CN114573515B - Preparation method of trimethoprim - Google Patents
Preparation method of trimethoprim Download PDFInfo
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- CN114573515B CN114573515B CN202011385502.2A CN202011385502A CN114573515B CN 114573515 B CN114573515 B CN 114573515B CN 202011385502 A CN202011385502 A CN 202011385502A CN 114573515 B CN114573515 B CN 114573515B
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- trimethoprim
- trimethoxybenzaldehyde
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- temperature
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960001082 trimethoprim Drugs 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims abstract description 87
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000003756 stirring Methods 0.000 claims abstract description 34
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 32
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 229960000583 acetic acid Drugs 0.000 claims description 19
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 239000001569 carbon dioxide Substances 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims 1
- 230000008014 freezing Effects 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 18
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 6
- 238000005580 one pot reaction Methods 0.000 abstract description 6
- 150000002085 enols Chemical class 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 239000002699 waste material Substances 0.000 abstract 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000010907 mechanical stirring Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QRQAQBPKKIIRIW-UHFFFAOYSA-N C=CC#N.NC1=CC=CC=C1 Chemical compound C=CC#N.NC1=CC=CC=C1 QRQAQBPKKIIRIW-UHFFFAOYSA-N 0.000 description 5
- 238000005265 energy consumption Methods 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 150000002357 guanidines Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- LMGNGGBSQVPQCO-SQFISAMPSA-N (z)-3-anilino-2-[(3,4,5-trimethoxyphenyl)methyl]prop-2-enenitrile Chemical compound COC1=C(OC)C(OC)=CC(C\C(=C\NC=2C=CC=CC=2)C#N)=C1 LMGNGGBSQVPQCO-SQFISAMPSA-N 0.000 description 3
- MTPJEFOSTIKRSS-UHFFFAOYSA-N 3-(dimethylamino)propanenitrile Chemical compound CN(C)CCC#N MTPJEFOSTIKRSS-UHFFFAOYSA-N 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000000711 cancerogenic effect Effects 0.000 description 3
- 231100000315 carcinogenic Toxicity 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960004198 guanidine Drugs 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- OLWOYWAPBQLQHR-UHFFFAOYSA-N CNC.C(C=C)#N Chemical compound CNC.C(C=C)#N OLWOYWAPBQLQHR-UHFFFAOYSA-N 0.000 description 2
- 229940117937 Dihydrofolate reductase inhibitor Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 1
- WMIQCCDZARURRI-UHFFFAOYSA-N 1,1-dichloroethane Chemical compound CC(Cl)Cl.CC(Cl)Cl WMIQCCDZARURRI-UHFFFAOYSA-N 0.000 description 1
- FQXDILDBTCMQLZ-UHFFFAOYSA-N 3-(dimethylamino)-2-[(3,4,5-trimethoxyphenyl)methyl]prop-2-enenitrile Chemical compound COC1=CC(CC(=CN(C)C)C#N)=CC(OC)=C1OC FQXDILDBTCMQLZ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000008360 acrylonitriles Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZZTURJAZCMUWEP-UHFFFAOYSA-N diaminomethylideneazanium;hydrogen sulfate Chemical compound NC(N)=N.OS(O)(=O)=O ZZTURJAZCMUWEP-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- OZRNSSUDZOLUSN-LBPRGKRZSA-N dihydrofolic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OZRNSSUDZOLUSN-LBPRGKRZSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000010808 liquid waste Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of trimethoprim, which comprises the steps of adding 3-hydroxy propionitrile, 3,4, 5-trimethoxybenzaldehyde and a condensation catalyst piperidine into an acetic acid solvent, stirring and dissolving, completing Knoevenagel condensation reaction at room temperature to generate enol condensate, adding guanidine carbonate, completing cyclization reaction under heating condition, and finally preparing the trimethoprim in a one-pot manner directly and high yield. The method has the advantages of simple operation, high yield, good atom economy, less environmental pollution, no auxiliary raw material, and the like, and the method has less waste atoms, further reduces the production cost, and directly prepares trimethoprim in a one-pot manner, so that the method is a green preparation method.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and relates to a preparation method for preparing Trimethoprim (Trimethoprim) serving as a raw material medicine in high yield.
Background
The Trimethoprim (TMP) serving as a dihydrofolate reductase inhibitor can effectively prevent the reduction of dihydrofolate to tetrahydrofolate, stop DNA replication in a folate biosynthesis pathway, and cause cell death in the proliferation process of bacteria and pathogens. Therefore, trimethoprim is widely used in medical and livestock industries as an antibacterial agent and an antibacterial synergist.
Trimethoprim has been used as a classical dihydrofolate reductase inhibitor for over sixty years, and has been loaded in multinational pharmacopoeia and veterinary pharmacopoeia due to its good antibacterial effect and antibacterial synergism. Trimethoprim is an important raw material medicine variety in China, and recently, trimethoprim is expanded from the combined application of sulfonamide to the combined application of antimalarial medicines, antibiotics, antidiarrheal medicines and the like, has a synergistic effect, is widely applied to clinical treatment and livestock breeding industry, and becomes a prop product for the production of raw material medicines in China. The abuse of antibiotics is limited at home and abroad, and the dosage of trimethoprim in clinic and animal husbandry has an increasing trend year by year.
At present, the domestic industrial production route is based on the technological process implemented by patent application CN101575303a (Ji Yafei, mo Huan, square peak, duan Meili, xu Xu, a preparation method of 3-anilino-2- (3, 4, 5-trimethoxybenzyl) acrylonitrile), and the route is as follows:
the production process comprises the steps of preparing 3-dimethylamino-2- (3, 4, 5-trimethoxybenzyl) acrylonitrile (acrylonitrile dimethylamine condensate) by using 3-dimethylamine propionitrile and 3,4, 5-trimethoxybenzaldehyde under the catalysis of potassium hydroxide in a high yield, continuously adding aniline, replacing dimethylamino functional groups in the acrylonitrile dimethylamine condensate with aniline under the controlled acidic condition, and finally preparing a key intermediate 3-anilino-2- (3, 4, 5-trimethoxybenzyl) acrylonitrile (acrylonitrile aniline condensate) in a one-pot manner. In the latter process of production, the key intermediate acrylonitrile aniline condensate is cyclized with guanidine nitrate in sodium methoxide environment to prepare trimethoprim as the material medicine. The existing production process has higher yield of the main raw material 3,4, 5-trimethoxybenzaldehyde, but auxiliary raw materials such as dimethylamine, dimethyl sulfoxide, aniline and the like are needed, so that the energy consumption for recycling the auxiliary raw materials is high. Meanwhile, the key intermediate acrylonitrile aniline condensate needs to be separated and refined, liquid and solid wastes are correspondingly generated, and the process operation is complicated. Particularly, a great amount of carcinogenic chemical raw material aniline is used in the trimethoprim production process, so that the labor protection of workers and the quality control of the trimethoprim are extremely strict, and the process becomes a fatal weakness of the existing production process. Furthermore, the use of guanidine nitrate also presents a safety risk.
In view of this, there is an urgent need in the art for a process for preparing trimethoprim with the least complexity, low cost and high efficiency, which further reduces the consumption of expensive 3,4, 5-trimethoxybenzaldehyde, eliminates the use of auxiliary raw materials such as dimethylamine, dimethylsulfoxide, aniline, etc., reduces environmental pollution, and improves the labor protection and safety production level, so as to meet the needs of industrial departments for producing trimethoprim.
Disclosure of Invention
The invention aims to eliminate dimethylamine and dimethyl sulfoxide raw materials used in the prior art, eliminate the use of aniline which is a strong carcinogenic raw material and guanidine nitrate which is an explosive raw material, and avoid separation and refining of reaction intermediates, thereby providing a trimethoprim green manufacturing process which has the advantages of high yield, low energy consumption, less environmental pollution, simple operation and good labor protection, is convenient for large-scale industrial production, and meets the needs of industrial departments.
The conception and principle of the invention are as follows:
the 3-hydroxy propionitrile as cheap acrylonitrile derivative is first reacted with 3,4, 5-trimethoxybenzaldehyde to produce Knoevenagel condensation, and the obtained enol condensate is then cyclized with guanidine carbonate to produce trimethoprim in one-pot mode. The reaction equation is as follows:
in order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a novel preparation method of trimethoprim, which comprises the following steps:
stirring glacial acetic acid, 3-hydroxy propionitrile and catalyst piperidine uniformly, adding 3,4, 5-trimethoxybenzaldehyde, stirring for dissolving, and stirring vigorously at room temperature overnight to complete Knoevenagel condensation reaction; the amount of glacial acetic acid is 1 to 10 times of the mass of 3,4, 5-trimethoxybenzaldehyde, and the molar ratio of 3,4, 5-trimethoxybenzaldehyde to 3-hydroxypropionitrile is 1 (1 to 1.5) (preferably 1 (1.05 to 1.3)); the molar ratio of 3,4, 5-trimethoxybenzaldehyde to piperidine catalyst is 1 (0.05-0.5) (preferably 1 (0.1-0.2)); then guanidine carbonate is slowly added in batches at room temperature for stirring and dissolution, and carbon dioxide gas is slowly released, wherein the molar ratio of 3,4, 5-trimethoxybenzaldehyde to guanidine carbonate is 1 (0.5-1) (preferably 1 (0.55-0.7)); after guanidine carbonate is added, stirring is continued at room temperature for 0.1-1 h, and the temperature is raised to 40-100 ℃ for reacting for 1-10 h to complete cyclization reaction; after the reaction is finished, acetic acid in the reaction system is distilled off under reduced pressure, deionized water is added, the temperature is raised to 50-100 ℃ (preferably 50-70 ℃) and stirred for dissolution, sodium hydroxide solution is slowly added dropwise to adjust the pH to 8.5-9.5, then the temperature is reduced and frozen to 5-0 ℃, off-white precipitate is separated out, the deionized water is used for washing, and the trimethoprim is obtained after drying.
The concentration of the sodium hydroxide solution is 30 to 50%, preferably 40%.
The yield of the trimethoprim to the 3,4, 5-trimethoxybenzaldehyde can reach more than 92%.
The consumption of the glacial acetic acid is 3-6 times of the mass of the 3,4, 5-trimethoxybenzaldehyde.
The temperature for completing Knoevenagel condensation reaction is 0-60 ℃ and the reaction time is 4-24 hours; preferably at 20-35 ℃ for 6-12 hours.
The temperature for completing the cyclization reaction is 50-70 ℃ and the time is 2-6 h.
The deionized water is added and heated to 50-100 ℃ and stirred for dissolution, and the addition amount of the deionized water is 3-10 times, preferably 4 times, the mass of the 3,4, 5-trimethoxybenzaldehyde.
By adopting the technical scheme, the invention has the following advantages and beneficial effects:
the new preparation method of trimethoprim provided by the invention has reasonable design of synthesis process, high yield of main raw material 3,4, 5-trimethoxybenzaldehyde, further reduces consumption of expensive raw material 3,4, 5-trimethoxybenzaldehyde, eliminates use of dimethylamine, high boiling point solvent dimethyl sulfoxide, strong carcinogenic raw material aniline and explosive raw material guanidine nitrate, reduces environmental pollution, avoids separation and refining of reaction intermediates, is a green preparation process of trimethoprim with low cost, simple operation, good safety, high yield, low energy consumption, less environmental pollution and simple operation, improves labor protection and safety production level, and is more convenient for large-scale industrial production so as to meet the needs of industrial departments.
The method has the advantages of simple operation, high yield, good atomic economy, less environmental pollution, no auxiliary raw materials and the like; the method of the invention has the advantages of further reduced production cost, and direct preparation of trimethoprim in a one-pot manner, which can be said to be a green preparation method.
By using the preparation method, under the preferable condition, the yield of trimethoprim to 3,4, 5-trimethoxybenzaldehyde is generally over 92 percent, even can reach 96 percent; whereas the yield of trimethoprim to 3,4, 5-trimethoxybenzaldehyde in the prior art (CN 101575303A (Ji Yafei, mo Huan, square peak, duan Meili, xu Xu, a method for preparing 3-anilino-2- (3, 4, 5-trimethoxybenzyl) acrylonitrile)) was only about 83%.
Using the preparation method of the present invention, only 3,4, 5-trimethoxybenzaldehyde, 3-hydroxypropionitrile, guanidine carbonate and acetic acid are required to prepare trimethoprim; in addition to 3,4, 5-trimethoxybenzaldehyde, 3-dimethylaminopropionitrile, guanidine nitrate and sodium methoxide, the prior art also needs dimethyl sulfoxide and aniline auxiliary raw materials, and has high recovery energy consumption, much pollution and high requirements on labor protection and product quality. 3-hydroxy propionitrile can be prepared from acrylonitrile and water cleanly, while 3-dimethylaminopropionitrile is prepared from acrylonitrile and dimethylamine. The guanidine carbonate releases free guanidine in the reaction smoothly, and inorganic salt pollution is avoided; the use of guanidine nitrate has the potential risk of explosion, and sodium nitrate pollution is generated when free guanidine is released from the reaction system.
By using the preparation method, trimethoprim can be conveniently prepared in a one-pot manner, and the working hours, the energy consumption and the reaction equipment are saved; in the prior art, the prior art needs to prepare, separate and dry the intermediate of the acrylonitrile aniline condensate, and then carry out the cyclization process to prepare the trimethoprim, which is a relatively complicated production process.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons of ordinary skill in the art that the following descriptions are intended to be illustrative, and not limiting, and that the scope of the present invention is not to be so limited.
Example 1
To a three-necked flask equipped with mechanical stirring, 750mL of glacial acetic acid, 3-hydroxypropionitrile (78.2 g,1.10 mol), and piperidine catalyst (8.5 g,0.10 mol) were sequentially added and stirred uniformly; adding 3,4, 5-trimethylOxybenzaldehyde (196.2 g,1.0 mol) was dissolved by stirring, and vigorously stirred at room temperature overnight to complete Knoevenagel condensation. Then guanidine carbonate solid (103.6 g,0.575 mol) was added slowly and batchwise at room temperature, dissolved with stirring, slowly releasing carbon dioxide gas, and stirring was continued at room temperature for 0.5h after addition of guanidine carbonate. The temperature was raised to 55℃and stirring was continued at this temperature for 5 hours to complete the cyclization reaction. After the reaction is finished, acetic acid in the reaction system is distilled off under reduced pressure, 800mL of deionized water is added, the temperature is raised to 60 ℃, stirring and dissolving are carried out, 40% of sodium hydroxide alkali liquor is slowly added dropwise, the pH is regulated to 8.5-9.5, then the temperature is reduced and frozen to 5-0 ℃, and a large amount of white trimethoprim solid is separated out. Washing with deionized water, and drying to obtain 272.9g of trimethoprim, mp 199-203 ℃ and yield 94%. 1 H NMR(DMSO-d 6 ):3.51(s,2H,CH 2 ),3.60(s,3H,OCH 3 ),3.71(s,6H,OCH 3 ),5.69(s,2H,NH 2 ),6.08(s,2H,NH 2 ),6.54(s,2H,aromatic),7.50(s,1H,pyrimidine)。EI-MS m/z:290(M + ,100),275(23),259(28),243(14)。
Example 2
Into a three-necked flask equipped with mechanical stirring, 800mL of glacial acetic acid, 3-hydroxypropionitrile (81.7 g,1.15 mol) and piperidine catalyst (12.8 g,0.15 mol) were successively added and stirred uniformly. 3,4, 5-trimethoxybenzaldehyde (196.2 g,1.0 mol) was added thereto, dissolved by stirring, and vigorously stirred at room temperature for 10 hours to complete Knoevenagel condensation reaction. Then guanidine carbonate solid (108.1 g,0.60 mol) was added slowly and batchwise at room temperature, dissolved by stirring, slowly releasing carbon dioxide gas, and stirring was continued at room temperature for 0.5h after addition of guanidine carbonate. The temperature was raised to 60℃and stirring was continued at this temperature for 5 hours to complete the cyclization reaction. After the reaction is finished, acetic acid in the reaction system is distilled off under reduced pressure, 800mL of deionized water is added, the temperature is raised to 60 ℃, stirring and dissolving are carried out, 40% of sodium hydroxide alkali liquor is slowly added dropwise, the pH is regulated to 8.5-9.5, then the temperature is reduced and frozen to 5-0 ℃, and a large amount of white trimethoprim solid is separated out. Washing with deionized water, and drying to obtain 278.7g of trimethoprim, wherein the mp is 199-203 ℃ and the yield is 96%.
Example 3
Into a three-necked flask equipped with mechanical stirring, 850mL of glacial acetic acid, 3-hydroxypropionitrile (81.7 g,1.15 mol), and piperidine catalyst (17.0 g,0.2 mol) were successively added and stirred well. 3,4, 5-trimethoxybenzaldehyde (196.2 g,1.0 mol) was added thereto, dissolved by stirring, and vigorously stirred at room temperature for 8 hours to complete Knoevenagel condensation reaction. Then guanidine carbonate solid (108.1 g,0.60 mol) was added slowly and batchwise at room temperature, dissolved by stirring, slowly releasing carbon dioxide gas, and stirring was continued at room temperature for 0.5h after addition of guanidine carbonate. The temperature was raised to 50℃and stirring was continued at this temperature for 6h to complete the cyclization reaction. After the reaction is finished, acetic acid in the reaction system is distilled off under reduced pressure, 750mL of deionized water is added, the temperature is raised to 65 ℃, stirring and dissolving are carried out, 40% of sodium hydroxide alkali liquor is slowly added dropwise, the pH is regulated to 8.5-9.5, then the temperature is reduced and frozen to 5-0 ℃, and a large amount of white trimethoprim solid is separated out. Washing with deionized water, and drying to obtain 275.8g of trimethoprim, mp 199-203 ℃ and yield 95%.
Example 4
Into a three-necked flask equipped with mechanical stirring, 850mL of glacial acetic acid, 3-hydroxypropionitrile (78.2 g,1.10 mol), and piperidine catalyst (17.0 g,0.2 mol) were successively added and stirred well. 3,4, 5-trimethoxybenzaldehyde (196.2 g,1.0 mol) was added thereto, dissolved by stirring, and vigorously stirred at room temperature for 12 hours to complete Knoevenagel condensation reaction. Then guanidine carbonate solid (108.1 g,0.60 mol) was added slowly and batchwise at room temperature, dissolved by stirring, slowly releasing carbon dioxide gas, and stirring was continued at room temperature for 0.5h after addition of guanidine carbonate. The temperature was raised to 55℃and stirring was continued at this temperature for 6h to complete the cyclization reaction. After the reaction is finished, acetic acid in the reaction system is distilled off under reduced pressure, 780mL of deionized water is added, the temperature is raised to 70 ℃, stirring and dissolving are carried out, 40% of sodium hydroxide alkali liquor is slowly added dropwise, the pH is regulated to 8.5-9.5, then the temperature is reduced and frozen to 5-0 ℃, and a large amount of white trimethoprim solid is separated out. Washing with deionized water, and drying to obtain 275.8g of trimethoprim, mp 199-203 ℃ and yield 95%.
Comparative example 1
The reaction procedure of example 2 was followed, only by varying the type of catalyst, to determine the effect of different secondary amines on trimethoprim yield.
TABLE 1
Catalyst | Trimethoprim yield |
Tetrahydropyrrole | 89% |
Cyclo-imine | 92% |
Diethylamine | 86% |
Dipropylamine | 86% |
Diisopropylamine | 85% |
Dibutyl amine | 85% |
As can be seen from the data in Table 1, the types of catalysts were varied and the amounts used were the same as in example 2, the trimethoprim yield was still the highest with the piperidine yield of the catalyst used in example 2, and thus piperidine was chosen as the catalyst in the present application.
Comparative example 2
The reaction procedure of example 2 was followed, except that the amount of piperidine used as a catalyst was changed, to determine the effect on the yield of trimethoprim.
TABLE 2
Dosage of piperidine catalyst | Trimethoprim yield |
4.3g,0.05mol | 86% |
6.0g,0.07mol | 89% |
7.7g,0.09mol | 91% |
46.8g,0.55mol | 91% |
51.1g,0.60mol | 91% |
59.6g,0.70mol | 89% |
As can be seen from the data in Table 2, by changing the amount of the catalyst, the molar ratio of 3,4, 5-trimethoxybenzaldehyde to piperidine catalyst is greater than 1:0.5 or less than 1:0.05, and the yield of trimethoprim is not as good as that of the defined range (the molar ratio of 3,4, 5-trimethoxybenzaldehyde to piperidine catalyst is 1 (0.05-0.5)); also, the molar ratio of 3,4, 5-trimethoxybenzaldehyde to piperidine catalyst is selected to be 1 (0.05 to 0.5), preferably 1 (0.1 to 0.2), considering that the amount of the catalyst used should not be too much or too little.
Comparative example 3
The reaction procedure of example 2 was followed, except that the amount of 3-hydroxypropionitrile was changed, to determine the effect of the amount of 3-hydroxypropionitrile on the yield of trimethoprim.
TABLE 3 Table 3
As can be seen from the data in Table 3, by changing the amount of 3-hydroxypropionitrile, the molar ratio of 3,4, 5-trimethoxybenzaldehyde to 3-hydroxypropionitrile is greater than 1:1.5 or less than 1:1, and the yield of trimethoprim is not as good as the yield of the limiting range (the molar ratio of 3,4, 5-trimethoxybenzaldehyde to 3-hydroxypropionitrile is 1 (1-1.5)) in the present application; at the same time, the molar ratio of 3,4, 5-trimethoxybenzaldehyde to 3-hydroxypropionitrile is 1 (1 to 1.5), preferably 1 (1.05 to 1.3), considering that the amount should not be excessively increased.
Comparative example 4
The reaction procedure of example 2 was followed to determine the effect of guanidine species on trimethoprim yield by changing only the guanidine salt species, not changing the equivalent of guanidine salt.
TABLE 4 Table 4
Types of guanidine salts | Trimethoprim yield |
Guanidine nitrate (1.20 mol) | 91% |
Guanidine hydrochloride (1.20 mol) | 92% |
Guanidine sulfate (0.60 mol) | 89% |
As can be seen from the data in Table 4, the guanidine carbonate was selected in this application by varying the type of guanidine salt used in the same amount as in example 2, and the yield of trimethoprim was also the highest as that of guanidine carbonate used in example 2.
Comparative example 5
The reaction procedure of example 2 was followed, except that the amount of guanidine carbonate was changed, and the effect of the amount of guanidine carbonate on the yield of trimethoprim was measured.
TABLE 5
As can be seen from the data in Table 5, changing the amount of guanidine carbonate, the molar ratio of 3,4, 5-trimethoxybenzaldehyde to guanidine carbonate is greater than 1:1 or less than 1:0.5, and the yield of trimethoprim is not as good as the yield of the limited range (the molar ratio of 3,4, 5-trimethoxybenzaldehyde to guanidine carbonate is 1 (0.5-1)) defined in the application; at the same time, the molar ratio of 3,4, 5-trimethoxybenzaldehyde to guanidine carbonate is 1 (0.5-1), preferably 1 (0.55-0.7), considering that the amount should not be excessively increased.
Comparative example 6
The reaction procedure of example 2 was followed, and the effect of the solvent type on the yield of trimethoprim was measured by changing only the solvent type.
TABLE 6
Type of solvent | Trimethoprim yield |
Formic acid | 85% |
Propionic acid | 78% |
Dichloroethane (dichloroethane) | 0 |
Toluene (toluene) | 0 |
As can be seen from the data in Table 6, the type of solvent was changed and the amount thereof was the same as in example 2, and the yield of trimethoprim was the highest as that of glacial acetic acid as the solvent used in example 2, so that glacial acetic acid was selected as the solvent in the present application.
Comparative example 7
Preparation of trimethoprim based on the patent application publication CN101575303 a:
into a three-necked flask equipped with mechanical stirring, 250mL of dimethyl sulfoxide, 3-dimethylaminopropionitrile (Compound 2) (127.6 g,1.30 mol) and a solution prepared from potassium hydroxide (11.8 g,0.21 mol) and 50mL of methanol were successively added, and the mixture was sufficiently stirred at 45℃for 0.5h. 3,4, 5-trimethoxybenzaldehyde (196.2 g,1.0 mol) was added in portions over 1h at this temperature, then the temperature was raised to 85℃and the stirring reaction was continued for 4h, and spot Thin Layer Chromatography (TLC) was followed until the 3,4, 5-trimethoxybenzaldehyde starting material spot disappeared. Cooling to 40 ℃, adding 250mL of methanol under stirring for dilution, adding aniline (98.7 g,1.06 mol), dropwise adding 2mol/L of dilute sulfuric acid in 1h until the pH is within the range of 3.0-3.5, heating and refluxing for 2 hours, and tracking by TLC untilThe spot of compound 3 disappeared. Methanol was distilled off under reduced pressure, 250mL of water was added, the reaction mixture was frozen to 3℃and a large amount of yellow precipitate was precipitated and filtered. The filter cake was washed with 500mL of a 15% (v/v) cold aqueous ethanol solution and dried in vacuo to give 294.5g of an acrylonitrile aniline compound 1 as a pale yellow solid. mp 130-132 deg.C, yield 90.8%. 1 H NMR(500MHz,CDCl 3 Compound 1 comprises both cis and trans isomers, with two chemical shifts for part of the proton) 3.44,3.53 (s, 2h, CH 2), 3.82 (s, 3h, och 3), 3.86 (s, 6h, och 3), 6.26,6.71 (d, j=13.0 hz,1h, nh), 6.46,6.52 (s, 2h, arh), 6.78,6.87 (d, j=7.4 hz,2h, arh), 7.01 (t, j=7.4 hz,1h, arh), 7.14,7.36 (d, j=13.0 hz,1h, =ch), 7.28-7.32 (m, 2h, arh). EI-MS M/z 324 (M+, 100), 293 (20), 232 (17), 168 (20).
120mL of methanol and sodium metal (5.3 g,0.23 mol) were sequentially added to a three-necked flask equipped with mechanical stirring, and the mixture was heated and refluxed until the sodium metal was completely dissolved, to prepare a fresh sodium methoxide methanol solution. Guanidine nitrate (18.5 g,0.15 mol) was added to this solution, heated to reflux for 20min, cooled to 45℃and compound 1 (32.4 g,0.10 mol) was added thereto, and heated to reflux for 10h. Methanol was distilled off under reduced pressure, 200mL of water was added, stirred, cooled to 5℃and a large amount of pale yellow precipitate was precipitated. Filtering, washing the filter cake with 150mL of water to obtain pale yellow crude trimethoprim. Dissolving the crude product in 20% dilute formic acid, adding active carbon for decoloring at 95 ℃, carrying out hot filtration, neutralizing the filtrate with ammonia water at 70 ℃ until the pH value is between 8.5 and 9.5, precipitating a large amount of off-white solid, cooling to room temperature, filtering, washing with 150mL of deionized water, and drying to obtain 27.0g of refined trimethoprim. mp 199-203 ℃ and the yield is 93.0 percent.
The yield of trimethoprim to 3,4, 5-trimethoxybenzaldehyde in the prior art is 84%, and a refining link is needed.
Compared with the prior art, the invention saves the raw material cost and other link cost of 3,4, 5-trimethoxybenzaldehyde, dimethyl sulfoxide and aniline, can reduce the production cost of trimethoprim per ton by more than 3.5 ten thousand yuan, and has good economic benefit.
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.
Claims (8)
1. The preparation method of trimethoprim is characterized by comprising the following steps:
stirring glacial acetic acid, 3-hydroxy propionitrile and catalyst piperidine uniformly, adding 3,4, 5-trimethoxybenzaldehyde, stirring for dissolving, and stirring vigorously at room temperature overnight to complete Knoevenagel condensation reaction; the consumption of glacial acetic acid is 1 to 10 times of the mass of 3,4, 5-trimethoxybenzaldehyde, and the molar ratio of 3,4, 5-trimethoxybenzaldehyde to 3-hydroxypropionitrile is 1 (1 to 1.5); the molar ratio of the 3,4, 5-trimethoxybenzaldehyde to the catalyst piperidine is 1 (0.05-0.5); then guanidine carbonate is slowly added in batches at room temperature for stirring and dissolution, carbon dioxide gas is slowly released, and the molar ratio of 3,4, 5-trimethoxybenzaldehyde to guanidine carbonate is 1 (0.5-1); after guanidine carbonate is added, stirring is continued at room temperature for 0.1-1 h, and the temperature is raised to 40-100 ℃ for reacting for 1-10 h to complete cyclization reaction; after the reaction is finished, acetic acid in the reaction system is distilled off under reduced pressure, deionized water is added, the temperature is raised to 50-100 ℃, stirring and dissolving are carried out, sodium hydroxide solution is slowly added dropwise to adjust the pH to 8.5-9.5, then cooling and freezing are carried out to 5-0 ℃, white-like sediment is separated out, deionized water is used for washing, and drying is carried out, thus obtaining the trimethoprim.
2. The method for preparing trimethoprim according to claim 1, wherein the concentration of sodium hydroxide solution is 30-50%.
3. The method for preparing trimethoprim according to claim 1, wherein the yield of trimethoprim to 3,4, 5-trimethoxybenzaldehyde is up to 92% or more.
4. The method for preparing trimethoprim according to claim 1, wherein the amount of glacial acetic acid is 3-6 times of the mass of 3,4, 5-trimethoxybenzaldehyde.
5. The method for preparing trimethoprim according to claim 1, wherein the temperature of Knoevenagel condensation reaction is 0-60 ℃ and the reaction time is 4-24 h.
6. The method for preparing trimethoprim according to claim 5, wherein the temperature of Knoevenagel condensation reaction is 20-35 ℃ and the reaction time is 6-12 h.
7. The method for preparing trimethoprim according to claim 1, wherein the cyclization reaction is carried out at a temperature of 50-70 ℃ for a time of 2-6 hours.
8. The method for preparing trimethoprim according to claim 1, wherein the deionized water is added in an amount of 3-10 times the mass of 3,4, 5-trimethoxybenzaldehyde.
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US4115650A (en) * | 1976-11-17 | 1978-09-19 | Hoffmann-La Roche Inc. | Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines |
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ES391719A1 (en) * | 1971-05-29 | 1973-06-16 | Hebron S A | New procedure for obtaining a bencil pirimidine substituted. (Machine-translation by Google Translate, not legally binding) |
US4115650A (en) * | 1976-11-17 | 1978-09-19 | Hoffmann-La Roche Inc. | Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines |
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Title |
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Percy S. Manchand等.Syntheses of Antibacterial 2,4-Diamino-5-benzylpyrimidines. Ormetoprim and Trimethoprim.Journal of Organic Chemistry.1992,第57卷(第13期),3531-3535. * |
合成甲氧节胺喀陡缩合反应产物中两种同分异构体的结构和稳定性的理论研究;王琳等;计算机与应用化学;20090428;第26卷(第4期);487-491 * |
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