JPS61257977A - Fluorine-containing heterocyclic compound - Google Patents

Abstract

NEW MATERIAL:A fluorine-containing heterocyclic compound shown by the formula I (Rf is fluoroalkyl; R<1> and R<2> are alkyl; X is O or S; Y is F, fluoroalkyl or dialkylamino). EXAMPLE:A compound shown by the formula II. USE:An intermediate for a fluoro compound showing physiological activity such as antiviral activity, etc. PREPARATION:A fluoroacylurea shown by the formula III (Rf<1> and Rf<2> are preferably <=5C fluoroalkyl like Rf) or a fluoroacylthiourea is subjected to a ring formation reaction of dehydrofluorination by the action of especially a base (e.g., tertiary amine such as triethylamine, etc.) to give a compound shown by the formula I. Preferably the compound shown by the formula III is produced by reacting a fluoroacylcarboxylic acid fluoride shown by the formula IV with an N,N'-dialkylurea or N,N'-dialkylthiourea shown by the formula V under dehydrofluorination condition.

Description

DETAILED DESCRIPTION OF THE INVENTION A. Field of Industrial Application The present invention relates to fluorine-containing cyclic compounds, particularly closed ring compounds of fluoroacylureas or fluoro-7-sylthioureas.

2. Description of the Related Art Compounds having a fluoroalkyl group such as a trifluoromethyl group are known to exhibit biological activity. Trifluoromethylmalonic acid ester is considered to be useful as a synthetic intermediate for such CF3-containing biologically active substances, and the applicant has proposed an excellent method for synthesizing this trifluoromethylmalonic acid ester and its derivatives in the patent application Sho. 56-1554
This was already proposed in No. 39. This synthesis method is expressed, for example, by the following formula.

In other words, the octafluoroisobutyne-methanol adduct 1 produced by the reaction of octafluoroisobutyne and methanol is reacted with 2 equivalents of triethylamine, and the resulting quaternary erulate anion 1 is reacted with methanol. The reaction produces a ketene acetal containing a small amount of monoester. If this ketene acetal is stirred in methanol for a long time, it becomes an orthoester, but when it is directly treated with concentrated sulfuric acid, trifluoromethylmalonic acid ester↓ is obtained. In addition, to alkylate this ester, RX (alkyl halide) is added in the presence of excess CsF.
When reacted, CF3CR(COOCR3)2 is obtained.

Process leading to the Invention The present inventor conducted various studies on reactions using such trifluoromethylmalonic acid ester or its alkylated ester as a synthetic intermediate, and came across one problem. In other words, it was found that it could not be used for the synthesis of the above-mentioned glycolic acid. This is explained by the following formula: B-COOCR□ゝ' Therefore, the product is only a methylmalonic acid ester or a derivative thereof that does not contain a CF3 group.

20 Object of the Invention The present invention has been made in consideration of these findings, and it is an object of the present invention to provide a fluorine-containing heterocyclic compound useful as a synthetic intermediate for a fluoro compound exhibiting physiological activities such as antiviral activity. The purpose is to

E1 Structure of the invention and its effects, that is, the present invention has the following general formula: (However, Rf is a fluoroalkyl group, Ri and R2 are the same -
or a different alkyl group, X is an oxygen atom or a sulfur atom, Y is a fluorine atom, a fluoroalkyl group or a dialkylamino group. ) This relates to a fluorine-containing heterocyclic compound characterized by the following.

This fluorine-containing heterocyclic compound of the present invention has a fluoroalkyl group at a predetermined position within the molecule, and is useful as an intermediate for the synthesis of fluorocompounds that have pharmacological effects such as antiviral activity and anticancer activity. It is believed that there is. That is, this fluorine-containing heterocyclic compound is a known 5-trifluoromethyl-27- compound that has pharmacological effects such as antiviral activity and anticancer activity.
This is because it has a similar structure to a synthetic intermediate that can lead to dioxyuridine or 5-trifluoromethylthymidine, so it can be expected to be a similar synthetic intermediate.

In the above general formula, Rf, which is important as a fluorine source, preferably consists of a fluoroalkyl group having 5 or less carbon atoms.

This includes -CF a, -CF2CF.

etc. Further, R1 and R2 may also have 5 or less carbon atoms, and examples thereof include -CH3, -C2HS, and the like. In addition to the fluorine atom, Y is a fluoroalkyl group having 5 or less carbon atoms, similar to Rf described above, or a fluoroalkyl group having 1 carbon atom.
0 or less dialkylamino groups (e.g. (CH3)2N-
2(CzHS)2N-1(C3H7)2N-).

The above-mentioned fluorine-containing heterocyclic compound of the present invention has the general formula: (However, Rfl and Rf2 are the same or different fluoroalkyl groups as the above-mentioned Rf, preferably having 5 or less carbon atoms, and R1 and R2 are the above-mentioned fluoroalkyl groups. fluoroacylureas or fluoroacylthioureas represented by X is an oxygen atom or a sulfur atom. Preferably, it is derived via a cyclization reaction under hydrogen.

The above-mentioned fluoroacylureas or fluoroacylthioureas can be prepared according to the following method using the general formula: ) and a fluoroalkylcarboxylic acid fluoride compound represented by the general formula: % formula % (However, R1 and R2 are the same or different alkyl groups as mentioned above, and X is an oxygen atom or a sulfur atom. ) N, N'-dialkyl urea or N, N'-
Preferably, it is produced by reacting it with a dialkylthiourea under dehydrofluorination.

In this production method, the above-mentioned fluoroalkylcarboxylic acid fluoride fully reacts with N,N'-dialkylurea or N,N'-dialkylthiourea under dehydrofluorination without decomposition, so that it can achieve the desired purpose. fluoroacylurea or fluoroacylthiourea can be obtained in good yield. These acylureas obtained can be further treated with a base (a tertiary amine such as newly 446 triethylamine, or a N
, N'-dialkyl urea), it can be converted into the above-mentioned cyclic compound.

In addition, the above-mentioned fluoroalkylcarboxylic acid fluoride is
It is preferable to synthesize it by the following method.

According to this, a fluoroalkene-alcohol adduct represented by the general formula: (However, Rfl and Rf2 are the same as those described above, and R4 is an alkyl group.) and a fluoroalkene-alcohol adduct represented by the general formula: Rs N (However, R5 is an alkyl group similar to R4, for example.) is reacted with a tertiary amine represented by (
Preferably, by reacting 1 equivalent of the fluoroalkene-alcohol adduct with 2 equivalents of tertiary amine, the compound expressed by (wherein Rfi, Rf2, R4 and RS are the same as above) A fluoroalkylcarboxylic acid fluoride is obtained by producing a quaternary amino enolate and acting on this quaternary amino enolate with a strong acid (in particular, a dry strong acid gas).

In the synthesis of this fluoroalkylcarboxylic acid fluoride, R4 in the general formula of the fluoroalkene-alcohol adduct can be selected from various types, and may be a lower alkyl group such as a methyl group, an ethyl group, or a propyl group. As this adduct, the octafluoroisobutyne-methanol adduct described above can be used.

Next, the present invention will be explained more specifically.

First, according to the following reaction, for example, octafluoroisobutyne-methanol adduct 1 is produced by reacting octafluoroisobutyne with methanol, and then this adduct! By reacting 1 equivalent with 2 equivalents of triethylamine in diglyme, the same quaternary aminophenolate 1 as described above was prepared.
The enolate was treated with dry hydrogen chloride gas in a water bath to give 2-trifluoromethyl-3,3,3,-
Synthesize trifluoropropionic acid fluoride i.

The fluoride compound thus synthesized was further reacted with ureas without being isolated. The reaction proceeded as follows, and the corresponding fluoroacylurea compounds were obtained from urea and methylurea.

From methylurea, only the product produced by nucleophilic attack of its -class amino group was obtained.

7 (R:H or methyl group) However, it was found that even when this acylurea 1 was treated with triethylamine, the expected ring-closing compound (CF3-containing heterocyclic compound) was not produced.

On the other hand, when the above fluoride compound is reacted with a dialkylurea (for example, N,N'-dimethylurea) according to the reaction described below, it is possible to react with the corresponding fluoroacylurea i (yield: 34%, for example). A closed ring compound side (yield: 50%, for example) was also produced.

i. That is, a fluoroacylurea is produced under dehydrofluorination through a nucleophilic reaction with the secondary amino group of the N,N'-dimethylurea, while the base action of the N,N'-dimethylurea itself It is thought that a part of the main acylurea self-condenses under dehydrofluorination as described below to produce a closed ring compound.

It was also found that by adding a base such as triethylamine to the above mixture, it was possible to convert ① into a river.

This indicates that the above cyclization reaction proceeds under the action of a base.

The structure of this first published cyclic compound was confirmed by F NMR spectrum analysis, but when a secondary amine such as diethylamine is further added as described below, an addition-elimination reaction easily occurs to obtain a diethylamino derivative.

Incidentally, this addition-elimination reaction proceeds in the same manner even if other reactants are used. In the above-mentioned use, other fluoroalkyl groups or alkyl groups having 5 or less carbon atoms can be used in place of the CF3 group or CH3 group, and the alkyl group of the secondary amine has 5 carbon atoms other than the ethyl group. The following can also be used: The above addition-elimination reaction proceeds at room temperature and is preferably carried out using an aprotic polar solvent such as dimethylformamide.

In the above example, 2-trifluoromethyl-3,3,3-)lifluoropropionic acid fluoride i was used as the starting material, but the same effect can be achieved even if the trifluoromethyl group is replaced with another fluoroalkyl group. The reaction proceeds.

For example, when a pentafluoroethyl group is used, the desired cyclic compound can be obtained by reacting as follows.

In this case, there are two types of cyclic compounds depending on the position where dehydrofluorination occurs in the acylurea as an intermediate product (one has a CF3 group at both the 4 and 5 positions, the other has a fluorine atom at the 4 position and a CF a CF at the 5 position). ) is obtained, in which the z group is bonded.

Next, when N,N'-dimethylthiourea and the above fluoride compound were reacted, fluoroacylthiourea was obtained as shown in the following formula, but its ring-closing compound was not obtained at the same time. However, a closed ring compound can be obtained by reacting the produced fluoroacylthiourea (1) with a base such as triethylamine.

CH3S ■■ Incidentally, this ring-closing compound can be converted into the corresponding dialkylamino derivative similar to the above-mentioned U by the action of a dialkylamine as in the above-mentioned river. In this case as well, the CF3 group and CH3 group in the ring-closing compound position can be replaced by other fluoroalkyl groups or alkyl groups mentioned above, and the amines used can also be other dialkylamines mentioned above other than diethylamine.

Next, the present invention will be explained in more detail with reference to Examples.
It will be understood that various modifications can be made to the following embodiments based on the technical idea of the present invention.

1 unit ±1 octafluoroisobutyne-methanol adduct ((CF
3) z CHCF 20Me): 4.64g
(20mm and 20cc of diglyme were placed in a 50cc Mitsuro flask. Triethylamine: 4.25
g (42 mmo j!) was added dropwise and the mixture was heated at room temperature for 9 to 1
When the mixture was stirred for 0 hours, quaternary ammonium erot was produced. When dry hydrogen chloride gas is blown into this for about 30 minutes under cooling, 3°3.3-)refluoro-2-trifluoromethyl-7'lobionic acid fluoride (1) is produced, and as it is, N,N '-Dimethylurea: 5.29 g (6
Add 0 mmol of chloride and stir overnight at room temperature. You can neutralize it.) The reaction solution was poured into water, the oil layer was separated, and extracted three times with diethyl ether. The extracted liquid and oil layer were combined and washed with water until diglyme disappeared from the ether layer (usually 5 or 6 times).

After drying with magnesium sulfate, the ether was distilled off under reduced pressure to obtain 3.82 g of an oily substance (from IHNMR (■):B/(DI) = 4:6, crude ratio 79% (the above metal addition from the body)).

The obtained mixture of (If) and (III) was dissolved in 15 cc of methylene chloride, and triethylamine: 1.42 g
(14 mmof) () The amount of diethylamine is (
(2 equivalents of (II) in the mixture of II) and (III) may be added), stirred for 12 hours, washed three times with water, and dried over magnesium sulfate. After distilling off methylene chloride under reduced pressure, 3.56 g of oily substance (crude ratio 79
%) obtained. Compound (III) was purified by distilling this under reduced pressure. (bp 112℃10.3IH
g) NMR of (III): ■R of (I[): (Solvent: CDCf 3) S] Direct 11 (III) (IV) (III): 0.678 g (3 mmof),
Put 3 cc of dimethylformamide into a 10 cc Mitsuro flask, and add 0.45 g of diethylamine (6,
2 mmoj was added dropwise. After stirring at room temperature for 1 hour, it was poured into water. A highly viscous oil was obtained, but when diethyl ether was added, it formed into clean crystals, which were filtered.
Dry in a desiccator. Product yield is 0.52
g (yield 62%). Carbon tetrachloride was used for recrystallization. The mp of the product was 125-126.5°C.

NMR of (IV): ■R of (IV): 1585 aa-1 (v c = c ) 1655 〃
(νc=o) 1710 〃(νc=o) (IV) E, A, (calculated value) (%): N: 15.
09 (15,05), C:47.49 (47
, 31), H: 5.89 (5,78) 1 monitoring plate (I) (V) (CF 3) 2 CHCF z OMe: 4.64
g (20 mmo 12 ) and 20 cc of diglyme were placed in a 50 cc Mitsuroh flask to produce acid fluoride (I) in the same manner as in Example 1. Stir overnight at room temperature.

After processing in the same manner as in Example 1, when the ether is distilled off,
Obtained 4.92 g of solid (crudeness 87%) (mpH 4~
117.5°C). It was purified by recrystallization with chloroform (mp 119-120.5°C).

NMR of (V): ! '] 3■, 39 (br) I, R, of (V): 1545 cm' (v - c - Nζ ) ball 1665 〃 (νc=o) E, A, of (V): N: 9.68 ( 9,93), C: 29.
21 (29,79), H: 2.75 (2,
86)

Claims (1)

[Claims] 1. General formulas: ▲ Numerical formulas, chemical formulas, tables, etc.▼ (However, Rf is a fluoroalkyl group, R^1 and R^2 are the same or different alkyl groups, and X is an oxygen atom or sulfur atom, Y is a fluorine atom, a fluoroalkyl group, or a dialkylamino group. 2. The compound according to claim 1, wherein the number of carbon atoms in Rf is 5 or less. 3. The compound described in claim 1 or 2, wherein the number of carbon atoms in R^1 and R^2 is 5 or less. 4. The compound described in any one of claims 1 to 3, wherein Y is a fluoroalkyl group having 5 or less carbon atoms. 5. The compound described in any one of claims 1 to 3, wherein Y is a dialkylamino group having 10 or less carbon atoms.