WO2018153381A1 - 一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 - Google Patents
一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 Download PDFInfo
- Publication number
- WO2018153381A1 WO2018153381A1 PCT/CN2018/077443 CN2018077443W WO2018153381A1 WO 2018153381 A1 WO2018153381 A1 WO 2018153381A1 CN 2018077443 W CN2018077443 W CN 2018077443W WO 2018153381 A1 WO2018153381 A1 WO 2018153381A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- isothiocyanate
- distillation
- ring
- reaction
- Prior art date
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
- C07C331/20—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
- C07C331/22—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
- C07C331/22—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C331/24—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
Definitions
- the present invention relates to a process for the preparation and purification of industrially produced high purity isothiocyanate compounds.
- isothiocyanates can also participate in a variety of organic reactions for the synthesis of various types of sulfur, nitrogen, oxygen containing compounds, especially heterocyclic compounds, and are widely used in pesticides, pharmaceuticals, dyes and other organic synthetic products. Preparation. It can also be used to determine the amino acid sequence in peptides and proteins and as a fluorescein label.
- isothiocyanate compounds especially high-purity, pharmaceutical-compliant, and industrially-produced preparation methods is particularly urgent.
- there are many methods for synthesizing isothiocyanates such as phosgene method, sulfur phosgene method, carbon disulfide method, bis(trichloromethyl)carbonate method, thiourea decomposition method, phenyl chloroformate method and Thiocyanate method, etc.
- phosgene method sulfur phosgene method
- carbon disulfide method carbon disulfide method
- bis(trichloromethyl)carbonate method bis(trichloromethyl)carbonate method
- thiourea decomposition method phenyl chloroformate method
- Thiocyanate method etc.
- Phosgene route Hodgkius et al. reported that phenethylamine and carbon disulfide were dissolved in an organic solvent, and phosgene was introduced in the presence of a base to form phenethyl isothiocyanate.
- the phosgene here can also be replaced by phosgene substitutes such as ethyl chloroformate, diphosgene, triphosgene, and the like.
- this reaction process still cannot avoid the formation of phosgene, is easy to pollute the environment, and has a large safety hazard.
- Sulfur phosgene route Direct reaction of thiophosgene with an amine compound to produce isothiocyanate. This route is widely used and responds quickly. It uses sulphur phosgene instead of phosgene to improve safety. However, sulphur phosgene is a toxic and volatile liquid with high environmental hazard and unsafe production and transportation. This route is not conducive to large-scale Industrial production;
- Isonitrile route The isothiocyanate is synthesized from an isonitrile and a sulfur powder or a vulcanizing agent in the presence of a metal catalyst.
- the main problem with this route is that it is difficult to synthesize and purify the isonitrile, and the isonitrile itself is also a highly toxic substance and cannot be used for industrial production.
- Thiocyanate route The isothiocyanate is produced by the reaction of a halogenated hydrocarbon and a thiocyanate. The route has a low yield and is cumbersome to operate.
- Carbon disulfide route the method is to dissolve the raw materials such as phenethylamine (or other amine organic matter) and carbon disulfide in an organic solvent, synthesize the amine dithioformate under the catalysis of the base, and then react under the action of the desulfurizing agent. Isothiocyanate compounds.
- desulfurizers mainly methyl chloroformate, p-toluenesulfonyl chloride, solid phosgene, elemental iodine, chlorosilane, chlorophosphate or dicyclohexylcarbodiimide.
- the method has the advantages of avoiding the use of highly toxic raw materials, unfortunately, the obtained product has more impurities, low purity, and is mostly purified by silica gel chromatography column, the operation is cumbersome, the reagent dosage is large, and it is more suitable for the experimental level reaction, while the industrial production is Not applicable.
- A is -XR 1 or -CR 2 R 3 R 4 , wherein
- X is -(CH 2 ) n -, and n is an integer from 0 to 6;
- R 1 is selected from the group consisting of methyl, tert-butyl, isopropyl, methylthio, methoxy, allyl, methallyl, cyclohexyl, methylsulfinyl, naphthyl, methyl Cyclohexyl, morpholinyl, diethylamino, benzoyl, ethoxycarbonyl, tert-octyl, chlorine atom, trimethylsilyl, substituted or unsubstituted phenyl;
- substituted means that one or more H groups in the group are substituted with a substituent selected from the group consisting of a halogen atom, a methyl group, a bromomethyl group, an ethyl group, a methoxy group, a nitro group, an azide group. , trifluoromethyl, difluoromethoxy, methylthio, cyano, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, ethoxycarbonyl;
- R 2 , R 3 , and R 4 are each independently H, phenyl or C 1-3 alkyl;
- the method comprises the steps of:
- the step (1) comprises: adding ANH 2 dropwise to the reaction system to which CS 2 is added to carry out the reaction.
- the organic solvent is a solvent capable of dissolving phenethylamine and dithiocarbamate and being immiscible with water; preferably, the organic The solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, butyl acetate, isobutyl acetate, amyl propionate, butanol, isobutanol, pentanol, secondary Pentanol, tert-amyl alcohol, 3-methyl-2-butanol, hexanol, heptanol, dichloromethane, dichloroethane, chloroform, diethyl ether, petroleum ether, cyclohexane, or a combination thereof.
- the organic base is selected from the group consisting of triethylamine, trimethylamine, diisopropylethylamine, triethylenediamine, pyridine, 4-N. , N-lutidine, potassium t-butoxide, sodium methoxide, sodium ethoxide, hydroxylamine, 3-methylpyridine, pyrrole, or a combination thereof.
- the desulfurizing agent is selected from the group consisting of methyl chloroformate, p-toluenesulfonyl chloride, solid phosgene, elemental iodine, chlorosilane, chlorophosphate, Dicyclohexylcarbodiimide, dicyandiamide, triphenylphosphine, di-tert-butyl dicarbonate, cyanuric chloride, or a combination thereof.
- the base catalyst is selected from the group consisting of triethylamine, triethylenediamine, pyridine, 4-dimethylaminopyridine, or a combination thereof.
- the organic amine and the triethylamine are put into an ethyl acetate solvent, the temperature of the mixture is controlled to be T1, and the carbon disulfide/ethyl acetate mixture is slowly added dropwise. Stirring, controlling the temperature T2 of the reaction liquid, after the completion of the dropwise addition, controlling the temperature T3, and stirring the reaction for 0.5-2 h.
- the temperature T1 in the step (1) is 0° C. to 30° C., preferably 0° C. to 20° C., more preferably 0° C. to 5° C.
- the temperature T 2 is 0° C. to 40° C.
- 0 ° C ⁇ 30 ° C more preferably 10 ° C ⁇ 25 ° C
- temperature T3 is 0 ° C ⁇ 40 ° C, preferably 10 ° C ⁇ 30 ° C;
- the step (2) includes controlling the temperature T4, adding a desulfurizing agent and a base catalyst to the reaction liquid, stirring the reaction at a temperature T5, and ending the reaction for 1-4 h.
- the ratio of ANH 2 to carbon disulfide is 1:1.0 to 10, preferably 1:1.0 to 5, more preferably 1:1.05 to 2;
- the ratio of the ANH 2 to the organic base is 1:0.5 to 5, preferably 1:0.8 to 3, more preferably 1:0.9 to 2; the mass to volume ratio of the ANH 2 to ethyl acetate is 10 to 25 %;
- the ratio of the ANH 2 and the desulfurizing agent charged in the first step is 1:0.9 to 5, preferably 1:0.9 to 2, more preferably 1:0.95 ⁇ 1.5;
- the mass ratio of the base catalyst to the ANH 2 feed of the first step is from 0 to 4% by weight, preferably from 0.01 to 2% by weight, more preferably from 0.05 to 1% by weight.
- the post-treatment purification method comprises the steps of:
- the crude distillation product was subjected to vacuum distillation to obtain a pure isothiocyanate product.
- the washing step comprises: washing with an acid solution, wherein the molar ratio of the total amount of the acid in the acid solution to the organic base in the step (1) is 0.8 to 5:1. Preferably, it is from 0.9 to 2:1, more preferably from 1 to 1.5:1 (calculated as monobasic acid and monobasic base).
- the wash liquor volume is from 20 to 100%, preferably from 25 to 50% by volume of the organic phase per wash.
- the concentration temperature is 30 ° C ⁇ 90 ° C, preferably 35 ° C ⁇ 60 ° C;
- the post-treatment purification comprises collecting the corresponding isothiocyanate fractions according to the boiling points of the different isothiocyanates.
- the pressure of vacuum distillation and vacuum distillation is from 10 to 1000 Pa, preferably from 10 to 500 Pa.
- the post-treatment purification comprises one or more characteristics selected from the group consisting of:
- the vacuum distillation is continuous distillation or batch rectification, preferably intermittent rectification;
- the rectification column adopts a structured packing or a random packing.
- the structured packing is selected from the group consisting of a corrugated type packing and a grid type packing;
- the random packing is selected from the group consisting of a Pall ring. , Raschig ring, flat ring, step ring, saddle ring, octagonal ring, conjugate ring, Taylor garland, Apex ring, Dixon ring, calendered ring, triangular spiral ring, spherical filler, or a combination thereof; or
- the rectified filler material is selected from the group consisting of stainless steel, plastic, glass, ceramic, or a combination thereof; preferably, the rectified filler material is selected from the group consisting of stainless steel, ceramics, or a combination thereof. .
- the reflux ratio of the front fraction is from 99:1 to 1:99 (preferably from 99:1 to 50:50, more preferably from 90:10 to 70:30);
- the reflux ratio of the middle fraction is from 99:1 to 1:99 (preferably from 90:10 to 10:90, more preferably from 70:30 to 30:70);
- the reflux ratio of the post-fraction is from 99:1 to 1:99 (preferably from 99:1 to 50:50, more preferably from 90:10 to 70:30).
- the crude distillation purity is greater than 95%, preferably greater than 97%; the purity of the rectified pure product is greater than 99.0%, preferably greater than 99.6%.
- the post-treatment purification method comprises the steps of: washing the reaction solution with a hydrochloric acid solution, repeating twice, taking the organic phase with saturated brine, repeating washing to neutral (pH 6-7), for organic phase After drying over anhydrous sodium sulfate, the mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a crude product.
- the crude product is acid-washed, and subjected to vacuum distillation using a rotary vane vacuum pump or a vacuum unit to collect the isothiocyanate fraction to obtain a crude distillation product. Distillation of crude product, using a two-stage rotary vane vacuum pump or vacuum unit, vacuum distillation, start full reflux, stabilize, set the appropriate reflux ratio, collect pure isothiocyanate.
- an apparatus for producing an isothiocyanate compound comprising:
- a main reaction kettle for performing a main reaction, an acidic water washing reaction, and a concentration operation
- a crude distillation kettle located downstream of the main reaction vessel, the crude distillation vessel being used for distillation of concentrated products;
- a rectification column for rectifying the crude distillation obtained by the distillation is a rectification column for rectifying the crude distillation obtained by the distillation.
- the apparatus further includes one or more feed tanks coupled to the main reactor.
- the apparatus further comprises: a first condenser located between the main reactor and the rectification column, a second condenser and a third condenser located between the crude distillation tank and the rectification column .
- Figure 1 Hydrogen spectrum nuclear magnetic map confirmed by structure of phenethyl isothiocyanate
- FIG. 2-1 HPLC chromatogram (208nn) of purity check of phenethyl isothiocyanate
- Figure 2-2 HPLC chromatogram of the purity check of phenethyl isothiocyanate (244nn);
- Figure 7 Flow chart of industrial production equipment.
- the inventors have conducted a long-term and intensive study to provide a one-pot method for preparing isothiocyanates.
- the method of the invention is safe, simple, environmentally friendly, and can realize industrial production.
- the method of the invention is simple to treat after purification, and the obtained product of the isothiocyanate compound has high purity and can meet the demand of the medicine. Based on the above findings, the inventors completed the present invention.
- the invention provides a preparation method of an isothiocyanate compound, the method comprising the steps of:
- A is -XR 1 or -CR 2 R 3 R 4 , wherein
- X is -(CH 2 ) n -, and n is an integer from 0 to 6;
- R 1 is selected from the group consisting of methyl, tert-butyl, isopropyl, methylthio, methoxy, allyl, methallyl, cyclohexyl, methylsulfinyl, naphthyl, methyl Cyclohexyl, morpholinyl, diethylamino, benzoyl, ethoxycarbonyl, tert-octyl, chlorine atom, trimethylsilyl, substituted or unsubstituted phenyl;
- substituted means that one or more H groups in the group are substituted with a substituent selected from the group consisting of a halogen atom, a methyl group, a bromomethyl group, an ethyl group, a methoxy group, a nitro group, an azide group. , trifluoromethyl, difluoromethoxy, methylthio, cyano, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, ethoxycarbonyl;
- R 2 , R 3 and R 4 are each independently H, phenyl or C 1-3 alkyl.
- the solvent system is not particularly limited, and a solvent capable of dissolving phenethylamine and dithiocarbamate and being immiscible with water may be used.
- a solvent capable of dissolving phenethylamine and dithiocarbamate and being immiscible with water may be used.
- Solvents such as diethyl ether, petroleum ether, and cyclohexane are used to reduce the generation of specific impurities and increase the reaction rate, thereby reducing the difficulty of post-treatment.
- the kind of the reactant is not particularly limited, and the preferred organic base is selected from the group consisting of triethylamine, trimethylamine, diisopropylethylamine, and triethylene glycol.
- the desulfurizing agent is selected from the group consisting of chlorine Methyl formate, p-toluenesulfonyl chloride, solid phosgene, elemental iodine, chlorosilane, chlorophosphate, dicyclohexylcarbodiimide, dicyandiamide, triphenylphosphine, di-tert-butyl dicarbonate, tripolychloride Cyanide, or a combination thereof; more preferably di-tert-butyl dicarbonate.
- the desulfurizing agent is preferably used in an amount of from 1:0.9 to 5, preferably from 1:0.92 to 2, more preferably from 1:0.95 to 1.5.
- the carbon disulfide is in excess relative to ANH 2 during the reaction of step (1).
- the preferred temperature of each step is not particularly limited, and a suitable reaction temperature may be employed depending on the actual reaction system.
- a series of post-treatments including pickling, washing with saturated brine, drying, solvent evaporation, distillation under reduced pressure, and the like are carried out in consideration of the formation of a part of by-products in the reaction.
- the solvent used in the post treatment is the same as the solvent used in the reaction.
- the post-treatment purification method comprises the steps of:
- the crude acid-washed product is subjected to vacuum distillation to obtain a crude distillation product containing isothiocyanate;
- the crude distillation product was subjected to vacuum distillation to obtain a pure isothiocyanate product.
- each post-purification treatment step can be designed according to the reaction scale actually used, the reaction raw material, and the like, wherein in the vacuum distillation process, it is preferred to use different reflux ratios for the front, middle and rear fractions.
- the front fraction reflux ratio is from 99:1 to 1:99 (preferably from 99:1 to 50:50, more preferably from 90:10 to 70:30); the reflux ratio of the middle fraction It is from 99:1 to 1:99 (preferably from 90:10 to 10:90, more preferably from 70:30 to 30:70); the reflux ratio of the post-fraction is from 99:1 to 1:99 (preferably from 99:1 to 50:50). More preferably, it is 90:10 to 70:30).
- the purified product finally prepared may have a purity of more than 99.7% (yield 80%).
- the former fraction in the rectification process refers to the first stage fraction from the start of the fraction receiving, and the receiving amount is 0% to 30% (preferably 0% to 20%, more preferably 5% to 10%) of the substrate;
- the middle fraction in the rectification process refers to the second fraction after the completion of the reception of the former fraction, and the receiving amount is 40% to 100% (preferably 60% to 100%, more preferably 80% to 90%) of the substrate;
- the post-fraction in the rectification process refers to the third fraction after completion of the reception of the previous fraction, and the amount received is from 0% to 30% (preferably from 0% to 20%, more preferably from 5% to 10%) of the substrate.
- the invention adopts one-pot method to prepare isothiocyanate, and the raw materials required for the reaction are cheap and easy to obtain, and a better reaction method is found, the reaction conversion rate is high, the condition is mild, the operation is convenient, the purification is easy, and the environment is friendly;
- the invention adopts a solvent represented by ethyl acetate, has low toxicity, high safety, and does not use any other organic solvent in the reaction process, thereby realizing steps of reaction, separation and purification, and greatly reducing the organic solvent.
- the invention adopts a purification method of pickling, distillation and rectification to obtain a high-purity isothiocyanate compound, and the product purity is more than 99.6%.
- Column chromatography is generally used in literature or patents, and a large amount of organic solvent is required, and the steps are cumbersome.
- the purification method of the present invention greatly reduces the use of organic solvents, simplifies the operation steps, and is easier to realize industrial production.
- the purity of the isothiocyanate prepared by the invention is greater than 99.6%, which can meet the demand of medicine.
- the crude product was pickled, placed in a flask, heated by a heating mantle, and a rotary vane vacuum pump, and a fraction of 130 ° C to 145 ° C / 10 mmHg was collected to obtain a crude product.
- the crude distillation is placed in a rectification tank, and the distillation column specifications Stainless steel sit ring Filler, model 2X-8A rotary vane vacuum pump, pot temperature 160-200 ° C, after full reflux for 0.5 h, collect 95 ° C ⁇ 110 ° C / 200 ⁇ 600 pa fraction.
- the former fraction has a reflux ratio of 90:10; after 0.5 hours, the reflux ratio is 50:50, and the middle fraction is collected; finally, the reflux ratio is 70:30, and the fraction is collected to obtain a phenethyl isothiocyanate product (yield 85%). , for identification and purity check.
- the mobile phase was gradient 0 min 40% acetonitrile, 15 min 62.5% acetonitrile, 23 min 100% acetonitrile, 25 min 100% acetonitrile, 25.1 min 40% acetonitrile, 30 min 40% acetonitrile
- Sample configuration take 15mg of phenethyl isothiocyanate product, accurately weighed, placed in a 25ml volumetric flask, acetonitrile dissolved to volume, filtered injection;
- Embodiment 7 Industrial production equipment flow chart
- the flow chart of the apparatus for industrial production is detailed in Fig. 7, wherein the apparatus mainly comprises a main reaction tank, a crude distillation tank located downstream of the main reaction tank, and a rectification column.
- the main reaction kettle is used to carry out a main reaction, an acidic water washing reaction and a concentration operation, and the apparatus further comprises a first condensation and receiving device connected to the upper portion of the main reaction vessel.
- the crude distillation vessel is used to distill the concentrated product to obtain a crude distillation product.
- the crude distillation passes through the second condensation and receiving unit and enters the evaporator and the rectification column from the tail end.
- the rectification column is used for rectifying the crude distillation obtained by the distillation.
- the apparatus also includes one or more feed tanks connected to the main reactor, upstream of the main reactor.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法,具体地,所述的方法用有机胺和CS2作为原料,制备得到硫代氨基甲酸盐,然后进行脱硫,经过纯化后处理等方法得到纯度极高的异硫氰酸酯化合物。本发明方法适合工业化生产,后处理简单,收率高且所得产物纯度高,适用于医药工业生产异硫氰酸酯类化合物。
Description
本发明涉及一种可工业化生产的高纯度异硫氰酸酯类化合物的制备和纯化方法。
异硫氰酸酯在天然产品和药物活性化合物中是一种很重要的功能物质,是一类具有R-N=C=S结构通式的化合物,是一类重要的有机合成中问体,在选矿、医药、农药和染料等方面有着广泛应用。在医药上用于抗菌消炎及癌症疾病的预防治疗;在农业上可作为抗菌剂、杀虫剂、除草剂等。此外,异硫氰酸酯也可参与多种有机反应,用于合成多种类型的含硫、氮、氧的化合物,特别是杂环化合物,并广泛用于农药、医药、染料等有机合成品的制备。也可以用于测定肽和蛋白质中氨基酸顺序以及作为荧光素标记物。
国内外对异硫氰酸酯的药物活性方面研究非常活跃,其有很好的药用前景。含异硫氰酸酯类化合物的十字花科蔬菜,在癌症化学预防中的应用研究已经持续了四十年。覆盖肺癌、乳腺癌、前列腺癌、膀胱癌、胃癌、结直肠癌和肾癌等的20多项流行病学研究报告表明,含异硫氰酸酯类化合物的十字花科蔬菜的摄入量与多种癌症患病率的风险负相关。目前,异硫氰酸酯类化合物用于健康人肺癌预防、前列腺增生和口腔癌方面的应用已经被美国或中国批准进入临床阶段。
因此异硫氰酸酯类化合物的制备,尤其是高纯度的、符合药用标准的,并可工业化生产的制备方法的开发尤为迫切。目前已报道的异硫氰酸酯合成方法众多,有光气法、硫光气法、二硫化碳法、二(三氯甲基)碳酸酯法、硫脲分解法、硫代氯甲酸苯酯法和硫氰酸盐法等。其中运用广泛的有:
光气路线:Hodgkius等报道,将苯乙胺和二硫化碳溶于有机溶剂,在碱存在下通入光气,生成苯乙基异硫氰酸酯。这里的光气也可以用光气的替代品,如氯甲酸乙酯、双光气、三光气等代替。但这一反应过程仍然不能避免光气的生成,易污染环境,并存在较大的安全隐患。
硫光气路线:由硫代光气和胺类化合物直接反应生产异硫氰酸酯。该路线使用广泛,反应迅速,用硫光气代替光气,提高了安全性,但硫光气是具有毒性的易挥发液体,环境危害大,生产和运输都不安全,此路线不利于大规模的工业生产;
异腈路线:在金属催化剂的存在下,由异腈和硫粉或硫化剂合成异硫氰酸酯。该路线的主要问题在于异腈的合成和提纯难度很大,而且异腈本身也是一种剧毒物,不能用于工业化大生产。
硫氰酸盐路线:由卤代烃和硫氰酸盐反应生产异硫氰酸酯。该路线收率较低,操作繁琐。
二硫化碳路线:该法是将苯乙胺(或其它胺类有机物)和二硫化碳等原料溶于有机溶剂,在碱的催化下合成胺基二硫代甲酸盐,再在脱硫剂作用下,反应得到异硫氰酸酯类化合物。关于脱硫剂的选择,研究很多,主要有氯甲酸甲酯、对甲苯磺酰氯、固体光气、单质碘、氯硅烷、氯磷酸酯或二环己基碳二亚胺等。此方法的优点在于避免使用剧毒原料,遗憾的是所得产品的杂质较多,纯度低,多通过硅胶层析柱进行纯化,操作繁琐,试剂用量大,较适合实验级别反应,而工业化生产则不适用。
鉴于此,迫切需要开发一种安全、简便、环境友好并可实现工业化生产的异硫氰酸酯类化合物的制备和纯化方法,生产出高纯度、高质量的异硫氰酸酯类化合物,满足日益增长的药用需求和工业化生产需求。
发明内容
本发明的目的是提供一种安全、简便、环境友好并可实现工业化生产的异硫氰酸酯类化合物的制备和纯化方法。
本发明的第一方面,提供了一种式(I)所示的异硫氰酸酯化合物的制备方法,
A-N=C=S (I)
在式I中:
-N=C=S为异硫氰酸酯基;
A为-XR
1或-CR
2R
3R
4,其中
X为-(CH
2)
n-,n为0-6的整数;
R
1选自下组:甲基、叔丁基、异丙基、甲硫基、甲氧基、烯丙基、甲代烯丙基、环己基、甲基亚硫酰基、萘基、甲基环己基、吗啉基、二乙基氨基、苯甲酰基、乙氧基羰基、叔辛基、氯原子、三甲基硅基、取代或未取代的苯基;
其中,所述的“取代”指基团中一个或多个H被选自下组的取代基所取代:卤素原子、甲基、溴甲基、乙基、甲氧基、硝基、叠氮基、三氟甲基、二氟甲氧基、甲硫基、氰基、三氟甲氧基、三氟甲硫基、叔丁氧基羰基、乙氧基羰基;
R
2、R
3、R
4各自独立地为H、苯基或C
1-3烷基;
其特征在于,所述方法包括步骤:
A-NH
2→二硫代氨基甲酸盐→A-N=C=S(I)
(1)在有机溶剂中,在有机碱存在下,用ANH
2与CS
2反应,得到含有二硫代氨基甲酸盐的第一反应混合物;
(2)在任选的碱催化剂存在下,在所述的第一反应混合物中加入脱硫剂进行脱硫反应,得到含有异硫氰酸酯化合物的第二反应混合物;
(3)对所述的第二反应混合物进行后处理纯化,得到式(I)所示的异硫氰酸酯。
在另一优选例中,所述的步骤(1)中包括:将ANH
2滴加入添加有CS
2的反应体系中进行反应。
在另一优选例中,所述的步骤(1)中,所述的有机溶剂为能够溶解苯乙胺和二硫代氨基甲酸盐且与水不互溶的溶剂;优选地,所述的有机溶剂选自下组:乙酸乙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、乙酸丁酯、乙酸异丁酯、丙酸戊酯、丁醇、异丁醇、戊醇、仲戊醇、叔戊醇、3-甲基-2-丁醇、己醇、庚醇、二氯甲烷、二氯乙烷、三氯甲烷、乙醚、石油醚、环己烷,或其组合。
在另一优选例中,所述的步骤(1)中,所述的有机碱选自下组:三乙胺、三甲胺、二异丙基乙胺、三乙烯二胺、吡啶、4-N,N-二甲基吡啶、叔丁醇钾、甲醇钠、乙醇钠,羟胺,3-甲基吡啶,吡咯,或其组合。
在另一优选例中,所述的步骤(2)中,所述的脱硫剂选自下组:氯甲酸甲酯、对甲苯磺酰氯、固体光气、单质碘、氯硅烷、氯磷酸酯、二环己基碳二亚胺、双氰胺、三苯基膦、二碳酸二叔丁酯、三聚氯氰,或其组合。
在另一优选例中,所述的步骤(2)中,所述的碱催化剂选自下组:三乙胺、三乙烯二胺、吡啶、4-二甲氨基吡啶,或其组合。
在另一优选例中,所述的步骤(1)中,有机胺和三乙胺投入乙酸乙酯溶剂中,控制混合液温度T1,缓慢滴加二硫化碳/乙酸乙酯混合液,边滴加边搅拌,控制反应液温度T2,滴加完毕后,控制温度T3,搅拌反应0.5-2h。
在另一优选例中,所述的步骤(1)中的温度T1为0℃~30℃,较优0℃~20℃,更优0℃~5℃;温度T2为0℃~40℃,较优0℃~30℃,更优10℃~25℃;温度T3为0℃~40℃,较优10℃~30℃;
在另一优选例中,所述的步骤(2)中包括,控制温度T4,往反应液中加入脱硫剂和碱催化剂,在温度T5下搅拌反应,反应1-4h结束。
所述的第二步反应中,温度T4为0℃~30℃,较佳地为0℃~20℃;温度T5为0℃~50℃,较佳地10℃~30℃,更佳地20℃~30℃。
在另一优选例中,所述的步骤(1)中,ANH
2与二硫化碳投料比为1:1.0~10,较佳地为1:1.0~5,更佳地为1:1.05~2;
所述的ANH
2与有机碱投料比为1:0.5~5,较优1:0.8~3,更优1:0.9~2;所述的ANH
2与乙酸乙酯的质量体积比为10~25%;
在另一优选例中,所述的步骤(2)中,第一步投料的ANH
2与脱硫剂的投料比为1:0.9~5,较佳地为1:0.9~2,更佳地为1:0.95~1.5;
碱催化剂与第一步投料的ANH
2投料的质量比为0~4wt%,较佳地为0.01~2wt%,更佳地为0.05~1wt%。
在另一优选例中,所述的步骤(3)中,所述的后处理纯化方法包括步骤:
对所述的第二反应混合物进行洗涤后,浓缩得酸洗粗品;
对所述的酸洗粗品进行蒸馏,得含有异硫氰酸酯的蒸馏粗品;优选地,所述的蒸馏为减压蒸馏;
对所述的蒸馏粗品进行减压精馏,得异硫氰酸酯纯品。
在另一优选例中,所述的洗涤步骤包括:使用酸溶液进行洗涤,其中,所述的酸溶液中的酸总量与步骤(1)中有机碱投料量摩尔比为0.8~5:1,优选0.9~2:1,更优选1~1.5:1(以一元酸和一元碱计算)。
在另一优选例中,每次洗涤时,洗涤液体积为有机相体积的20-100%,优选25-50%。
在另一优选例中,所述的后处理纯化中,浓缩的温度为30℃~90℃,优选35℃~60℃;
在另一优选例中,所述的后处理纯化中包括:按照不同异硫氰酸酯的沸点收集相应的异硫氰酸酯馏分。
在另一优选例中,所述的后处理纯化中,减压蒸馏和减压精馏的压力为10-1000pa,优选10-500pa。
在另一优选例中,所述的后处理纯化包括选自下组的一个或多个特征:
所述的减压精馏为连续精馏或间歇性精馏,优选间歇性精馏;
所述的精馏柱采用规整填料或散堆填料,优选地,所述的规整填料选自下组:波纹类填料、格栅类填料;所述的散堆填料选自下组:鲍尔环、拉西环、扁环、阶梯环、矩鞍环、八字环、共轭环、泰勒花环、埃派克环、狄克松环、压延孔环、 三角螺旋环、球形填料,或其组合;或
所述后处理纯化中,精馏填料材质选自下组:不锈钢、塑料、玻璃、陶瓷,或其组合;优选地,所述的精馏填料材质选自下组:不锈钢、陶瓷,或其组合。
在另一优选例中,所述减压精馏过程中,前馏分回流比为99:1~1:99(优选99:1~50:50,更优选90:10~70:30);
中馏分回流比为99:1~1:99(优选90:10~10:90,更优选70:30~30:70);
后馏分回流比为99:1~1:99(优选99:1~50:50,更优选90:10~70:30)。
在另一优选例中,所述后处理纯化中,蒸馏粗品纯度大于95%,优选大于97%;精馏纯品的纯度大于99.0%,优选大于99.6%。
在另一优选例中,所述的后处理纯化方法包括步骤:反应液用盐酸溶液洗涤,重复2次,取有机相用饱和食盐水,重复洗涤至中性(pH6-7),有机相用无水硫酸钠干燥后,过滤,滤液减压旋转蒸发,浓缩得酸洗粗品;酸洗粗品,采用旋片式真空泵或真空机组,进行减压蒸馏,收集异硫氰酸酯馏分,得蒸馏粗品;蒸馏粗品,采用二级旋片式真空泵或真空机组,进行减压精馏,开始全回流,稳定后,设定合适的回流比,收集异硫氰酸酯纯品。
本发明的第二方面,提供了一种异硫氰酸酯类化合物生产装置,所述装置包括:
主反应釜,所述的主反应釜用于进行主反应、酸性水洗反应和浓缩操作;
位于所述主反应釜下游的粗蒸釜,所述的粗蒸釜用于对浓缩产物进行蒸馏;
精馏塔,所述的精馏塔用于对所述蒸馏得到的蒸馏粗品进行精馏。
在另一优选例中,所述的装置还包括与主反应釜相连的一个或多个投料罐。
在另一优选例中,所述的装置还包括:位于主反应釜和精馏塔之间的第一冷凝器,位于粗蒸釜和精馏塔之间的第二冷凝器和第三冷凝器。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
图1:苯乙基异硫氰酸酯结构确认的氢谱核磁图;
图2-1:苯乙基异硫氰酸酯纯度检查的HPLC色谱图(208nn);
图2-2:苯乙基异硫氰酸酯纯度检查的HPLC色谱图(244nn);
图3:烯丙基异硫氰酸酯结构确认的氢谱核磁图;
图4:甲氧基异硫氰酸酯结构确认的氢谱核磁图;
图5:4-氯苄基异硫氰酸酯结构确认的氢谱核磁图;
图6:乙基异硫氰酸酯结构确认的氢谱核磁图;
图7:工业生产设备流程图。
本发明人经过长期而深入的研究,提供了一种一锅法制备异硫氰酸酯的方法。本发明方法安全、简便、环境友好,并可实现工业化生产。且本发明方法纯化后处理简单,得到的终产物异硫氰酸酯类化合物的产物纯度高,可以满足医药需求。基于上述发现,发明人完成了本发明。
异硫氰酸酯化合物的制备
本发明提供了一种异硫氰酸酯化合物的制备方法,所述方法包括步骤:
在式I中:
N=C=S为异硫氰酸酯基;
A为-XR
1或-CR
2R
3R
4,其中
X为-(CH
2)
n-,n为0-6的整数;
R
1选自下组:甲基、叔丁基、异丙基、甲硫基、甲氧基、烯丙基、甲代烯丙基、环己基、甲基亚硫酰基、萘基、甲基环己基、吗啉基、二乙基氨基、苯甲酰基、乙氧基羰基、叔辛基、氯原子、三甲基硅基、取代或未取代的苯基;
其中,所述的“取代”指基团中一个或多个H被选自下组的取代基所取代:卤素原子、甲基、溴甲基、乙基、甲氧基、硝基、叠氮基、三氟甲基、二氟甲氧基、甲硫基、氰基、三氟甲氧基、三氟甲硫基、叔丁氧基羰基、乙氧基羰基;
R
2、R
3、R
4各自独立地为H、苯基或C
1-3烷基。
(1)在有机溶剂中,在有机碱存在下,用ANH
2与CS
2反应,得到含有二硫代氨基甲酸盐的第一反应混合物;
(2)在碱催化剂存在下,在所述的第一反应混合物中加入脱硫剂进行脱硫反应,得到含有异硫氰酸酯化合物的第二反应混合物;
(3)对所述的第二反应混合物进行后处理纯化,得到式(I)所示的异硫氰酸酯。
在步骤(1)中,溶剂体系没有特别的限制,可以采用能够溶解苯乙胺和二硫代氨基甲酸盐且与水不互溶的溶剂。优选可以采用例如乙酸乙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、乙酸丁酯、乙酸异丁酯、丙酸戊酯、二氯甲烷、二氯乙烷、三氯甲烷、乙醚、石油醚、环己烷等溶剂,以便减少特定杂质的产生并提高反应率,降低后处理难度。
所述的反应中,反应物(有机碱,脱硫剂)种类没有特别的限制,优选的所述的有机碱选自下组:三乙胺、三甲胺、二异丙基乙胺、三乙烯二胺、吡啶、4-N,N-二甲基吡啶、叔丁醇钾、甲醇钠、乙醇钠,或其组合;更优选地为三乙胺;优选的所述脱硫剂选自下组:氯甲酸甲酯、对甲苯磺酰氯、固体光气、单质碘、氯硅烷、氯磷酸酯、二环己基碳二亚胺、双氰胺、三苯基膦、二碳酸二叔丁酯、三聚氯氰,或其组合;更优选地为二碳酸二叔丁酯。
在反应过程中,各反应物的投料比可以根据实际情况进行设计,综合考虑收率、含量、纯度和有关物质等指标,有机碱投料比优选为ANH
2:有机碱=1:0.5~5,较优选1:0.8~3,更优选1:0.9~2;二硫化碳投料比优选为ANH
2:二硫化碳=1:1.0~10,较佳地为1:1.0~5,更佳地为1:1.05~2。
在步骤(2)中,脱硫剂的用量优选为1:0.9~5,较佳地为1:0.92~2,更佳地为1:0.95~1.5。
在本发明的一种优选情况下,在步骤(1)的反应过程中,二硫化碳相对于ANH
2是过量的。
所述反应中,各步骤的优选温度没有特别的限制,可以根据实际反应体系采用合适的反应温度。
反应结束后,考虑到反应中有一部分副产物生成,进行一系列的后处理,包括酸洗、饱和食盐水洗、干燥、旋蒸溶剂、减压蒸馏等。优选地,后处理采用的溶剂和反应中采用的反应溶剂是同一种。
在本发明的优选实施例中,所述的后处理纯化方法包括步骤:
对所述的第二反应混合物进行洗涤后,浓缩得酸洗粗品;
对所述的酸洗粗品进行减压蒸馏,得含有异硫氰酸酯的蒸馏粗品;
对所述的蒸馏粗品进行减压精馏,得异硫氰酸酯纯品。
各纯化后处理步骤的条件可以根据实际使用的反应规模,反应原料等进行设计,其中,所述的减压精馏过程中,优选地对前、中、后馏分采用不同的回流比。 在本发明的一个优选实施例中,所述的前馏分回流比为99:1~1:99(优选99:1~50:50,更优选90:10~70:30);中馏分回流比为99:1~1:99(优选90:10~10:90,更优选70:30~30:70);后馏分回流比为99:1~1:99(优选99:1~50:50,更优选90:10~70:30)。最终制备得到的精制产品纯度可大于99.7%(收率80%)。
所述精馏过程中的前馏分指从馏分接收开始起的第一段馏分,接收量为底物的0%~30%(优选0%~20%,更优选5%~10%);
所述精馏过程中的中馏分指从前馏分接收完成后第二段馏分,接收量为底物的40%~100%(优选60%~100%,更优选80%~90%);
所述精馏过程中的后馏分指从前馏分接收完成后第三段馏分,接收量为底物的0%~30%(优选0%~20%,更优选5%~10%)。
与现有技术相比,本发明的优点主要体现在:
1)本发明采用一锅法制备异硫氰酸酯,反应所需原料价廉易得,摸索出较佳的反应方法,反应转化率高,条件温和,操作方便,易于纯化,环境友好;
2)本发明采用以乙酸乙酯为代表的溶剂,毒性低,安全性高,且反应过程中没有使用任何其他的有机溶剂,就实现了反应、分离和纯化等步骤,大大减少了有机溶剂的使用,尤其是避免了低沸点、高挥发性溶剂的使用,提高生产的安全性和减少环境污染,非常利于工业化生产;
3)本发明采用酸洗、蒸馏、精馏的纯化方法,制得高纯度的异硫氰酸酯类化合物,产品纯度大于99.6%。文献或专利中一般采用柱层析法,需要使用大量有机溶剂,步骤繁琐,本发明的纯化方法大大减少了有机溶剂的使用,简化操作步骤,更易实现工业化生产。
4)本发明制备的异硫氰酸酯纯度大于99.6%,可以满足医药需求。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1苯乙基异硫氰酸酯的制备
取300.0g苯乙胺(2.48mol)和350.6g三乙胺(3.46mol)置于5000mL三口圆底烧瓶中,加入1000mL乙酸乙酯,置冰浴冷却并用机械搅拌。当混合液温度降至0℃~5℃时,用恒压滴液漏斗缓慢滴加339.2g二硫化碳(4.45mol),边滴加边磁力搅拌,控制反应液温度在30℃以下。滴加完毕后,室温(10-30度范围)磁力搅拌一小时;在此温度下,向反应液中加入535.1g BOC
2O(2.45mol)和DMAP催化剂,在30±2.5℃搅拌反应1.5h。反应结束后,反应液用酸溶液洗涤2次,洗涤消耗的总酸量为三乙胺的1.5倍,再用饱和食盐水洗涤至中性。有机相旋蒸浓缩,得酸洗粗品。
酸洗粗品,置于烧瓶中,电热套加热,旋片式真空泵,收集130℃~145℃/10mmHg之馏份,得蒸馏粗品。
蒸馏粗品置于精馏釜中,精馏塔规格
不锈钢西塔环
填料,型号2X-8A型旋片式真空泵,釜温160-200℃,全回流0.5h后,收集95℃~110℃/200~600pa的馏分。前馏分,回流比90:10;0.5h后回流比为50:50,收集中馏分;最后回流比70:30,收集后馏分,得苯乙基异硫氰酸酯产品(收率85%),进行鉴定和纯度检查。
实施例2苯乙基异硫氰酸酯结构和纯度检查
1.结构鉴定-H谱结果及图谱
核磁检测结果如下,与我们的目标产物相同。
1H NMR(400MHz,CDCl
3)δ7.37–7.31(m,1H),7.28(ddd,J=10.2,5.0,2.1Hz,1H),7.23–7.19(m,1H),3.72(t,J=7.0Hz,1H),2.99(t,J=7.0Hz,1H).
核磁检测见附图1。
2.苯乙基异硫氰酸酯纯度检测
仪器条件:Dionex U3000,C18键合硅胶柱,208/244nm,1.0ml/min,柱温30度,进样10ul,分析时长30min;
流动相为梯度0min 40%乙腈、15min 62.5%乙腈、23min 100%乙腈、25min100%乙腈、25.1min40%乙腈、30min40%乙腈
样品配置:取苯乙基异硫氰酸酯产品15mg,精密称定,置25ml量瓶中,乙腈溶解定容至刻度,过滤进样;
结果:
色谱图见附图2-1和附图2-2。
实施例3烯丙基异硫氰酸酯的制备
取300.0g烯丙基胺(5.25mol),743.0g三乙胺(7.34mol),718.9g CS
2(9.45mol),1134.1g BOC酸酐(5.20mol)和0.18g DMAP(烯丙基胺量的0.06%)和1800ml乙酸乙酯,按照实施例1中的方法进行反应和后处理纯化,并最终得到纯品。结构确认见附图3。
实施例4 4-甲氧基苄基异硫氰酸酯的制备
取300.0g4-甲氧基苄胺(2.19mol),309.2g三乙胺(3.06mol),299.2gCS
2(3.93mol),471.9gBOC酸酐(2.16mol)和0.18gDMAP(烯丙基胺量的0.06%)和1000ml乙酸乙酯,按照实施例1中的方法进行反应和后处理纯化,并最终得到纯品。结构确认见附图4。
实施例5 4-氯苄基异硫氰酸酯的制备
取300.0g 4-氯苄胺(2.12mol),299.6g三乙胺(2.96mol),289.8gCS
2(3.81mol),457.2gBOC酸酐(2.10mol)和0.18gDMAP(烯丙基胺量的0.06%)和900ml乙酸乙酯,按照实施例1中的方法进行反应和后处理纯化,并最终得到纯品。结构确认见附图5。
实施例6乙基异硫氰酸酯的制备
取300.0g乙胺(6.65mol),940.9g三乙胺(9.30mol),910.4gCS
2(11.96mol),1436.2gBOC酸酐(6.58mol)和0.18gDMAP(烯丙基胺量的0.06%)和2300ml乙酸乙酯,按照实施例1中的方法进行反应和后处理纯化,并最终得到纯品。结构确认见附图6。
实施例7工业生产设备流程图
用于工业生产的设备流程图详见附图7,其中,所述的装置主要包括主反应釜、位于所述主反应釜下游的粗蒸釜、和精馏塔。
所述的主反应釜用于进行主反应、酸性水洗反应和浓缩操作,所述的装置还包括第一冷凝与接收装置,所述装置与主反应釜上部相连。
所述的粗蒸釜用于对浓缩产物进行蒸馏,得到蒸馏粗品。蒸馏粗品通过第二冷凝与接收装置后,由尾端进入蒸发器和精馏塔中。所述的精馏塔用于对所述蒸馏得到的蒸馏粗品进行精馏。
所述的装置还包括与主反应釜相连,位于主反应釜上游的一个或多个投料罐。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
- 一种式(I)所示的异硫氰酸酯化合物的制备方法,A-N=C=S (I)在式I中:-N=C=S为异硫氰酸酯基;A为-XR 1或-CR 2R 3R 4,其中X为-(CH 2) n-,n为0-6的整数;R 1选自下组:甲基、叔丁基、异丙基、甲硫基、甲氧基、烯丙基、甲代烯丙基、环己基、甲基亚硫酰基、萘基、甲基环己基、吗啉基、二乙基氨基、苯甲酰基、乙氧基羰基、叔辛基、氯原子、三甲基硅基、取代或未取代的苯基;其中,所述的“取代”指基团中一个或多个H被选自下组的取代基所取代:卤素原子、甲基、溴甲基、乙基、甲氧基、硝基、叠氮基、三氟甲基、二氟甲氧基、甲硫基、氰基、三氟甲氧基、三氟甲硫基、叔丁氧基羰基、乙氧基羰基;R 2、R 3、R 4各自独立地为H、苯基或C 1-3烷基;其特征在于,所述方法包括步骤:A-NH 2→二硫代氨基甲酸盐→A-N=C=S(I)(1)在有机溶剂中,在有机碱存在下,用ANH 2与CS 2反应,得到含有二硫代氨基甲酸盐的第一反应混合物;(2)在任选的碱催化剂存在下,在所述的第一反应混合物中加入脱硫剂进行脱硫反应,得到含有异硫氰酸酯化合物的第二反应混合物;(3)对所述的第二反应混合物进行后处理纯化,得到式(I)所示的异硫氰酸酯。
- 如权利要求1所述的方法,其特征在于,所述的步骤(1)中,所述的有机溶剂为能够溶解苯乙胺和二硫代氨基甲酸盐且与水不互溶的溶剂;优选地,所述的有机溶剂选自下组:乙酸乙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、乙酸丁酯、乙酸异丁酯、丙酸戊酯、丁醇、异丁醇、戊醇、仲戊醇、叔戊醇、3-甲基-2-丁醇、己醇、庚醇、二氯甲烷、二氯乙烷、三氯甲烷、乙醚、石油醚、环己烷,或其组合。
- 如权利要求1所述的方法,其特征在于,所述的步骤(1)中,所述的有机碱选自下组:三乙胺、三甲胺、二异丙基乙胺、三乙烯二胺、吡啶、4-N,N-二甲基吡啶、叔丁醇钾、甲醇钠、乙醇钠,羟胺,3-甲基吡啶,吡咯,或其组合。
- 如权利要求1所述的方法,其特征在于,所述的步骤(2)中,所述的脱硫剂选自下组:氯甲酸甲酯、对甲苯磺酰氯、固体光气、单质碘、氯硅烷、氯磷酸酯、二环己基碳二亚胺、双氰胺、三苯基膦、二碳酸二叔丁酯、三聚氯氰,或其组合。
- 如权利要求1所述的方法,其特征在于,所述的步骤(2)中,所述的碱催化剂选自下组:三乙胺、三乙烯二胺、吡啶、4-二甲氨基吡啶,或其组合。
- 如权利要求1所述的方法,其特征在于,所述的步骤(1)中,ANH 2与二硫化碳投料比为1:1.0~10,较佳地为1:1.0~5,更佳地为1:1.05~2;所述的ANH 2与有机碱投料比为1:0.5~5,较优1:0.8~3,更优1:0.9~2;所述的ANH 2与乙酸乙酯的质量体积比为10~25%;所述的步骤(2)中,第一步投料的ANH 2与脱硫剂的投料比为1:0.9~5,较佳地为1:0.9~2,更佳地为1:0.95~1.5;和/或碱催化剂与第一步投料的ANH 2投料的质量比为0~4wt%,较佳地为0.01~2wt%,更佳地为0.05~1wt%。
- 如权利要求1所述的方法,其特征在于,所述的步骤(3)中,所述的后处理纯化方法包括步骤:对所述的第二反应混合物进行洗涤后,浓缩得酸洗粗品;对所述的酸洗粗品进行蒸馏,得含有异硫氰酸酯的蒸馏粗品;优选地,所述的蒸馏为减压蒸馏;对所述的蒸馏粗品进行减压精馏,得异硫氰酸酯纯品;优选地,所述的洗涤步骤包括:使用酸溶液进行洗涤,其中,所述的酸溶液中的酸总量与步骤(1)中有机碱投料量摩尔比为0.8~5:1,优选0.9~2:1,更优选1~1.5:1(以一元酸和一元碱计算)。
- 如权利要求7所述的方法,其特征在于,所述的后处理纯化包括选自下组的一个或多个特征:所述的减压精馏为连续精馏或间歇性精馏,优选间歇性精馏;所述的精馏柱采用规整填料或散堆填料,优选地,所述的规整填料选自下组:波纹类填料、格栅类填料;所述的散堆填料选自下组:鲍尔环、拉西环、扁环、阶梯环、矩鞍环、八字环、共轭环、泰勒花环、埃派克环、狄克松环、压延孔环、三角螺旋环、球形填料,或其组合;或所述后处理纯化中,精馏填料材质选自下组:不锈钢、塑料、玻璃、陶瓷, 或其组合;优选地,所述的精馏填料材质选自下组:不锈钢、陶瓷,或其组合。
- 如权利要求7所述的方法,其特征在于,所述减压精馏过程中,前馏分回流比为99:1~1:99(优选99:1~50:50,更优选90:10~70:30);中馏分回流比为99:1~1:99(优选90:10~10:90,更优选70:30~30:70);后馏分回流比为99:1~1:99(优选99:1~50:50,更优选90:10~70:30)。
- 一种异硫氰酸酯类化合物生产装置,其特征在于,所述装置包括:主反应釜,所述的主反应釜用于进行主反应、酸性水洗反应和浓缩操作;位于所述主反应釜下游的粗蒸釜,所述的粗蒸釜用于对浓缩产物进行蒸馏;精馏塔,所述的精馏塔用于对所述蒸馏得到的蒸馏粗品进行精馏。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/489,226 US11897838B2 (en) | 2017-02-27 | 2018-02-27 | High-purity isothiocyanate compound preparation method for industrial production |
EP18756601.3A EP3611163B1 (en) | 2017-02-27 | 2018-02-27 | High-purity isothiocyanate compound preparation method for industrial production |
CN201880014423.5A CN110446697A (zh) | 2017-02-27 | 2018-02-27 | 一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710108328.9A CN108503568A (zh) | 2017-02-27 | 2017-02-27 | 一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 |
CN201710108328.9 | 2017-02-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2018153381A1 true WO2018153381A1 (zh) | 2018-08-30 |
WO2018153381A9 WO2018153381A9 (zh) | 2018-10-11 |
Family
ID=63252414
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2018/077443 WO2018153381A1 (zh) | 2017-02-27 | 2018-02-27 | 一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US11897838B2 (zh) |
EP (1) | EP3611163B1 (zh) |
CN (2) | CN108503568A (zh) |
WO (1) | WO2018153381A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114644582A (zh) * | 2022-04-11 | 2022-06-21 | 中原工学院 | 一种苯基双硫脲类化合物的制备方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112158851B (zh) * | 2020-09-30 | 2023-03-03 | 武汉工程大学 | 一种异硫氰基功能化的二氧化硅材料的制备方法 |
CN113754572A (zh) * | 2021-09-02 | 2021-12-07 | 无锡杰西医药股份有限公司 | 高质量的苯乙基异硫氰酸酯的制备方法 |
CN116396196B (zh) * | 2023-03-15 | 2024-04-23 | 华南理工大学 | 一种一锅制备酰胺基异硫氰酸酯/酰胺基硫脲类化合物的方法 |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1880302A (zh) * | 2006-01-06 | 2006-12-20 | 杭州师范学院 | 一种异硫氰酸酯的合成方法 |
CN101759614A (zh) * | 2008-12-26 | 2010-06-30 | 华东理工大学 | 一种异硫氰酸酯的制备方法 |
CN102229551A (zh) * | 2011-04-29 | 2011-11-02 | 浙江工业大学 | 一种异硫氰酸酯的制备方法 |
WO2012073314A1 (ja) * | 2010-11-29 | 2012-06-07 | 日産化学工業株式会社 | イソチオシアナト化合物の製造方法 |
CN102503872A (zh) * | 2011-12-15 | 2012-06-20 | 常州大学 | 一种制备异硫氰酸酯的方法 |
CN102702056A (zh) * | 2012-05-31 | 2012-10-03 | 北京师范大学 | 一种一锅法合成取代间苯二异硫氰酸酯的方法、合成的取代间苯二异硫氰酸酯化合物 |
CN103086933A (zh) * | 2013-01-23 | 2013-05-08 | 安徽工程大学 | 一种苯基异硫氰酸酯的制备方法 |
CN103102296A (zh) * | 2013-01-14 | 2013-05-15 | 常州大学 | 一种两步合成异硫氰酸酯的方法 |
CN103159691A (zh) * | 2011-12-19 | 2013-06-19 | 天津市国际生物医药联合研究院 | 异硫氰酸酯类化合物的制备及应用 |
CN103360282A (zh) * | 2013-05-16 | 2013-10-23 | 甘肃银光聚银化工有限公司 | 一种连续制备六亚甲基二异氰酸酯的装置和方法 |
CN103833780A (zh) * | 2014-03-26 | 2014-06-04 | 天津普莱化工技术有限公司 | 一种连续反应精馏制备硼酸三甲酯的新工艺方法 |
CN104072395A (zh) * | 2013-03-25 | 2014-10-01 | 黄蓬 | 一种异硫氰酸酯及其制备方法与抗癌应用 |
CN104860856A (zh) * | 2015-05-14 | 2015-08-26 | 常州大学 | 一种无碱绿色合成异硫氰酸酯的方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2859235A (en) * | 1954-01-26 | 1958-11-04 | Bayer Ag | Process for the production of isothiocyanates |
BRPI0517555A (pt) * | 2004-10-13 | 2008-10-14 | Upjohn Co | n-alquilpirimidinonas substituìdas |
IN2014DN10764A (zh) * | 2012-06-01 | 2015-09-04 | Pharmagra Labs Inc | |
CN103965079A (zh) * | 2014-05-23 | 2014-08-06 | 上海沣勃新材料科技有限公司 | 一种连续制备脂肪族或环族二异氰酸酯的方法 |
CN105001087B (zh) * | 2015-07-10 | 2016-08-24 | 黄冈银河阿迪药业有限公司 | 综合利用甲硝唑羟化合成废水生产甲酸酯类的方法及装置 |
CN105601520B (zh) * | 2016-03-16 | 2018-07-03 | 临沂远博化工有限公司 | 一种硝基甲烷合成及产物分离装置 |
CN105854941B (zh) * | 2016-04-06 | 2018-07-10 | 上海应用技术学院 | (S)-1-(1-苯乙基)硫脲修饰的Cr-Anderson型杂多酸催化剂、制备方法及其应用 |
CN105797771B (zh) * | 2016-04-06 | 2018-05-15 | 上海应用技术学院 | (R)-1-(1-苯乙基)硫脲修饰的Mn-Anderson型杂多酸催化剂、制备方法及其应用 |
-
2017
- 2017-02-27 CN CN201710108328.9A patent/CN108503568A/zh active Pending
-
2018
- 2018-02-27 US US16/489,226 patent/US11897838B2/en active Active
- 2018-02-27 CN CN201880014423.5A patent/CN110446697A/zh active Pending
- 2018-02-27 EP EP18756601.3A patent/EP3611163B1/en active Active
- 2018-02-27 WO PCT/CN2018/077443 patent/WO2018153381A1/zh unknown
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1880302A (zh) * | 2006-01-06 | 2006-12-20 | 杭州师范学院 | 一种异硫氰酸酯的合成方法 |
CN101759614A (zh) * | 2008-12-26 | 2010-06-30 | 华东理工大学 | 一种异硫氰酸酯的制备方法 |
WO2012073314A1 (ja) * | 2010-11-29 | 2012-06-07 | 日産化学工業株式会社 | イソチオシアナト化合物の製造方法 |
CN102229551A (zh) * | 2011-04-29 | 2011-11-02 | 浙江工业大学 | 一种异硫氰酸酯的制备方法 |
CN102503872A (zh) * | 2011-12-15 | 2012-06-20 | 常州大学 | 一种制备异硫氰酸酯的方法 |
CN103159691A (zh) * | 2011-12-19 | 2013-06-19 | 天津市国际生物医药联合研究院 | 异硫氰酸酯类化合物的制备及应用 |
CN102702056A (zh) * | 2012-05-31 | 2012-10-03 | 北京师范大学 | 一种一锅法合成取代间苯二异硫氰酸酯的方法、合成的取代间苯二异硫氰酸酯化合物 |
CN103102296A (zh) * | 2013-01-14 | 2013-05-15 | 常州大学 | 一种两步合成异硫氰酸酯的方法 |
CN103086933A (zh) * | 2013-01-23 | 2013-05-08 | 安徽工程大学 | 一种苯基异硫氰酸酯的制备方法 |
CN104072395A (zh) * | 2013-03-25 | 2014-10-01 | 黄蓬 | 一种异硫氰酸酯及其制备方法与抗癌应用 |
CN103360282A (zh) * | 2013-05-16 | 2013-10-23 | 甘肃银光聚银化工有限公司 | 一种连续制备六亚甲基二异氰酸酯的装置和方法 |
CN103833780A (zh) * | 2014-03-26 | 2014-06-04 | 天津普莱化工技术有限公司 | 一种连续反应精馏制备硼酸三甲酯的新工艺方法 |
CN104860856A (zh) * | 2015-05-14 | 2015-08-26 | 常州大学 | 一种无碱绿色合成异硫氰酸酯的方法 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3611163A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114644582A (zh) * | 2022-04-11 | 2022-06-21 | 中原工学院 | 一种苯基双硫脲类化合物的制备方法 |
CN114644582B (zh) * | 2022-04-11 | 2024-03-29 | 中原工学院 | 一种苯基双硫脲类化合物的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
US20200079731A1 (en) | 2020-03-12 |
EP3611163B1 (en) | 2023-06-07 |
EP3611163A4 (en) | 2020-12-09 |
WO2018153381A9 (zh) | 2018-10-11 |
CN110446697A (zh) | 2019-11-12 |
CN108503568A (zh) | 2018-09-07 |
EP3611163A1 (en) | 2020-02-19 |
US11897838B2 (en) | 2024-02-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2018153381A1 (zh) | 一种适用于工业化生产的高纯度异硫氰酸酯类化合物制备方法 | |
CN102584893B (zh) | 一种草铵膦的制备方法 | |
US20130281695A1 (en) | Intermediates of sitagliptin and preparation process thereof | |
CN109265464B (zh) | 一种手性共价有机框架材料及其制备方法和应用 | |
AU2021314375A1 (en) | Method for large-scale synthesis of tetrodotoxin | |
CN113603653A (zh) | 一种可见光促进硒基噁唑烷-2.4-二酮的合成方法 | |
CN111170893B (zh) | Lefamulin的中间体化合物及其在Lefamulin制备中的应用 | |
CN101914174B (zh) | 线型聚苯乙烯支载(4s)-噁唑烷-2-苯亚胺及其制备方法和用途 | |
CN102002012A (zh) | 一种合成1,3-噁唑-2,4-二酮类化合物的方法 | |
CN104402813B (zh) | 一种索拉非尼的制备方法 | |
CN106631857B (zh) | 芳胺氮芥衍生物n,n-二(2-氯乙基)-n′-丙酰基-1,4-苯二胺及其制备方法 | |
CN108727214B (zh) | 一种麻醉剂丁哌卡因杂质的合成方法 | |
CN109574866A (zh) | 一种2,6-二甲基苯胺类长链化合物的制备方法 | |
CN101525310B (zh) | 1-苯甲酰基-3-(2-羟基-1,1-二甲基乙基)硫脲的合成方法 | |
CN103965104A (zh) | 一种酪氨酸激酶抑制剂及其中间体的制备方法 | |
CN102381954B (zh) | 一种乌药环戊烯二酮及其类似物的合成方法 | |
CN114105836B (zh) | 一种乙二醇的衍生化合物 | |
CN110857299B (zh) | 3-硫氰基咪唑并[1,5-a]喹啉化合物的合成方法 | |
JP5870197B2 (ja) | タキサン誘導体の製造方法 | |
CN112194606A (zh) | 一种n-boc-顺式-4-羟基脯氨酸甲酯合成工艺 | |
CN116003271A (zh) | 一种季铵类脂质的合成方法 | |
CN117343125A (zh) | 一种抗体偶联药物连接子的合成方法 | |
CN116813500A (zh) | 氟代双氯芬酸和瑞戈非尼的合成方法 | |
CN105085541A (zh) | 一种普拉格雷类似物的制备方法 | |
RU2459815C1 (ru) | Способ получения производных 1-циклогексен-1,2-дикарбоновых кислот |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18756601 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2018756601 Country of ref document: EP Effective date: 20190927 |