) | Processes for the preparation of Niraparib and intermediates thereof | |
| CN101486753A (en) | Novel method for synthesizing finasteroid | |
| WO2007147374A2 (en) | Process for the preparation of solifenacin | |
| CN104140410A (en) | Preparation method of lubiprostone | |
| CN112047883A (en) | Preparation method of cisatracurium besylate | |
| WO2009139002A2 (en) | An improved process for the preparation of solifenacin and its pharmaceutically acceptable salts thereof | |
| CN114105800B (en) | Preparation method of 2, 3-diaminomethyl benzoate | |
| CN112679363B (en) | Method for preparing pentazocine intermediate | |
| CN105968103B (en) | The synthetic method of anti-tumor drug Afatinib | |
| CN113801027B (en) | Synthesis process of dapoxetine hydrochloride | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN103755577B (en) | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor | |
| CN103373956A (en) | Method for preparing clevidipine butyrate | |
| CN109705042B (en) | Preparation method of ambrisentan | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN103288742A (en) | Preparation method for high-purity ingavirin raw material | |
| CN110835319B (en) | Synthesis method of benazepril intermediate and benazepril hydrochloride | |
| CN114605337B (en) | Preparation method of high-purity bosentan | |
| CN103739502A (en) | Process for separating and refining ambroxol alkali | |
| CN102911171A (en) | Semisynthesis method of vinpocetine | |
| CN115490626B (en) | Key chiral compound of PF-07321332 and preparation method thereof | |
| CN110938107B (en) | Process and intermediates for the preparation of fulvestrant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |