CN111574461A - Salt forming purification method of oxalagogrel intermediate and obtained refined oxalagogrel intermediate - Google Patents
Salt forming purification method of oxalagogrel intermediate and obtained refined oxalagogrel intermediate Download PDFInfo
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- CN111574461A CN111574461A CN202010472957.1A CN202010472957A CN111574461A CN 111574461 A CN111574461 A CN 111574461A CN 202010472957 A CN202010472957 A CN 202010472957A CN 111574461 A CN111574461 A CN 111574461A
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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 invention relates to the field of pharmacy, in particular to a salifying purification method of an oxarogue intermediate and an obtained refined oxarogue intermediate, wherein the salifying purification method comprises the following steps: (1) dissolving the coarse product of the oxagoril intermediate in a benign solvent, and then adding organic acid to form salt; (2) dropwise adding the solution into a poor solvent, and stirring to separate out a solid; (3) filtering and drying to obtain organic acid salt of the high-purity oxa-goril intermediate; (4) dissolving the salified solid in an ester or halogenated alkane solvent, adding a sodium hydroxide solution to adjust the pH value to 9, and extracting and layering to remove organic acid to obtain an organic layer; (5) and concentrating the organic layer to obtain a high-purity refined product of the intermediate of the oxagoril. The method avoids complex purification steps, is simple and convenient to operate, has good process repeatability, high purity and good stability of the product after salification, is convenient to store, and accords with industrial production.
Description
Technical Field
The invention relates to the field of pharmacy, and particularly relates to a salt-forming purification method of an oxarogue intermediate and an obtained refined product of the oxarogue intermediate.
Background
Elagolix, a GnRH receptor antagonist that inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland, is useful in the treatment of moderate to severe pain associated with endometriosis, and has the following structural formula:
the synthetic route is as follows:
the method is not suitable for industrial production and the trifluoroacetic acid is relatively expensive.
Patent WO2018189212A proposes to obtain corresponding salt forms of Elagolix with strong acids, such as hydrochloric acid or sulfuric acid, mainly to solve the problem of hygroscopicity of the product, with low practical yields and without significant removal of impurities.
In patent WO2018224063A, the intermediate II of the oxalagril and various organic acids such as pamoic acid, D-dibenzoyltartaric acid, maleic acid, fumaric acid, oxalic acid, succinic acid, glutamic acid, methanesulfonic acid and other acids with pKa less than or equal to 5 are proposed to form corresponding salt forms, the method reduces lactam impurities in the Elagolx, and improves the stability of the product.
At present, other literature reports that the intermediate II and the Elagox are mainly subjected to column chromatography or an ion exchange mode to obtain high-purity oxaagoli, and the purification mode inevitably increases the production cost of the product greatly and is not beneficial to the industrial production of the product. However, the intermediate II is not as basic as the intermediate I, the crude purity is far lower than that of the intermediate I, and the solid stability and the impurity removal effect after salification are still not as good as those of the intermediate I. Therefore, from the perspective of atom economy and the purity and quality of the final product, the purification step is shifted forward to the intermediate I, so that the yield can be improved, the solvent consumption and the discharge of three wastes can be reduced, the cost can be reduced, and the Elagolix is more convenient for industrial large-scale production.
Disclosure of Invention
The invention aims to provide a salt-forming purification method of an oxagolide intermediate, which can stably obtain an organic acid salt solid of the oxagolide intermediate I and has the advantages of good impurity removal effect, stable process, simplicity and convenience in operation, and high product purity and yield.
The invention provides a salifying and purifying method of an oxa-goril intermediate, which adopts the following technical scheme and comprises the following steps:
(1) dissolving the coarse product of the oxagoril intermediate in a benign solvent, and then adding organic acid to form salt;
(2) dropwise adding the solution into a poor solvent, and stirring to separate out a solid;
(3) filtering and drying to obtain organic acid salt of the high-purity oxa-goril intermediate;
(4) dissolving the salified solid in an ester or halogenated alkane solvent, adding a sodium hydroxide solution to adjust the pH value to 9, and extracting and layering to remove organic acid to obtain an organic layer;
(5) and concentrating the organic layer to obtain a high-purity refined product of the intermediate of the oxagoril.
Preferably, the benign solvent in step (1) is selected from: one or more of ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane and chloroform.
Further, the benign solvent is preferably dichloromethane.
Preferably, the organic acid in step (1) is selected from: one or more of benzoic acid, phthalic acid, mandelic acid, benzenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid and citric acid.
Further, the organic acid is preferably citric acid.
Preferably, the weight-to-volume ratio of the crude product of the oxalagril intermediate to the benign solvent in the step (1) is 1: 2-8, and more preferably 1: 3.
Preferably, the molar weight ratio of the crude product of the oxalagril intermediate to the organic acid in the step (1) is 1: 0.4-1.2, and more preferably 1: 0.4.
Preferably, the poor solvent in step (2) is selected from: cyclohexane, n-hexane, n-heptane, diethyl ether, isopropyl ether, and methyl tert-butyl ether, preferably methyl tert-butyl ether.
Preferably, the volume ratio of the benign solvent to the poor solvent is 1:3 to 7, and more preferably 1: 4.
Preferably, in step (4), the ester or haloalkane solvent is selected from: one or more of ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane and chloroform, preferably dichloromethane;
preferably, the weight-to-volume ratio of the solid after salification in the step (4) to the ester or halogenated alkane solvent is 1: 2-6, and more preferably 1: 3.
The invention also provides a refined product of the oxagoril intermediate, which is obtained by the salifying purification method and has high purity and good stability.
The invention has the beneficial effects that: the method avoids complex purification steps, is simple and convenient to operate, has good process repeatability, high purity and good stability of the product after salification, is convenient to store, and accords with industrial production.
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 spectrum of a crude product of an oxalagogrel intermediate i according to example 1 of the present invention;
fig. 2 is a detection spectrum after purification of the intermediate i of oxalagogrel into citrate according to 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 SUPELCO Ascentis Express C182.7 μm, 150 mm. times.4.6 mm (PN: 53829-U), the detector was a UV detector, the wavelength was 210nm, the mobile phase A was water: methanol: phosphoric acid =900: 100: 1 (v/v/v), mobile phase B is acetonitrile: methanol: phosphoric acid =900: 100: 1 (v/v/v), elution program 97% mobile phase a and 3% mobile phase B for 0-3min, 30% mobile phase a and 70% mobile phase B for 3-30min, 5% mobile phase a and 95% mobile phase B for 30-40min, 97% mobile phase a and 3% mobile phase B for 40-45 min.
Example 1:
dissolving 5g of the crude product of the intermediate I of the oxarogue (with the purity of 81.2%) in 15g of dichloromethane, adding 0.77g of citric acid, stirring and dissolving, dropwise adding the solution into 45ml of methyl tert-butyl ether to precipitate a solid, stirring for 15min, and filtering to obtain 6g of citrate of the intermediate I of the oxarogue. The obtained solid was dissolved in 18g of dichloromethane, 10ml of 5% sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted and layered to obtain an organic layer, and the organic layer was concentrated to dryness at room temperature to obtain 4.5g of refined product of intermediate I of oxa-rogle (purity 99.9%).
Example 2:
following the same procedure as in example 1, 1.5g of citric acid was replaced with 0.77g of citric acid, to obtain 3.5g of refined intermediate I of oxalagogrel (purity 98.6%).
Example 3:
the procedure of example 1 was followed, changing the solution in 15g of dichloromethane to 15g of isopropanol, to obtain 3g of a refined product of oxarogrel intermediate I (purity 99.2%).
Example 4:
dissolving 5g of an oxalagrange intermediate I crude product (with the purity of 81.2%) in 25g of ethanol, adding 1.54g of benzenesulfonic acid, stirring for dissolving, dropwise adding the solution into 200ml of diethyl ether to precipitate a solid, stirring for 15min, and filtering to obtain 4.8g of benzene sulfonate of the oxalagrange intermediate I. The obtained solid was dissolved in 14.4g of ethyl acetate, 8ml of 5% sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted and layered to obtain an organic layer, which was concentrated at 45 ℃ to dryness to obtain 4g of fine intermediate I of oxarogel (purity 93.3%).
Example 5:
5g of the crude product of the intermediate I of the oxadiargyl (with the purity of 81.2%) is dissolved in 20g of isopropyl acetate, then 1.35g of benzoic acid is added and stirred for dissolution, the solution is dripped into 150ml of n-heptane to precipitate a solid, and after stirring for 15min, 4.7g of benzoate of the intermediate I of the oxadiargyl is obtained by filtration. The obtained solid was dissolved in 12g of isopropyl acetate, 7ml of 5% sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted and layered to obtain an organic layer, which was concentrated to dryness at 45 ℃ to obtain 3.8g of a fine product of the intermediate I of oxarogue (purity 92.6%).
Example 6:
dissolving 5g of the crude product of the Oxagolide intermediate I (with the purity of 81.2%) in 10g of chloroform, adding 1.53g of mandelic acid, stirring for dissolving, dropwise adding the solution into 150ml of cyclohexane to precipitate solids, stirring for 15min, and filtering to obtain 6.1g of mandelate of the Oxagolide intermediate I. The obtained solid was dissolved in 36g of ethyl acetate, 8ml of 5% sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted and layered to obtain an organic layer, which was concentrated to dryness at 45 ℃ to obtain 4.1g of refined product of the intermediate I of oxalagogri (purity 98.8%).
Example 7:
dissolving 5g of the crude product of the intermediate I of the oxadiargyl (with the purity of 81.2%) in 25g of dichloromethane, adding 1.92g of p-toluenesulfonic acid, stirring and dissolving, dropwise adding the solution into 100ml of isopropyl ether to precipitate a solid, stirring for 15min, and filtering to obtain 5.5g of p-toluenesulfonic acid salt of the intermediate I of the oxadiargyl. The obtained solid was dissolved in 16.5g of dichloromethane, 10ml of 5% sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted and layered to obtain an organic layer, which was concentrated to dryness at room temperature to obtain 4.4g of refined product of intermediate I of oxalagogri (purity 97.2%).
Example 8:
dissolving 5g of the crude product of the intermediate I of the oxadiargyl (with the purity of 81.2%) in 40g of dichloromethane, adding 2.56g of camphorsulfonic acid, stirring for dissolving, dropwise adding the solution into 200ml of methyl tert-butyl ether, precipitating a solid, stirring for 15min, and filtering to obtain 5.2g of camphorsulfonate of the intermediate I of the oxadiargyl. The obtained solid was dissolved in 26g of dichloromethane, 10ml of 5% sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted and layered to obtain an organic layer, and the organic layer was concentrated to dryness at room temperature to obtain 3.9g of refined product of intermediate I of oxa-rogle (purity 97.5%).
Comparative example 1:
the difference from example 1 is that: following the same procedure as in example 1, instead of adding 0.77g of citric acid to 1g of 5mol/L isopropanol hydrochloride solution, only 2g of a refined form of intermediate I of oxalagogrel (purity 88.5%) was obtained.
Comparative example 2:
the difference from example 1 is that: following the same procedure as in example 1, 0.53g of citric acid was replaced with 0.77g of citric acid, to obtain only 3.4g of refined form of intermediate I of oxalagogrel (purity 98.6%).
Comparative example 3:
the difference from example 1 is that: in the same manner as in example 1, 5g of the crude loragol intermediate i (81.2% pure) was dissolved in 15g of dichloromethane instead of 15g of methanol, and no solid could be precipitated, so that no citrate solid of the loragol intermediate i was obtained.
Claims (10)
1. A salifying and purifying method of an oxalagogri intermediate is characterized by comprising the following steps:
(1) dissolving the coarse product of the oxagoril intermediate in a benign solvent, and then adding organic acid to form salt;
(2) dropwise adding the solution obtained in the step (1) into a poor solvent, and stirring to separate out a solid;
(3) filtering and drying to obtain organic acid salt of the high-purity oxa-goril intermediate;
(4) dissolving the salified solid in an ester or halogenated alkane solvent, adding a sodium hydroxide solution to adjust the pH value to 9, and extracting and layering to remove organic acid to obtain an organic layer;
(5) and concentrating the organic layer to obtain a high-purity refined product of the intermediate of the oxagoril.
2. The process for salifying purification of an oxalagril intermediate according to claim 1, characterized in that the benign solvent in step (1) is selected from the group consisting of: one or more of ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane and chloroform.
3. The process for salifying purification of an oxalagril intermediate according to claim 1, characterized in that the organic acid in step (1) is selected from the group consisting of: one or more of benzoic acid, phthalic acid, mandelic acid, benzenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid and citric acid.
4. The method for salifying and purifying the oxadiargoid intermediate according to claim 1, wherein the weight to volume ratio of the crude oxadiargoid intermediate to the benign solvent in step (1) is 1:2 to 8.
5. The method for salifying and purifying the oxadiargyl intermediate according to claim 1, wherein the molar weight ratio of the crude oxadiargyl intermediate to the organic acid in step (1) is 1:0.4 to 1.2.
6. The process for salifying purification of an oxalagril intermediate according to claim 1, characterized in that the poor solvent in step (2) is selected from the group consisting of: cyclohexane, n-hexane, n-heptane, diethyl ether, isopropyl ether, and methyl tert-butyl ether.
7. The method for salifying and purifying the oxarogue intermediate according to claims 2 and 6, wherein the volume ratio of the benign solvent to the poor solvent is 1: 3-7.
8. The process for salifying purification of an oxarogril intermediate according to claim 1, characterized in that in step (4) the ester or haloalkane solvent is selected from: one or more of ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane and chloroform.
9. The method for salifying and purifying the oxagolide intermediate according to claim 8, wherein the weight to volume ratio of the solid after salification in the step (4) to the ester or halogenated alkane solvent is 1: 2-6.
10. A refined loragol intermediate obtained by the salt-forming purification method of any one of claims 1-9.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112494425A (en) * | 2020-12-14 | 2021-03-16 | 珠海优润医药科技有限公司 | Oral solution of oxaagolide sodium and preparation method thereof |
| CN112763598A (en) * | 2020-12-21 | 2021-05-07 | 上海博悦生物科技有限公司 | Method for separating and determining key intermediate and related impurities of oxadegril sodium by HPLC (high Performance liquid chromatography) method |
| CN114280176A (en) * | 2021-12-11 | 2022-04-05 | 丽珠集团新北江制药股份有限公司 | Method for detecting related substances in oxaagolide by using HPLC (high Performance liquid chromatography) |
| CN114835650A (en) * | 2021-02-01 | 2022-08-02 | 上海漠澳浩医药科技有限公司 | Salt and crystal of oxalagogri intermediate, and preparation method and application thereof |
| CN115466224A (en) * | 2021-06-11 | 2022-12-13 | 成都倍特药业股份有限公司 | Salt forming method and purification method of oxalagogri intermediate I |
| CN115804774A (en) * | 2022-08-26 | 2023-03-17 | 济川(上海)医学科技有限公司 | Oxagolide pharmaceutical composition, pharmaceutical preparation containing same and application of pharmaceutical composition |
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| WO2020023459A1 (en) * | 2018-07-23 | 2020-01-30 | Abbvie Inc. | Elagolix sodium compositions and processes |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112494425A (en) * | 2020-12-14 | 2021-03-16 | 珠海优润医药科技有限公司 | Oral solution of oxaagolide sodium and preparation method thereof |
| 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 |
| CN112763598A (en) * | 2020-12-21 | 2021-05-07 | 上海博悦生物科技有限公司 | Method for separating and determining key intermediate and related impurities of oxadegril sodium by HPLC (high Performance liquid chromatography) method |
| CN112763598B (en) * | 2020-12-21 | 2021-09-17 | 上海博悦生物科技有限公司 | Method for separating and determining key intermediate and related impurities of oxadegril sodium by HPLC (high Performance liquid chromatography) method |
| CN114835650A (en) * | 2021-02-01 | 2022-08-02 | 上海漠澳浩医药科技有限公司 | Salt and crystal of oxalagogri intermediate, and preparation method and application thereof |
| CN115466224A (en) * | 2021-06-11 | 2022-12-13 | 成都倍特药业股份有限公司 | Salt forming method and purification method of oxalagogri intermediate I |
| CN114280176A (en) * | 2021-12-11 | 2022-04-05 | 丽珠集团新北江制药股份有限公司 | Method for detecting related substances in oxaagolide by using HPLC (high Performance liquid chromatography) |
| CN115804774A (en) * | 2022-08-26 | 2023-03-17 | 济川(上海)医学科技有限公司 | Oxagolide pharmaceutical composition, pharmaceutical preparation containing same and application of pharmaceutical composition |
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