JPH05502246A - Method for producing substituted nitrogen-containing heterocyclic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Process for producing substituted nitrogen-containing heterocyclic compounds The present invention provides a method for producing substituted nitrogen-containing heterocyclic compounds. and similar substituted heterocyclic compounds.

Aromatic nitrogen-containing heterocycles substituted with chloro or bromo and aliphatic alkaline Various methods are known for carrying out reactions with Cole. An example of this type of reaction is 1,3,5-1-riazine substituted with rogene, epoxy, phosphate, etc. or substituted alcohols, including alcohols substituted with orthoesters, or This is a reaction with an unsubstituted alcohol. The product, unsubstituted alcohol or Chlorotriazines containing residues derived from substituted alcohols are as a reactive camping reagent for polyphenylene ethers and similar polymers. Useful.

For example, U.S. Pat. No. 4,895.945 also describes cyanuric chloride or alkyl chloride. Alternatively, react arylchlorocyanurate with glycidol to form monoglycidol. has been described to form triazines substituted with cy or diglycidoxy. Ru. This reaction involves glycidol and water in an organic solvent such as methylene chloride. It is carried out by gradually adding a base to a solution of a chloro-substituted triazine. be called.

In the examples of this patent, an excess of glycidol is present in an amount greater than 200% of the stoichiometric amount. It is used. Such a high proportion of glycidol is associated with relatively high price and risk. undesirable due to its tendency to Another area that has room for improvement is product yield. There is a maximization of efficiency and a simplification of the reaction procedure.

The present invention provides the above reaction process in a minimum amount of time and under relatively simple conditions. various modifications that make a substantial contribution to the possibility of carrying out the reaction and to the improvement of the yield. It is based on what was discovered. Both mandatory and optional modifications are included. Ru. This method is used for the nitrogen-containing heterocyclization of aromatics substituted with many halogens. It is widely applicable to compounds and many unsubstituted and substituted aliphatic alcohols.

Therefore, the present invention provides (A) an aliphatic hydroxy compound; and (B) (1) at least (2) At least one nuclear nitrogen atom and at least one Electron-withdrawing group (this atom or group is a chloro or bromine atom adjacent to the nitrogen atom) activating the substituted carbon atom) , a method for producing a halogen substitution reaction product. This method is carried out under alkaline conditions. A phase transfer catalyst is present and the reaction is carried out in a solution of an organic solvent that is substantially immiscible with water. Reagents A and B are brought into contact in the substantial absence of water and inorganic salts other than those produced in the reaction. It consists of things.

Reagent A used in the method of the invention is an aliphatic hydroxy compound. like that Any compound can be used, including unsubstituted alkanols and substituted alkanols. Both canols are included. Reagent A is methanol, ethanol, 1-propanol. tool, 2-propertool, 1-butanol, 1-hexanol, 2-ethylhexyl Simple alkanols such as xanol, glycidol (i.e. 2,3-ethyl epoxy-substituted alkanols such as poxy-1-propanol), Rolo-1-ethanol, dimethyl 2-hydroxyethyl phosphate, di-n- phosphate Halo- or phosphate-substituted amines such as butyl 2-hydroxyethyl Lukanol, or 4-hydroxymethyl-2-methoxy-2-methyl-1,3 -dioxolane and 4-hydroxy-1-methyl-2,6,7-dryoxabisic It can be a cyclic orthoester such as 2,2,2 cooctane. Book The invention provides epoxy, dialkyl phosphate or cyclic orthoester substituted epoxy-substituted alkanols are particularly useful; epoxy-substituted alkanols are particularly useful. It has been found to be particularly useful.

Reagent B has several molecular features, e.g. on the carbon atom adjacent to the nitrogen atom. a chloro or bromo substituent; and (1) at least two nuclear nitrogen atoms. or (2) at least one such atom and said chloro substituent or is any combination with at least one electron-withdrawing group that activates the bromo substituent. It is an aromatic nitrogen-containing heterocyclic compound having one of the following: A suitable electron withdrawing group is Toro substituent, carbalkoxy substituent, perfluoroalkyl substituent, acyl substituent substituents, and other nitrogen heteroatoms.

Heterocyclic compounds usually contain 6-membered rings. Such compounds include the following complex A wide variety of compounds can be used, including compounds with cyclic nuclei. However, below In the formula, all substituents other than the chloro substituent or bromo substituent are omitted.

2-chloropyridine 2-bromopyrimidine 3-chloropyrazine 3-chloropyridazine 4-bromo-1,2,3,) riazine 3-chloro-1,2,4-triazine 2-chloro-1,3,5-)riazine Preferred heterocyclic compounds have at least two, preferably three, nuclei (i.e. (heterocyclic) containing a nitrogen atom. However, in this case, such nitrogen source The second of the children serves as the activating group for the chloro or bromo substituent. Function. 1.3.5-triazines are particularly preferred, alkoxy or aryl Oxy-substituted chloro-1,3,51-riazine is most preferred. As an example are 2,4-dichloro-4-n-butoxy-1,3,5-triazine and 2. '4-dichloro4-(2,4,6-dolimethylphenoxy)-1,,3,5 - There are triazines.

According to the present invention, the halogen substitution reaction of reagents A and B is performed using substantially water-immiscible organic solvents. It is done in a medium. Suitable solvents include aromatic carbons such as toluene and xylene. Hydrogen chloride, chlorinated aromatic hydrocarbons such as chlorobenzene and 0-dichlorobenzene , and chlorinated aliphatic hydrocarbons such as methylene chloride and chloroform. Ru. Methylene chloride and toluene are particularly suitable and relatively harmless to the environment Therefore, toluene is often preferred.

The present invention requires the use of a phase transfer catalyst.

Any such catalyst known in the industry may be used and the appropriate type Examples of compounds are quaternary ammonium salts, quaternary phosphonium salts, hexaalkyl guanidinium salts, and crown ethers. Quaternary ammonium salts are It is often preferred because of its efficacy and relative ease of availability. Particularly preferred is about 8 to having up to 5 carbon atoms apart from one alkyl group containing 20 carbon atoms Quaternary ammonium salts such as octadecyltrimethylammonium An example is chloride.

Another essential feature is that, except for the water and inorganic salts formed by the reaction of reagents A and B, Other than that, water and inorganic salts are substantially absent. For example, manufacturing reagent B Other inorganic salts, such as those that may be formed during the reaction, are should be removed by filtration, decantation of the liquid, etc.

For example, cyanuric chloride and n-butanol and 2. 4. 6-Dorimethylphenol monoalkyl or or monoaryl dichlorocyanurate, which is then further processed into glycide. 2-chloro-4-butoxy-6-gelisidoxy by reacting with 1. 3.　 5-triazine or 2-chloro-4-mesitoxy6-glycidoxy-1,3 , 5-) It is often convenient to form a riazine. Na chloride during the first reaction water is added, usually in the form of an aqueous base. More glycido If this sodium chloride and water are not removed from the reaction mixture before reacting with the It has been found that the time required for the reaction is relatively long. According to the invention Removal of salt and water can significantly shorten reaction times and typically This is 1/6th of the time required when not doing so. But in this example, There is no need to continuously remove the ring opening of the reaction between the intermediate and glycidol.

The method of the present invention is carried out under alkaline conditions and contains sodium hydroxide and potassium hydroxide. It is most often carried out in the presence of an aqueous metal hydroxide such as silica. Usually quite a bit A concentrated aqueous base solution is most often used, at least about 40% by weight.

This proportion of base is usually in excess of about 10-25% of the stoichiometric amount. The base gradually most commonly added to other reagents in increments.

The reaction temperature in the present invention may range from about θ to 70°C.

Typically, a temperature of about 10-25°C is preferred as by-product formation is minimized.

One of the advantages of the method of the invention is that the amount of reagent A required is considerably reduced. vinegar As previously pointed out, U.S. Pat. No. 4,895,945 overgly Discloses the use of lysidol. - In the invention of strength wood, the stoichiometric amount Reagent A may be used in an excess of up to about 30%. Nevertheless, the desired of reaction products are obtained in high yields (often over 90% of theory).

In a preferred embodiment of the invention, reagents A and B are added to at least about 25% of the organic phase by weight. present in an amount of %. That is, the total of reagents A and B is reagent A, reagent B, and Constitutes at least about 25% of the total weight of organic solvents. At such concentrations the reaction The speed is increased and the time required for reaction completion is further reduced. Particular preference for reagents A and B The desired proportion is from about 25% to the amount that results in a saturated solution.

After the reaction is complete, the product is removed by conventional means including stripping of organic solvents. It is possible to recover. However, substituted triazines can be used in organic solvents (typically polyphenylene ether in the form of a solution in an aromatic hydrocarbon (such as toluene) It is often desirable to use it as a capping agent for The method of the present invention When using chlorinated aliphatic hydrocarbons such as ethylene chloride, the boiling point Addition of high solvent (e.g. toluene) and vacuum stripping or atmospheric pressure Alternatively, the desired solvent can be substituted by a combination of vacuum distillation and vacuum distillation. This space The tripping and/or distillation steps are carried out in one or two stages. for example , to replace methylene chloride with toluene, it is first distilled at atmospheric pressure. After removing most of the methylene chloride, toluene is added to remove the remaining methylene chloride. The chloride can be vacuum stripped.

The invention is illustrated by the following examples.

Example 1 1 equipped with stirrer, thermocouple probe, reflux condenser, addition funnel and nitrogen filling means 147 kg of methylene chloride and molten metal were added to a 0.00 gallon reactor at 80°C. 24.4 kg (179.4 mol) of Ditol was charged. Cool the reactor to 5℃ Then, 31.5 kg (170.8 mol) of cyanuric chloride and cetyltrimethylammo 920 g of nium chloride was added. The reactor was further cooled to 2°C and then 15 kg of 50% sodium hydroxide solution while cooling and keeping the temperature below 15°C. (187.9 mol) was added slowly. After completing the sodium hydroxide addition, mix the Stirred for 1 hour under nitrogen.

The precipitated salt was precipitated and the organic solution was separated. Add this salt to 38 liters of deionized water. and 11.4 liters of methylene chloride. This methylene chloride layer were combined with the reaction mixture in a cleaned reactor.

The mixture was cooled again to 5°C and 15.8 kg (213.5 mol) of glycidol was added. After that, slowly add an additional 16.4 kg (205 mol) of sodium hydroxide solution. added. The temperature was maintained below 25°C during the sodium hydroxide addition for an additional 1 hour. The temperature was maintained at 25°C.

The organic solution was washed four times with deionized water and distilled at atmospheric pressure to give methylene chloride 14. Remove 4 kg of methylene chloride, add 160 kg of 80 toluene, and remove the remaining methylene chloride. The residue was removed by vacuum distillation at 50 torr. desired 2-chloro-4-mesitoxy6 -Glycidoxy1. 3. 54 riazine 1゜Toluene in the reactor of Example 1 96 kg of menthol was charged, and 14 kg of menthol (102.9 mol) was added as a melt. I got it.

The solution was cooled to 5°C, and 18 kg (97.6 mol) of cyanuric chloride and cetyltrimethane were added. 500 g of tylammonium chloride was added. The mixture was then heated to 5-15°C. 50% sodium hydroxide aqueous solution 8°6k while stirring under nitrogen. g (107.4 mol) was added over 2 hours. Leave the mixture to warm up to room temperature 76 liters of deionized water was added with stirring to dissolve the inorganic salts.

The aqueous layer was discarded, the organic layer was returned to the reactor at 10°C, and then 9 kg of glycidonyl (122 mol) was added. Thereafter, the reaction mixture was heated with water at 15-20°C while stirring. 9.4 kg (117.1 mol) of sodium oxide aqueous solution was slowly introduced. salt Stirring was continued for 1 hour after the group addition was complete.

Add the mixture to water until it is neutral and the glycidol level is 50 ppm. Washed with. Next, 18 kg of toluene-water azeotrope was removed by distillation under reduced pressure. Ta. The residue is the desired 2-chloro-4-mesitoxy-6-glycidoxy.

3.5-1-Ryazine in 0.75M toluene (84% of theory).

Example 3 500m with mechanical stirrer, addition funnel, nitrogen inlet and thermometer In a three-necked Morton flask, add 40 g of cyanuric chloride (217 mmol), meditol 31g (228 mmol), methylene chloride 150 m1 and a toluene solution of methyltrialkylammonium chloride (10 parts (% volume/volume, alkyl group has 8 to 10 carbon atoms) 8 ml was charged.

(Reagents A and B accounted for approximately 29% by weight of the total organic phase.) Cool the solution to 0°C. and, with stirring, add 50% sodium hydroxide at such a rate that the temperature does not rise above 5°C. 19.0 g (238 mmol) of aqueous lithium solution was added. Base addition completed Afterwards, the mixture was stirred at 0-5 °C for 30 min and analyzed by high-pressure chromatography. However, the reaction was completed and the product distribution was mesitoxydichlorocyanurate. is approximately 95.6% and dimesitoxychlorocyanurate is 4.4%. It was.

White chunks of water and salt stuck to the side walls of the reaction flask due to decantation The clear reaction solution was removed from the solution. Rinse the flask clean and reintroduce the solution, 20 g (270 mmol) of glycidol was added. Next, increase the temperature to 15-20℃ 21 g (262 mmol) of aqueous sodium hydroxide solution at a rate such that Added and introduced. Analysis after stirring the mixture for 1 hour at room temperature revealed the desired 2- Chloro-4-menthoxy-6-glycidoxy-1,3,5-triazine is 90. It was shown to contain 8% total yield. By-product dimesitoxychlorosia Nurate was present in an amount of 9.2%.

The mixture was washed three times with water and then neatly separated into aqueous and organic layers. Take the organic layer The methylene chloride was then replaced with toluene as described in Example 1.

The total yield of product isolated in toluene solution was 75-80%.

In the control reaction (reagents A and B account for approximately 20% of the total organic phase) methylene chloride 250 ml of Ride and 29.5 g (217 mmol) of Meditol were used.

- The amount of sodium hydroxide added each time was 17.36 g (21 7 mmol) and 19.1 g (239 mmol). This reaction mixture is No separation from salt and water after the first step. After addition of glycidol 3 Analysis after stirring for an hour showed that the product yield was only 72.2%. Ma As a by-product, 9.0% of dimesitoxychlorocyanurate and mesitoxy Dichlorocyanurate was present at 16.8%. After stirring for 24 hours at room temperature However, the analytical value of product yield did not increase to 86.4%. aqueous layer and organic There was a narrow emulsion layer at the interface between the layers, making separation difficult. moreover, Each wash creates additional emulsion, which causes significant product loss. It was the cause. The yield of isolated product was only 60-70%.

These results compare with the example method of U.S. Pat. No. 4,895.945. 1 illustrates the advantages of using the method of the invention. using a phase transfer catalyst to generate water and salts are removed, and reagents A and B account for at least about 25% of the organic phase. yields are improved and processing is much easier. Yield and ease of processing A small change in the proportion of mesitol and base is trivial in terms of the difference. .

Summary book Aliphatic hydroxy compounds and aromatic nitrogen-containing complexes substituted with chloro or bromo The halogen substitution reaction product with a ring compound undergoes a phase transfer catalyst under alkaline conditions. A medium is present, and water and inorganic bases other than those produced by the reaction are substantially absent. It will be held in This method is particularly useful for producing substituted chlorotriazines . In preferred embodiments, the reagent comprises at least about 25% by weight of the organic phase of the reaction mixture. to be accomplished.

International investigation notice. trtn<　(H10h

Claims (18)

[Claims] (1) (A) Aliphatic hydroxy compound and (B) alkoxy or aryloxy The halogen substitution reaction product with dichloro-1,3,5-triazine substituted with A method for producing substantially water-immiscible organic solvents under alkaline conditions. A phase transfer catalyst is present in the medium solution, and water and free water other than those formed in the reaction are present. The molar ratio of Reagent A to Reagent B is up to about 1.6:1 in the substantial absence of organic salts. Reagents A and B are brought into contact using up to 30% excess of reagent A over the stoichiometric amount. A method consisting of letting. (2) Maintaining alkaline conditions by gradual addition of aqueous base, claims The method described in Scope 1. (3) Phase transfer catalyst is quaternary ammonium salt or phosphonium salt, hexa Claim 2, which is an alkylguanidinium salt or a crown ether. Method. (4) The method of claim 3, wherein the reaction temperature is in the range of about 10-25°C. (5) Reagent A is used in an amount that exceeds the stoichiometric amount by at most about 25%. How to put it on. (6) The method according to claim 5, wherein the solvent is methylene chloride or toluene. Law. (7) Reagent A is epoxy, dialkyl phosphate or cyclic orthoester 7. The method of claim 6, wherein the alkanol is a substituted alkanol. (8) Reagent A is glycidol, dimethyl 2-hydroxyethyl phosphate, phosphoric acid di-n-butyl 2-hydroxyethyl or 4-hydroxymethyl-2-meth 8. The method according to claim 7, wherein the xy-2,3-dioxolane is xy-2,3-dioxolane. (9) Reagent B is 3,4-dichloro-4-n-butoxy1,3,5-triazine or 2,4-dichloro-4-(2,4,6-trimethylphenoxy)-1,3 , 5-triazine. (10) The phase transfer catalyst has one alkyl group containing about 8 to 20 carbon atoms. quaternary ammonium salts having 5 or less carbon atoms A method according to claim 9. (11) Claims in which Reagent A and Reagent B are at least about 25% by weight of the organic phase. The method described in 4. (12) Reagent A is epoxy, dialkyl phosphate or cyclic orthoester 12. The method according to claim 11, wherein the alkanol is substituted with . (13) Reagent A is glycidol, dimethyl 2-hydroxyethyl phosphate, phosphorus di-n-butyl 2-hydroxyethyl, or 4-hydroxymethyl-2-meth The method according to claim 12, which is toxy-2-methyl-1,5-dioxolane. . (14) Reagent B is 3,4-dichloro-4-n-butoxy-1,3,5-tria gin or 2,4-dichloro-4-(2,4,6-trimethylphenoxy)-1 , 3,5-triazine. (15) The phase transfer catalyst has one alkyl group containing about 8 to 20 carbon atoms. quaternary ammonium salts having 5 or less carbon atoms 15. The method of claim 14. (16) The method according to claim 4, wherein the solvent is toluene. (17) The method according to claim 4, wherein the solvent is methylene chloride. (18) Claim 1, in which methylene chloride is replaced with toluene after the reaction is completed. 7. The method described in 7.