JPS58152857A - Fluoroacylurea compound of fluoroacylthiourea compound, and their cyclized compound - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(Rf<1> and Rf<2> are fluoroalkyl; R<1> and R<2> are alkyl; X is O or S) and its cyclized compound. EXAMPLE:The compound of formula II. USE:Useful as a synthetic intermediate of urea-based fluoro-compound. PROCESS:The compound of formulaIcan be prepared by the dehydrofluorination reaction of the fluoroalkylcarboxylic acid fluoride of formula III (Rf<1> and Rf<2> are preferably <=5C fluoroalkyl) with the N, N'-dialkylurea or N, N'-dialkylthiourea of formula IV. The compound of formula III reacts sufficiently with the compound of formula IV without decomposition.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to fluoroacylureas or fluoroacylthioureas and closed ring compounds thereof.

Compounds having a fluoroalkyl group such as a trifluoromethyl group are known to exhibit biological activity.
As described above, trifluoromethylmalonic acid ester is considered to be useful as a synthetic intermediate for the biologically active substance CFs, and the present applicant has proposed nine excellent synthetic methods for this trifluoromethylmalonic acid ester and its derivatives. 56-15
Already proposed in No. 5439. This synthesis method is carried out using, for example, the following formula: %Formula %: In other words, the octafluoroisobutyne-methanol adduct produced by the reaction of octafluoroisobutyne 1 and methanol is reacted with 2 equivalents of triethylane, and the resulting 9 #I quaternary Elto anion fi tome! Reaction with nol produces ketene acetal containing a small amount of monoester. Then, 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, a trifluoromethylmalonic acid ester is obtained. In addition, when K that alkylates this ester is reacted with RX (alkyl halide) in the presence of excess CsF, CFsCR (COOCH3) is formed.
2 is obtained.

The present inventor conducted various studies on the reaction using ζ9-trifluoromethylmalonic acid ester or its alkylated ester as a synthetic intermediate, and encountered one problem. It was found that the derivative cannot be used for the synthesis of CFs-containing barbituric acid due to the reaction with ureas because it is easily decomposed by base. This is explained by the following formula:

Therefore, the product is only a methylmylonate ester or a derivative thereof that does not contain a CFx group.

The present invention was made in consideration of these findings, and has the general formula: (However, Rf' and Rf'' are the same or different fluoroalkyl groups, nl and I are the same or different alkyl groups, and X is oxygen This invention relates to novel fluoroacylureas or fluoroacylthioureas characterized by the following:

Since this new acylurea or acylthiourea is composed of a dialkylurea containing a fluoroalkyl group in the molecule, it is considered to be useful as an intermediate for the synthesis of urea thread fluoro compounds that exhibit unique physiological activity.

In the above general formula of this fluoroacylurea or fluoroacylthiourea, Rf'' and Rf'', which are important as fluorine sources, are fluorocarbons having 5 or less carbon atoms. It is preferable that a ring-closing compound represented by the following general formula according to the present invention is derived through a cyclization reaction under dehydrofluorination under the action of a base (for example, a tertiary amine such as triethyl or amine).

(However, Rf3 is a fluoroalkyl group, R1 and ♂ are the same -
or a different alkyl group as in 9 above, X is an oxygen atom or a sulfur atom, and Y is one 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.

And in the above general formula, Rf'' is the above-mentioned 9Rf' or Rf
It is preferable that the group consists of a fluoroalkyl group having 5 or less carbon atoms similar to ``. group, or dialkylamino group having less than or equal to the number of carbon atoms lθ (e.g. (CHs)zN-1(CzHs)
zN% (CmHy)*N-).

Furthermore, the above fluoroacylureas or fluoroacylthioureas according to the present invention can be prepared according to the following method by the general formula: A fluoroalkylcarboxylic acid heptatride represented by the following formula: In this production method, it is preferable to produce by reacting N,N-dialkylurea or N,N-dialkylthiourea, which is an oxygen atom or a sulfur atom, under dehydrogenation. The above-mentioned fluoroalkylcarboxylic acid fluoride is a decomposable fluoride (because it fully reacts with N,N-dialkylurea or N,N'-dialkylthiourea under dehydrofluorination,
The desired fluoroacylurea or fluoroacylthiourea can be obtained in good yield. These obtained acylureas are further converted into the above-mentioned round cyclic compounds by a cyclization reaction in the presence of a base (newly added and a tertiary amine such as 9-triethyl aquine, or an N,N-dialkyl motive force). can be done.

First, the above 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, Rf" and Rf" are the same as above, and t is an alkyl group.)
A reaction with a tertiary amine represented by the general formula: R's N (wherein R1 is, for example, the same alkyl group as R4) (preferably, the tertiary amine is reacted with one equivalent of the fluoroalkene-alcohol adduct. (reaction of 2 equivalents) to produce a quaternary asonoenolate represented by the general formula: Strong acid to quaternary annoenolate (%, dry strong acid gas)
A fluoroalkylcarboxylic acid fluoride is obtained by reacting with fluoroalkylcarboxylic acid fluoride.

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.

First, according to the following reaction, for example, an octafluoroisobutyne-methanol adduct zt is produced by the reaction of octafluoroisobutyne 1 and methanol, and further, this adduct 1 is reacted with 1 equivalent KZ weight of triethyl 7one in diglyme. The quaternary amino enolate l as described above and similar to 9.
The enolate was treated with dry hydrogen chloride gas in a water bath to produce 2-trifluoromethyl-3,3,3-).
Synthesizing refluoropropionic acid fluoride 01
The fluoride chloride synthesized in this way was not isolated, but was further reacted with ureas. The reaction proceeded as follows, and the corresponding fluoroacylurea chloride was obtained from urea and methylurea. It will be done.

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

1 ヱ(R:H or methyl group) However, it was found that even if this acylurea ヱ was treated with triethylamine, the expected ring-closing compound (CFm-containing heterocyclic compound) was not produced. In contrast, according to the following reaction according to the present invention, the above 7
When a thuride and a dialkylurea (e.g., N,N-dimethylurea) are reacted, the corresponding fluoroacylurea (yield, e.g., 34 qb) and its ring-closed compound W (yield, e.g., 50%) are produced. was also generated.

Reciprocally, fluoroacylurea is produced by the nucleophilic reaction of the secondary adenogroup of the above-mentioned N,N-dimethylurea under the dehydrogeneptaminated state, while the above-mentioned N,N'-dimethylurea itself is produced by a nucleophilic reaction. It is believed that a part of the acylurea self-condenses under dehydrofluorination as described below due to the action of the base, producing a closed field compound W.

It has been found that by adding a base such as triethylamine to a mixture of the above and W, it is possible to convert it into a conventional product.

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

The structure of this cyclic compound W was confirmed by F NMR spectrum analysis, and when a secondary atone such as diethylamine was further added as shown below, it easily undergoes an addition-elimination reaction.
A diethylamino derivative U is obtained.

Hs Note that this addition-elimination reaction proceeds in the same way even if other reactants are used. In the above [), other fluoroalkyl groups or alkyl groups having 5 or less carbon atoms can be used as substitutes for the CFs group or CHs group, and other fluoroalkyl groups or alkyl groups having 5 or less carbon atoms can be used as substitutes for the CFs group or CHs group. Those having 5 or less carbon atoms 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. - Trifluoropropionic acid fluoride was used, but the reaction proceeds in the same way if the trifluoromethyl group is replaced with another fluoroalkyl group. For example, when using pentafluoroethyl group, the reaction is as follows. The desired cyclic compound can be obtained.

Hs 0 In this case, de7 in the acylurea as intermediate product
Two types of cyclic compounds are obtained depending on the position where hydrogen fluoride occurs (one type has a co-KCFs group at the 4- and 5-positions, and the other has a fluorine atom at the 4-position and a KCFsCF* group at the 5-position).

Next, when N,N-dimethylthiourea and the above fluoride are reacted, a fluoroacylthiourea compound is obtained as shown in the following formula, but the closed field compound is not obtained at the same time. A closed ring compound υ can be obtained by reacting a base such as triethylamine with the fluoroacylthiourea compound obtained.

Furthermore, this closed-field compound S can be converted into the corresponding dialkylaano derivative similar to the above-mentioned 9U by the action of a dialkylamine in the same manner as described above. In this case as well, the CFn group and C6 group of the closed-field compound Hiiragi can be replaced with the other fluoroalkyl groups and alkyl groups mentioned above, and the ann to be used can also be any of the above-mentioned dialkylamines other than diethylamine.

However, it will be understood that the following embodiments can be modified from time to time based on the technical idea of the present invention.

Example 1 Octafluoroisobutyne-methanol adduct ((CF
n) mcHcFzOMe): 4.641 (20
mmot) and diglyme 2eCc: were placed in 50 cc of Mitsulov Tusco.

Triethylamine: 4.25 g (42 mmoj) was added dropwise and stirred at room temperature for 9 to 10 hours to produce quaternary ammonium salt. When dry hydrogen chloride gas is blown into this under water cooling for approximately 1 minute, 3,3.3-)refluoro-2-trifluoromethyl-propionic acid fluoride l) is produced, and its 11XN,N- Dimethylurea: 5
．． 29 Jir (60 mmoA) was added and stirred overnight at room temperature. (-If the reaction is not completed even after stirring overnight, it is because urea and salt are generated due to excess hydrogen chloride gas, and the pyridine In addition, it may be necessary to neutralize it.) Pour the reaction solution into water, separate the oil layer, extract 3 times with diethyl ether, combine the extract and oil layer,
Washed with water until diglyme disappeared from the ether layer (usually 5.6 times). After drying with magnesium sulfate, ether was distilled off under reduced pressure to obtain an oily substance of 3.82% ('HNMR analysis (IF): (III) =
4:e, crude yield 79% (from the above metal adduct))
0 The obtained mixture of (II) and (m) was diluted with methylene chloride.
Dissolve secK, triethylamine: 1.42JF (1
4 mmoj) () The amount of diethylamine is (II)
2 equivalents of (II) in the mixture of
After drying over magnesium sulfate and removing methylene chloride under reduced pressure, 3.56 g (crude yield 79) of an oily substance was obtained.
) was purified. (bp 112V0.8sw city t) (I
NMR of II): I of (III)
R: (solvent: cncz,) Example 2 (11) (TV) (II
I): 0.678 # (3 mmoj), dimethylformamide 3 Cct, put in a 10 cc Mitsuro flask, under ice cooling, diethylamine: 0.459 (6.2 mmo
A) was added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into water. A highly viscous oil was obtained, but upon addition of diethyl ether, clean crystals appeared), which was filtered and dried in a digitizer. Product yield is 0.52II
Carbon tetrachloride was used for Top-P0 recrystallization (yield: 62 cm). The mp of the product was 125-126.5°C.

NMR of (IV): IR of (IV): 1585IM″1 (νe = c) 1655#(ν
c = o) 1710# (νc = o) (IV) E, A, (calculated value) (%) :N:
15. os (15,05), C: 47.49 (4
7,31), H: 5.89 (5,78) Example 3 (I) (V) (CFs)
2CHCFzOM*: 4.64Ji'G! Omm
oA), 20 cc of diglyme was placed in a 5 occ Mituro flask, acid fluoride (I) was produced in the same manner as in Example 1, and then 6.25 J of ttNXN'-dimethylthiourea was produced.
il (60 mmot) was added and stirred overnight at room temperature. After treatment in the same manner as in Example 1, the ether was distilled off to obtain a solid of 4.92Ii (crude fraction &71).
14-117.5°C) and purified by recrystallization with chloroform.

(1.R, of (v): E, A, of (V): N: 9.68 (9,93) C: 29.21 (2
9,79) H: 2.75 (2,81)＼ Representative Patent Attorney Hiroshi Aisaka

Claims (1)

[Claims] 1. General formula: (However, Rf' and Rf'' are the same or different fluoroalkyl groups, nl and t are the same or different alkyl groups, and X is an oxygen atom or a sulfur atom.) Fluoroacylureas or fluoroacylthioureas characterized by the following: 2. The ureas described in claim 1, wherein Rf' and Rf'' have 5 or less carbon atoms. 3.8 Ureas according to claim 1 or 2, wherein the number of carbon atoms in 1 and - is 5 or less. 4. General formula: (However, Rf" is a fluoroalkyl group ul and ♂ 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 dialkylanno group. ) A ring-closed compound of fluoroacylureas or fluoroacylthioureas 05, R
The ring-closed compound according to claim 4, wherein f'' has 5 or less carbon atoms. 6, R1 and I have 5 or less carbon atoms, or A ring-closing compound as described in Section 5. ?, Y is fluorotetraalkyl 4 having 5 or less carbon atoms; Closed-field compound 08 described in Claim 1. The closed ring compound described in any one of Claims 4 to 6, wherein Y is a dialkylamino group having 10 or less carbon atoms.