WO2015135439A1 - Triazolo pyrimidine sulfydryl compound preparation method - Google Patents

Abstract

Disclosed is a preparation method of triazolo pyrimidine sulfydryl compound, the method rearranging and substituting the compound represented by formula (II) under the action of alcohol and alkali to obtain triazolo pyrimidine sulfydryl compound represented by formula (I). The method expands the approach of the original preparation method and raw material sources, with no environmentally unfriendly by-products, and has a great industrial application value.

Description

Method for preparing triazolopyrimidine pyridinium type compound Technical field

This invention relates to the synthesis of organic heterocyclic compounds, and in particular to the preparation of triazolopyrimidine pyridyl compounds.

technical background

The triazolopyrimidine indenyl compound (I) is an important intermediate for the preparation of triazolopyrimidinesulfonamide herbicides.

No. 6,612,915 and US Pat. No. 5,488,109 disclose a process for the preparation of triazolopyrimidinium fluorenyl compounds. For example, compound (V) is prepared by reacting a compound of formula (IV) with sodium ethoxide.

Although the conversion rate of the method is high, there is a serious environmental problem associated with the generation of a large amount of malodorous methyl mercaptan (VI) in the reaction.

Summary of the invention

The present inventors have conducted intensive studies and found that the compound of the formula (II) is reacted with an alcohol base to prepare a compound represented by the formula (I). Since the method can not only rearrange the sulfhydryl group on the triazole ring in the formula (II), but also replace the methoxy group on the pyrimidine ring, the method and raw material for preparing the triazolopyrimidinium fluorenyl compound can be broadened in a wider range. The source provides a new method for further reducing the raw material cost of preparing the triazole pyrimidine sulfonamide type herbicide original drug, and the by-product is environmentally friendly and has important industrial application value.

The technical route for carrying out the present invention is as follows: a method for preparing a triazolopyrimidine pyridinium type compound having the following steps: a compound of the formula (II)

Wherein R ¹ and R ² are each independently hydrogen, halogen, nitro, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy;

Alcohol base (III) in a molar ratio of 1.0 times to 10.0 times

R ³ OM(III)

Wherein R ³ is a C ₂ -C ₁₂ alkyl group and M is an alkali metal;

Under the action, preferably 1.5-3 times the molar amount of the alcohol base, the rearrangement is carried out in an organic solvent at a certain temperature, and post-treatment to obtain the compound of the formula (I).

The reaction temperature described in the method is generally carried out at a temperature of from -50 ° C to 50 ° C, and the temperature of from 0 to 30 ° C is a preferred reaction temperature.

The organic solvent used in the process includes methanol, ethanol, acetonitrile, dichloromethane, dichloroethane, toluene, xylene, tetrahydrofuran, dioxane, DMSO, DMF, DMAC, NMP, or a mixture thereof.

The invention adopts a novel reaction strategy, and prepares compound (I) by using a compound of formula (II) as a raw material and a rearrangement reaction of an alcohol base, and the new reaction by-product is methanol, which effectively solves the problem of malodor of methyl mercaptan, and more Conducive to industrial production.

detailed description

The following examples further illustrate some of the features of the present invention, but the scope and scope of the present invention are not limited by the following examples.

Example 1

Preparation of 5-ethoxy-7-fluoro-[1,2,4]-triazolo-[1,5-C]-pyrimidine-2(3H)thione

Add 10.0 g (0.048 mol, purity 96%) of 5-methoxy-7-fluoro-[1,2,4]-triazolo-[4,3-C]-pyrimidine-3(2H)thione Into 40g of ethanol. 5.4 g of sodium ethoxide was added to the above solution at 0 ° C to 10 ° C. The mixture was stirred at 0 °C - 10 °C for 2 h. Then the mixture was treated with 9.5 g of 36% concentrated salt. After acidification, 50 g of water was added, and the mixture was stirred at -5 ° C for 30 min, filtered, and the filter cake was washed with 20 ml of cold water and 20 ml of cold ethanol, and dried to give 9.2 g of the title compound.

NMR (CDCl ₃ ) δ: ¹ H: 1.47 (t, 3H), 4.69 (q, 2H), 7.04 (d, 1H).

Example 2

Preparation of 5-ethoxy-7-chloro-[1,2,4]-triazolo-[1,5-C]-pyrimidine-2(3H)thione

10.8 g (0.048 mol, purity 96%) of 5-methoxy-7-chloro-[1,2,4]-triazolo-[4,3-C]-pyrimidine-3(2H)thione was added Into 40g of ethanol. 5.4 g of sodium ethoxide was added to the above solution at 0 ° C to 10 ° C. The mixture was stirred at 0 °C - 10 °C for 2 h. Then the mixture was acidified with 9.5 g of 36% concentrated hydrochloric acid, added with 50 g of water, stirred at -5 ° C for 30 min, filtered, and the filter cake was washed with 20 ml of cold water and 20 ml of cold ethanol, and dried to give 9.5 g of the title compound. .

Example 3

Preparation of 5-ethoxy-8-fluoro-[1,2,4]-triazolo-[1,5-C]-pyrimidine-2(3H)thione

Add 10.0 g (0.048 mol, purity 96%) of 5-methoxy-8-fluoro-[1,2,4]-triazolo-[4,3-C]-pyrimidine-3(2H)thione Into 40g of ethanol. 5.4 g of sodium ethoxide was added to the above solution at 0 ° C to 10 ° C. The mixture was stirred at 0 °C - 10 °C for 2 h. The mixture was then acidified with 9.5 g of 36% concentrated hydrochloric acid, added with 50 g of water, stirred at -5 ° C for 30 min and then filtered, and the filter cake was washed with 20 ml of cold water and 20 ml of cold ethanol, and dried to give 9.2 g of the title compound. .

Example 4-9

Preparation of 5-ethoxy-7-fluoro-[1,2,4]-triazolo-[1,5-C]-pyrimidine-2(3H)thione by reaction under different conditions

Example 4 - Example 9 Referring to Example 1, the raw material input was 10.0 g, and the reaction conditions and product yield are shown in the following table:

Alcohol Solvent Molar ratio of raw materials to alkali temperature reflex product weight Example 4 Sodium ethoxide Ethanol 1:5 0°C 9.0g Example 5 Lithium lauryl alcohol Ethanol 1:10 -50 ° C 8.0g Example 6 Potassium ethoxide Acetonitrile 1:10 -50 ° C 7.9g Example 7 Potassium ethoxide Dichloromethane 1:1.1 -10 ° C 8.1g Example 8 Lithium ethoxide DMSO 1:1.8 50 ° C 7.5g Example 9 Sodium ethoxide Toluene 1:1.8 50 ° C 9.0g

Claims (8)

A method for preparing a triazolopyrimidine pyridinium type compound, which comprises: subjecting compound (II) to a rearrangement reaction at a certain temperature in an organic solvent under the action of an alcohol base (III) to obtain a compound (I), Wherein the structural formula of the compound (I) is:

Wherein R ¹ and R ² are each independently hydrogen, halogen, nitro, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, and R ³ is C ₂ -C ₁₂ alkyl; The structural formula of the compound (II) is:

Wherein R ¹ and R ² are each independently hydrogen, halogen, nitro, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy; The structural formula of the alcohol base (III) is: R ³ OM(III) Wherein R ³ is a C ₂ -C ₁₂ alkyl group and M is an alkali metal. The method of claim 1 wherein said R ¹ , R ² are hydrogen or halogen and R ³ is a C ₂ - C ₅ alkyl group. The method according to claim 1 or 2, wherein R ¹ is H, R ² is fluorine, and R ³ is ethyl. The method according to claim 1, wherein R ³ in the alcohol base is a C ₂ - C ₅ alkyl group, and the alkali metal is one or more of Li, Na, and K. The method according to claim 1, wherein the molar ratio of the compound (II) to the alcohol base (III) is from 1:1 to 1:10. The method according to claim 1, wherein said organic solvent is methanol, ethanol, acetonitrile, dichloromethane, dichloroethane, toluene, xylene, tetrahydrofuran, dioxane, DMSO, DMF, DMAC. One or more of NMPs. The method of claim 1 wherein said rearrangement substitution reaction temperature is from -50 to 50 °C. The method according to claim 1 or 7, wherein said rearrangement substitution reaction temperature is preferably from 0 ° C to 30 ° C.