JPH0125738B2 - - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula Rf-N(NO)-A-R () (wherein, Rf is a perfluoroalkyl group having 1 to 4 carbon atoms, and A is a sulfonyl group or a carbonyl group. (R is an alkyl group having 1 to 4 carbon atoms, a phenyl group-substituted vinyl group, a phenyloxy group, a diphenylamino group, a phenyl group or a nitro group, a halogen atom, or a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms.) Novel N-perfluoroalkyl-
The present invention relates to N-nitrosamine derivatives and methods for producing the same. The N-perfluoroalkyl-N-nitrosamine derivatives of the present invention represented by the general formula () are useful as intermediates in the synthesis of useful substances. For example, N-trifluoromethyl-N-
Nitrososulfonamide derivatives can be reacted with disulfide compounds to form trifluoromethylthioacetic acid and its esters, which are important modifiers for cephalosporins and other products [THE JOURNAL OF
ANT-IBIOTICS, VOL.XXVNo.6463 (1975)
], to β-trifluoromethylthiopropionic acid and its esters useful as agricultural chemicals [see US Pat. No. 3,522,293], and to trifluoromethionine which has antibacterial effects [Can.J.Microbi-ol.
(1), 143 (1966) and Biochem.Bio-phys.Res.
Commun.1975, 63(3), 625, etc.] can be derived (see reference examples below). Conventionally, methods for producing trifluoromethylthioacetic acid or its ester include (1) a method in which trifluoromethylsulfenyl silver salt obtained by reacting silver fluoride and carbon disulfide is reacted with iodoacetic acid; Zhurnal Obschchei Khimii,
35, 1628 (1965)], (2) Trifluoromethyldithioacetate obtained by reacting trifluoromethylsulfenyl chloride produced from trichloromethylsulfenyl chloride with mercaptoacetate is converted into triphenyl Method of obtaining by desulfurization with phosphine [J.Org.Chem, 25 ,
2016 (1960) and JP-A-52-144617], (3) A method in which trifluoromethylsulfenyl chloride obtained in the same manner as in (2) above is reacted with orthoacetic ester and then hydrolyzed. [J.Org.Chem.,
25, 2016 (1960) and JP-A-52-128322],
(4) Trichloromethyldithioacetate obtained by reacting trichloromethylsulfenyl chloride with mercaptoacetate is reacted with potassium fluoride in the presence of crown ether to obtain trifluoromethyldithioacetate, Then, it is obtained by desulfurization using triphenylphosphine [see JP-A-52-144617], (5)
From the reaction between silver salt of trifluoroacetic acid and iodine,
Alternatively, iodotrifluoromethane obtained from the reaction of fluoroform and iodine is obtained by irradiating mercaptoacetic acid with liquid ammonia as a solvent in a glass container [J.Chem,
Soc., 1951 , 584, JP-A-52-68110 and
Zhurnal Organicheskoi Khimii, 13 . 1057
(1977)] is known. However(1)
This method cannot be called an economical method because it uses an expensive silver salt and the reaction takes a long time. Methods (2), (3), and (4) use gases that are extremely toxic to raw materials, etc., and involve long steps with low yields, so they are problematic as industrial production methods. In method 5), expensive silver salts or iodine are used, and in addition, iodotrifluoromethane, which is a gas at room temperature and pressure, and ammonia, which is highly toxic, are liquefied and the photoreaction is carried out in a glass container. It is difficult to use as an industrial manufacturing method because it is complicated and has safety problems. In addition, as a method for producing β-trifluoromethylthiopropionic acid and its ester, mercuric fluoride and carbon disulfide are reacted to form trifluoromethylsulfenylmercury salt, and then treated with hydrogen chloride. A method is known in which trifluoromethyl mercaptan is prepared and then reacted with an acrylic ester under light irradiation [J.Org.
Chem., 22 , 1275 (1957) and U.S. Patent No. 3522293.
[See No.] However, this conventional method uses a highly toxic mercuric salt, and furthermore, the reaction between trifluoromethyl mercaptan and acrylic ester produces a large amount of by-products in addition to the desired product.
Moreover, since the manufacturing process is long and includes steps with low yield, it is difficult to say that it is an economical manufacturing method. In addition, as a method for producing trifluoromethionine, mercuric fluoride and carbon disulfide are reacted to form trifluoromethylsulfenylmercury salt, which is then treated with hydrogen chloride, and then trifluoromethylmercaptan is produced. A known method is to react this with acrolein under light irradiation to form β-trifluoromethylthiopropionaldehyde, and then to react with sodium cyanide to form 5-(β-trifluoromethylthioethyl)hydantoin, which is then hydrolyzed. [J.Org.Chem., 22 ,
1275 (1957)]. However, this conventional method cannot be called an industrial production method because it uses a highly toxic mercuric salt and the production process is long and includes steps with low yields. As a result of repeated studies to overcome the drawbacks of conventional methods, the present inventors have discovered a substance that can be easily derived into a perfluoroalkylthio compound, and have completed the present invention. The production method of the present invention uses a perfluoronitrosoalkane represented by the general formula Rf-NO (), a hydroxylamine and a general formula R-A-X () (where Rf, R and A are the same as above) under basic conditions. and
X is a leaving group. ) is reacted to produce an N-perfluoroalkyl-N-nitrosamine derivative represented by the general formula (). The perfluoronitrosoalkanes of the general formula () which are raw materials for the production of the compounds of the present invention include:
For example, trifluoronitrosomethane, pentafluoronitrosoethane, n-heptafluoronitrosopropane, 2-nitrosoheptafluoropropane, n-perfluoronitrosoptan, etc. can be used. Further, as described above, the compound represented by the general formula () is a substituted sulfonyl compound and a substituted carbonyl compound having a leaving group. Here, the leaving group is generally under nucleophilic reaction conditions,
It represents an easily substitutable functional group, such as a halogen atom, a carbonyloxy group, a sulfonyloxy group, an alkoxy group, or an aryloxy group. Compounds represented by the general formula () having these groups include benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-toluenesulfonyl bromide, nitrobenzenesulfonyl chloride, chlorobenzenesulfonyl chloride, dichlorobenzenesulfonyl chloride, methanesulfonyl chloride, butanesulfonyl bromide, benzenesulfonic anhydride,
Substituted sulfonyl compounds such as methanesulfonic anhydride, benzoyl chloride, benzoyl fluoride, p-methylbenzoyl bromide, nitrobenzoyl chloride, chlorobenzoyl chloride, fluorobenzoyl chloride, acetyl chloride,
halogenoformic acid esters such as butyryl chloride, cinnamoyl chloride, and chloroformic acid phenyl ester; acid anhydrides such as acetic anhydride and benzoic anhydride;
Examples include carbonate esters such as diphenyl carbonate, and substituted carbonyl compounds such as carbamoyl halides such as N,N-diphenylcarbamoyl chloride. The production method of the present invention needs to be carried out under basic conditions. Basic conditions include, for example, sodium methoxide, sodium ethoxide, potassium t
- This can be achieved by the presence of a base such as an alkali metal alkoxide such as butoxide, a metal hydride such as sodium hydride or calcium hydride, a metal hydroxide such as sodium hydroxide or potassium hydroxide, or an organic amine such as triethylamine. . The production method of the present invention is carried out by reacting the three raw materials as described above, but more preferably, after reacting the perfluoronitrosoalkane represented by the general formula () with hydroxylamine, This is carried out by adding a base together with the compound represented by the general formula (). When carrying out the production method of the present invention, it is desirable to use a solvent, such as methanol,
Alcohols such as ethanol and isopropyl alcohol, ethers such as diethyl ether and tetrahydrofuran (THF), polar solvents such as acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, etc. can be used. The reaction is-
The reaction proceeds at a temperature of 100°C to room temperature, but preferably -80°C to -10°C in order for the reaction to proceed smoothly with good yield. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 After dissolving 0.46 g of hydroxylamine hydrochloride in a mixture of 4 ml of DMF and 1 ml of ether, potassium t
-0.77 g of butoxide was added under stirring. After 20 minutes, it was filtered to obtain a hydroxylamine solution. THF5ml
was added, the solution was cooled to −75° C., and trifluoronitrosomethane was blown into the solution while stirring until a blue color remained. Then sodium hydride (50%
inoil) 0.36g and benzenesulfonyl chloride 1.27
A solution prepared by dissolving 1.g in 5 ml of ether was added thereto, and the mixture was stirred for 4 hours and then returned to room temperature. Water was added, extracted with ether, and dried over magnesium sulfate. It was filtered, the solvent was distilled off, and recrystallized from pentane to give 0.95 g of N-
Trifluoromethyl-N-nitrosobenzenesulfonamide was obtained as colorless crystals. Yield 57%. The physical properties of this product were as follows. Melting point: 57-58℃・^19F -NMR (in deuterated chloroform, CCl ₃ F internal standard): -70.5ppm (bs, CF ₃ ). ^1H -NMR (in deuterated chloroform): 7.74ppm
(m, 3H), 8.13 (m, 2H). IR (nujol): 1510 (NO), 1450, 1360 ( _SO2 ),
1310, 1260, 1160, 1130, 1080, 910, 760, 730,
600, 560cm ^-1 . Molecular weight measurement: 262 (calculated value 254). Elemental analysis: Actual values: C: 33.09, H: 1.95, N: 11.21%. Calculated values: C; 33.08, H; 1.98, N; 11.02%. Examples 2 to 15 The reaction was carried out in the same manner as in Example 1 under the conditions shown in Table 1. The results are shown in Table 1. The physical properties of the obtained substance are shown in Table 2. [Table] [Table] [Table] Reference Example 1 22 ml of acetone, 2 g of dithiodiacetic acid, 2.79 g of N-trifluoromethyl-N-nitrosobenzenesulfonamide and diacetyl in a Pyrex container.
0.095 ml was added thereto, argon was blown into it to replace the argon, and the mixture was irradiated with light using a 400W high-pressure mercury lamp for 14 hours. After the reaction, acetone was distilled off and vacuum distillation was performed to obtain 1.1 g of trifluoromethylthioacetic acid.
(63%). Boiling point: 64°C/15mmHg. ¹⁹ F-NMR (in deuterated chloroform, CCl ₃ F internal standard): -42.4 ppm (s, CF ₃ ). ¹ H-NMR (in deuterated chloroform): δ3.70 (-
CH ₂ −). IR (neat): 3100 (broad absorption), 1725, 1420,
1390, 1110, 900, 755, 640cm ^-1 . Mass spectrum: 160 (M ⁺ ). Reference Example 2 42.1 mg of β,β'-dithiodipropionic acid, 50.9 mg of N-trifluoromethyl-N-nitrosobenzenesulfonamide and 2.0 mg of benzyl were mixed with 1.1 mg of acetone.
ml, and after spraying with argon, it was irradiated with a high-pressure mercury lamp for 3.5 hours. After the reaction, the solvent was distilled off, and the residue was fractionated and purified by gas chromatography to obtain β-trifluoromethylthiopropionic acid as an oil (yield: 50%). The physical properties were as follows. ¹⁹ F-NMR (in deuterated chloroform, CCl ₃ F internal standard): -41.7 ppm (s, CF ₃ ). ¹ H-NMR (in deuterated chloroform): 2.83ppm
(m, 2H), 3.14 (m, 2H). IR (neat): 3100 (broad absorption), 1720, 1420,
1110, 940, 755 cm ^-1 . Reference example 3 β, β'-dithiodipropionic acid dimethyl ester 47.0 mg, N-trifluoromethyl-N-nitrosobenzenesulfonamide 50.4 mg and benzyl
2.0 mg was dissolved in 0.8 ml of acetone, and after purging with argon, it was irradiated with a high-pressure mercury lamp for 4 hours. After treatment in a conventional manner, β-trifluoromethylthiopropionic acid methyl ester was obtained in a yield of 52%. Structure confirmation is ^19F
-1H -NMR and IR spectra. Reference example 4 N,N'-bis(trifluoroacetyl)homocystine dimethyl ester in a Pyrex container
1.0g, N-trifluoromethyl-N-nitrosobenzenesulfonamide 0.56g, diacetyl 0.19
Add 11 ml of acetone and 25 ml under argon atmosphere.
℃ and 7 hours of irradiation using a 400W high-pressure mercury lamp.
After the reaction, the solvent was distilled off and 0.38 g of N-trifluoroacetyltrifluoromethionine methyl ester (2-trifluoroacetamino-4-trifluoromethylthio-n-methyl butyrate) was obtained as an oil by silica gel column chromatography. (yield 59%). Its physical property values are shown below. ^1H -NMR (in deuterated chloroform): 7.1ppm (bs,
NH), 4.60 (q, J=6.5Hz, CHCO), 3.79 (s,
CH ₃ ), 2.88 (t, J = 7.0Hz, SCH ₂ ), 2.6 to 1.9
(m, CH ₂ ). ¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform): -41.4 ppm (s, CF ₃ S), -75.8 (s,
CF ₃ CO). IR (neat): 3350, 1720, 1560, 1440, 1220,
1170, 1120cm ^-1 . Elemental analysis: Actual values: C: 30.52, H: 2.85, N: 4.52%. Calculated values: C: 30.68, H: 2.90, N: 4.47%. Next, dissolve 0.35 g of the oily substance obtained in the above reaction in 4 ml of methanol, and add a 2N aqueous sodium hydroxide solution.
1.5 ml was added and stirred at room temperature for 5 hours. Thereafter, the solvent was distilled off, a small amount of water was added, and the mixture was neutralized with dilute acid. The resulting precipitate was filtered, washed with water, then acetone, and dried.
0.17g trifluoromethionine (2-amino-
4-trifluoromethylthio-n-butyric acid) was obtained (yield 75%). Purification was performed by recrystallization from methanol. Next, the physical property values are shown. Melting point: 224-225°C (both decomposed) [Literature value 230°C (both decomposed)]. ¹⁶ F-NMR (CCl ₃ F internal standard in heavy methanol): -40.9 ppm (s, CF ₃ ). ^1H -NMR (in heavy methanol): 3.59ppm (t,
J = 6.5Hz, CHCO), 3.1 (m, SCH ₂ )・2.2 (m,
_CH2 ). IR (nujol): 1590, 1510, 1100 cm ^-1 . Elemental analysis: Actual values: C: 29.74, H: 3.91, N: 6.78%. Calculated values: C: 29.56, H: 3.97, N: 6.89%.

Claims (1)

[Scope of Claims] 1 N-perfluoroalkyl-N-nitrosamine derivatives represented by the general formula Rf-N(NO)-A-R (wherein Rf is a perfluoroalkyl group having 1 to 4 carbon atoms, A is a sulfonyl group or a carbonyl group, and R is an alkyl group having 1 to 4 carbon atoms, a phenyl group-substituted vinyl group, a phenyloxy group, a diphenylamino group, a phenyl group or a nitro group, a halogen atom or an alkyl group having 1 to 4 carbon atoms. is a substituted phenyl group). 2 General formula Rf-N(NO)-A, which consists of reacting a perfluoronitrosoalkane represented by the general formula Rf-NO, hydroxylamine, and a compound represented by the general formula R-A-X under basic conditions. A method for producing an N-perfluoroalkyl-N-nitrosamine derivative represented by -R (wherein, Rf is a perfluoroalkyl group having 1 to 4 carbon atoms, A is a sulfonyl group or a carbonyl group, and R is a carbon number 1 to 4 alkyl groups, phenyl group-substituted vinyl groups, phenyloxy groups, diphenylamino groups, phenyl groups or nitro groups, halogen atoms or C1 to C4 alkyl group substituted phenyl groups,
X is a leaving group). 3. The method according to claim 1 or 2, wherein X is a halogen atom, a carbonyloxy group, a sulfonyloxy group, an alkoxy group, or an aryloxy group.