CN116947623A - Method for preparing loxoprofen acid and loxoprofen sodium - Google Patents
Method for preparing loxoprofen acid and loxoprofen sodium Download PDFInfo
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- CN116947623A CN116947623A CN202310901796.7A CN202310901796A CN116947623A CN 116947623 A CN116947623 A CN 116947623A CN 202310901796 A CN202310901796 A CN 202310901796A CN 116947623 A CN116947623 A CN 116947623A
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- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 38
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 26
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 238000002156 mixing Methods 0.000 claims abstract description 20
- 229940126062 Compound A Drugs 0.000 claims abstract description 18
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 18
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims abstract description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006482 condensation reaction Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007859 condensation product Substances 0.000 claims abstract description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 14
- 239000012044 organic layer Substances 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000047 product Substances 0.000 abstract description 10
- 230000005494 condensation Effects 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 5
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 15
- 238000010992 reflux Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QQXBRVQJMKBAOZ-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(CBr)C=C1 QQXBRVQJMKBAOZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- OXFCILAOEGBINA-UHFFFAOYSA-N methyl 2-[4-(bromomethyl)phenyl]propanoate Chemical compound COC(=O)C(C)C1=CC=C(CBr)C=C1 OXFCILAOEGBINA-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- KEPNSIARSTUPGS-UHFFFAOYSA-N 2-n,4-n,6-n-trichloro-1,3,5-triazine-2,4,6-triamine Chemical compound ClNC1=NC(NCl)=NC(NCl)=N1 KEPNSIARSTUPGS-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 238000002848 electrochemical method Methods 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- LJRSKOFNPMYRSO-UHFFFAOYSA-N ethyl 2-[4-(chloromethyl)phenyl]propanoate Chemical compound CCOC(=O)C(C)C1=CC=C(CCl)C=C1 LJRSKOFNPMYRSO-UHFFFAOYSA-N 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
-
- 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
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of loxoprofen acid and loxoprofen sodium, and relates to the technical field of organic synthesis. The invention mixes 1- (1-pyrrolidine) cyclopentene, a compound A and an organic solvent for condensation reaction, removes the solvent from the obtained condensation reaction liquid, and obtains a condensation product; and mixing the condensation product with acetic acid, hydrochloric acid and water to perform hydrolysis reaction to obtain loxoprofen acid. The invention takes 1- (1-pyrrolidine) cyclopentene and a compound A as starting materials, and can prepare the loxoprofen acid through condensation and hydrolysis. The reaction raw materials adopted by the invention are easy to obtain; the condensation and the hydrolysis adopt a one-step method, and the operation steps are simple; the invention synthesizes loxoprofen acid from 1- (1-pyrrolidine) cyclopentene by adopting continuous reaction, and the intermediate is not separated, thereby improving the reaction yield and the equipment utilization rate; moreover, the reaction conditions of the invention are easy to control. The invention provides a preparation method of loxoprofen sodium, which has high yield and high product purity and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of loxoprofen acid and loxoprofen sodium.
Background
Loxoprofen sodium (loxoprofen sodium), which is 2- [4- [ (2-oxo-cyclopentyl) methyl ] phenyl ] sodium propionate dihydrate, is developed by Japanese Sanco-company, is marketed in Japan in 1986, is an important 2-phenylpropionic acid nonsteroidal analgesic and anti-inflammatory drug, and is widely used for relieving pain and diminishing inflammation of rheumatoid arthritis, lumbago, scapulohumeral periarthritis, neck-shoulder-wrist syndrome, acute upper airway inflammation and the like, and is characterized by strong analgesic effect, quick response and small adverse reaction. The structure of loxoprofen sodium is as follows:
loxoprofen acid is an intermediate for preparing loxoprofen sodium, and the loxoprofen sodium is prepared by salifying loxoprofen acid. Japanese patent JP200181066 reports the preparation of loxoprofen acid from p-halomethylstyrene as starting material by condensation, hydrolysis, bromination, electrolysis and reduction, the synthetic route being as follows:
the method is characterized in that the loxoprofen acid is prepared by an electrochemical method. The method has the defects that the reaction conditions are harsh (high temperature is 145 ℃ and low temperature is-60 ℃), and the control is not easy; meanwhile, the initial raw material of the para-halomethyl styrene is not easy to obtain; finally, a catalytic hydrogenation method is adopted, and a high-pressure hydrogenation kettle is needed. These disadvantages limit the industrial application of this route.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing loxoprofen acid and loxoprofen sodium. The preparation method provided by the invention has the advantages of easily available raw materials, easily controllable reaction conditions, simple steps and high yield.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of loxoprofen acid, which comprises the following steps:
mixing 1- (1-pyrrolidine) cyclopentene, a compound A and an organic solvent for condensation reaction, and removing the solvent from the obtained condensation reaction liquid to obtain a condensation product;
mixing the condensation product with acetic acid, hydrochloric acid and water for hydrolysis reaction to obtain loxoprofen acid;
the compound A has a structure shown in a formula I:
in the formula I, X is-Cl or-Br, R is-H, -CH 3 or-CH 2 CH 3 。
Preferably, the mass ratio of the compound A to the 1- (1-pyrrolidine) cyclopentene is 1: (0.4-0.8).
Preferably, the organic solvent comprises 1,4 dioxane and/or toluene.
Preferably, the temperature of the condensation reaction is 50-120 ℃ and the time is 12-36 h.
Preferably, the mass fraction of the acetic acid is 80-100%, and the mass fraction of the hydrochloric acid is 20-37%.
Preferably, the mass ratio of the compound A to the acetic acid to the hydrochloric acid is 1: (0.5-3.0): (0.5-5.0).
Preferably, the temperature of the hydrolysis reaction is 50-120 ℃ and the time is 0.5-5 h.
Preferably, the hydrolysis reaction further comprises post-treatment of the obtained hydrolysis reaction liquid, and the post-treatment method comprises the following steps:
cooling the hydrolysis reaction liquid, mixing with toluene for liquid separation, and collecting an organic layer;
and (3) washing the organic layer, mixing the organic layer with n-heptane for crystallization, and carrying out solid-liquid separation and drying to obtain the loxoprofen acid.
Preferably, the temperature after cooling is 20-70 ℃; the crystallization temperature is-5-15 ℃ and the time is 0.3-12 h.
The invention provides a preparation method of loxoprofen sodium, which comprises the steps of mixing loxoprofen acid, an organic solvent and a sodium hydroxide aqueous solution for salifying reaction to obtain loxoprofen sodium; the loxoprofen acid is prepared according to the preparation method of the technical scheme, and the organic solvent is ethyl acetate or isopropyl acetate.
The invention provides a preparation method of loxoprofen acid, which comprises the following steps: mixing 1- (1-pyrrolidine) cyclopentene, a compound A and an organic solvent for condensation reaction, and removing the solvent from the obtained condensation reaction liquid to obtain a condensation product; mixing the condensation product with acetic acid, hydrochloric acid and water for hydrolysis reaction to obtain loxoprofen acid; the compound A has a structure shown in a formula I, wherein X is-Cl or-Br, R is-H, -CH 3 or-CH 2 CH 3 . According to the invention, 1- (1-pyrrolidine) cyclopentene and a compound A are used as starting materials, and the loxoprofen acid can be prepared through condensation and hydrolysis reaction. The reaction raw materials adopted by the invention are easy to obtain; the preparation process only needs two steps of condensation and hydrolysis, and the operation steps are simple; the invention synthesizes loxoprofen acid from 1- (1-pyrrolidine) cyclopentene by adopting continuous reaction, wherein the intermediate is not separated and purified and directly carries out the next reaction, thereby improving the reaction yield and the equipment utilization rate; moreover, the reaction conditions of the invention are easy to control. Furthermore, the invention adopts a single solvent, can be recycled, reduces three wastes and is suitable for industrial production.
The invention provides a preparation method of loxoprofen sodium, which comprises the steps of mixing loxoprofen acid, an organic solvent and a sodium hydroxide aqueous solution for salifying reaction to obtain loxoprofen sodium; the loxoprofen acid is prepared according to the preparation method of the technical scheme, and the organic solvent is ethyl acetate or acetone. The preparation method of loxoprofen sodium provided by the invention has high yield and high product purity, and is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic pattern of loxoprofen acid prepared in example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of loxoprofen sodium prepared in example 7;
FIG. 3 is a chromatogram of the purity detection of the sodium loxoprofen product prepared in example 7.
Detailed Description
The invention provides a preparation method of loxoprofen acid, which comprises the following steps:
mixing 1- (1-pyrrolidine) cyclopentene, a compound A and an organic solvent for condensation reaction, and removing the solvent from the obtained condensation reaction liquid to obtain a condensation product;
mixing the condensation product with acetic acid, hydrochloric acid and water for hydrolysis reaction to obtain loxoprofen acid;
the compound A has a structure shown in a formula I:
in the formula I, X is-Cl or-Br, R is-H, -CH 3 or-CH 2 CH 3 。
In the present invention, unless otherwise specified, the starting materials involved are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.
The invention mixes 1- (1-pyrrolidine) cyclopentene, compound A and organic solvent for condensation reaction, and removes solvent from the obtained condensation reaction liquid to obtain condensation product. In the present invention, the mass ratio of the compound a to 1- (1-pyrrolidine) cyclopentene is preferably 1: (0.4 to 0.8), more preferably 1: (0.5-0.6). In the present invention, the organic solvent preferably includes 1,4 dioxane and/or toluene, more preferably 1,4 dioxane; the invention has no special requirement on the dosage of the organic solvent, and can ensure that the reaction is carried out smoothly. In the present invention, it is preferable to add compound A, an organic solvent and 1- (1-pyrrolidine) cyclopentene in this order to the reaction vessel.
In the present invention, the temperature of the condensation reaction is preferably 50 to 120 ℃, more preferably 100 to 105 ℃, and the time is preferably 12 to 36 hours, more preferably 24 hours; the condensation reaction is preferably carried out under reflux conditions.
In the present invention, the method of removing the solvent is preferably distillation under reduced pressure; after the distillation under reduced pressure, the resulting product is preferably cooled to room temperature to give a condensation product. In the invention, the organic solvent obtained by collecting the desolventizing agent is preferably recycled.
After the condensation product is obtained, the condensation product is mixed with acetic acid, hydrochloric acid and water to carry out hydrolysis reaction, so as to obtain the loxoprofen acid. In the invention, the mass fraction of the acetic acid is preferably 80-100%, and the mass fraction of the hydrochloric acid is preferably 20-37%; the mass ratio of the compound A to the acetic acid to the hydrochloric acid is preferably 1: (0.5-3.0): (0.5 to 5.0), more preferably 1: (1.0-2.0): (0.6-2.0). The invention has no special requirement on the water consumption, and can ensure that the hydrolysis reaction is smoothly carried out. The invention preferably adds acetic acid, hydrochloric acid and water to the condensation product in sequence, and hydrolyzes in a mixed acid system.
In the present invention, the temperature of the hydrolysis reaction is preferably 50 to 120 ℃, more preferably 100 to 105 ℃, and the time is preferably 0.5 to 5 hours, more preferably 2 hours; the hydrolysis reaction is preferably carried out under reflux.
In the present invention, the hydrolysis reaction is preferably followed by subjecting the resulting hydrolysis reaction liquid to a post-treatment, and the method of the post-treatment preferably comprises the steps of:
cooling the hydrolysis reaction liquid, mixing with toluene for liquid separation, and collecting an organic layer;
and (3) washing the organic layer, mixing the organic layer with n-heptane for crystallization, and carrying out solid-liquid separation and drying to obtain the loxoprofen acid.
In the invention, the temperature after the temperature reduction is preferably 20-70 ℃, more preferably 50 ℃; the number of water washes is preferably two. In the invention, n-heptane is preferably added into the organic layer under the condition of stirring, and then the mixed system after the n-heptane is added is cooled to the crystallization temperature under the condition of stirring. In the present invention, the crystallization temperature is preferably-5 to 15 ℃, more preferably 5 ℃, and the time is preferably 0.3 to 12 hours, more preferably 2 hours. In the present invention, the solid-liquid separation is preferably performed by suction filtration.
The reaction route for preparing loxoprofen acid is as follows:
the reaction raw materials adopted by the invention are easy to obtain; the condensation and the hydrolysis adopt a one-step method, and the operation steps are simple; the invention synthesizes loxoprofen acid from 1- (1-pyrrolidine) cyclopentene by adopting continuous reaction, and the intermediate is not separated and purified, and directly carries out the next reaction, thereby improving the reaction yield and the equipment utilization rate; moreover, the reaction conditions of the invention are easy to control.
The invention provides a preparation method of loxoprofen sodium, which comprises the steps of mixing loxoprofen acid, an organic solvent and a sodium hydroxide aqueous solution for salifying reaction to obtain loxoprofen sodium; the loxoprofen acid is prepared according to the preparation method of the technical scheme, and the organic solvent is ethyl acetate or isopropyl acetate.
The invention adopts ethyl acetate or isopropyl acetate as the organic solvent, and can improve the yield and the product purity compared with the common acetone or ethanol solvent.
In the present invention, the concentration of the aqueous sodium hydroxide solution is preferably 30 to 45%, more preferably 40%; the mass ratio of the loxoprofen acid to the organic solvent to the sodium hydroxide aqueous solution is preferably 1 (0.7-1.4) to 0.35-0.55. The organic solvent and the loxoprofen acid are added into a reaction container in sequence; then, an aqueous sodium hydroxide solution was added dropwise to the resulting mixture with stirring. In the invention, the temperature of the salification reaction is preferably 0-50 ℃, more preferably 0-25 ℃, the time of the salification reaction is preferably 5 min-2 h, more preferably 10 min-1 h, and the time of the salification reaction is calculated from the completion of the dropwise addition of the sodium hydroxide aqueous solution; the salt-forming reaction is preferably carried out under stirring.
In the present invention, after the salt-forming reaction, the resulting salt-forming reaction liquid is preferably subjected to a post-treatment, and the method of the post-treatment preferably comprises the steps of:
mixing the salifying reaction liquid with activated carbon for decoloring, and carrying out solid-liquid separation to obtain filtrate;
and mixing the filtrate with ethyl acetate for crystallization, and carrying out solid-liquid separation and solid-phase drying to obtain loxoprofen sodium.
In the present invention, the temperature of the decoloring is preferably 30 to 60 ℃, more preferably 35 to 45 ℃, and the time of the decoloring is preferably 30min; the decolorization is preferably carried out under stirring. The ethyl acetate is preferably added dropwise to the filtrate under stirring; the mass ratio of the ethyl acetate to the loxoprofen acid is preferably (4.3-8.6): 1, the crystallization temperature is preferably 10-35 ℃, more preferably 15-25 ℃, and the crystallization time is preferably 0.5-5 h, more preferably 1-2 h. The solid-liquid separation mode is not particularly required, and can be adopted by a solid-liquid separation mode known to a person skilled in the art, such as filtration or suction filtration.
The reaction formula for preparing loxoprofen sodium is as follows:
the preparation method of loxoprofen sodium provided by the invention has high yield and high product purity, and is suitable for industrial production.
In order to further illustrate the present invention, the methods for preparing loxoprofen acid and loxoprofen sodium provided in the present invention are described in detail with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The synthesis of loxoprofen acid comprises the following steps:
50g of 2- (4-bromomethylphenyl) propionic acid, 500g of 1, 4-dioxane and 29.7g of 1- (1-pyrrolidine) cyclopentene are added into a 1000mL reaction bottle, the mixture is heated to reflux for 24 hours, and the solvent is removed under reduced pressure; cooling to room temperature, adding 50g of acetic acid (acetic acid mass fraction 100%), 30g of hydrochloric acid (hydrochloric acid mass fraction 36%) and 30g of water, and heating to reflux for 2 hours; cooling to 50 ℃, adding 100g of toluene, separating liquid, washing an organic layer twice with 50g of water, adding 100g of n-heptane with stirring, cooling to 5 ℃ with stirring, crystallizing for 2 hours, filtering, drying to obtain 47.5g of off-white solid, and obtaining 93.3 percent of yield.
The nuclear magnetic spectrum of the product is shown in figure 1, and the nuclear magnetic data are as follows: 1 H-NMR(500MHz,DMSO-d6)δ:12.25(1H,s),7.20(4H,m),3.66(1H,dd),2.98(1H,m),2.47(2H,d),2.27(1H,m),2.12(1H,m),1.97(2H,m),1.72(1H,m),1.53(1H,m),1.48(3H,d).
example 2
Loxoprofen acid was prepared by substituting 2- (4-bromomethylphenyl) propionic acid with 2- (4-chloromethylphenyl) propionic acid, and the other steps were the same as in example 1.
Example 3
The synthesis of loxoprofen acid comprises the following steps:
50g of methyl 2- (4-bromomethylphenyl) propionate, 500g of 1, 4-dioxane and 28.2g of 1- (1-pyrrolidine) cyclopentene are added into a 1000mL reaction bottle, the mixture is heated to reflux for reaction for 24 hours, and the solvent is removed under reduced pressure; cooling to room temperature, adding 50g of acetic acid (acetic acid mass fraction 100%), 100g of hydrochloric acid (hydrochloric acid mass fraction 36%) and 50g of water, and heating to reflux for 2 hours; cooling to 50 ℃, adding 100g of toluene, separating liquid, washing an organic layer twice with 50g of water, adding 100g of n-heptane with stirring, cooling to 5 ℃ with stirring, crystallizing for 2 hours, filtering, drying to obtain 45.5g of off-white solid, and obtaining 94.6 percent of yield.
Example 4
Loxoprofen acid was obtained by substituting methyl 2- (4-bromomethylphenyl) propionate with methyl 2- (4-chloromethylphenyl) propionate, and the other steps were the same as in example 3.
Example 5
The synthesis of loxoprofen acid comprises the following steps:
50g of ethyl 2- (4-bromomethylphenyl) propionate, 500g of 1,4 dioxane and 26.7g of 1- (1-pyrrolidine) cyclopentene are added into a 1000mL reaction bottle, the mixture is heated to reflux for 24 hours, and the solvent is removed under reduced pressure; cooling to room temperature, adding 50g of acetic acid (acetic acid mass fraction 100%), 100g of hydrochloric acid (hydrochloric acid mass fraction 36%) and 50g of water, and heating to reflux for 2 hours; cooling to 50 ℃, adding 100g of toluene, separating liquid, washing an organic layer twice with 50g of water, adding 100g of n-heptane with stirring, cooling to 5 ℃ with stirring, crystallizing for 2 hours, filtering, drying to obtain 43.1g of off-white solid, and obtaining 94.5% of yield.
Example 6
Loxoprofen acid was prepared by substituting ethyl 2- (4-bromomethylphenyl) propionate with ethyl 2- (4-chloromethylphenyl) propionate and by the same procedure as in example 5.
Example 7
Loxoprofen sodium is synthesized as follows:
100g of ethyl acetate and 100g of loxoprofen acid are added into a 500mL reaction bottle, 40.6g of 40% sodium hydroxide aqueous solution is added dropwise under stirring, the temperature is controlled to be 25 ℃, and the mixture is stirred for 10 minutes after the addition; then heating to 45 ℃, adding 10g of active carbon, preserving heat, stirring for 30 minutes, filtering, dropwise adding 630g of ethyl acetate under stirring, cooling to 25 ℃ after adding, preserving heat, crystallizing for 2 hours, filtering, drying to obtain 117.4g of white solid, and the yield is 95.1%.
The nuclear magnetic pattern of the product is shown in fig. 2, and nuclear magnetic data are as follows: 1 H-NMR(500MHz,DMSO-d6)δ:7.19(4H,m),3.27(1H,dd),2.91(1H,m),2.42(2H,d),2.29(1H,m),2.10(1H,m),1.94(2H,m),1.73(1H,m),1.52(1H,m),1.24(3H,d).
the purity detection chart of the product is shown in figure 3, and the purity of the liquid phase is 99.868%. The water content was 10.8% in the karl fischer test.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A method for preparing loxoprofen acid, which is characterized by comprising the following steps:
mixing 1- (1-pyrrolidine) cyclopentene, a compound A and an organic solvent for condensation reaction, and removing the solvent from the obtained condensation reaction liquid to obtain a condensation product;
mixing the condensation product with acetic acid, hydrochloric acid and water for hydrolysis reaction to obtain loxoprofen acid;
the compound A has a structure shown in a formula I:
in the formula I, X is-Cl or-Br, R is-H, -CH 3 or-CH 2 CH 3 。
2. The preparation method according to claim 1, wherein the mass ratio of the compound A to the 1- (1-pyrrolidine) cyclopentene is 1: (0.4-0.8).
3. The method of claim 1, wherein the organic solvent comprises 1,4 dioxane and/or toluene.
4. The method according to claim 1, wherein the condensation reaction is carried out at a temperature of 50 to 120 ℃ for a time of 12 to 36 hours.
5. The preparation method according to claim 1, wherein the mass fraction of the acetic acid is 80-100%, and the mass fraction of the hydrochloric acid is 20-37%.
6. The preparation method according to claim 5, wherein the mass ratio of the compound A to acetic acid to hydrochloric acid is 1: (0.5-3.0): (0.5-5.0).
7. The method according to claim 1, 5 or 6, wherein the hydrolysis reaction is carried out at a temperature of 50 to 120 ℃ for a time of 0.5 to 5 hours.
8. The method according to claim 7, wherein the hydrolysis reaction further comprises subjecting the obtained hydrolysis reaction liquid to a post-treatment, the post-treatment comprising the steps of:
cooling the hydrolysis reaction liquid, mixing with toluene for liquid separation, and collecting an organic layer;
and (3) washing the organic layer, mixing the organic layer with n-heptane for crystallization, and carrying out solid-liquid separation and drying to obtain the loxoprofen acid.
9. The method according to claim 8, wherein the temperature after cooling is 20 to 70 ℃; the crystallization temperature is-5-15 ℃ and the time is 0.3-12 h.
10. The preparation method of loxoprofen sodium is characterized in that loxoprofen acid, an organic solvent and a sodium hydroxide aqueous solution are mixed for salifying reaction to obtain loxoprofen sodium; the loxoprofen acid is prepared according to the preparation method of any one of claims 1 to 9, and the organic solvent is ethyl acetate or isopropyl acetate.
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