CN101898925A - Green synthesis and industrialization method of chloro-substituted heterocyclic ring - Google Patents

Abstract

The invention provides an industrialized method for synthesizing various heterocyclic rings containing chlorine taking solid triphosgene as a raw material, which uses a heterocyclic compound containing hydroxyl and the triphosgene to prepare the heterocyclic ring containing the chlorine under the action of an amine or acid amides catalyst or without the catalyst. The method has the advantages of easily-obtained raw materials, low cost, mild reaction, easy control, simple treatment, high yield and easy amplified production, and is suitable for preparing almost all heterocyclic rings containing the chlorine, including but not limited to contain chlorinated aromatic compounds and the heterocyclic rings; waste is generated rarely and three wastes (a solvent can be recycled and hydrogen chloride can be recycled to prepare a hydrochloric solution) are not generated hardly except carbon dioxide. The invention provides a practical and feasible method for synthesizing the various heterocyclic rings containing the chlorine for green chemical industry.

Description

Synthetic and the industrial method of the green of chloro-substituted heterocyclic ring

I. background is summarized

Chloride heterocycle is an intermediate important in the organic synthesis, and this compounds reactive behavior height is widely used on chemical industry and medicine are synthetic, and general synthetic method is with hydroxyl heterocycle and thionyl chloride (US6348462; JCS PERKIN I 1225 (1986)), (JMC 49 635 (2006) for phosphorus trichloride; JACS 70 1363 (1948); JCS 899 (1947); US6350750; EP1426366), (JHC 171213 (1980) for phosphorus pentachloride; JCS 227 (1949); US4839366; CH139450), (BMC 11 2541 (2003) for phenyl phosphonyl chloride; WO2004/58759) or oxalyl chloride (WO2008/121687) prepared in reaction, the loaded down with trivial details difficulty of this type of post-reaction treatment, the cost height, the three wastes are many, pollute big.Therefore the scientific research personnel is still constantly seeking more easy synthetic method.

The purpose of this invention is to provide one is the synthetic chloride heterocyclic industrial method of raw material from triphosgene.This synthetic chloride heterocyclic method raw material is easy to get, and cost is low, and the three wastes are few, pollutes for a short time, handle simply, and the yield height, and be easy to a kind of suitability for industrialized production.

II. main contents of the present invention

Synthetic method reaction formula of the present invention (I) is as follows:

The 3-7 of the various replacements of n=unit cycloaliphatic ring, aromatic nucleus or contain heteroatomic aromatic nucleus wherein; Various 3-7 unit's aromatic nucleus that do not replace or replace of m=or contain heteroatomic aromatic nucleus.

For helping further to understand the present invention, the structural formula of this class chlorizate can further be expressed as structural formula (II), (III) and (IV):

Wherein X=CH, N, O or S etc. are preferably CH, N; Y=CH, CE, N, O or S etc. are preferably CH, N, CE, wherein E=CN or CO ₂R ₃R ₃=CH ₃, Et, Pr, i-Pr or t-Bu); Various 3-7 unit's cycloaliphatic ring, aromatic nucleus that do not replace or replace of n=or contain heteroatomic aromatic nucleus; Be preferably phenyl ring, pyridine ring, pyrazoles, thiophene, pyrroles; Furans, tetrahydrofuran (THF), tetramethylene, pentamethylene or hexanaphthene; R ₁=H, methyl, ethyl, aromatic base, halogen atom, first sulfydryl, methylsulfonyl, ester group, cyano group or carboxyl etc. are preferably H, methyl, chlorine, bromine, first sulfydryl, methylsulfonyl, trifluoromethyl, cyano group; R ₂=H, methyl, ethyl, aromatic base, halogen atom, formyl radical, ester group, trifluoromethyl or cyano group etc. are preferably H, methyl, ester group, formyl radical, trifluoromethyl, cyano group; W=CH ₂, heteroatoms such as NH, O, S, be preferably O, S; Z=CH, N etc.; Be preferably the N atom.

The synthetic method can further describe as follows: replace the heterocycle contain hydroxyl and triphosgene or two phosgene and be dissolved in the appropriate solvent, make chloride heterogeneous ring compound.Oxy-compound and triphosgene mol ratio are 1: 0.3-1: 3 (triphosgene is calculated by 1 molar weight), recommending used triphosgene molar weight is 0.33-0.5, the recommendation solvent for use is a methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, toluene, dioxane, dimethylbenzene, aprotic solvent such as t-butyl methyl ether and acetonitrile, the recommendation response temperature is the 0-150 degree, can add little amount of catalyst in the reaction, the catalyzer of recommending has methane amide, N, dinethylformamide (DMF), N, the N-N,N-DIMETHYLACETAMIDE, triethylamine, Diisopropylamine, or small molecule amine and acid amides such as diisopropyl ethyl amine, speed of response is fast and yield is very high, and the recommendation response time is 2-12 hour.

Present method reaction temperature and, be easy to control, be easy to amplify to produce, and be fit to the chloride heterocycle of the nearly all classification of preparation, include but not limited to chloride aromatic series and heterocyclic; The waste material that produces is few, and (solvent can be recycled to produce the removing carbon dioxide three wastes in addition hardly; Hydrogenchloride can reclaim makes hydrochloric acid soln).The present invention provides practicable all kinds of chloride heterocyclic synthetic methods for green chemical industry.

III. invention example

1. will help further to understand the present invention by following example; They are not only limited by example for the practical ranges of giving an example.

Example 1

(250g 1.72mol) is dissolved in the 1250ml ethylene dichloride with the 2-hydroxyquinoline.(255.6g, 0.86mol 0.5eq) are dissolved in the 500ml ethylene dichloride to triphosgene, splash in the reaction solution under the room temperature, and reflux was reacted 4 hours, and TLC detects (EA: PE=1: 2), react and finish.Reaction solution be spin-dried for the tawny solid, the underpressure distillation of gained solid gets colourless liquid, is cooled to white solid (154g, productive rate 54.8%).

H-NMR(300MHz，CDCl3)δ7.42(d，1H)，7.6(t，1H)，7.76(t，1H)，7.85(d，1H)，8.06(d，1H)，8.10(d，1H).

Example 2

(14.6g 0.1mol) is suspended in the 140ml ethylene dichloride with raw material.(14.85g, 0.05mol 0.5eq) are dissolved in the 28ml ethylene dichloride to triphosgene, splash in the reaction solution under the room temperature, splash into the DMF of 1mL, and reflux is spent the night, and TLC detects (EA: PE=1: 4), react and finish.Be cooled to room temperature, add saturated sodium bicarbonate solution, tell organic layer, water dichloromethane extraction 1-2 time merges organic phase, and dried over sodium sulfate is spin-dried for, and PE heat is extracted, and the EA crystallization gets pure product, productive rate 50%.H-NMR(300MHz，CDCl3)δ7.74(t，1H)，7.96(t，1H)，8.07(d，1H)，8.27(d，1H)，9.04(s，1H).

Example 3

(14.6g 0.1mol) is suspended in the 140ml ethylene dichloride with raw material.(14.85g, 0.05mol 0.5eq) are dissolved in the 28ml ethylene dichloride to triphosgene, splash in the reaction solution under the room temperature, splash into the DMA of 1mL, and reflux is spent the night, and TLC detects (EA: PE=1: 4), react and finish.Be cooled to room temperature, add saturated sodium bicarbonate solution, tell organic layer, water dichloromethane extraction 1-2 time merges organic phase, and dried over sodium sulfate is spin-dried for, and PE heat is extracted, and the EA crystallization gets pure product, productive rate 55%.H-NMR(300MHz，CDCl3)δ7.74(t，1H)，7.96(t，1H)，8.07(d，1H)，8.27(d，1H)，9.04(s，1H).

Example 4

Throw raw material 5g (34.5mmol) 4-hydroxyquinoline to the 25mL methylene dichloride, (17.2mmol 0.5eq) goes in the reaction solution with the mixing solutions of 10mL methylene dichloride to add triphosgene 5.12g, dropwise, be heated to backflow, react about 4h, TLC detects (P/E=8/1), has reacted.Be spin-dried for, cross post, (annotations and comments: be adsorbed on the pillar, direct crystallization can be better) gets 1g, yield: 18%.H-NMR(300MHz，CDCl3)δ7.45(d，1H)，7.61(t，1H)，7.74(t，1H)，8.11(d，1H)，8.19(d，1H)，8.89(d，1H).

Example 5

Throwing raw material 5g (23.04mmol) drops in the 25mL ethylene dichloride, with triphosgene 3.42g (11.52mmol, 0.5eq) and the mixing solutions of 10mL ethylene dichloride splash in the reaction solution, drip off reflux, react about 4h, TLC detects (P/E=8/1), reacted, be spin-dried for, crossed post, get 3.5g, yield: 64%.H-NMR(300MHz，CDCl3)δ1.44(t，3H)，4.48(q，2H)，7.65(t，1H)，7.80(t，1H)，8.09(d，1H)，9.17(s，1H).

Example 6

Throw raw material 15g (0.134mol 1eq) drops in the 250mL acetonitrile, adds N, N-diisopropylethylamine 35g (0.27mol, 2eq), add in batches triphosgene 81g (0.27mol, 2eq), room temperature is stirred 10min, 55 ℃ of stirrings are spent the night again.TLC detects P/E=1/1, reacts completely.Be spin-dried for, add water 250mL, dichloromethane extraction 250mL*3 merges organic phase, the 200mL washing, and the MgSO4 drying is spin-dried for.The PE/EA recrystallization gets 4.8g, yield: 24%.H-NMR(300MHz，CDCl3)δ7.45(s，1H)，8.82(s，1H).

Example 7

Throw raw material 16.9g (100mmol) and drop in the 150mL ethylene dichloride, with triphosgene 148.5g (50mmol, 0.5eq) and the mixing solutions of 100mL ethylene dichloride splash in the reaction solution, splash into the DMA of 1mL, drip off reflux, TLC detects, and has reacted, and is spin-dried for, cross post, get 7.48g, yield: 40%.H-NMR(300MHz，CDCl3)δ7.33(d，1H)，7.42(d，1H)，7.66(s，1H).

IV. claims

1. synthetic, the production method of a chloride heterocyclic compound, it is characterized in that this method comprises the following step: use triphosgene as chlorination reagent, in the presence of amides, amines catalyst or catalyst-free, directly the hydroxyl heterocyclic is converted into chloride heterocyclic compound.

2. the synthetic production method of a kind of chloride heterocyclic compound according to claim 1 can be as synthetic as structural formula (II), (III) with the chloride heterogeneous ring compound (IV).

Wherein X=CH, N, O or S etc. are preferably CH, N; Y=CH, CE, N, O or S etc. are preferably CH, N, CE, wherein E=CN or CO ₂R ₃R ₃=CH ₃, Et, Pr, i-Pr or t-Bu); Various 3-7 unit's cycloaliphatic ring, aromatic nucleus that do not replace or replace of n=or contain heteroatomic aromatic nucleus; Be preferably phenyl ring, pyridine ring, pyrazoles, thiophene, pyrroles; Furans, tetrahydrofuran (THF), tetramethylene, pentamethylene or hexanaphthene; R ₁=H, methyl, ethyl, aromatic base, halogen atom, first sulfydryl, methylsulfonyl, ester group, cyano group or carboxyl etc. are preferably H, methyl, chlorine, bromine, first sulfydryl, methylsulfonyl, trifluoromethyl, cyano group; R ₂=H, methyl, ethyl, aromatic base, halogen atom, formyl radical, ester group, trifluoromethyl or cyano group etc. are preferably H, methyl, ester group, formyl radical, trifluoromethyl, cyano group; W=CH ₂, heteroatoms such as NH, O, S, be preferably O, S; Z=CH, N etc.; Be preferably the N atom.

3. according to claim 2, synthetic contains pyridine, pyrazine, pyridazine, quinoline, isoquinoline 99.9, pyrimidine, triazine, oxazole, benzoxazole, quinazoline, quinoxaline, purine, thiophene, thionaphthene, the thieno-[3 of chloro heterogeneous ring compound for not replacing or replace, 2-d] pyrimidine, thieno-[2,3-d] pyrimidine, pyrrolo-[3,2-d] pyrimidine, pyrrolo-[2,3-d] pyrimidine and naphthyridine;

4. the synthetic production method of a kind of chloride heterocyclic compound according to claim 1, the molar ratio that it is characterized in that triphosgene and carboxylic acid is 0.3: 1-3: 1; The preferred molar ratio example is 0.33: 1-0.5: 1; Solvent for use is non-protonic solvents such as methylene dichloride, 1,2-ethylene dichloride, chloroform, chlorobenzene, toluene, dioxane, t-butyl methyl ether and acetonitrile, and preferred solvent is 1,2-ethylene dichloride, chlorobenzene, dimethylbenzene, toluene and acetonitrile; Temperature of reaction is the 0-150 degree, and preferable reaction temperature is the 25-90 degree

5. the synthetic production method of a kind of chloride heterocyclic compound according to claim 1, it is characterized in that using amine, amides catalyzer or without catalyzer, preferred catalyzer has methane amide, N, dinethylformamide (DMF), N, small molecule amine and acid amides such as N-N,N-DIMETHYLACETAMIDE, triethylamine, Diisopropylamine or diisopropyl ethyl amine, further preferred catalyzer is methane amide, diisopropyl ethyl amine, N, dinethylformamide (DMF), N,N-dimethylacetamide.

V. brief summary/Abstract

The invention provides one is the synthetic various chloride heterocyclic industrial methods of raw material with the solid triphosgene.Utilization contain hydroxyl heterocyclic compound and triphosgene under amine or amides catalyst action or catalyst-free make chloride heterocycle.Present method raw material is easy to get, and cost is low, reaction temperature and, be easy to control, handle simply, the yield height is easy to amplify and produces, and is fit to the chloride heterocycle of the nearly all classification of preparation, includes but not limited to contain chlorine aromatic series and heterocyclic; The waste material that produces is few, and (solvent can be recycled to produce the removing carbon dioxide three wastes in addition hardly; Hydrogenchloride can reclaim makes hydrochloric acid soln).The present invention provides practicable all kinds of chloride heterocyclic synthetic methods for green chemical industry.

Claims (5)

1. synthetic, the production method of a chloride heterocyclic compound, it is characterized in that this method comprises the following step: use triphosgene as chlorination reagent, in the presence of amides, amines catalyst or catalyst-free, directly the hydroxyl heterocyclic is converted into chloride heterocyclic compound.

2. the synthetic production method of a kind of chloride heterocyclic compound according to claim 1 can be as synthetic as structural formula (II), (III) with the chloride heterogeneous ring compound (IV).

Wherein X=CH, N, O or S etc. are preferably CH, N; Y=CH, CE, N, O or S etc. are preferably CH, N, CE, wherein E=CN or CO ₂R ₃R ₃=CH ₃, Et, Pr, i-Pr or t-Bu); Various 3-7 unit's cycloaliphatic ring, aromatic nucleus that do not replace or replace of n=or contain heteroatomic aromatic nucleus; Be preferably phenyl ring, pyridine ring, pyrazoles, thiophene, pyrroles; Furans, tetrahydrofuran (THF), tetramethylene, pentamethylene or hexanaphthene; R ₁=H, methyl, ethyl, aromatic base, halogen atom, first sulfydryl, methylsulfonyl, ester group, cyano group or carboxyl etc. are preferably H, methyl, chlorine, bromine, first sulfydryl, methylsulfonyl, trifluoromethyl, cyano group; R ₂=H, methyl, ethyl, aromatic base, halogen atom, formyl radical, ester group, trifluoromethyl or cyano group etc. are preferably H, methyl, ester group, formyl radical, trifluoromethyl, cyano group; W=CH ₂, heteroatoms such as NH, O, S, be preferably O, S; Z=CH, N etc.; Be preferably the N atom.

3. according to claim 2, synthetic contains pyridine, pyrazine, pyridazine, quinoline, isoquinoline 99.9, pyrimidine, triazine, oxazole, benzoxazole, quinazoline, quinoxaline, purine, thiophene, thionaphthene, the thieno-[3 of chloro heterogeneous ring compound for not replacing or replace, 2-d] pyrimidine, thieno-[2,3-d] pyrimidine, pyrrolo-[3,2-d] pyrimidine, pyrrolo-[2,3-d] pyrimidine and naphthyridine.

4. the synthetic production method of a kind of chloride heterocyclic compound according to claim 1, the molar ratio that it is characterized in that triphosgene and carboxylic acid is 0.3: 1-3: 1; The preferred molar ratio example is 0.33: 1-0.5: 1; Solvent for use is non-protonic solvents such as methylene dichloride, 1,2-ethylene dichloride, chloroform, chlorobenzene, toluene, dioxane, t-butyl methyl ether and acetonitrile, and preferred solvent is 1,2-ethylene dichloride, chlorobenzene, dimethylbenzene, toluene and acetonitrile; Temperature of reaction is the 0-150 degree, and preferable reaction temperature is the 25-90 degree.

5. the synthetic production method of a kind of chloride heterocyclic compound according to claim 1, it is characterized in that using amine, amides catalyzer or without catalyzer, preferred catalyzer has methane amide, N, dinethylformamide (DMF), N, small molecule amine and acid amides such as N-N,N-DIMETHYLACETAMIDE, triethylamine, Diisopropylamine or diisopropyl ethyl amine, further preferred catalyzer is methane amide, diisopropyl ethyl amine, N, dinethylformamide (DMF), N,N-dimethylacetamide.