CN111116490A - Preparation and purification method of oxalagogri intermediate salicylate - Google Patents
Preparation and purification method of oxalagogri intermediate salicylate Download PDFInfo
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- CN111116490A CN111116490A CN202010039361.2A CN202010039361A CN111116490A CN 111116490 A CN111116490 A CN 111116490A CN 202010039361 A CN202010039361 A CN 202010039361A CN 111116490 A CN111116490 A CN 111116490A
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- salicylate
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- oxalagril
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- acetate
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- 229960001860 salicylate Drugs 0.000 title claims abstract description 32
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000000746 purification Methods 0.000 title abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 45
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000012044 organic layer Substances 0.000 claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 29
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000000243 solution Substances 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 24
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000010410 layer Substances 0.000 claims abstract description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 10
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 6
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 6
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 20
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000012043 crude product Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 12
- -1 Boc group Chemical group 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- OXCYXNLVSUILPV-UHFFFAOYSA-N 2-hydroxybenzoic acid;propan-2-ol Chemical compound CC(C)O.OC(=O)C1=CC=CC=C1O OXCYXNLVSUILPV-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 3
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- HEAUOKZIVMZVQL-VWLOTQADSA-N Elagolix Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NCCCC(O)=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F HEAUOKZIVMZVQL-VWLOTQADSA-N 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229950004823 elagolix Drugs 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000007281 aminoalkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- HEILIGJNYTWOHU-UHFFFAOYSA-N ethanol 2-hydroxybenzoic acid Chemical compound CCO.OC(=O)C1=CC=CC=C1O HEILIGJNYTWOHU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of pharmacy, in particular to a preparation and purification method of an oxalagril intermediate salicylate, which comprises the following steps: (1) dissolving the crude product of the oxa-goril intermediate in a solvent; (2) dissolving salicylic acid in an alcohol solvent, and then adding the alcohol solvent into the step (1); (3) adding water or an alkane solvent into the step (2), stirring, and cooling to room temperature; (4) separating out solids; (5) dissolving the solid obtained in the step (4) in an ester solvent, adding a phosphoric acid aqueous solution, and extracting to obtain an acid water layer; (6) adding an ester solvent into the acid water layer, adding a sodium hydroxide solution, and extracting and layering to obtain an organic layer; (7) and (4) concentrating and drying the organic layer to obtain a refined product of the intermediate of the oxagoril. According to the invention, the preparation and purification of the oxalagogri intermediate salicylate simplify the production process of subsequent products, reduce the production cost, and are suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a preparation and purification method of an oxalagril intermediate salicylate.
Background
Endometriosis refers to a common gynecological disease in women, wherein intimal cells are planted in abnormal positions. Ebervia (AbbVie) and the gynecological drug orilisa (elagolix) developed by neurokrine Biosciences are oral gonadotropin releasing hormone (GnRH) antagonists that inhibit endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland. In 2018, month 7, the drug was approved by the U.S. food and drug administration for the treatment of pain due to endometriosis. In addition, a new indication for Elagolix in combination with low dose hormones for the treatment of severe menstrual bleeding (HMB) associated with uterine fibroids in women is also in clinical trials.
The structural formula of the oxalagogrel key intermediate is as follows:
in patent WO2005007165, 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl]-6-methylpyrimidine-2, 4 (1)H,3H) And (3) carrying out alkylation and Suzuki coupling reaction on diketone, then hydrolyzing to remove Boc group, carrying out amino alkylation, and finally hydrolyzing to obtain the oxagolide sodium salt. As shown in the following route, column chromatography is used for purifying the intermediate in the route, and the oxogolide sodium salt is prepared and purified by using a cation exchange column, so that the whole process is too high in cost and is not suitable for industrial production.
Patent CN109651265A proposes the use of (R) -3- (2-amino-2-phenylethyl) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methylpyrimidine-2, 4 (1)H,3H) Reaction of-diketones with 4-oxobutanoic acid to give oxa-acidsThe final post-treatment of the method, namely the laggolide, adopts column chromatography to purify the product, and the yield is too low.
From the synthesis route of the oxa-rogue, the aim of purifying the product is achieved by passing an intermediate through a column or adopting an ion exchange column when the high-purity oxa-rogue is obtained at present, and the process cost is too expensive due to the operation, so that the large-scale production of the product is not facilitated. Therefore, the method for purifying the oxa-rogue intermediate is developed, and the operation of column chromatography or ion exchange column is reduced, so that the production cost can be greatly reduced, and the method is convenient for industrial large-scale production.
Disclosure of Invention
The invention aims to provide a method for preparing and purifying an oxagoril intermediate salicylate aiming at the defects of the prior art, and the method has the characteristics of simple and convenient operation, low cost, high product purity and yield, and accordance with industrial production.
The invention aims to provide a preparation method of an oxalagogri intermediate salicylate, which adopts the following technical scheme and comprises the following steps:
(1) dissolving the coarse product of the oxagoril intermediate in a solvent, and heating to 30-55 ℃;
(2) dissolving salicylic acid in an alcohol solvent, adding the alcohol solvent into the step (1), and stirring for 1-2 h;
(3) adding water or an alkane solvent into the step (2), stirring for 1-2 hours, and then cooling to room temperature;
(4) separating out solid, and filtering to obtain salicylate of the oxa-golide intermediate.
Preferably, the weight-to-volume ratio of the crude product of the oxalagril intermediate to the solvent in the step (1) is 1: 2-7, and more preferably 1: 3.
Preferably, in step (1), the solvent is methanol, ethanol, isopropanol, acetone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, or methyl t-butyl ether, and more preferably isopropyl acetate.
Preferably, the weight volume ratio of the salicylic acid to the alcohol solvent in the step (2) is 1: 1-5, and more preferably 1: 2.
Preferably, the molar weight ratio of the crude product of the oxalagril intermediate to the salicylic acid in the step (2) is 1: 1-1.4, and more preferably 1: 1.2.
Preferably, the alcohol solvent in step (2) is methanol, ethanol, isopropanol, more preferably isopropanol;
preferably, the weight-to-volume ratio of the water or alkane solvent to the crude product of the oxagoril intermediate in the step (3) is 1: 5-10, and further preferably 1: 8;
preferably, the alkane solvent in the step (3) is cyclohexane, n-hexane or n-heptane, more preferably n-heptane;
the invention also provides a method for purifying the salicylate of the oxagoril intermediate, which comprises the following steps:
s-1, dissolving the solid obtained in the step (4) in an ester solvent, adding a 5-10% phosphoric acid water solution to adjust the pH value to 2-3, and extracting and layering to obtain an acid water layer;
s-2, adding the ester solvent in the step S-1 into the acid water layer, adding a 5-10% sodium hydroxide solution to adjust the pH value to 8-9, and extracting and layering to obtain an organic layer;
and (4) concentrating and drying the S-3 organic layer to obtain a refined product of the high-purity Oxagolide intermediate.
Preferably, the volume ratio of the ester solvent to the phosphoric acid aqueous solution in the step S-1 is 1-3: 1, and more preferably 2: 1.
Preferably, the weight-to-volume ratio of the solid to the ester solvent in steps S-1 and S-2 is 1:5 to 15, and more preferably 1: 8.
Preferably, the ester solvent in steps S-1 and S-2 is ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and more preferably isopropyl acetate.
Preferably, the volume ratio of the ester solvent to the sodium hydroxide solution in the step S-2 is 2-5: 1, and more preferably 3: 1.
The invention has the beneficial effects that: compared with the traditional method for refining by column chromatography and ion exchange column, the method simplifies the production process of subsequent products and reduces the production cost of the oxagoril sodium salt by preparing and purifying the oxagoril intermediate salicylate, and is suitable for industrial large-scale production. In addition, the method is simple and convenient to operate, the obtained intermediate is low in cost, and the product purity and yield are high.
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 an oxalagril intermediate i before purification according to inventive example 1;
fig. 2 is a detection profile of an oxalagril intermediate i purified according to inventive example 1.
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. 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 the oxalagrange intermediate I (purity 87.2%) in 30ml of methanol, heating to 40 ℃, adding a previously dissolved methanol solution of salicylic acid (3 g of salicylic acid in 6ml of methanol), stirring for 1 hour, adding 80ml of water, continuing stirring for 1 hour, then cooling to room temperature, and filtering to obtain 12.4g of the salicylate of the oxalagrange intermediate I. Dissolving the obtained solid in 96ml of ethyl acetate, adding 48ml of 10% phosphoric acid aqueous solution to adjust the pH value to 2, extracting and layering to obtain an acid aqueous layer, adding 96ml of ethyl acetate, adding 32ml of 10% sodium hydroxide solution to adjust the pH value to 9, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 8.9g of refined product of the intermediate I of the oxalagogrel (the purity is 99.3%).
Example 2:
dissolving 10g of the oxalagrange intermediate I (with the purity of 87.2%) in 30ml of isopropanol, heating to 45 ℃, adding a previously dissolved salicylic acid isopropanol solution (3.2 g of salicylic acid in 9ml of isopropanol), stirring for 1h, adding 50ml of water, continuing stirring for 1h, then cooling to room temperature, and filtering to obtain 11.7g of the salicylate of the oxalagrange intermediate I. Dissolving the obtained solid in 90ml of ethyl acetate, adding 85ml of 5% phosphoric acid aqueous solution to adjust the pH value to 2, extracting and layering to obtain an acid aqueous layer, adding 90ml of ethyl acetate, adding 45ml of 8% sodium hydroxide solution to adjust the pH value to 9, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 8.5g of refined product of the intermediate I of the oxalagogrel (the purity is 98.9%).
Example 3:
dissolving 10g of the oxadiargyl intermediate I (purity 87.2%) in 20ml of isopropyl acetate, heating to 30 ℃, adding a previously dissolved salicylic acid ethanol solution (3.3 g of salicylic acid in 6ml of ethanol), stirring for 1h, adding 50ml of n-heptane, continuing stirring for 1h, then cooling to room temperature, and filtering to obtain 12.2g of the salicylate of the oxadiargyl intermediate I. Dissolving the obtained solid in 100ml of isopropyl acetate, adding 62.5ml of 8% phosphoric acid aqueous solution to adjust the pH value to 3, extracting and layering to obtain an acid aqueous layer, adding 100ml of isopropyl acetate, adding 28.5ml of 7% sodium hydroxide solution to adjust the pH value to 8, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 8.8g of refined product of the intermediate I of the oxargoline (the purity is 99.2%).
Example 4:
dissolving 10g of the intermediate II of the oxalagrange (purity 92.3%) in 40ml of acetone, heating to 50 ℃, adding a pre-dissolved isopropanol salicylic acid solution (2.5 g of salicylic acid in 5ml of isopropanol), stirring for 1h, adding 90ml of water, continuing stirring for 1h, then cooling to room temperature, and filtering to obtain 10.8g of the salicylate of the intermediate II of the oxalagrange. Dissolving the obtained solid in 110ml of butyl acetate, adding 91.6ml of 6% phosphoric acid aqueous solution to adjust the pH value to 2, extracting and layering to obtain an acid water layer, adding 110ml of butyl acetate, adding 43.3ml of 6% sodium hydroxide solution to adjust the pH value to 9, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 9.4g of refined product of the intermediate II of the Oxagolide (purity 99.4%).
Example 5:
dissolving 10g of the oxalagrol intermediate II (with the purity of 92.3%) in 40ml of methyl tert-butyl ether, heating to 30 ℃, adding a previously dissolved salicylic acid isopropanol solution (2.6 g of salicylic acid dissolved in 4ml of isopropanol), stirring for 1h, adding 70ml of cyclohexane, continuing stirring for 1h, then cooling to room temperature, and filtering to obtain 10.3g of the salicylate of the oxalagrol intermediate II. Dissolving the obtained solid in 130ml of isobutyl acetate, adding 62.5ml of 8% phosphoric acid aqueous solution to adjust the pH value to 2, extracting and layering to obtain an acid aqueous layer, adding 130ml of isobutyl acetate, adding 30ml of 10% sodium hydroxide solution to adjust the pH value to 9, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 9.1g of refined product of the intermediate II of the Oxagolide (purity is 99.1%).
Example 6:
dissolving 10g of the intermediate II of oxalagogrel (purity 92.3%) in 60ml of methanol, heating to 40 ℃, adding a previously dissolved methanol solution of salicylic acid (2.3 g of salicylic acid in 3ml of methanol), stirring for 1 hour, adding 50ml of water, continuing stirring for 1 hour, then cooling to room temperature, and filtering to obtain 9.9g of the salicylate of the intermediate II of oxalagogrel. Dissolving the obtained solid in 120ml of ethyl acetate, adding 45ml of 10% phosphoric acid aqueous solution to adjust the pH value to 3, extracting and layering to obtain an acid aqueous layer, adding 120ml of ethyl acetate, adding 30ml of 9% sodium hydroxide solution to adjust the pH value to 8, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 8.8g of refined product of the intermediate II of the oxalagogrel (the purity is 99.3%).
Example 7:
10g of the intermediate iii of oxalagril (purity 93.5%) was dissolved in 30ml of methanol, heated to 40 ℃, and then a previously dissolved methanol solution of salicylic acid (2.6 g of salicylic acid in 4ml of methanol) was added thereto, stirred for 1 hour, 70ml of water was added thereto, followed by stirring for 1 hour, then cooled to room temperature, and filtered to obtain 11.5g of the salicylate of the intermediate iii of oxalagril. Dissolving the obtained solid in 88ml of ethyl acetate, adding 50ml of 6% phosphoric acid aqueous solution to adjust the pH value to 2, extracting and layering to obtain an acid aqueous layer, adding 88ml of ethyl acetate, adding 20ml of 10% sodium hydroxide solution to adjust the pH value to 8, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 9.4g of refined product of the intermediate III of the oxalagogrel (purity of 99.5%).
Example 8:
dissolving 10g of the intermediate III (with the purity of 93.5%) of the oxalagril in 45ml of ethanol, heating to 55 ℃, adding a pre-dissolved ethanol solution of salicylic acid (2.8 g of salicylic acid in 6ml of ethanol), stirring for 1h, adding 100ml of water, continuing stirring for 1h, then cooling to room temperature, and filtering to obtain 11.8g of the salicylate of the intermediate III of the oxalagril. Dissolving the obtained solid in 118ml of isopropyl acetate, adding 35ml of 10% phosphoric acid aqueous solution to adjust the pH value to 2, extracting and layering to obtain an acid aqueous layer, adding 118ml of ethyl acetate, adding 30ml of 10% sodium hydroxide solution to adjust the pH value to 9, extracting and layering to obtain an organic layer, and concentrating the organic layer at 45 ℃ until the organic layer is dried to obtain 9.2g of refined product of the intermediate III of the oxalagogrel (the purity is 99.2%).
Comparative example 1:
the difference from example 1 is that: in the same manner as in example 1, 30ml of methanol was changed to 100ml of methanol to obtain 7.8g of a refined product of intermediate I of oxarogrel (purity: 98.5%).
Comparative example 2:
the difference from example 1 is that: following the same procedure as in example 1, 3g of salicylic acid was changed to 2.5g of salicylic acid to obtain 7.2g of refined product of intermediate I of oxarogrel (purity: 90.6%).
Comparative example 3:
the difference from example 1 is that: in the same manner as in example 1, pH was adjusted to 9 with 32ml of 10% sodium hydroxide solution, and pH was adjusted to 12 with 60ml of 10% sodium hydroxide solution, to thereby obtain 8.1g of refined form of intermediate I of oxalagogri (purity 95.6%).
Claims (13)
1. A preparation method of an oxalagori intermediate salicylate is characterized by comprising the following steps:
(1) dissolving the coarse product of the oxagoril intermediate in a solvent, and heating to 30-55 ℃;
(2) dissolving salicylic acid in an alcohol solvent, adding the alcohol solvent into the step (1), and stirring for 1-2 h;
(3) adding water or an alkane solvent into the step (2), stirring for 1-2 hours, and then cooling to room temperature;
(4) separating out solid, and filtering to obtain salicylate of the oxa-golide intermediate.
2. The method for preparing the oxalagril intermediate salicylate according to claim 1, wherein the weight-to-volume ratio of the crude oxalagril intermediate to the solvent in the step (1) is 1: 2-7.
3. The method for preparing the intermediate salicylate of oxaroglide of claim 1, wherein the solvent in step (1) is one or more selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and methyl tert-butyl ether.
4. The method for preparing the oxalagril intermediate salicylate according to claim 1, wherein the weight-to-volume ratio of the salicylic acid to the alcohol solvent in the step (2) is 1: 1-5.
5. The method for preparing the oxadary intermediate salicylate according to claim 1, wherein the molar weight ratio of the crude oxadary intermediate to salicylic acid in the step (2) is 1: 1-1.4.
6. The method for preparing the salicylate intermediate of oxalagril according to claim 1, wherein the alcoholic solvent in the step (2) is one or more of methanol, ethanol and isopropanol.
7. The method for preparing the oxadary intermediate salicylate according to claim 1, wherein the weight-to-volume ratio of the water or alkane solvent to the crude oxadary intermediate in the step (3) is 1: 5-10.
8. The method for preparing the oxadary intermediate salicylate according to claim 1, wherein the alkane solvent in the step (3) is one or a mixture of cyclohexane, n-hexane and n-heptane.
9. A method for purifying an oxalagogri intermediate salicylate is characterized by specifically comprising the following steps:
s-1, dissolving the solid obtained in the step (4) in the claim 1 in an ester solvent, adding a 5-10% phosphoric acid water solution to adjust the pH value to 2-3, and extracting and layering to obtain an acid water layer;
s-2, adding the ester solvent in the step S-1 into the acid water layer, adding a 5-10% sodium hydroxide solution to adjust the pH value to 8-9, and extracting and layering to obtain an organic layer;
and (4) concentrating and drying the S-3 organic layer to obtain a refined product of the high-purity Oxagolide intermediate.
10. The method for purifying an oxalagril intermediate salicylate according to claim 9, wherein the volume ratio of the ester solvent to the phosphoric acid aqueous solution in the step S-1 is 1-3: 1.
11. The method for purifying the oxalagril intermediate salicylate of claim 9, wherein the weight to volume ratio of the solid to the ester solvent in steps S-1 and S-2 is 1:5 to 15.
12. The method for purifying an oxa-golide intermediate salicylate of claim 9, wherein the ester solvent in steps S-1 and S-2 is one or more selected from ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate.
13. The method for purifying the oxalagril intermediate salicylate according to claim 9, wherein the volume ratio of the ester solvent to the sodium hydroxide solution in the step S-2 is 2-5: 1.
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