CN106431969B - 一种制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法 - Google Patents
一种制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 22
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 title claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical class CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- -1 filter Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- SNANINYFIFMJBX-UHFFFAOYSA-N 3-bromo-2,4-dimethylbenzoic acid Chemical class CC1=CC=C(C(O)=O)C(C)=C1Br SNANINYFIFMJBX-UHFFFAOYSA-N 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- NIDKGLRXRBFGEN-UHFFFAOYSA-N 4-cyano-2-methylbenzoic acid Chemical compound CC1=CC(C#N)=CC=C1C(O)=O NIDKGLRXRBFGEN-UHFFFAOYSA-N 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- PDQNYPAJSAVURS-UHFFFAOYSA-N methyl 4-cyano-2-methylbenzoate Chemical class COC(=O)C1=CC=C(C#N)C=C1C PDQNYPAJSAVURS-UHFFFAOYSA-N 0.000 claims description 3
- 229940095102 methyl benzoate Drugs 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000010936 aqueous wash Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000276 potassium ferrocyanide Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 2
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 claims description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- WJIFKOVZNJTSGO-UHFFFAOYSA-N 1-bromo-3-methylbenzene Chemical class CC1=CC=CC(Br)=C1 WJIFKOVZNJTSGO-UHFFFAOYSA-N 0.000 claims 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 abstract description 4
- 230000032050 esterification Effects 0.000 abstract description 3
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 abstract 1
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- MLBZKOGAMRTSKP-UHFFFAOYSA-N fluralaner Chemical compound C1=C(C(=O)NCC(=O)NCC(F)(F)F)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 MLBZKOGAMRTSKP-UHFFFAOYSA-N 0.000 description 3
- 229960004498 fluralaner Drugs 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241001427556 Anoplura Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 241000258242 Siphonaptera Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- ROPLCSFPUPWHGJ-UHFFFAOYSA-N hydroxycyanamide Chemical compound ONC#N ROPLCSFPUPWHGJ-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
一种制备式2‑甲基‑4‑甲醛肟基苯甲酸甲酯的方法,是由2‑甲基‑4‑溴苯甲酸经酰氯化、甲醇酯化、氰基取代,然后与盐酸羟胺在碱性条件下亲核加成消除得到目标产物,其优点是工艺路线简单,反应条件温和,产品收率高,总收率达61%,产品质量好,外观为白色固体,纯度达99.2%。
Description
技术领域
本发明涉及药物中间体制备领域,具体地说,是关于一种制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法。
背景技术
新型杀虫剂的研发对于预防和治理畜牧业害虫抗药性及控制其危害具有非常重要的作用。化合物fluralaner 是一种新型的、对哺乳动物安全、杀虫活性高且广谱性的异唑啉类杀虫剂,如对蜱目、蚤目、虱目、半翅目和双翅目等害虫均具有良好的杀虫活性。目前fluralaner 作为兽药已在欧洲和美国等国家开始销售和推广,但在中国还处于初步研究阶段,还没有形成商业化生产。2-甲基-4-甲醛肟基苯甲酸甲酯是合成异唑啉类化合物fluralaner的重要中间体,目前国外主要是参照以下工艺路线(WO2008122375A2)进行合成:
该路线是以2-甲基-4-溴苯甲酸为原料,经过Vilsmeier-Haack反应、酯化反应、亲核加成消除等多步反应得到目标产物2-甲基-4-甲醛肟基苯甲酸甲酯。在该路线第一步的Vilsmeier-Haack反应中要使用正丁基锂于-78 oC下反应,这在工业上反应条件较为苛刻,而且大量使用正丁基锂存在较大的安全风险,并且在第二步酯化反应过程中使用的原料试剂种类较多,反应后处理复杂,从而导致了生产原料成本较高、产物杂质较多和收率较低。
发明内容
本发明的目的是针对现有技术的不足,提供了一种操作简单、收率高、成本低,适合工业化大规模生产2-甲基-4-甲醛肟基苯甲酸甲酯的方法。
本发明的目的是通过以下方式来实现的:
一种制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,包括以下步骤:
(1)将2-甲基-4-溴苯甲酸溶于甲醇,然后向其中加入酰氯化试剂,于20-80 oC反应1-10小时,冷却,将其加入到饱和碳酸钠的水溶液中洗涤后,用乙酸乙酯萃取,有机相依次用水和饱和氯化钠溶液洗涤,减压浓缩,得到棕红色的2-甲基-4-溴苯甲酸甲酯;
(2)将上步产物在N,N-二甲基甲酰胺溶剂中溶解后,向其中加入氰基化试剂,在40-180 oC反应5-72小时后,冷却至室温,将其加入到饱和碳酸钠溶液中,过滤,滤液用乙酸乙酯萃取,浓缩,结晶,过滤,得到白色固体2-甲基-4-氰基苯甲酸甲酯;
(3)将2-甲基-4-氰基苯甲酸甲酯用醇类溶剂溶解,加入盐酸羟胺、碱和水,20-130oC反应2-12小时,减压浓缩,过滤,得到白色固体粗产物,再用乙酸乙酯和石油醚混合溶剂重结晶,得到2-甲基-4-甲醛基苯甲酸甲酯白色固体。
所述的酰氯化试剂为二氯亚砜、三氯化磷、五氯化磷或草酰氯。
所述的氰基化试剂为氰化亚铜、氰化锌、亚铁***、***、***或三甲基氰基硅烷。
所述的醇类溶剂为甲醇、乙醇、丙醇或丁醇,各溶剂分别对应的反应温度依次为20-80 oC、20-100 oC、20-110 oC、20-130 oC,各溶剂分别对应的反应时间为2-12 h、2-10h、2-8h、2-6h。
和盐酸羟胺一起加入的碱为碳酸钠、碳酸钾、碳酸铵、碳酸氢钠、碳酸氢钾、碳酸氢铵、氢氧化钠、氢氧化钾、氨水、三乙胺、吡啶或哌啶中的任意一种。
6. 根据权利要求1所述的制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于:所述的酰氯化试剂加入量与2-甲基-4-溴苯甲酸的摩尔比为1.0-2.0:1;氰基化试剂加入量与2-甲基-4-溴苯甲酸的摩尔比为2.0-10.0:1;盐酸羟胺和碱的加入量分别与2-甲基-4-溴苯甲酸的摩尔比为1.0-1.8:1 和2.0-3.6:1。
与现有技术相比,本发明的有益效果在于:
本发明解决了原工艺中工艺路线长,操作复杂,反应条件苛刻,生产安全风险较大,收率低,三废量大且不易处理等缺点。本发明合成路线较短,工艺操作简单,反应条件更温和,所使用的原材料便宜易得,使用的溶剂及副产物均可回收利用,生产成本更低,更符合工业化生产要求。
本发明以2-甲基-4-溴苯甲酸为起始原料,经酰氯化、酯化、氰基取代,最后与盐酸羟胺一步法肟化得到目标产物。其优点是工艺路线短,方法操作简单,产品收率高,总收率到61%,产品质量好,纯度达99.2%且外观为白色。
本发明合成路线如下:
具体实施方式
下面通过实例来说明本发明,但本发明不局限于这些实例。
本发明合成路线如下:
实施例1
(1)2-甲基-4-溴苯甲酸甲酯的制备:将2-甲基-4-溴苯甲酸1,5 g溶于30 ml甲醇,向其中加入2 ml二氯亚砜,于70 oC回流反应6小时,溶液冷却至室温,加入30 ml饱和碳酸钠溶液,充分搅拌,用乙酸乙酯萃取15 ml 两次,有机层依次用水洗10 ml两次,和饱和食盐水10 ml洗涤,无水硫酸镁干燥,过滤,减压浓缩,得到棕红色的2-甲基-4-溴苯甲酸甲酯2,5.17 g,收率97%。
(2)2-甲基-4-氰基苯甲酸甲酯的制备:将步骤(1)所得2-甲基-4-溴苯甲酸甲酯2,5.17g中加入20 ml DMF溶解后,再加入10.2 g氰化亚铜,搅拌,固体物质很快溶解,溶液呈澄清色,加热至160 oC反应12小时,冷却至室温,将反应溶液倾入到100 ml饱和碳酸钠溶液中,有黄色固体析出,过滤,滤液用乙酸乙酯萃取25 ml 三次,有机层依次用水洗15 ml 两次,和饱和食盐水15 ml洗涤,无水硫酸镁干燥,过滤,减压浓缩,冷却结晶,过滤,得到白色固体2-甲基-4-氰基苯甲酸甲酯(3,2.86 g),收率72%。
(3)2-甲基-4-甲醛肟基苯甲酸甲酯的制备:将步骤(2)所得2-甲基-4-氰基苯甲酸甲酯3,2.86 g中加入20 ml甲醇溶解,再加入1.15 g羟胺盐酸和1.73g无水碳酸钠,最后加入20 ml蒸馏水,于70 oC回流反应8小时,冷却到室温,减压浓缩,得到粗产物。用乙酸乙酯和石油醚混合溶剂对粗产物进行重结晶,得到纯的目标产物2-甲基-4-甲醛肟基苯甲酸甲酯4,2.53 g,收率87%。产品外观为白色结晶,含量99.2%HPLC。[流动相:水:甲醇5:2;检测波长:240 nm;流速:1 ml/min;溶液配制:取样品0.01g用流动相稀释至25 ml;进样量5。
Claims (6)
1.一种制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于该方法包括以下步骤:
(1)将2-甲基-4-溴苯甲酸溶于甲醇,然后向其中加入酰氯化试剂,于20-80 oC反应1-10小时,冷却,将其加入到饱和碳酸钠的水溶液中洗涤后,用乙酸乙酯萃取,有机相依次用水和饱和氯化钠溶液洗涤,减压浓缩,得到棕红色的2-甲基-4-溴苯甲酸甲酯;
(2)将上步产物在N,N-二甲基甲酰胺溶剂中溶解后,向其中加入氰基化试剂,在40-180oC反应5-72小时后,冷却至室温,将其加入到饱和碳酸钠溶液中,过滤,滤液用乙酸乙酯萃取,浓缩,结晶,过滤,得到白色固体2-甲基-4-氰基苯甲酸甲酯;
(3)将2-甲基-4-氰基苯甲酸甲酯用醇类溶剂溶解,加入盐酸羟胺、碱和水,20-130 oC反应2-12小时,减压浓缩,过滤,得到白色固体粗产物,再用乙酸乙酯和石油醚混合溶剂重结晶,得到2-甲基-4-甲醛基苯甲酸甲酯白色固体。
2.根据权利要求1所述的制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于:所述的酰氯化试剂为二氯亚砜、三氯化磷、五氯化磷或草酰氯。
3.根据权利要求1所述的制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于:所述的氰基化试剂为氰化亚铜、氰化锌、亚铁***、***、***或三甲基氰基硅烷。
4.根据权利要求1所述的制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于:所述的醇类溶剂为甲醇、乙醇、丙醇或丁醇,各溶剂分别对应的反应温度依次为20-80 oC、20-100 oC、20-110 oC、20-130 oC,各溶剂分别对应的反应时间为2-12 h、2-10h、2-8h、2-6h。
5.根据权利要求1所述的制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于:所述的和盐酸羟胺一起加入的碱为碳酸钠、碳酸钾、碳酸铵、碳酸氢钠、碳酸氢钾、碳酸氢铵、氢氧化钠、氢氧化钾、氨水、三乙胺、吡啶或哌啶中的任意一种。
6.根据权利要求1所述的制备2-甲基-4-甲醛肟基苯甲酸甲酯的方法,其特征在于:所述的酰氯化试剂加入量与2-甲基-4-溴苯甲酸的摩尔比为1.0-2.0:1;氰基化试剂加入量与2-甲基-4-溴苯甲酸的摩尔比为2.0-10.0:1;盐酸羟胺和碱的加入量分别与2-甲基-4-溴苯甲酸的摩尔比为1.0-1.8:1 和2.0-3.6:1。
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