High-purity isothiocyanate compound preparation method for industrial production
11897838 ยท 2024-02-13
Assignee
Inventors
Cpc classification
C07C331/24
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention provides a high-purity isothiocyanate compound preparation method for industrial production. Specifically, in the method, organic amine and CS2 are used as raw materials to prepare the thiocarbamate, and then desulfurization is carried out, and the high-purity isothiocyanate compound is obtained by using purification, post-processing and other methods. The method in the present invention is suitable for industrial production, is simple in the post-processing, has a high yield rate, and allows the product to have a high purity, and is suitable for the production of the isothiocyanate compound in the pharmaceutical industry.
Claims
1. A method for preparing an isothiocyanate compound of formula (I),
A-NCS(I) in formula I: NCS is isothiocyanate group; A is XR.sub.1 or CR.sub.2R.sub.3R.sub.4, wherein X is (CH.sub.2).sub.n, and n is an integer of 0-6; R.sub.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, trimethylsilyl, substituted or unsubstituted phenyl; wherein, one or more hydrogen in the substituted phenyl are substituted by substituents selected from the following group: halogen, methyl, bromomethyl, ethyl, methoxy, nitro, azido, trifluoromethyl, difluoromethoxy, methylthio, cyano, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, and ethoxycarbonyl; R.sub.2, R.sub.3, and R.sub.4 are each independently H, phenyl or C.sub.1-3 alkyl; wherein the method comprises: (1) reacting, in the presence of an organic base, A-NH.sub.2 with CS.sub.2 in organic solvent so as to obtain a first reaction mixture containing dithiocarbamate, wherein the organic solvent is an ethyl acetate, and ratio of the A-NH.sub.2 to the CS.sub.2 is 1:1.05-2; (2) adding, in the presence of an optional base catalyst, a desulfurizing agent to the first reaction mixture to carry out a desulfurization reaction so as to obtain a second reaction mixture containing the isothiocyanate compound of formula (I), wherein 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 combinations thereof; (3) purifying the second reaction mixture by post-processing to obtain the isothiocyanate compound of formula (I); wherein in (3), the post-processing comprises: washing the second reaction mixture and concentrating so as to obtain an acid-washed crude product; distilling the acid-washed crude product so as to obtain a distilled crude product containing the isothiocyanate compound of formula (I); and subjecting the distilled crude product to rectification under vacuum so as to obtain a pure isothiocyanate compound of formula (I).
2. The method of claim 1, wherein in (1), the organic base is selected from the group consisting of triethylamine, trimethylamine, diisopropylethylamine, triethylene diamine, pyridine, 4-N,N-dimethyl pyridine, potassium t-butoxide, sodium methoxide, sodium ethoxide, hydroxylamine, 3-methylpyridine, pyrrole, or combinations thereof.
3. The method of claim 1, wherein in (2), the desulfurizing agent is di-tert-butyl dicarbonate.
4. The method of claim 1, wherein in (2), the base catalyst is selected from the group consisting of triethylamine, triethylene diamine, pyridine, 4-dimethylamiopryidine, or combinations thereof.
5. The method of claim 1, wherein in (1), a ratio of the A-NH.sub.2 to the organic base is 1:0.5-5, and a mass volume ratio of the A-NH.sub.2 to the ethyl acetate is 10-25%; and in (2), ratio of the A-NH.sub.2 in (1) to the desulfurizing agent is 1:0.9-5.
6. The method of claim 1, wherein in (1), ratio of the A-NH.sub.2 to the organic base is 1:0.8-3 and a mass volume ratio of the A-NH.sub.2 to the ethyl acetate is 10-25%; and in (2), a ratio of the A-NH.sub.2 in (1) to the desulfurizing agent is 1:0.9-2, and/or when the base catalyst is present, mass ratio of the base catalyst to the A-NH.sub.2 in (1) is 0.01-2 wt %.
7. The method of claim 1, wherein in (1), ratio of the A-NH.sub.2 to the organic base is 1:0.9-2 and mass volume ratio of the A-NH.sub.2 to the ethyl acetate is 10-25%; and in (2), ratio of the A-NH.sub.2 in (1) to the desulfurizing agent is 1:0.95-1.5, and/or when the base catalyst is present, mass ratio of the base catalyst to the A-NH.sub.2 in (1) is 0.05-1 wt %.
8. The method of claim 1, wherein in (3), the distilling is a reduced pressure distilling; and wherein the washing comprises: washing with an acid solution, wherein molar ratio of a total amount of the acid in the acid solution to the organic base in (1) is 0.8-5:1, calculated as monobasic acid and monobasic base.
9. The method of claim 8, wherein a molar ratio of a total amount of the acid in the acid solution to the organic base in (1) is 0.9-2:1.
10. The method of claim 9, wherein a molar ratio of a total amount of the acid in the acid solution to the organic base in (1) is 1-1.5:1.
11. The method of claim 1, wherein the post-processing comprises one or more characteristics selected from the group consisting of: the rectification under vacuum is a continuous rectification or a batch rectification; a rectifying column used for the rectification adopts a structured packing or a random packing; and a rectified packing material used for the post-processing purification is selected from the group consisting of a stainless steel, a plastic, a glass, a ceramic, or combinations thereof.
12. The method of claim 11, wherein the structured packing is selected from the group consisting of a corrugated packing or a grid packing; and the random packing is selected from the group consisting of a Pall ring packing, a Raschig ring packing, a flat ring packing, a cascade packing ring, an intalox saddles packing, an octagonal ring packing, a conjugate ring packing, a Teller Rosette packing, a HY-PAK packing, a Dixon ring packing, a Cannon ring packing, a Triangular spiral ring packing, a spherical packing, and a combination thereof.
13. The method of claim 11, wherein the rectified packing material is selected from the group consisting of the stainless steel, the ceramics, or combinations thereof.
14. The method according to claim 8, wherein in the reduced pressure distilling, a reflux ratio of a front fraction is 99:1-1:99; a reflux ratio of a middle fraction is 99:1-1:99; and a reflux ratio of a post-fraction is 99:1-1:99.
Description
DESCRIPTION OF THE DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
EMBODIMENTS FOR CARRYING OUT THE INVENTION
(9) Through long-term and intensive study, the inventors have provided a one-pot method for preparing isothiocyanates. The method of the invention is safe, simple, environmental friendly, and can be used in industrial production. Moreover, the post-processing purification of the method is simple, and the obtained isothiocyanate compound is of high-purity, thus being qualified for medical demands. Based on the above findings, the inventors completed the present invention.
(10) Preparation of Isothiocyanate Compound
(11) The invention provides a preparation method of isothiocyanate compounds, the method comprises the steps of:
(12) ##STR00001##
(13) in formula I:
(14) NCS is isothiocyanate group;
(15) A is XR.sub.1 or CR.sub.2R.sub.3R.sub.4, wherein
(16) X is (CH.sub.2).sub.n, and n is an integer of 0-6;
(17) R.sub.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, trimethylsilyl, substituted or unsubstituted phenyl;
(18) wherein, the substituted means that one or more hydrogen in the group are substituted by substituents selected from the group consisting of halogen, methyl, bromomethyl, ethyl, methoxy, nitro, azido, trifluoromethyl, difluoromethoxy, methylthio, cyano, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, ethoxycarbonyl;
(19) R.sub.2, R.sub.3, and R.sub.4 are each independently H, phenyl or C.sub.1-3 alkyl.
(20) (1) in the presence of organic base, ANH.sub.2 reacts with CS.sub.2 in organic solvent to obtain a first reaction mixture containing dithiocarbamate;
(21) (2) in the presence of an optional base catalyst, desulfurizing agent is added to the first reaction mixture to carry out a desulfurization reaction and obtain a second reaction mixture containing isothiocyanate compound;
(22) (3) purifying the second reaction mixture by post-processing to obtain the isothiocyanate as shown in formula (I).
(23) In the step (1), there are no special restrictions on the solvent system. A solvent that can dissolve phenethylamine and dithiocarbamate and is not miscible with water can be used. Preferably, solvents such as, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, butyl acetate, isobutyl acetate, amyl propionate, dichloromethane, dichloroethane, chloroform, 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-processing.
(24) In the reaction, the type of the reactant (organic base, desulfurizing agent) is not particularly limited, and the preferred organic base is selected from the group consisting of triethylamine, trimethylamine, diisopropylethylamine, triethylene diamine, pyridine, 4-N,N-dimethyl pyridine, potassium t-butoxide, sodium methoxide, sodium ethoxide, or the combinations thereof; more preferably triethylamine; preferably, the desulfurizing agent is selected from the group consisting of methylclhlorofonmate, p-toluenesulfonyl chloride, solid phosgene, elemental iodine, chlorosilane, chlorophosphate, dicyclohexylcarbodiimide, dicyandiamide, triphenylphosphine, di-tert-butyl dicarbonate, cyanuric chloride, or a combination thereof; more preferably di-tert-butyl dicarbonate.
(25) During the reaction, the feed ratio of each reactant can be designed according to the actual situation, taking into account the yield, content, purity and related substances, preferably, the ratio of ANH.sub.2:organic base=1:0.5-5, preferably 1:0.8-3, more preferably 1:0.9-2; preferably the ratio of ANH.sub.2:carbon disulfide=1:1.0-10, preferably 1:1.0-5, more preferably 1:1.05-2.
(26) In the step (2), the desulfurizing agent is preferably in an amount of 1:0.95, preferably 1:0.92-2, more preferably 1:0.951.5.
(27) In a preferred aspect of the invention, in the step (1) the carbon disulfide is in excess relative to ANH.sub.2.
(28) In the reaction, the preferred temperature of each step is not particularly limited, and a suitable reaction temperature may be employed depending on the actual reaction system.
(29) After completion of the reaction, a series of post-processing including pickling, washing with saturated brine, drying, solvent evaporation, reduced pressure distillation, etc. are carried out in consideration of the formation of the by-products in the reaction. Preferably, the solvent used in the post-processing is the same as the solvent used in the reaction.
(30) In a preferred embodiment of the invention, the post-processing purification method comprises the steps of:
(31) washing the second reaction mixture, and then concentrating to obtain an acid pickling crude product;
(32) the acid pickling crude product is subjected to vacuum distillation to obtain a crude distillation product containing isothiocyanate;
(33) the crude distillation product was subjected to reduced pressure distillation to obtain a pure isothiocyanate product.
(34) The conditions of each post-processing purification step can be designed according to the reaction scale, raw material, etc. which is actually used. Preferably, different reflux ratios are used in the front, middle and post fractions during the reduced pressure rectification. In a preferred embodiment of the invention, the reflux ratio of the front fraction is 99:1-1:99 (preferably 99:1-50:50, more preferably 90:10-70:30); the reflux ratio of the middle fraction is 99:1-1:99 (preferably 90:10-10:90, more preferably 70:30-30:70); the reflux ratio of the post-fraction is 99:1-1:99 (preferably 99:1-50:50, more preferably 90:10-70:30). The purity of the final obtained product is more than 99.7% (yield 80%).
(35) The front fraction in the rectification process refers to the first stage fraction from the start of the fraction receiving, and the receiving amount is 0%-30% (preferably 0%-20%, more preferably 5%-10%) of the substrate;
(36) 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%-100% (preferably 60%-100%, more preferably 80%-90%) of the substrate;
(37) The post-fraction in the rectification process refers to the third fraction after completion of the reception of the previous fraction, and the receiving amount is 0%-30% (preferably 0%-20%, more preferably 5%-10%) of the substrate.
(38) Compared with the Prior Art, the Advantages of the Present Invention are Mainly Embodied in:
(39) 1) The invention adopts one-pot method to prepare isothiocyanate, in which the raw materials required for the reaction are cheap and readily available, and a better reaction condition with high reaction conversion rate, mild conditions, convenient operation, easy purification and environmental friendly is explored;
(40) 2) the invention adopts a solvent represented by ethyl acetate with low toxicity, high safety, and the reaction, separation and purification steps are realized without using any other organic solvents, thus greatly reducing the use of organic solvents, the use of solvents of low boiling point and high volatility, thus improving the safety of production and reducing environmental pollution, thus very conducive to industrial production;
(41) 3) the invention adopts a purification method of pickling, distillation and rectification to obtain an isothiocyanate compound of high-purity, and the product purity is more than 99.6%. Generally, column chromatography method is used in literature or patents, which requires a large amount of organic solvent as well as cumbersome operation. The purification method of the present invention greatly reduces the use of organic solvents, thus simplifying the operation steps and making it easy to adapt to industrial production.
(42) 4) The purity of the isothiocyanate prepared by the invention is greater than 99.6%, which can meet the demand of medicine.
(43) The invention is further illustrated with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or recommended by the manufacturer. Percentage and portion are calculated by weight unless otherwise stated.
Example 1 Preparation of Phenethyl Isothiocyanate
(44) Phenethylamine (300.0 g, 2.48 mol) and triethylamine (350.6 g, 3.46 mol) were placed in a 5000 mL three-neck round bottom flask, and ethyl acetate (1000 mL) was added, and then the mixture was cooled in an ice bath and mechanically stirred. When the temperature of the mixed solution was dropped to 0 C.-5 C., carbon disulfide (339.2 g, 4.45 mol) was slowly added dropwise by a constant pressure dropping funnel, magnetic stirring as dropping, and the temperature of the reaction liquid was controlled to be less than 30 C. After the dropwise addition was completed, magnetic stirring was carried out for one hour at room temperature (10-30 C.); BOC.sub.2O (535.1 g, 2.45 mol) and DMAP catalyst were added to the reaction solution at this temperature, and then the mixture was stirred to react at 302.5 C. for 1.5 h. After the completion of the reaction, the reaction solution was washed twice with acid solution, and the total amount of acid consumed by washing was 1.5 times that of triethylamine, and then washed with a saturated saline solution until neutral. The organic phase was concentrated by rotary evaporation to give an acid pickling crude.
(45) The acid pickling crude was placed in a flask heated by a heating mantle, and a rotary vane vacuum pump was adopted, and a fraction of 130 C.-145 C./10 mmHg was collected to obtain a crude product.
(46) The crude distillation product was placed in a rectifying still. The rectifying column specification was 30*1000 mm, with stainless dixon packing (44 mm), 2X-8A model rotary vane vacuum pump, the kettle temperature was kept at 160-200 C. After fully refluxed for 0.5 h, the fractions at 95 C.-110 C./200-600 Pa were collected. The front fraction had a reflux ratio of 90:10; after 0.5 hours, the reflux ratio was 50:50, and the middle fraction was collected; finally, the reflux ratio was 70:30, and the post fraction was collected to obtain phenethyl isothiocyanate product (yield 85%), and then identification and purity check was performed.
Example 2 Structure and Purity Check of Phenylethyl Isothiocyanate
(47) 1. Structure Identification Result of H-NMR and Spectrum
(48) The results of the nuclear magnetic test are as follows, which is the same as our target product.
(49) ##STR00002##
(50) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37-7.31 (m, 1H), 7.28 (ddd, J=10.2, 5.0, 2.1 Hz, 1H), 7.23-7.19 (m, 1H), 3.72 (t, J=7.0 Hz, 1H), 2.99 (t, J=7.0 Hz, 1H).
(51) Nuclear magnetic detection is shown in
(52) 2. Purity Detection of Phenethyl Isothiocyanate
(53) Instrument conditions: Dionex U3000, C18 bonded silica gel column, 208/244 nm, 1.0 ml/min, column temperature was 30 C., 10 ul of injection sample, and analysis for 30 min;
(54) The mobile phase was with the gradient of 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.
(55) Sample configuration: about 15 mg of phenethyl isothiocyanate was weighed precisely, and then placed in a 25 ml measuring flask, dissolved with acetonitrile to volume to scale, filtered and injected;
(56) Result:
(57) TABLE-US-00001 Phenylethyl Normalized isothiocyanate main peak related substances 208 nm 99.85% A total of 2 major impurities, accounting for 0.04% and 0.05% respectively 244 nm 99.92% One impurity, accounting for 0.08%
(58) Chromatograms are shown in
Example 3 Preparation of Allyl Isothiocyanate
(59) Allylamine (300.0 g, 5.25 mol), triethylamine (743.0 g, 7.34 mol), CS.sub.2 (718.9 g, 9.45 mol), BOC anhydride (1134.1 g, 5.20 mol) and 0.18 g of DMAP (0.06 of the amount of allylamine) %) and 1800 ml of ethyl acetate were subjected to the reaction and post-processing purification in the same manner as in Example 1, and finally obtained a pure product. The structure was confirmed in
Example 4 Preparation of 4-Methoxybenzyl Isothiocyanate
(60) 4-methoxybenzylamine (300.0 g, 2.19 mol), triethylamine (309.2 g, 3.06 mol), CS.sub.2 (299.2 g, 3.93 mol), BOC anhydride (471.9 g, 2.16 mol), 0.18 g of DMAP (0.06% of the amount of allylamine) and 1000 ml of ethyl acetate were subjected to the reaction and post-processing purification in the same manner as in Example 1, and finally obtained a pure product. The structure was confirmed in
Example 5 Preparation of 4-Chlorobenzyl Isothiocyanate
(61) 4-chlorobenzylamine (300.0 g, 2.12 mol), triethylamine (299.6 g, 2.96 mol), CS.sub.2 (289.8 g, 3.81 mol), BOC anhydride (457.2 g, 2.10 mol), 0.18 g of DMAP (0.06% of the amount of allylamine) and 900 ml of ethyl acetate were subjected to the reaction and post-processing purification in the same manner as in Example 1, and finally obtained a pure product. The structure was confirmed in
Example 6 Preparation of Ethyl Isothiocyanate
(62) Ethylamine (300.0 g, 6.65 mol), triethylamine (940.9 g, 9.30 mol), CS.sub.2 (910.4 g, 11.96 mol), BOC anhydride (1436.2 g, 6.58 mol), 0.18 g of DMAP (0.06% of the amount of allylamine) and 2300 ml of acetic acid were subjected to the reaction and post-processing purification in the same manner as in Example 1, and finally obtained a pure product. The structure was confirmed in
Example 7 Industrial Production Equipment Flow Chart
(63) The equipment flow chart for industrial production was detailed in
(64) The main reactor was used to carry out main reaction, acidic water washing reaction and concentration operation, and the equipment further comprises a first condensation and receiving device connected to the upper portion of the main reactor.
(65) The crude distillation tank was used to distill the concentrated product to obtain a crude distillation product. The crude distillation product passed through the second condensation and receiving device to enter into the evaporator and the rectification column from the tail end. The rectifying column was used for rectifying the crude distillation product.
(66) The equipment also includes one or more feeding tanks connected to the main reactor, and located upstream of the main reactor.
(67) All literature mentioned in the present application are incorporated herein by reference, as though each one is individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents also fall within the scope defined by the appended claims.