HU196360B - Process for production of disubstituated carbomiimides - Google Patents

Abstract

The cpds. of general formula I and their salts are prepd. by reacting N-substd. phosphoric-acid-amides of general fomula III in an aprotic solvent in the presence of at least 1 mole equiv. water free alkali-metal-carbonate and opt. a phase transfer catalyst with isocyanates of general formula IV, and opt. transforming the resulting prod. of formula I into a salt. - In the formula n has the value of 2 or 3, R1 stands for cyclo-alkyl with 1 or 2 rings having 5-10 carbons, phenyl opt. substd. with halogen, alkyl, alkoxy, an alkyl-thio or alkylene-dioxy gp., or a phenyl-alkyl opt. substd. on the phenyl with halogen, alkyl, alkoxy, an alkyl-thio or alkylene-dioxy gp., R2 and R3 are independently alkyl, phenyl opt. substd. with halogen, alkyl, alkoxy, and alkyl-thio or alkylene-dioxy gp., or phenyl-alkyl opt. substd. on the phenyl with halogen, alkyl, alkoxy, and alkyl-thio or alkylene-dioxy gp. alternately R2 and R3 can form a 5 or 6 membered ring with the intervening nitogen, the ring may be satd. or unsatd. and may contain opt. further hetero-elements like oxygen, sulphur and/or nitrogen, where the nitrogen may in turn be substd. with a short chain alkyl gp.

Description

The present invention relates to a novel process for the preparation of the disubstituted carbodiimides of the formula I and their quaternary ammonium salts, wherein n is 2 or 3,

R ^{1 is C} 1 -C 6 alkyl, C 5 -C 7 cycloalkyl or phenyl, and

R ² and R ^{3 are C} 1 -C 4 alkyl, or R ² and R ³ together with the nitrogen atom to which they are attached are optionally substituted with one to four carbon atoms optionally substituted with one to four carbon atoms and optionally substituted with one to four carbon atoms. can form a group.

This group of carbodynidc was first used by Slicc and Hess in peptide synthesis (J. Am. Chem. Soc. 77, 1067 (1955)). Since then, compounds of this type have been widely used, especially for the immobilization of proteins.

According to the most widely known process currently used, the compounds of formula I are prepared by desulfurization of thioureas of formula 11, wherein R ¹ , R ² and R ³ are as defined above. Nebula metal salts, generally yellow mercury oxide (U.S. Patent No. 2,938,892) or aromatic sulfonic acid chlorides (U.S. Patent No. 3,155,748) are used as desulfurizing reagents. The first method has the disadvantage that the reaction produces a large amount of heavy metal sulfide which is pollutant to the environment and the second method produces the desired carbodinides in very low yields.

Wandsworth and Emmons described in 1964 the observation that the phosphoramidate anion reacts with isocyanates and the resulting adduct decomposes into heat-substituted carbodiimide and dialkyl phosphate (J. Org. Chem. 29, 2816 [1964]). This reaction is illustrated in Scheme A, wherein R is phenyl, tert-butyl or tert-octyl, and R 'is cyclohexyl or dimethylamino.

The starting phosphoramidate anion was prepared using sodium hydride in an aprotic solvent under argon. The industrial application of the method is precluded by the high cost of sodium hydride, the risk of operations with it, and the fact that super-absolute conditions must be ensured during the reaction. By this method, no attempt has been made to prepare disubstituted carbodiimides of formula (I) of relatively complex structure.

In our experiments, it has been found that the disubstituted carbodiimides of formula (I) can be prepared in a simple, harmless and high yield manner by reacting the N-substituted phosphoric acid amides of formula (III) wherein R ² , R ³ and n are as defined above. R ⁴ is an C 1-4 alkyl group - at least 2.5 molar equivalents of anhydrous alkali metal carbonate in an aprotic solvent at a temperature of 80-150 ° C rcagáltatjuk (IV) kcpletű isocyanates: - wherein R * is as defined above. This reaction is illustrated in Scheme (B). Under the reaction conditions, the continuously formed phosphoramidate anion without a solvate envelope under the influence of the solubilized carbonate anion reacts immediately with the isocyanate compound and then cleaves the dialkyl phosphate anion from the formed adduct. The cleaved dialkyl phosphate anion precipitates from the reaction mixture with the alkali metal cation present, while the final product of formula (I) remains in the reaction mixture and can be easily and conveniently isolated by known methods (by evaporation of the solvent).

The reaction employs at least 2.5 molar equivalents, preferably at least 3 molar equivalents, of alkali metal carbonate per mole of the compound of formula (III). The upper limit of the amount of alkali metal carbonate is not critical to the reaction and is essentially limited by economic and operational considerations. It should be noted that mixtures containing more than 8 molar equivalents of alkali metal carbonate are generally difficult to mix, so that more than 8 molar equivalents of alkali metal carbonate is unnecessary.

Suitable aprotic solvents are preferably water immiscible solvents such as benzene, toluene, xylene, chlorobenzene or mixtures thereof. The reaction is carried out at 80-150 ° C, preferably at the boiling point of the solvent or solvent mixture used.

If desired, the compounds of formula (I) may be converted into their quaternary ammonium salts in known manner. Particularly preferred are salts with lower alkyl halides (e.g. methyl iodide) or p-toluenesulfonic acid (lower) alkyl esters, which are crystalline, water-soluble, relatively stable compounds.

Most of the N-substituted phosphoric acid amides of formula (H1) used as starting materials are new compounds. These compounds are preferably prepared by phosphorylating the corresponding amines with di- (lower) alkyl phosphites. The reaction is carried out in an organic solvent, such as carbon tetrachloride, optionally in the presence of an acid acceptor, or under liquid-liquid phase transfer conditions.

The invention is illustrated in detail by the following non-limiting Examples.

Example 1 Preparation of 1-Cyclohexyl-3- [3- (dimethylamino) propyl] carbodiimide

Dissolve 3.4 g (0.01 mol) of O, O-diethyl-N- [3- (dimethylamino) propyl] phosphoric acid amide in 40 ml of anhydrous xylene, and 4.8 g (0.035 mol) of calcined potassium. carbonate and 0.012 mole (1.42 g) of cyclohexyl isocyanate were added and the reaction mixture was heated under reflux (130 ° C) for 14 hours. The consumption of the starting material is monitored by gas chromatography. After refluxing for about 6 hours, an additional 0.2 g of cyclohexyl isocyanate was added. After consuming the starting material, the reaction mixture was cooled, the insoluble material was filtered off and the solvent was evaporated from the filtrate. The oily residue was fractionally distilled at 0.1-0.2 mm Hg. 1.55 g (74.16%) of t-cyclohexyl-3- [3- (dunethylamino) propyl] carbodiimide are obtained as an oil. IR: γ NCN: 2150 cm -1.

196 g (0.0048 mole) of the product obtained above are dissolved in 10 ml of anhydrous ether, 0.89 g (0.0048 mole) of p-oliolulfonic acid m.carbonyl is added and the mixture is left standing overnight. The precipitated crystals are filtered off and the 1-cyclohexyl-3-β-dimethylamino-propyl] -carbodiimide-meth-p-toluene sulfonate is isolated.

82.7%; m.p. 155-162 ° C, IR (KBr):? NCC: 2120 cm?

The starting material Ο, Ο-dimethyl-N- [3- (dimethylamino) propyl] phosphoric acid amide was prepared as follows:

of 20% aqueous sodium hydroxide solution, 0.95 g of tetrabutylammonium chloride, 26 ml of carbon tetrachloride and 26 ml of dichloromethane at 0-10 ° C with stirring 9.65 g (0 (07 moles) of diethyl phosphite and 6.935 g (0.067 moles) of 3- (dimethylamino) propylamine in 25 ml of dichloromethane are added dropwise. After stirring for 2 hours at room temperature, the organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 8 mL). The organic phases are combined, dried over anhydrous calcium chloride, filtered and the filtrate is concentrated under reduced pressure. A pale yellow oily residue is obtained, 0.08-diethyl-N- [3- (diethylamino) -propyl] -phosphoric acid amide (13 g, 81.43%) which is used directly in the reaction according to the invention.

Example 2 Preparation of 1-Cyclohexyl-3- [3- (dictylamoyl) propyl] carbodiimide

The procedure of Example 1 was followed except that 2.65 g (0.01 mol) of O, O-diethyl-N- [3- (dimethylamino) -propyl] -phosphoric acid amide was used. Starting from 0-diethyl-N- [3- (diethylamino) propyl] phosphoric acid amide. The oily residue (3.6 g) was fractionally distilled at 0.1 mm Hg. 2.1 g (88.6%) of 1-cyclohexyl-3- [3- (diethylamino) propyl] carbodiimide are obtained as an oil; b.p.: 120 ° C / 0.1 mm Hg, IR: γ NCN: 2150 cm ^-1 .

of the product obtained above was dissolved in 10 ml of anhydrous ether and 0.79 g (0.0042 mole) of methyl p-toluenesulfonic acid was added. The next day, 1.5 g (84%) of 1-cyclohexyl- [3- (diethylamino) -propyl] -carbodiimide metho-p-toluenesulfonate were precipitated as an oil; IR: y NCN: 2140 cm ^- '.

Analysis Data:

H, 7.33; N, 9.93 Found: C, 62.39; Found: C, 61.89; H, 7.53; N, 9.77.

The starting material 0.0-diethyl-N- [3- (diethylamino) propyl] phosphoric acid amide was prepared according to the procedure described in the last paragraph of Example 1, except that 3- (dimethylamino) 0.067 mol (8.67 g) of 3- (diethylamino) propylamine was used in place of -propylamine. Obtained as an oil, 16.2 g (87%) of O, O-diethyl-N- [3- (diethylamino) -propyl] -phosphoric acid amide, which can be purified by low pressure distillation. Fp .: I ΙΟΙ 15 ^° C / 0.07-0, <) 8 Hgmm.

Example 3

Preparation of 1-cyclohexyl-3- (3-piperidinopropyl) carbodiimide

The procedure of Example I was followed except that 2.78 g (0.01 mol) of 0.08 g (0.01 mol) was replaced by O, O-diethyl-N- [3- (dimethylamino) propyl] -phosphoric acid amide. starting from trielyl-N- (3-piperidinopropyl) -phosphoric acid amide. It was obtained after evaporation of the solvent

The yellowish oily residue (2.36 g) was fractionally distilled at 0.1 mmHg. 1.62 g (65%) of 1-cyclohexyl-3- (3-piperidinopropyl) carbodiimide are obtained; b.p .: 140 ° C / 0, l mmHg IR: yNCN: 2120 c _m - '.

The product obtained above was dissolved in 20 ml of anhydrous ether and 2.24 g (0.012 mole) of p-toluenesulfonic acid m.c. The next day crystals crystallize out of the mixture, which liquefies in the air. 4.3 g (82.3%) of 1-cyclohexyl-3- (3-piperidinopropyl) carbodiimide metho-p-toluene sulfonate are obtained; IR: γ NCN: 2125 cm ^-1 .

Analysis Data:

N, 9.93 Found: C, 63.45; 11, 7.12; Found: C, 63.74; H, 7.52; N, 9.71.

The N- (3-piperidinopropyl) phosphoric acid amyl diethyl ester used as starting material was prepared as described in the last paragraph of Example 1, except that instead of 5 g (0.067 mol) of 3-piperidinopropylamine were used. 15.5 g (83.1%) of N- (3-piperidinopropyl) -phosphoric acid amide diethyl ester as a pale yellow oil are used directly in the reaction according to the invention.

Example 4 Preparation of 1-Cyclohexyl-3- (2-morpholinoethyl) carbodiimide

The procedure of Example I was followed, except that 2.66 g (0.01 mol) of 0.06 g (0.01 mole) of 0.0-diethyl-N- [3- (dimethylamino) propyl] phosphoric acid amide was used. starting from diethyl N - (2 - morpholinoethyl) phosphoric acid amide. After evaporation of the solvent, 1.15 g (68.25%) of 1.15 g (68.25%) of 1-cyclohexyl-3- (2-morpholino) are distilled by fractional distillation at 120-122 [deg.] C. (1.60 g, 68.25%). (ethyl) -carbodiimide, IR (film): δ NCN: 2140 cm ^-1 .

The product obtained above was dissolved in 10 ml of anhydrous ether and 0.79 g (0.0042 mole) of methyl p-toluenesulfonic acid was added. The next day, 1.5 g (83.8%) of 1-cyclohexyl-3- (2-morpholinoctyl) -carbodiimide-meta-p-toluenesulfonate is precipitated as an oily substance.

Analysis Data:

Found: C, 59.62; H, 7.7; N, 9.90; Found: C, 59.21; H, 7; I, N, 9.71.

The starting material used is Ü.O-dictyl-N-35

196 360

- (2-Morpholinoethyl) phosphoric acid amide was prepared as described in the last paragraph of Example 1, except that 8.71 g (0.067 mol) of 2- (instead of 3- (dimethylamino) propylamine) were obtained. morpholinoctylamine is used. 13.93 g of yellow oily O, O-diethyl-N- (2-morpholinoethyl) -phosphoric acid amide are obtained, which can be purified by fractional distillation at 0.1 mm Hg. The boiling point of the distillate is 130 ° C / 0.1 mm Hg.

Example 5 Preparation of 1-Phenyl-3- (3-piperidinopropyl) carbodiimide

Example 1 was repeated except that 2.78 g (0.01 mol) of 0.08 g (0.01 mole) of 0.0-diethyl-N- (3-dimethylamino) propyl] phosphoric acid amide was used. diethyl N- [3- (piperidinopropyl) phosphoric acid] amide and 1.44 g (0.012 mol) phenyl isocyanate was used in place of cyclohexyl isocyanate. Evaporation of the solvent afforded 2.1 g (86.44%) of a yellowish oily 1-phenyl-3- (3-piperidinopropyl) carbodiimide, IR (film): γ NCN: 2125 cm -1.

The product obtained above was dissolved in 10 ml of anhydrous ether and 0.76 g (0.0041 mol) of p-toluenesulfonic acid methyl ester was added. The next day, 1.42 g (80.7%) of 1-phenyl-3- (3-piperidinopropyl) carbodiimide-metho-p-toluenesulfonate were precipitated as an oil; IR (film): NCN: 2122cm ^-1 .

Analysis Data:

Calculated: C, 64.2; H, 5.8; N, 9.78.

Found: C, 63.8; H, 5.9; N, 9.62.

Example 6 Preparation of 1-Ethyl-3- [3- (dimethylamino) propyl] carbodiimide

Example 1 was repeated except that 0.85 g (0.012 mol) of ethyl isocyanate was used in place of cyclohexyl isocyanate.

Evaporation of the solvent afforded 1.32 g of a yellow oil which was purified by fractional distillation at 1 mm Hg. 0.78 g (50.3%) of purified product is obtained; b.p. 73-75 ° C / 1 mm Hg.

The product obtained above is dissolved in 10 ml of anhydrous ether and 0.92 g (0.0065 mole) of methyl iodide are added. After a few minutes, a white microcrystalline substance begins to precipitate which is filtered off after 2 days of standing. 1.53 g (79.3%) of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide methiodide are obtained; m.p. 92-95 ° C.

Analysis Data:

Calculated: C, 36.40; H, 6.74; N, 14.15; Found: C, 36.48; H, 6.83; N, 14.07.

Example 7 Preparation of n-butyl-3- [3- (dimethylamino) propyl] carbodiimide

A procedure I ¹ 'as described in Example I, except for using n-butyl isocyanate (1.2 g, 0.012 mol) instead of cyclohexyl isocyanate. After evaporation of the solvent, 1.4 g of a yellow oil are obtained, which is purified by fractional distillation at 0.1 mm Hg. 0.85 g (46.4%) of purified product is obtained; mp: 75-79 ° C / δ, 1 mmHg.

g (0.0055 mol) of the product obtained above is dissolved in 1 ml of anhydrous ether and 0.78 g (0 0055 mol) of methyl iodide are added to the solution. After a few minutes, a white microcrystalline substance begins to precipitate, which is After standing, 1.48 g of n-butyl-3- [3- (dimethylamino) propyl] carbodiimide methiodide were obtained, yield 82.75%, mp 74-76 ° C.

Analysis Data:

Calculated: C, 40.66; H, 7.39; N, 12.93; Found: C, 40.51; H, 7.42; N, 12.76.

Example 8 Preparation of 1-Cyclohexyl-3- [3- (4-methylpiperazino) -propyl] -carbodiimide

Example 1 was repeated except that 2.93 g (0.01 mole) of O, O-diethyl-N- (3-dimethylamino-propyl) -phosphoric acid amide was used. , 0-Diethyl-N- [3- (4-methyl-piperazino) -propyl] -carboxylic acid amide The product obtained after evaporation of the solvent was dissolved in 20 ml of benzene and 0.5 g of silica gel was added thereto. the mixture was stirred for 15 minutes, the silica gel was filtered off and the filtrate was evaporated to give 2.0 g (76%) of a yellow oily product: IR: γ NCN: 2180 cm-1.

The product thus obtained is dissolved in 10 ml of anhydrous ether and 0.71 g (6, 1038 moles) of p-sulfosulfonic acid methyl ester are added. The precipitated crystals are filtered off after 2 days, 41 g (82.4%) of 1-cyclohexyl-3- [3- (4-methylpiperazino) propyl] carbodiimide metho-p-toluenesulfonate are obtained, m.p. 154-156 ° C.

Analysis Data:

Calculated: C, 61.3; H, 8.5; N, 12.4;

Found: C, 61.54; H, 8.62; N, 12.53.

The starting material, Ο, Ο-diethyl-N- [3- (dimethylamino) -propyl] -phosphoric acid amide, was prepared as described in the last paragraph of Example 1, except that 3- (dimethylamino) 3- (4-piperazinopropyl) amine (10.5 g, 0.067 mol) was used in place of -propylamine. Before evaporation of the solvent, a solution of the product in dichloromethane was stirred with 8 g of silica gel for 15 minutes. The silica gel is filtered off and the filtrate is tube-47

The reaction mixture was concentrated under reduced pressure to yield 19.97 g (76.2%) of O, O-diethyl-N- [3- (dimethylamino) -propyl] -phosphoric acid amide as a pale yellow oil.

Analysis Data:

Calculated: C, 49.14; 11, 9.55; N, 14.32. Found: C, 49.25; H, 9.42; N, 14.41.

Example 9 Preparation of 1-Cyclohexyl-3- (3-pinololidinopropyl) cabodiimide

The procedure of Example 1 was followed except that 2.64 g (0.01 mole) of O, O-diethyl-N- [3- (dimethylamino) propyl] -phosphoric acid was replaced. We start from 0.0 - diethyl - N - (3 - pyrrolidino - propyl) - phosphoric acid amide. Evaporation of the solvent gave 2.3 g of an oil which was purified by distillation to a fraction of 0.2 mm Hg. 2.02 g (86.0%) of the purified product are obtained; mp: 125-127 ° C / 0.2 mmHg.

The product obtained above was dissolved in 10 ml of anhydrous ether and 0.6 g (0.0042 mole) of methyl iodide was added. After standing for 2 days, the precipitated crystals are filtered off. The crystalline product liquefies in air. 1.28 g (81.0%) of 1-cyclohexyl-3- (3-pyrrolidinopropyl) carbodiimide methiodide are obtained; IR: γ NCN: 2170 cm '.

Analysis Data:

Calculated: C3 47.74, 11: 7.48, N: 11.94; Found: C, 47.42; N, 7.81; N, 12.50.

Example 10

Preparation of 1-Cyclohexyl-3- (3-morpholinopropyl) -carbodiimide

Ski

The procedure described in Example 1 was followed except that 2.52 g (0.01 mole) of O, instead of 0.0-diethyl-N- [3- (dimethylamino) -propyl] -phosphoric acid amide, was used. Starting with O-dinielyl-N- (3-morpholino-propyl) -phosphoric acid amidylxal. After evaporation of the solvent, the product obtained is dissolved in 20 ml of benzene, 0.5 g of silica gel is added and the mixture is stirred for 15 minutes. The silica gel was filtered off and the filtrate was evaporated. 1.96 g (78%) of a pale yellow oily product are obtained. IR: γ NCN: 2210 cm ^-1 .

The product obtained above is dissolved in 10 ml of anhydrous ether and 0.56 g (0.004 mol) of methyl iodide are added. The precipitated crystals were filtered off after 2 days of standing. 1.32 g (84.1%) of 1-cyclohexyl-3- (3-morpholino-propyl) -carbodiimide-methiodine are obtained; mp 115-117 ° C.

Analysis Data:

Calculated: C, 45.80; H, 7.18; N, 10.68. Found: C, 45.91; H, 7.32; N, 10.73.

Example 11

Preparation of cyclohexyl-3- (3-morpholinopropyl) carbodiimide

The procedure described in Example 10 was followed except that 3.08 g (0.01 mole) of O, O-di-di was replaced with 0.08-dimethyl-N- (3-morpholinopropyl) -phosphoric acid amide. starting from isopropyl-N- (3-morpholinopropyl) phosphoric acid amide. 1.8 g (45.77%) of a pale yellow oily product are obtained; IR: y NCN: 2210 cm ''.

Example 12 Preparation of 1-Cyclohexyl-3- [3- (dimethylamino) propyl] carbodiimide

The procedure described in Example I was followed, except that 40 ml of benzene was used in place of xylene and the reaction mixture was refluxed for 25 hours (80 ° C) instead of 14 hours. Fractional distillation of the product gave 1.1 g (52.6%) of 1-cyclohexyl-3- [3- (dimethylamino) propyl] carbodiimide; IR: NC NCN: 2150 cm '.

Example 13 Preparation of 1-Cyclohexyl-3- [3- (dimethylamino) propyl] carbodiimide

The procedure of Example I was followed, except that 3.46 g (0.025 mol) of calcined potassium carbonate was used instead of 4.8 g. 1.2 g (57.4%) of 1-cyclohexyl-3- [3- (dimethylamino) propyl] carbodiimide are obtained; IR: γ NCN: 2150 cm ^-1 .

Claims (3)

Patent claims A process for the preparation of disubstituted carbodiimides of the formula I and their quaternary ammonium salts, wherein π is 2 or? R, R 'is C 1-6 alkyl, C 5-7 cycloalkyl or phenyl, and R ² and R ^{3 are C} 1-4 alkyl, or R ² and R ^{3 taken} together with the nitrogen atom to which they are attached may form a 5- or 6-membered saturated heterocyclic group optionally substituted with 1 to 4 carbon atoms optionally substituted with another oxygen or nitrogen heteroatom. Characterized in that an N-substituted phosphoric acid amide of formula (111) wherein n, R ² and R ³ are as defined above and R ⁴ is C 1 -C 4 alkyl is at least 2.5 molar equivalents of anhydrous 196 360 alkali metal carbonate, an isocyanate of the formula in the presence of an aprotic solvent, from 80 to 150 ^D C (IV): - wherein ^R1 is as defined above - are reacted, if desired, converting the product into a quaternary ammonium salt in a known manner. Process according to claim 1, characterized in that from 3 to 8 molar equivalents of the anhydrous alkali metal carbonate are used with respect to the starting material of the formula (III). The process according to claim 1, wherein the aprotic solvent is a water immiscible solvent, preferably benzene or xylene.