JPS628431B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to fluoroacylureas or fluoroacylthioureas. Some 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 filed a patent application for an excellent synthetic method for trifluoromethylmalonic acid ester and its derivatives. It was already proposed in No. 155439 of 1982. This synthesis method is expressed, for example, by the following formula. That is, the octafluoroisobutene-methanol adduct 2 produced by the reaction of octafluoroisobutene 1 and methanol is reacted with 2 equivalents of triethylamine, and a small amount is reacted with the resulting quaternary enolate anion 3 and methanol. A ketene acetal containing a monoester of is produced. Then, if this ketene acetal is stirred in methanol for a long time, it becomes an orthoester, but it is directly treated with concentrated sulfuric acid to obtain trifluoromethylmalonic acid ester 4. Also, to alkylate this oster, reacting RX (alkyl halide) in the presence of excess CsF results in CF ₃ CR
(COOCH ₃ ) ₂ is obtained. The present inventor conducted various studies on reactions using such trifluoromethylmalonic acid ester 4 or its alkylated ester as a synthetic intermediate, and encountered one problem. In other words, it was found that the above-mentioned ester 4 or a derivative thereof cannot be used for the synthesis of CF ₃ -containing barbituric acid by reaction with ureas because it is easily decomposed by a base. This is explained by the following formula: Therefore, the product is only a methylmalonic acid ester or a derivative thereof that does not contain CF ₃ groups. The present invention has been made in consideration of these findings, and has the following general formula: (However, Rf ¹ and Rf ² are the same or different perfluoroalkyl groups, R ¹ and R ² are the same or different alkyl groups, and X is an oxygen atom or a sulfur atom.) It relates to fluoroacylureas or fluoroacylthioureas. Since this new acylurea or acylthiourea consists of a dialkylurea containing a perfluoroalkyl group in its molecule, it is considered to be useful as an intermediate for the synthesis of urea-based fluorocompounds that exhibit physiological activities such as antiviral activity. It will be done. In the above general formula of the fluoroacylurea or fluoroacylthiourea, Rf ¹ and Rf ² , which are important as fluorine sources, preferably consist of a perfluoroalkyl group having 5 or less carbon atoms. This includes −
CF ₃ , −CF ₂ CF ₃ , −CF ₂ CF ₂ CF ₃ ,

[Formula] −CF ₂ CF ₂ CF ₂ CF ₃ ,

Examples include [Formula]. Further, R ¹ and R ² may also have 5 or less carbon atoms, and may include -CH ₃ , -C ₂ H ₅ , -CH ₂ CH ₂ CH ₃ ,

[Formula] −CH ₂ CH ₂ CH ₂ CH ₃ ,

Examples include [Formula]. Furthermore, from the above-mentioned fluoroacylurea or fluoroacylthiourea according to the present invention, a ring-closing compound represented by the following general formula can be obtained through a cyclization reaction under dehydrofluorination under the action of a base (for example, a tertiary amine such as triethylamine). Preferably, the compound is derived. General formula: (However, Rf ³ is a perfluoroalkyl group, R ¹ and
R ² is the same or different alkyl group as described above, X is an oxygen atom or a sulfur atom, and Y is a fluorine atom, a fluoroalkyl group or a dialkylamino group. ) This ring-closed compound is useful as a physiologically active substance or a synthetic intermediate thereof. For example, this ring-closed compound is a synthetic intermediate that can lead to 5-trifluoromethyl-2'-deoxyuridine or 5-trifluoromethylthymidine, which has known pharmacological effects such as antiviral activity and anticancer activity. Since it has a similar structure, it can be expected to be a similar synthetic intermediate. In the above general formula, Rf ³ is the above-mentioned Rf ¹ or
It is preferably composed of a perfluoroalkyl group having 5 or less carbon atoms, similar to Rf ² . In addition to the fluorine atom, Y is a perfluoroalkyl group having 5 or less carbon atoms similar to Rf ¹ or Rf ² described above, or a dialkylamino group having 10 or less carbon atoms (for example, (CH ₃ ) ₂ N- , (C ₂ H ₅ ) ₂ N−, (C ₃ H ₇ ) ₂ N−). Furthermore, the above fluoroacylureas or fluoroacylthioureas according to the present invention can be prepared according to the following method by the general formula: (However, Rf ¹ and Rf ² are the same as those mentioned above, and preferably consist of a perfluoroalkyl group having 5 or less carbon atoms.) A fluoroalkylcarboxylic acid fluoride represented by the general formula: (However, R ¹ and R ² are the same or different alkyl groups as mentioned above, and X is an oxygen atom or a sulfur atom.)
Preferably, it is produced by reacting N'-dialkylthiourea under dehydrofluorination. In this production method, the above-mentioned fluoroalkylcarboxylic acid fluoride is N,N'-
Since it reacts sufficiently with dialkylurea or N,N'-dialkylthiourea under dehydrofluorination, the desired fluoroacylurea or fluoroacylthiourea can be obtained in good yield. These acylureas obtained are further treated with a base (a newly added tertiary amine such as triethylamine, or a
The above-mentioned cyclic compounds can be converted by a cyclization reaction in the presence of N'-dialkyl urea). Further, the above-mentioned fluoroalkylcarboxylic acid fluoride is preferably synthesized by the following method. According to this, the general formula: (However, Rf ¹ and Rf ² are the same as above, R ⁴
is an alkyl group. ⁾ _is reacted ^{( preferably} By reacting 1 equivalent of fluoroalkene-alcohol adduct with 2 equivalents of tertiary amine, the general formula: (However, Rf ¹ , Rf ² , R ⁴ and R ⁵ are the same as above.) The quaternary amino enolate represented by
A fluoroalkylcarboxylic acid fluoride is obtained by reacting with dry strong acid gas). In the synthesis of this fluoroalkylcarboxylic acid fluoride, R ⁴ 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, ethyl group, or propyl group. As this adduct, the octafluoroisobutene-methanol adduct described above can be used. Next, the present invention will be explained more specifically. First, according to the following reaction, for example, octafluoroisobutene-methanol adduct 2 is produced by reacting octafluoroisobutene 1 with methanol, and then 2 equivalents of this adduct is reacted with 2 equivalents of triethylamine in diglyme. , the same quaternary amino enolate 3 as previously described is produced, and this enolate is treated with dry hydrogen chloride gas in an ice bath to produce 2-trifluoromethyl-3,3,3-trifluoropropionic acid fluoride. Synthesize 5. The fluoride 5 synthesized in this way was not isolated and was further reacted with ureas. The reaction proceeded as follows, and the corresponding fluoroacylureas 6 were obtained from urea and methylurea. From methylurea, only the product produced by nucleophilic attack of its primary amino group was obtained. However, it was found that this acylurea 7 did not produce the expected ring-closing compound (CF ₃ -containing heterocyclic compound) even when treated with triethylamine. In contrast, according to the following reaction according to the present invention, the above fluoride 5 and dialkylurea (e.g.
When reacted with N,N'-dialkyl urea 8), the corresponding fluoroacylurea 9 (yield, e.g. 34%) and its ring-closed compound 10 (yield, e.g. 50%) were also produced. That is, a nucleophilic reaction with the secondary amino group of the N,N'-dimethylurea produces fluoroacylurea 9 under dehydrofluorination, while the N,N'-
It is thought that due to the basic action of dimethylurea itself, a part of acylurea 9 undergoes self-condensation under dehydrofluorination as described below to produce ring-closed compound 10. It was also found that 9 could be converted to 10 by adding a base such as triethylamine to the mixture of 9 and 10. This indicates that the above cyclization reaction proceeds under the action of a base. The structure of this cyclic compound 10 was confirmed by ¹⁹ FNMR spectrum analysis, but when a secondary amine such as diethylamine is further added as described below, an addition-elimination reaction easily occurs to obtain diethylamino derivative 11. Note that this addition-elimination reaction proceeds in the same manner even if other reactants are used. In 10 above, ₃ CF or
In place of the CH ₃ group, other fluoroalkyl groups or alkyl groups having up to 5 carbon atoms can be used, and groups other than ethyl groups with up to 5 carbon atoms can also be used as the alkyl group of the secondary amine. It is possible. 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-trifluoropropionic acid fluoride 5 was used as the starting material, but the reaction can be performed in the same way by using the trifluoromethyl group as another fluoroalkyl group. progresses. For example, when using a pentafluoroethyl group,
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 CF ₃ group at both the 4 and 5 positions, the other has a fluorine atom at the 4 position and a fluorine atom at the 5 position). ) is obtained, in which _two CF ₃ CF groups are bonded. Next, when N,N'-dimethylthiourea and the above fluoride 5 were reacted, fluoroacylthiourea 12 was obtained as shown in the following formula, but its ring-closed compound was not obtained at the same time. However, by reacting the generated fluoroacylthiourea 12 with a base such as triethylamine, a ring-closing compound 13 can be obtained.
can be obtained. Note that this ring-closing compound 13 can be converted into a corresponding dialkylamino derivative similar to the above-mentioned 11 by the action of a dialkylamine, similarly to the above-mentioned 10. Again, the _CF3 of the closed ring compound 13
group, CH ₃ group to other fluoroalkyl groups mentioned above,
It can be an alkyl group, and the amine used can also be the above-mentioned dialkylamines other than diethylamine. Next, the present invention will be described in more detail with reference to examples, but it will be understood that various modifications can be made to the following examples based on the technical idea of the present invention. Example 1 Octafluoroisobutene-methanol adduct ((CF ₃ ) ₂ CHCF ₂ OMe): 4.64 g (20 mmol) and diglyme 20 cc. were placed in a 50 cc. three-necked flask. Triethylamine: 4.25g (42mmol) was added dropwise,
Stirring at room temperature for 9-10 hours produced quaternary ammonium enolate. When dry hydrogen chloride gas is blown into this under ice cooling for about 30 minutes, 3,3,3-trifluoro-2-trifluoromethyl-propionic acid fluoride () is produced, and as it is, N,
Add N'-dimethylurea: 5.29g (60mmol),
Stir overnight at room temperature. (If the reaction is not complete even after stirring overnight, this is because the excess hydrogen chloride gas will generate urea and salts. Neutralize by adding pyridine.) ). Pour the reaction solution into water, separate the oil layer, extract three times with diethyl ether, combine the extract and oil layer, and add water.
Washing was performed until the diglyme disappeared from the ether layer (usually 5 or 6 times). After drying with magnesium sulfate, the ether was distilled off under reduced pressure, leaving 3.82 g of an oily substance.
Obtained ( ^1HNMR ():()=4:6,
Crude yield 79% (from the above metal adduct). The analytical data of the product () was as follows. ¹ HNMR of () (solvent: CDCl ₃ ): δ = 2.94 (d, J = 4.8Hz, 3H) 3.41 (s, 3H) 4.46 (sep, J = 6.2Hz, 1H) 8.73 (br, 1H) () ¹⁹ FNMR (external standard: CF ₃ CO ₂ H): δ = −13.3 (d, J = 6.2 Hz) The obtained mixture of () and () was dissolved in 15 c.c. of methylene chloride, and triethylamine: 1.42 g
(14 mmol) (the amount of triethylamine can be determined by adding 2 equivalents of () in the mixture of () and ()), and after stirring for 12 hours, the mixture was washed with water three times and dried over magnesium sulfate. After distilling off methylene chloride under reduced pressure, 3.56 g of oily substance (crude yield 79
%) obtained. By distilling this under reduced pressure,
Compound () was purified. (bp112℃/0.3mmH
g) NMR of (): IR of (): 1500cm ^-1 (νc=c) 1685 〃 (νc=o) 1735 〃 (νc=o) Reference example (): 0.678 g (3 mmol) and 3 c.c. of dimethylformamide were placed in a 10 c.c. three-necked flask, and cooled on ice.
Diethylamine: 0.45 g (6.2 mmol) was added dropwise. After stirring at room temperature for 1 hour, it was poured into water. A highly viscous oil was obtained which, upon addition of diethyl ether, formed into clean crystals which were filtered and dried 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 (): IR of (): 1585cm ^-1 (νc=c) 1655 〃 (νc=o) 1710 〃 (νc=o) EA (calculated value) (%) of (): N: 15.09 (15.05), C: 47.49 ( 47.31), H:
5.89 (5.78) Example 2 (CF ₃ ) ₂ CHCF ₂ OMe: 4.64 g (20 mmol) and diglyme 20 c.c. were placed in a 50 c.c. three-necked flask to produce acid fluoride () in the same manner as in Example 1, and then N, N'-dimethylthiourea 6.25g
(60 mmol) was added and stirred overnight at room temperature. After treatment in the same manner as in Example 1, ether was distilled off to obtain 4.92 g of solid (crude yield: 87%) (mp114~
117.5℃). It was purified by recrystallization with chloroform (mp119-120.5°C). NMR of (): IR of (): 1545cm ^-1

[Formula] 1665 〃 (νc=o) () EA: N: 9.68 (9.93), C: 29.21 (29.79), H:
2.75 (2.86).

Claims (1)

[Claims] 1. General formula: (However, Rf ¹ and Rf ² are the same or different perfluoroalkyl groups, R ¹ and R ² are the same or different alkyl groups, and X is an oxygen atom or a sulfur atom.) Acyl ureas or fluoroacyl thioureas. 2. The ureas described in claim 1, wherein the number of carbon atoms in Rf ¹ and Rf ² is 5 or less. 3. The ureas described in claim 1 or ² , wherein the number of carbon atoms in R ¹ and R 2 is 5 or less.