CN108863797B - Preparation method of 3- (substituted/unsubstituted phenyl) -3-hydroxy-propionyl hydroxamic acid - Google Patents
Preparation method of 3- (substituted/unsubstituted phenyl) -3-hydroxy-propionyl hydroxamic acid Download PDFInfo
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- 239000002253 acid Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 229920001429 chelating resin Polymers 0.000 claims description 15
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- MNQRLUIPNWGMMM-UHFFFAOYSA-N ethyl 3-(3-chlorophenyl)-3-hydroxypropanoate Chemical compound CCOC(=O)CC(O)C1=CC=CC(Cl)=C1 MNQRLUIPNWGMMM-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- -1 3- (3-chlorphenyl) -3-hydroxyl propionyl hydroxamic Chemical compound 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 48
- 239000003054 catalyst Substances 0.000 abstract description 41
- 239000002994 raw material Substances 0.000 abstract description 7
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract description 6
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 37
- 150000001875 compounds Chemical class 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 7
- CDXSJGDDABYYJV-UHFFFAOYSA-N acetic acid;ethanol Chemical compound CCO.CC(O)=O CDXSJGDDABYYJV-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- UUWJBXKHMMQDED-UHFFFAOYSA-N 1-(3-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(Cl)=C1 UUWJBXKHMMQDED-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 108010046334 Urease Proteins 0.000 description 3
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000003512 Claisen condensation reaction Methods 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000588770 Proteus mirabilis Species 0.000 description 2
- 241000588767 Proteus vulgaris Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000202921 Ureaplasma urealyticum Species 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 239000002638 heterogeneous catalyst Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229940007042 proteus vulgaris Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000002601 urease inhibitor Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- RGSGSSVNDBRBSG-UHFFFAOYSA-N 3-(3-chlorophenyl)-n,3-dihydroxypropanamide Chemical compound ONC(=O)CC(O)C1=CC=CC(Cl)=C1 RGSGSSVNDBRBSG-UHFFFAOYSA-N 0.000 description 1
- 208000004300 Atrophic Gastritis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010006987 Calculus bladder Diseases 0.000 description 1
- 206010007027 Calculus urinary Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 238000006680 Reformatsky reaction Methods 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229940090496 Urease inhibitor Drugs 0.000 description 1
- 208000006568 Urinary Bladder Calculi Diseases 0.000 description 1
- 208000009911 Urinary Calculi Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 201000000210 bladder calculus Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- PWGQHOJABIQOOS-UHFFFAOYSA-N copper;dioxido(dioxo)chromium Chemical compound [Cu+2].[O-][Cr]([O-])(=O)=O PWGQHOJABIQOOS-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000011587 gastric lymphoma Diseases 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid, which takes diethyl carbonate and acetophenone or derivatives thereof as starting raw materials and realizes the preparation of the 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid through three-step reaction. The invention optimizes the synthesis route, elaborately designs the reaction conditions and the catalyst, greatly improves the total yield, has mild reaction and simple operation, adopts cheaper raw materials and green and environment-friendly process, and greatly reduces the preparation cost.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an aryl propionyl hydroxamic acid compound.
Technical Field
Human body is infected with various diseases such as gastritis, gastric ulcer, duodenal ulcer, gastric atrophy, intestinal metaplasia, gastric cancer, gastric lymphoma, renal calculus, bladder calculus and the like caused by pathogenic bacteria such as Helicobacter pylori (Helicobacter pylori), Proteus vulgaris (Proteus vulgaris), Proteus mirabilis (Proteus mirabilis), Ureaplasma urealyticum (Ureaplasma urealyticum) and the like. The pathogenic causes of these pathogens are that they can produce urease, which can hydrolyze the metabolite urea in the body to produce ammonia, which affects the permeability of gastric mucosa and produces toxicity to gastric wall cells to cause gastric diseases such as ulcer, etc., and in the urinary system, ammonia can alkalize urine to cause calcium and magnesium ions in urine to precipitate to form urinary calculus. Research shows that urease is not produced in mammals, so that urease becomes an ideal target for treating the diseases, and research on urease inhibitors also becomes a hot field.
The aryl propionyl hydroxamic acid compound is an effective urease inhibitor, and Chinese patent 201210590437.6 and academic paper Eur.J.Med.chem.2013,68,212-221 disclose an aryl propionyl hydroxamic acid compound and a preparation method thereof, wherein an intermediate 3- (substituted/unsubstituted phenyl) -3-ethyl hydroxypropionate is completed by utilizing substituted/unsubstituted benzaldehyde and ethyl bromoacetate under the action of zinc powder based on a Reformsky reaction (Reformatsky reaction), and then the intermediate is reacted with NH2 OH. HCl and sodium methoxide to obtain the 3- (substituted/unsubstituted phenyl) -3-hydroxypropanohydroxamic acid. However, this method cannot be applied to production practice. In the first step of preparation, on one hand, ethyl bromoacetate which is a raw material is expensive and has high production cost, on the other hand, zinc powder needs to be activated before reacting, so that the complexity of operation is increased, and meanwhile, side reactions are more, so that the yield is low and is only 41%. In the final step of synthesizing the target product 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid, excessive hydroxylamine hydrochloride and excessive sodium methoxide are used, but the excessive sodium methoxide in the reaction solution causes a lot of side reactions, and the large excessive hydroxylamine hydrochloride generates a large amount of NaCl, which not only causes waste of raw materials but also increases production cost (including three-waste treatment cost), and meanwhile, the reaction yield in the step is not high (76%), and a large yield improvement space exists. These all indicate that the production of 3- (substituted/unsubstituted phenyl) -3-hydroxypropanohydroxamic acid requires a new preparation method.
Disclosure of Invention
Aiming at the defects of the prior art, the invention researches the production process of an aryl propionyl hydroxamic acid compound, namely 3- (substituted/unsubstituted phenyl) -3-hydroxyl propionyl hydroxamic acid, screens reaction conditions, adopts unconventional reagents, and provides a new preparation method, wherein the material ratio of reactants is close to 1:1, the waste of raw materials is greatly reduced, the process is more environment-friendly, and the total yield is greatly improved.
The technical scheme of the invention is as follows:
an object of the present invention is to provide an intermediate of 3- (substituted or unsubstituted phenyl) -3-hydroxypropanohydroxamic acid: a preparation method of 3- (substituted/unsubstituted phenyl) -3-hydroxypropionic acid ethyl ester, wherein the 3- (substituted/unsubstituted phenyl) -3-hydroxypropionic acid ethyl ester has the following structure,
the R is1，R2，R3，R4Same or different and selected from H, F, Cl, Br, NH2，NO2OH, alkyl of C1 to C6, alkoxy of C1 to C6, alkylamino of C1 to C6 or haloalkyl of C1 to C6,
the method comprises the following steps:
(1) diethyl carbonate (II) and substituted or unsubstituted acetophenone shown as a compound III are subjected to Claisen Condensation reaction (Claisen Condensation) in the presence of a catalyst 1 to prepare an intermediate compound IV;
preferably, the catalyst 1 is a base and is selected from one or more of 201X 4, 213, D201 and Amberlite IRA-400 strong base resin, and Amberlite IRA-400 is more preferred.
Preferably, the molar ratio of the compound II to the compound III is (1-5): 1.
Preferably, the amount of the catalyst 1 is 1-20% of the mass of the compound III.
Preferably, the reaction temperature is 40-100 ℃, and the reaction time is 2-48 h.
Preferably, the reaction solvent is selected from one or more of methanol, ethanol and ethanol-THF, further preferably ethanol-THF is used as the solvent, and more preferably the volume ratio of ethanol to THF is 1: 1.
One specific reaction operation is: dissolving diethyl carbonate (compound II) in a proper solvent, adding 5-20 mL of the solvent to each gram of the compound II, adding a catalyst while stirring, heating to 40-100 DEG CDissolving substituted or unsubstituted acetophenone (compound III) in the solvent, and after dropwise addition in 0.5-3 h, adding 2-20mL of the solvent into each gram of the compound III, wherein the mass ratio of the substances is as follows: and (3) continuing stirring for 2-48 h, recovering most of the solvent (for heterogeneous catalysts, filtering and recovering the catalyst), and adding 5-10 times of water and CH (CH) while stirring2Cl2Extracting, washing with saturated salt water to neutrality, and anhydrous MgSO4Drying, filtering, evaporating the solvent, and distilling under reduced pressure to obtain colorless oily liquid 3- (substituted or unsubstituted phenyl) ethyl propionate-3-ketone (compound IV);
(2) the intermediate compound IV is dissolved in a suitable solvent using H in the presence of catalyst 22Reducing to obtain an intermediate compound V;
preferably, the catalyst 2 is selected from Pd-C or Pd (OH)2One or more of-C, more preferably Pd-C.
Preferably, the amount of the catalyst 2 is 0.5-20% of the mass of the compound IV.
Preferably, the reaction temperature is 25-60 ℃, and the reaction time is 5-10 h.
Preferably, the reaction solvent is selected from one or more of methanol, ethanol, methanol-acetic acid and ethanol-acetic acid. Preferably, ethanol-acetic acid is used as a solvent, and the ratio of ethanol: the volume ratio of acetic acid is 1: 0.05.
One specific reaction operation is: dissolving a compound IV in a proper solvent, using 5-30 mL of the solvent per gram of the compound IV, and introducing H while stirring2Removing air in the reaction system, adding a catalyst with the mass of 0.5-20% of that of the compound IV, heating to 25-60 ℃, and continuing to perform reaction in the presence of H2Reacting for 5-10 h under atmosphere, filtering, recovering the catalyst, and concentrating the filtrate to obtain a light yellow oily substance 3- (substituted or unsubstituted phenyl) -3-hydroxypropionic acid ethyl ester (compound V).
Another object of the present invention is to provide a method for preparing 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid, wherein the 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid has the following structure,
the preparation method adopts the steps (1) and (2) of the method to prepare the intermediate: after the ethyl 3- (substituted/unsubstituted phenyl) -3-hydroxypropionate, further comprising the step (3),
(3) dissolving a compound V in a proper solvent, and reacting with an ethanol solution of hydroxylamine (VI) in the presence of a catalyst 3 to obtain the 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid (I);
preferably, the catalyst 3 is selected from one or more of KOBu-t and Amberlite IRA-400. Amberlite IRA-400 is preferred.
Preferably, the molar ratio of the compound VI to the compound V is (1-3): 1.
Preferably, the amount of the catalyst 3 is 2-30% of the mass of the compound V.
Preferably, the reaction temperature is 20-40 ℃, and the reaction time is 1-3 h.
Preferably, the reaction solvent is selected from one or more of methanol and ethanol. Ethanol is preferred.
One specific reaction operation is: dissolving hydroxylamine hydrochloride in ethanol, adding 2mL of ethanol into every gram of hydroxylamine hydrochloride, adding equimolar NaOH powder, stirring for 4 hours, and filtering to obtain an ethanol solution of hydroxylamine VI for later use, dissolving a compound V in a proper solvent, adding 8-20 mL of the solvent into every gram of the compound V, adding a proper catalyst, wherein the dosage of the catalyst is 2-30% of the mass of the compound V, adjusting the temperature to 20-40 ℃, dropwise adding the ethanol solution of hydroxylamine within 0.5-1 hour, and the mass ratio of the substances is as follows: and VI, continuously reacting for 1-3h, evaporating the solvent (for the heterogeneous catalyst, filtering and recovering the catalyst at first), adding 10 times of water into the residue, adjusting the pH value to about 6 by using dilute hydrochloric acid, separating out a precipitate, performing suction filtration and drying to obtain white powder, and recrystallizing by using ethanol to obtain the colorless crystalline compound I.
The invention relates to 3- (substituted or unsubstituted phenyl) -3-hydroxypropionyloxyoxime acid (compound I) and 3- (substituted or unsubstituted phenyl) -3-hydroxypropionic acid ethyl ester (compound V), preferably R1，R2，R3，R4Same or different and selected from H, F, Cl, Br, NH2，NO2，OH，Me，Et，OMe，OEt，OBn，NMe2Or NEt2。
A preferred class of compounds is selected from the following structures:
R1，R2，R3represents H, R4Represents H, F, Cl, Br, NH2，NO2，OH，Me，Et，OMe，OEt，OBn，NMe2Or NEt2。
The invention has the advantages that:
(1) the invention takes diethyl carbonate and acetophenone shown by a compound II or derivatives thereof as starting raw materials, thereby not only reducing the production cost, but also having mild reaction and simple operation, and the reaction yield of the step (1) can reach 90 percent to the maximum.
(2) The step (3) of the invention avoids the defect that excessive sodium methoxide can cause a plurality of side reactions, the using amount of hydroxylamine hydrochloride is more reasonable, the waste of materials is avoided, and the reaction yield of the step is improved.
The invention optimizes the synthetic route of the 3- (substituted/unsubstituted phenyl) -3-hydroxyl acryloyl hydroxamic acid, elaborately designs reaction conditions and catalysts, greatly improves the total yield, increases the total yield from 31 percent of the original preparation method to 70 percent, adopts cheaper raw materials and a green and environment-friendly process, and greatly reduces the preparation cost.
Detailed Description
The following examples illustrate specific steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The invention is described in further detail below with reference to specific examples and data, it being understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
The present invention will be described in further detail with reference to 3- (3-chlorophenyl) -3-hydroxypropanohydroxamic acid as an example, but it should be noted that the scope of the present invention is not limited to these examples.
Example 1: preparation of intermediate ethyl 3- (3-chlorophenyl) propionate-3-one (IV)
Dissolving 141.6 g diethyl carbonate in 1000mL1:1 ethanol-Tetrahydrofuran (THF), adding 12.4 g catalyst 1Amberlite IRA-400 under stirring, heating to 45 deg.C, dissolving 154.5 g m-chloroacetophenone in 1000mL ethanol-THF mixed solvent, adding dropwise within 1h, continuing stirring for 6h, filtering to recover Amberlite IRA-400, washing Amberlite IRA-400 with the ethanol-THF mixed solvent for 3 times, combining filtrates, evaporating most of solvent, adding 1500mL water, CH and THF under stirring2Cl2Extracting, washing with saturated salt water to neutrality, and anhydrous MgSO4Drying, filtering, evaporating the solvent, and distilling under reduced pressure to obtain 204 g of colorless oily liquid 3- (3-chlorophenyl) ethyl propionate-3-ketone with the yield of 90%;
example 2 according to a method similar to that of example 1, the reaction conditions were investigated from the solvent type, catalyst type and material ratio, and the results are shown in Table 1.
Table 1 yield of compound iv under each reaction condition.
Note: other conditions of the above study: the reaction temperature is 60 ℃; tracking the reaction time by TLC until the m-chloroacetophenone is reacted completely or reacts for 48 hours; the dosage of the catalyst is calculated by m-chloroacetophenone.
As can be seen from the table:
1. for most catalysts, three solvents, namely methanol, ethanol and ethanol-THF are beneficial to the reaction, and the yield can exceed 50% in many cases, particularly the yield can reach 87% when ethanol-THF is used as the solvent; solvents such as diethyl ether and water are disadvantageous to the reaction.
2. As for the catalyst, NaOH and NaOEt, which are commonly used as catalysts in the reaction, are moderate, and the catalytic effect of some resins such as 201X 4, 213, D201, Amberlite IRA-400 and the like is good, so that the reaction can obtain the yield of 60 percent or more in many cases, and particularly, the Amberlite IRA-400 can obtain the yield of 87 percent when ethanol-THF is used as a solvent.
3. The combined conditions of ethanol-THF and Amberlite IRA-400 are the appropriate solvent and catalyst for the reaction.
Therefore, on the basis of the above research, ethanol-THF as solvent and Amberlite IRA-400 as catalyst were continuously used, and their proportion, amount, reaction temperature and reaction time were further optimized to obtain the optimal reaction conditions shown in example 1, which resulted in the highest yield of 90%.
Example 3: preparation of intermediate ethyl 3- (3-chlorophenyl) -3-hydroxypropionate (V)
226.5 g of ethyl 3- (3-chlorophenyl) propionate-3-one are dissolved in 1500mL of ethanol, 80mL of glacial acetic acid are added, and H is passed in with stirring2Air in the reaction system is removed, 11.3 g of Pd-C is added, the temperature is raised to 40 ℃, and the reaction is continued in H2Reacting for 6h under the atmosphere, filtering, recovering the catalyst, and evaporating the solvent under reduced pressure to obtain a light yellow oily 3- (3-chlorphenyl) -3-hydroxypropionic acid ethyl ester with the yield of 92 percent.
Example 4 the kind of solvent, the kind of catalyst and the amount of catalyst used were investigated in a similar manner to example 3, and the results are shown in Table 2.
Table 2 yield of compound v under each reaction condition.
Note: other conditions of the above study: the reaction temperature is 25 ℃; the reaction pressure is 1 atm; tracking the reaction time by TLC until the 3- (3-chlorphenyl) ethyl propionate-3-ketone is reacted completely or for 48 hours; the amount of the catalyst is calculated according to the 3- (3-chlorphenyl) ethyl propionate-3-ketone.
1. As can be seen from Table 2, the solvent such as methanol, ethanol, methanol-acetic acid, ethanol-acetic acid and the like can make the reaction obtain the yield of 50% or more in many cases, the solvent such as methanol-acetic acid, ethanol-acetic acid and the like is more favorable for the reaction, and particularly, the solvent such as ethanol-acetic acid can reach the yield of 86% under proper conditions.
2. The amount of acetic acid added into the ethanol has great influence on the reaction, and the best ratio of the acetic acid to the ethanol is 1:0.05, so that the yield can reach 86%.
3. The catalysts for catalytic reduction of aldehydes and ketones, such as copper oxide-chromite, alumina-zinc oxide-chromium oxide, which are commonly used, do not perform well and yield up to 60% is obtained only in very large amounts, whereas Pd-C, Pd (OH), which is a catalyst commonly used for reduction of olefinic bonds2In many cases, the result is more than ideal, and the yield of 86% is best achieved when Pd-C is used as the catalyst.
4. Ethanol-acetic acid, Pd-C combined conditions are suitable solvents and catalysts for this reaction.
Therefore, based on the above studies, further optimization of the amount of Pd-C, the reaction temperature and the reaction time was carried out using 1:0.05 ethanol-acetic acid as solvent and Pd-C as catalyst to obtain the optimum reaction conditions shown in example 3, which resulted in a maximum yield of 92%.
Example 5: preparation of intermediate 3- (3-chlorophenyl) -3-hydroxypropionyloxyoxime acid (I)
Dissolving 83.4 g of hydroxylamine hydrochloride in 167mL of ethanol, adding 48 g of NaOH powder, stirring for 4h, filtering to obtain an ethanol solution of hydroxylamine for later use, dissolving 228.5 g of ethyl 3- (3-chlorophenyl) -3-hydroxypropionate in 1600mL of ethanol, adding 19.4 g of Amberlite IRA-400, adjusting the temperature to 35 ℃, dropwise adding the ethanol solution of hydroxylamine within 40min, continuing to react for 2h, filtering, evaporating to remove ethanol, adding 2200mL of water to the residue, precipitating, filtering, drying to obtain white powder, and recrystallizing with ethanol to obtain colorless crystals I with the yield of 85%.
Example 6 the kind of solvent, the kind of catalyst and the amount of catalyst used in the reaction were investigated in a similar manner to example 5, and the results are shown in Table 3.
Table 3 yield of compound i under each reaction condition. 78
Note: other conditions of the above study: the reaction temperature is 25 ℃; the mass ratio of hydroxylamine to ethyl 3- (3-chlorophenyl) -3-hydroxypropionate was 1.5: 1; the dosage of the solvent is calculated by 10mL per gram of 3- (3-chlorphenyl) -3-hydroxypropionic acid ethyl ester; tracking the reaction time by TLC until the 3- (3-chlorphenyl) -3-hydroxy ethyl propionate is reacted completely or reacts for 48 hours; the amount of the catalyst is calculated by 3- (3-chlorphenyl) -3-hydroxypropionic acid ethyl ester.
1. As can be seen from Table 3, methanol, ethanol and other solvents are suitable solvents for the reaction, and in most cases, 50% or more yield can be obtained, especially, when ethanol is used as a solvent, 81% yield can be obtained under suitable conditions;
2. the conventional catalysts NaOEt and NaOH cannot obtain good yield, and alkaline resins such as 213 and D201 cannot obtain good yield, but KOBu-t and resin Amberlite IRA-400 are very beneficial to the reaction, and particularly the Amberlite IRA-400 can obviously improve the yield of the reaction and can reach 81% of the yield at best;
therefore, based on the above studies, further optimization of the material ratio of hydroxylamine to ethyl 3- (3-chlorophenyl) -3-hydroxypropionate, the amount of catalyst used, the reaction temperature and the reaction time, with ethanol as solvent and Amberlite IRA-400 as catalyst, resulted in the optimum reaction conditions shown in example 5, which gave a maximum yield of 85%.
Claims (1)
- A preparation method of 3- (3-chlorphenyl) -3-hydroxyl propionyl hydroxamic acid is characterized by adopting the following method:dissolving 83.4 g of hydroxylamine hydrochloride in 167mL of ethanol, adding 48 g of NaOH powder, stirring for 4h, filtering to obtain an ethanol solution of hydroxylamine for later use, dissolving 228.5 g of ethyl 3- (3-chlorophenyl) -3-hydroxypropionate in 1600mL of ethanol, adding 19.4 g of Amberlite IRA-400, adjusting the temperature to 35 ℃, dropwise adding the ethanol solution of hydroxylamine within 40min, continuing to react for 2h, filtering, evaporating ethanol, adding 2200mL of water into the residue, precipitating, filtering, drying to obtain white powder, and recrystallizing with ethanol to obtain 3- (3-chlorophenyl) -3-hydroxypropanoxyhydroxamic acid.
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| 3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation;Wei-Kang Shi等;《Bioorganic & Medicinal Chemistry》;20160725;第24卷;第4519-4527页 * |
| PawełBorowiecki等.Studies on the chemoenzymatic synthesis of (R )- and ( S )-methyl 3-aryl-3-hydroxypropionates: the influence of toluene-pretreatment of lipase preparations on enantioselective transesterifications.《Tetrahedron:Asymmetry》.2013,第24卷 * |
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Application publication date: 20181123 Assignee: Hunan Shuangmu Pharmaceutical Co.,Ltd. Assignor: JISHOU University Contract record no.: X2023980045929 Denomination of invention: Preparation method of a type of 3- (substituted/unsubstituted phenyl) -3-hydroxypropionyloxoximic acid Granted publication date: 20210115 License type: Exclusive License Record date: 20231108 |
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