CN115583903A - Method for rapidly preparing racecadotril - Google Patents
Method for rapidly preparing racecadotril Download PDFInfo
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- CN115583903A CN115583903A CN202211112318.XA CN202211112318A CN115583903A CN 115583903 A CN115583903 A CN 115583903A CN 202211112318 A CN202211112318 A CN 202211112318A CN 115583903 A CN115583903 A CN 115583903A
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- racecadotril
- acid
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- benzyl
- benzylacrylic
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- ODUOJXZPIYUATO-UHFFFAOYSA-N 2-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]acetic acid (phenylmethyl) ester Chemical compound C=1C=CC=CC=1COC(=O)CNC(=O)C(CSC(=O)C)CC1=CC=CC=C1 ODUOJXZPIYUATO-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960002281 racecadotril Drugs 0.000 title claims abstract description 70
- 108700040249 racecadotril Proteins 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 66
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims abstract description 38
- RYNDYESLUKWOEE-UHFFFAOYSA-N 2-benzylprop-2-enoic acid Chemical compound OC(=O)C(=C)CC1=CC=CC=C1 RYNDYESLUKWOEE-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000047 product Substances 0.000 claims abstract description 28
- BCAAXVOKLXDSPD-UHFFFAOYSA-N 2-(acetylsulfanylmethyl)-3-phenylpropanoic acid Chemical compound CC(=O)SCC(C(O)=O)CC1=CC=CC=C1 BCAAXVOKLXDSPD-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000006184 cosolvent Substances 0.000 claims abstract description 22
- 238000007670 refining Methods 0.000 claims abstract description 15
- UAWVZBDVSNLPDT-UHFFFAOYSA-N methyl 2-(benzylamino)acetate Chemical compound COC(=O)CNCC1=CC=CC=C1 UAWVZBDVSNLPDT-UHFFFAOYSA-N 0.000 claims abstract description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims abstract description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 41
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000003208 petroleum Substances 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
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- 239000011259 mixed solution Substances 0.000 claims description 4
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- 238000004090 dissolution Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
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- 239000012043 crude product Substances 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 20
- 238000002474 experimental method Methods 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
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- 238000001953 recrystallisation Methods 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 108010092674 Enkephalins Proteins 0.000 description 5
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 5
- 230000003321 amplification Effects 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- -1 acetylthio group Chemical group 0.000 description 2
- 201000009840 acute diarrhea Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
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- 230000028327 secretion Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- UJQQYSQISUVJDR-UHFFFAOYSA-N 2-phenylmethoxyprop-2-enoic acid Chemical compound OC(=O)C(=C)OCC1=CC=CC=C1 UJQQYSQISUVJDR-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
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- 239000013078 crystal Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
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- 238000006479 redox reaction Methods 0.000 description 1
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- 229910052717 sulfur Inorganic materials 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for rapidly preparing racecadotril, and belongs to the technical field of chemical drug synthesis. The method comprises the following steps: s1, 2-benzyl acrylic acid and thioacetic acid react for 5 hours at 50-70 ℃ in the presence or absence of a cosolvent to synthesize 3- (acetylthio) -2-benzyl propionic acid; s2, benzyl glycine methyl ester or benzyl glycine methyl ester salt reacts with the 3- (acetylthio) -2-benzyl propionic acid for 4 hours in the presence of HOBT and DCC to synthesize a crude product of racecadotril; and S3, refining the crude product of the racecadotril by matching two solvents to obtain a refined product. The method has the advantages of less raw material consumption, lower energy consumption, simple operation steps, shorter reaction time and higher purity and yield of the refined racecadotril product.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a method for rapidly preparing racecadotril.
Background
The chemical name of Racecadotril (Racecadotril) is: benzyl N- [ (R, S) -3-acetylmercapto-2-benzylpropionyl) ] glycinate, developed by the company Bioprojet, france and marketed in 1993, is known under the name of Tiorfan as a therapeutic agent for acute diarrhea in adults and children. The racecadotril is an enkephalinase inhibitor, and can selectively and reversibly inhibit enkephalinase, so that endogenous enkephalin is protected from being degraded, and the physiological activity of the endogenous enkephalin in a digestive tract is prolonged. In peripheral tissues, racecadotril can be rapidly hydrolyzed to the more effective enkephalin inhibitor, acetolene, and inhibit the activity of enkephalin, but does not affect the activity of enkephalin in the central nervous system; can also increase the utilization of opioid and activate opioid receptors of intestinal tract, and does not affect gastrointestinal peristalsis and intestinal tract basal secretion; eventually, the mucosal level of cAMP (cyclic adenosine monophosphate) is reduced, and excessive secretion of water and electrolytes is inhibited. The racecadotril has quick response when being used for treating acute diarrhea, can be taken together with food, water or breast milk, and has the advantages of safe and convenient administration and less adverse reaction.
U.S. patent application No. 5945548A discloses the use of benzylacrylic acid and thioacetic acid in the absence of solvent at 70 deg.C for 24h, followed by distillation under reduced pressure to remove excess thioacetic acid, absorption of the residue with diethyl ether three times, distillation of diethyl ether at atmospheric pressure each time to remove residual thioacetic acid and obtain the intermediate 2-acetylthiomethyl-3-phenylpropionic acid; reacting the intermediate with benzyl glycinate at 0 deg.C in the presence of HOBT and DCC, wherein CaCl is used in the reaction process 2 And (3) removing water, wherein solvents are anhydrous tetrahydrofuran and chloroform, filtering DCU precipitate after the reaction is finished, evaporating filtrate to dryness to obtain crude racecadotril, and recrystallizing the crude racecadotril with diethyl ether after the crude racecadotril is dissolved in ethyl acetate, washed with water, washed with a salt solution, and dried to obtain a refined racecadotril product. The molar yield of the product was 61.4% based on benzylacrylic acid. The low boiling point solvent ether used in the process for synthesizing the intermediate is very easy to volatilize, and the consumption is very large; the synthesis reaction time is longer, and the consumption of the raw material thioacetic acid is larger; the refining steps of crude racecadotril are complex and no purity data are provided.
Disclosure of Invention
In order to solve the problems, the invention provides a method for quickly preparing racecadotril, which has the advantages of milder reaction conditions, shorter reaction time, less raw material consumption, and higher product purity and yield.
In order to achieve the purpose, the invention specifically adopts the following technical scheme:
a method for rapidly preparing racecadotril comprises the following steps:
s1, synthesizing 3- (acetylthio) -2-benzyl propionic acid: 2-benzyl acrylic acid reacts with thioacetic acid for 5 hours at 50-70 ℃ in the presence or absence of a cosolvent; after the reaction is finished, the 3- (acetylthio) -2-benzyl propionic acid is obtained through the steps of extracting, drying and removing the solvent; the cosolvent is ethyl acetate or/and tetrahydrofuran; the molar ratio of the thioacetic acid to the 2-benzyl acrylic acid is (1.1-1.3) to 1;
s2, synthesizing racecadotril: reacting benzyl glycine methyl ester or benzyl glycine methyl ester salt with the 3- (acetylthio) -2-benzyl propionic acid in the presence of HOBT and DCC for 4 hours, and obtaining crude racecadotril through the steps of precipitation, filtration, precipitation dissolution, drying and solvent removal;
s3, refining: dissolving the crude racecadotril product with a first solvent, adding a second solvent, uniformly stirring, crystallizing the obtained mixed solution at 0-5 ℃, filtering, and drying a filter cake to obtain a refined racecadotril product.
The reaction equation involved in the above preparation method is as follows:
preferably, 2-benzylacrylic acid is reacted with thioacetic acid in the presence of ethyl acetate at 50-70 ℃ for 5h in step S1.
Preferably, 2-benzyl acrylic acid and thioacetic acid react for 5h at 50 ℃ in the presence of tetrahydrofuran, and the molar ratio of the thioacetic acid to the 2-benzyl acrylic acid is 1.3; or at 60 ℃ for 5h, and the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.2.
Preferably, 2-benzylacrylic acid is reacted with thioacetic acid in the absence of a solvent at 60 ℃ for 5h, and the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.3.
Preferably, the cosolvent in the step S1 is ethyl acetate, and the molar ratio of the thioacetic acid to the 2-benzyl acrylic acid is (1.2-1.3): 1.
Preferably, 2-benzyl acrylic acid and thioacetic acid react for 5 hours at 50 ℃ in the presence of ethyl acetate; the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.2.
Preferably, the first solvent is ethanol or/and n-hexanol; the second solvent is water or/and petroleum ether.
Further preferably, the first solvent is n-hexanol; the second solvent is petroleum ether; the volume ratio of the n-hexanol to the petroleum ether is preferably (1-4) to 10; more preferably (2.33-4) 10; still more preferably 1.
Compared with the prior art, the invention has the beneficial effects that: in the invention, ethyl acetate or/and tetrahydrofuran are/is used as cosolvent or in the absence of solvent, thioacetic acid and the 2-benzyl acrylic acid react for 5 hours at 50-70 ℃ according to the molar ratio (1.1-1.3) to synthesize the intermediate 3- (acetylthio) -2-benzyl propionic acid, the raw material consumption is less in the reaction process, the energy consumption is lower, the reaction time is shorter, and the yield and the purity of the obtained intermediate are higher. The racecadotril is refined by matching two solvents, the refining step is simple, the generated three wastes are less, the purity and the yield of the obtained racecadotril product are higher, and the purity of more than 99.0 percent can be achieved by one-time recrystallization.
Drawings
FIG. 1 is a 400MHz NMR spectrum of 3- (acetylthio) -2-benzylpropionic acid synthesized by the present invention;
FIG. 2 is a carbon spectrum of 100MHz NMR of 3- (acetylthio) -2-benzylpropionic acid synthesized by the present invention;
FIG. 3 is a 400MHz NMR spectrum of racecadotril synthesized by the present invention;
FIG. 4 is a 100MHz NMR carbon spectrum of racecadotril synthesized by the present invention;
FIG. 5 is a diagram showing the result of purity measurement of a refined racecadotril synthesized by the present invention.
Detailed Description
The technical solution of the present invention is described in detail and fully with reference to the following examples, it is obvious that the described examples are only a part of the examples of the present invention, and not all of the examples. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention. Any equivalent alterations or substitutions made by those skilled in the art according to the following embodiments are all within the protection scope of the present invention.
Examples
The embodiment provides a preparation method of racecadotril, which specifically comprises the following steps:
s1, synthesis of 3- (acetylthio) -2-benzylpropionic acid
S1-1, adding 0.1mol of 2-benzyl acrylic acid into a reaction bottle, adding 0.1mol of thioacetic acid into the reaction bottle, heating the mixture to 90 ℃ for reaction for 20 hours, and detecting the reaction process by using Thin Layer Chromatography (TLC) until the reaction is finished;
s1-2, adding 200mL of ethyl acetate into the reaction solution, uniformly stirring, washing with 200mL of water, repeating the washing for 3 times, and dissolving the product in the ethyl acetate; separating out an organic phase after each washing, and combining the organic phases;
s1-3, adding 400mL of 2wt% sodium hydroxide solution (pH = 9.0) into the organic phase obtained in the step S1-2, extracting and separating the liquid, extracting the organic phase twice with water, wherein the amount of the water is 100mL each time, and combining the water phases extracted each time (the product is in the water phase);
s1-4, adding 300mL of 1mol/L hydrochloric acid solution (pH = 5.0) into the water phase obtained in the step S1-3, extracting twice with ethyl acetate, wherein the using amount of the ethyl acetate is 500 mL/time, and combining organic phases separated after each extraction (the product is dissolved in the ethyl acetate);
s1-5, adding anhydrous sodium sulfate into the organic phase obtained in the step S1-4, drying, and evaporating the solvent to obtain 18.96g of viscous yellow oily matter, namely the intermediate 3- (acetylthio) -2-benzyl propionic acid, wherein the purity is 98.5%.
A plurality of parallel experiments are carried out simultaneously according to the method of the step S1, the yield of the obtained 3- (acetylthio) -2-benzyl propionic acid is 74-86%, and the purity is more than 98%.
The reaction equation in step S1 is:
in order to solve the problems, in the method of the step S1, a cosolvent is added in the synthesis process of the step S1, and the cosolvent and the reaction conditions are screened, because thioacetic acid with high viscosity is used in the synthesis process, and the reaction temperature is high, the preparation time is long, the reaction of the raw material is incomplete (the thioacetic acid is continuously distilled out as the raw material, which is not beneficial to the full reaction), the yield and the purity of the intermediate are not high enough.
(1) Co-solvent screening
Four cosolvents were selected in this example: DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), THF (tetrahydrofuran), EA (ethyl acetate), comparative experiments were performed; synthesizing 3- (acetylthio) -2-benzylpropionic acid according to the method in the step S1, wherein the difference is that a cosolvent is added into a reaction bottle in the step S1-1, and the reaction temperature is set to be 70 +/-2 ℃; the screening results are shown in Table 1.
TABLE 1 screening of co-solvents in the synthesis of 3- (acetylthio) -2-benzylpropionic acid
In the synthesis process, when DMSO is used as a cosolvent, raw materials do not react, but yellow solid precipitates are generated. And determining the yellow precipitate as sulfur simple substance by detecting that the melting point of the yellow precipitate is 116-119 ℃. Through analysis, the thioacetic acid raw material and DMSO undergo a redox reaction to generate elemental sulfur. DMSO is not suitable as a co-solvent for the synthesis reaction in step S1. When DMF is taken as a cosolvent, the reaction process can be normally carried out, but the reaction system has more residual raw materials and incomplete reaction, and in the post-treatment process, the DMF is not suitable to be used as a solvent for the reaction because the product in the system cannot be extracted due to the unique solubility of the DMF. Ethyl acetate and THF are used as co-solvents, the yield of the obtained intermediate is high, and considering the characteristic that THF is easy to become peroxide during storage and has high storage requirement, the optimal co-solvent is selected to be ethyl acetate.
(2) Screening of reaction conditions
9 sets of experimental conditions are designed through orthogonal software, and an orthogonal experiment is carried out according to the method of the step S1 to synthesize the intermediate 3- (acetylthio) -2-benzyl propionic acid. Except that 5mL of cosolvent is added into the reaction bottle in the step S1-1, the dosage of thioacetic acid is respectively 0.1mol times (1.1 times, 1.2 times and 1.3 times), the reaction temperature is respectively 50 ℃, 60 ℃ and 70 ℃, and the reaction time is 5 hours. The reaction conditions and results of the orthogonal experiments are shown in Table 2.
TABLE 2 reaction parameters and results of orthogonal experiments
From the experimental results in table 2, it can be seen that, in the solvent-free reaction system, or the reaction system using ethyl acetate as a cosolvent, or the reaction system using THF as a cosolvent, when the reaction temperature is 50-70 ℃ and the molar ratio of thioacetic acid to 2-benzylacrylic acid is (1.1-1.3): 1, the yield of the intermediate 3- (acetylthio) -2-benzylpropionic acid can reach more than 77%, and the purity of the intermediate can reach more than 95%; especially, when the cosolvent is ethyl acetate, the reaction temperature is 50-70 ℃, the molar ratio of the thioacetic acid to the 2-benzyl acrylic acid is (1.1-1.3): 1, the product yield reaches more than 86 percent, and the purity can reach more than 96 percent; the method has the advantages that when the cosolvent is not used, the reaction temperature is 60 ℃, and the molar ratio of thioacetic acid to 2-benzyl acrylic acid is 1.3. The reaction time is greatly shortened no matter the intermediate is synthesized with or without a solvent, and the period of industrial production can be obviously shortened.
The preferred parameters in table 2 were verified by scale-up experiments, which are consistent with the experiments in table 2, with a molar ratio of thioacetic acid to 2-benzylacrylic acid of 1.2, 5-fold and 10-fold respectively, and the results are shown in table 3.
TABLE 3 Experimental results of parameter amplification of intermediate synthesis process
| Serial number | 2-Benzyloxyacrylic acid | Raw material molar ratio | Amount of ethyl acetate mL | Reaction temperature/. Degree.C | Yield of the product | Purity of |
| 1 | 0.5mol | 1.2:1 | |
50 | 91.2％ | 98.4％ |
| 2 | 1mol | 1.2:1 | |
50 | 91.5％ | 98.8％ |
As can be seen from Table 3, the preferred process parameters selected from Table 2 are used in the amplification experiment, the yield of the obtained intermediate can reach more than 91%, and the purity is more than 98%. The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the intermediate 3- (acetylthio) -2-benzylpropionic acid are respectively shown in figure 1 and figure 2, and as can be seen from figure 1, a single peak of methyl in acetyl is 2.239ppm, a multiple signal peak of two methylene groups and one methine group is 2.882-3.149 ppm, and a multiple signal peak of a benzene ring in benzyl is 7.184-7.319 ppm; as can be seen from FIG. 2, the peak of the carbonyl signal of the acetylthio group is 195.224ppm, the peak of the carboxylic acid signal is 178.601ppm, and the peak of the four aliphatic carbon signals is between 29.7 and 47.1 ppm.
S2, synthesizing racecadotril
S2-1, benzyl glycine methyl ester p-toluenesulfonate (168g, 0.5 mol) and Hydroxybenzotriazole (HOBT) (67.5 g,0.5 mol) are taken to be dissolved in 1100mL of DMF in a reaction bottle;
s2-2, adding a mixed solution of an intermediate 3- (acetylthio) -2-benzylpropionic acid (119g, 0.5 mol) and triethylamine (50.5 g,0.5 mol), stirring, adding N, N' -Dicyclohexylcarbodiimide (DCC) (103g, 0.5 mol), and monitoring by TLC until the reaction is completely performed (namely the reaction solution is changed from an initial yellow brown clear liquid to a white turbid liquid), wherein the reaction time is 4 hours;
and S2-3, dropwise adding the mixed solution after the reaction into 5L of ice water to generate white turbidity, naturally precipitating at room temperature for 15h, filtering out the white turbidity solution, adding ethyl acetate to dissolve the white turbidity solution, adding anhydrous sodium sulfate to dry, filtering, and performing rotary evaporation until no solvent is distilled off to obtain 165g of crude racecadotril with the molar yield of 85.6%.
The reaction equation in step S2 is:
s3, refining crude racecadotril
Weighing a crude product of the racecadotril, adding the crude product into a 250mL distillation flask, adding a certain amount of first solvent, heating and dissolving the crude product in water bath at 40 ℃, then adding a second solvent, uniformly stirring, standing, cooling to normal temperature, and then putting the mixture into a refrigerating chamber (0-5 ℃) for crystallization for 8 hours; and (4) performing suction filtration, and putting the filter cake into a vacuum drying oven for drying until the weight of the dried solid does not change any more, so as to obtain the racecadotril crystalline solid.
In order to improve the yield and purity of the product in the refining process, the solvent and the amount of the solvent used in the refining process were selected in this example.
A. Selection of solvent type
Refining crude racecadotril according to the method of step S3, wherein dichloromethane (CH) is selected as the first solvent 2 Cl 2 ) Toluene (PhMe), ethyl Acetate (EA), ethanol and n-hexanol, and the second solvent is water or petroleum ether. The screening results of the solvent types are shown in Table 4, wherein 10 times of parallel experiments are carried out in total in Table 4, and the mass of the crude racecadotril weighed in each experiment is 1.93g.
TABLE 4 screening results of racecadotril refined solvent species
| Serial number | A first solvent | Dosage (mL) | A second solvent | Dosage (mL) | Yield (g) | Yield of |
| 1 | |
30 | Water (I) | 100 | 0 | 0 |
| 2 | |
30 | |
100 | 0 | 0 |
| 3 | |
30 | Water (W) | 100 | 0 | 0 |
| 4 | |
30 | |
100 | 0 | 0 |
| 5 | |
30 | Water (W) | 100 | 0 | 0 |
| 6 | |
30 | |
100 | 0 | 0 |
| 7 | |
30 | Water (W) | 100 | 0.8153 | 42.3％ |
| 8 | |
30 | |
100 | 0.9984 | 51.8％ |
| 9 | N- |
30 | Water (I) | 100 | 1.5131 | 78.5％ |
| 10 | N- |
30 | |
100 | 1.6480 | 85.5％ |
According to the experimental process and the results in table 4, whether the second solvent is water or petroleum ether, the crude racecadotril can be mixed and dissolved with dichloromethane, toluene and ethyl acetate as the first solvent, but can not be used for recrystallization; the first solvent can be used for recrystallization when ethanol is used, but the yield is low; in the experiment, the combination of n-hexanol and water and the combination of n-hexanol and petroleum ether have higher recrystallization yield; therefore, the first solvent is preferably ethanol or/and n-hexanol in the refining process of the crude racecadotril, and the second solvent is preferably water or/and petroleum ether; most preferably, the first solvent is n-hexanol and the second solvent is petroleum ether.
B. Solvent dosage optimization
And (4) according to the screened solvent types, continuously optimizing the dosage of the solvent according to the method in the step (S3), wherein the first solvent is n-hexanol, the second solvent is petroleum ether, and the optimization result is shown in a table 5. A total of 8 replicates were performed in Table 5, each weighing 15g of crude racecadotril.
TABLE 5 optimized results of the amount of racecadotril refined solvent
| Serial number | n-hexanol/mL | Petroleum Ether/mL | Refined racecadotril product/g | Yield of | Purity of |
| 1 | 10 | 100 | 13.62 | 90.8％ | 98.1％ |
| 2 | 20 | 100 | 12.91 | 86.1％ | 98.4％ |
| 3 | 30 | 100 | 12.78 | 85.2％ | 99.1％ |
| 4 | 40 | 100 | 13.98 | 93.2％ | 99.9％ |
| 5 | 35 | 40 | 5.60 | 37.3％ | 97.5％ |
| 6 | 35 | 80 | 9.54 | 63.6％ | 98.4％ |
| 7 | 35 | 100 | 13.77 | 91.8％ | 99.7％ |
| 8 | 35 | 150 | 13.53 | 90.2％ | 99.1％ |
As is clear from the experimental procedures and the results shown in Table 5, when the volume ratio of the first solvent to the second solvent is (1-4): 10, the yield of the refined racecadotril product obtained can be 85% or more, and the purity can be 98% or more. When the volume ratio of the first solvent to the second solvent in the crystallization system exceeds 0.4, the racecadotril crystallization speed becomes slow, and the yield is also obviously reduced. When the volume ratio of the first solvent to the second solvent is less than 0.233, the solution is turbid during crystallization, the crystallization is too fast, the product is viscous and is not easy to filter, although the yield and the purity are high. When the volume ratio of the first solvent to the second solvent is 0.233-0.4, the crystal particles of the product in the crystallization process are obvious, and the yield and the purity of the refined racecadotril product are high; particularly, when the volume ratio of the first solvent to the second solvent is 0.4 (the 4 th experiment in table 5), the yield and purity of the refined racecadotril product are the highest, and the spectrum for detecting the purity is shown in fig. 5. The solvent dosage and the raw material cost are comprehensively considered, and the volume ratio of the first solvent to the second solvent is selected to be 0.35 for carrying out an amplification experiment.
The preferred parameters in table 5 are verified by amplification experiments, the method is consistent with the experiments in table 5, the input amount of the racecadotril crude product is respectively amplified by 2 times, 4 times and 8 times, and the experimental results are shown in table 6.
TABLE 6 amplification experimental verification results of optimized parameters of crude racecadotril refining process
As can be seen from Table 6, the preferred process parameters of the racecadotril refining process selected in Table 5, when used in the scale-up experiment, resulted in high yields and purities of the intermediates, and the refined racecadotril product having a purity of 99.0% or more was obtained by recrystallization once. The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the prepared refined racecadotril product are respectively shown in fig. 3 and fig. 4, and as can be seen from fig. 3, a single peak signal of methyl in acetyl is 2.321ppm, a multiple signal peak of two methylene groups and one methine is 2.613 to 3.136ppm, a multiple signal peak of benzene ring in benzyl is 7.184 to 7.319ppm, a dd peak of N-methylene is 4.037 to 4.097ppm, a single peak methylene of benzyloxy is 5.890ppm, and a multiple peak proton signal of two benzene rings is 7.155 to 7.386 ppm; as can be seen from FIG. 4, the carbonyl signal peak of the acetylthio group is 196.103ppm, the carbon signal peaks of the ester carbonyl group and the amide are respectively 173.077ppm and 169.457ppm, and the six aliphatic carbon signals peak between 30.656 and 67.215 ppm.
In conclusion, the synthesis process of the intermediate 3- (acetylthio) -2-benzylpropionic acid is optimized, so that the purposes of reducing the reaction temperature, shortening the reaction time, reducing the consumption of the raw material thioacetic acid and simultaneously improving the yield and the purity of the intermediate are achieved, and the yield and the purity of the product are improved when the racecadotril is synthesized subsequently; by optimizing the refining process of the crude racecadotril product, the refined racecadotril product with the purity of more than 99.0 percent can be obtained by one-time recrystallization. Based on 2-benzyl acrylic acid, the yield of the intermediate 3- (acetylthio) -2-benzyl propionic acid is 91.2%, the synthesis yield of crude racecadotril is 85.6%, the refining yield of the crude racecadotril is 88.2%, and the total molar yield of the racecadotril obtained by final refining is 68.9%.
The above description is only for the preferred embodiment of the present invention and should not be used to limit the scope of the present invention. The present invention may be subject to various modifications and changes by any person skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A method for rapidly preparing racecadotril is characterized by comprising the following steps:
s1, synthesizing 3- (acetylthio) -2-benzyl propionic acid: 2-benzyl acrylic acid and thioacetic acid react for 5 hours at 50-70 ℃ in the presence or absence of a cosolvent; after the reaction is finished, 3- (acetylthio) -2-benzyl propionic acid is obtained through the steps of extraction, drying and solvent removal; the cosolvent is ethyl acetate or/and tetrahydrofuran; the molar ratio of the thioacetic acid to the 2-benzyl acrylic acid is (1.1-1.3) to 1;
s2, synthesizing racecadotril: reacting benzyl glycine methyl ester or benzyl glycine methyl ester salt with the 3- (acetylthio) -2-benzyl propionic acid in the presence of HOBT and DCC for 4 hours, and obtaining crude racecadotril through the steps of precipitation, filtration, precipitation dissolution, drying and solvent removal;
s3, refining: dissolving the crude racecadotril product with a first solvent, adding a second solvent, uniformly stirring, crystallizing the obtained mixed solution at 0-5 ℃, filtering, and drying a filter cake to obtain a refined racecadotril product.
2. The method for rapidly preparing racecadotril according to claim 1, wherein in step S1 2-benzylacrylic acid is reacted with thioacetic acid in the presence of ethyl acetate at 50-70 ℃ for 5h;
or 2-benzylacrylic acid and thioacetic acid in the presence of tetrahydrofuran, at 50 ℃ for 5h, and the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.3; or at 60 ℃ for 5h, and the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.2;
or 2-benzylacrylic acid and thioacetic acid in the absence of a solvent at 60 ℃ for 5h, and the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.3.
3. The method for rapidly preparing racecadotril according to claim 1, wherein the cosolvent in step S1 is ethyl acetate, and the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is (1.2-1.3): 1.
4. The method for rapidly preparing racecadotril according to claim 1, characterized in that 2-benzylacrylic acid is reacted with thioacetic acid in the presence of ethyl acetate at 50 ℃ for 5h; the molar ratio of the thioacetic acid to the 2-benzylacrylic acid is 1.2.
5. The method for rapidly preparing racecadotril according to claim 1, wherein the first solvent is ethanol or/and n-hexanol; the second solvent is water or/and petroleum ether.
6. The method for rapidly preparing racecadotril according to claim 5, wherein the first solvent is n-hexanol; the second solvent is petroleum ether.
7. The method for rapidly preparing racecadotril according to claim 6, wherein the volume ratio of the n-hexanol to the petroleum ether is (1-4): 10.
8. The method for rapidly preparing racecadotril according to claim 7, wherein the volume ratio of the n-hexanol to the petroleum ether is (2.33-4): 10.
9. The method for rapidly preparing racecadotril according to claim 7, wherein the volume ratio of the n-hexanol to the petroleum ether is 1.
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| US5786494A (en) * | 1995-03-03 | 1998-07-28 | Societe Civile Bioprojet | Process for the synthesis of α-substituted acrylic acids and their application |
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