JPS6317055B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for making useful chemical intermediates.

West German Patent Application No. P28170788 describes the use of dimethyl (N-cyanoimide) carbonate and diethyl (N-cyanoimide) carbonate to produce histamine H-2 antagonists useful in the treatment of peptic ulcers and other related conditions. It is stated that it is manufactured. Other histamine H-2 antagonists, Belgian Patent No. 866155 and European Patent Publication No. 0003640, European Patent Publication No. 0006286 and European Patent Publication No.
0006679, as well as the materials described for example in GB 1338169 and GB 1397436, can be prepared using the same intermediates. The production of dimethyl (N-cyanoimide) carbonate from dimethyl (N-cyanoimide) dithiocarbonate is described in the Journal of Organic Chemistry (J.
Diethyl (N-cyanoimide) -
The production of carbonate by reacting diethylimide carbonate with cyanamide in a non-aqueous solvent at 0°C is described in "Chem. Ber." [Vol. 100, p. 2604, 1967].
It is described in.

According to the invention, it has now been found that the above compounds can be prepared in high yields and in pure form by reacting the corresponding imidocarbonate with cyanamide under aqueous conditions.

According to the invention the formula: [In the formula, R ¹ and R ² are the same, and the number of C atoms is 1
-6 alkyl group or phenyl group, or
R ¹ and R ² are bonded and each has a C-atom number of 1 to
Forms an ethylene or propylene group optionally substituted with one or two alkyl groups of 3]
A di-substituted (N-cyanoimide) carbonate with the formula: A method is obtained by reacting a di-substituted imidocarbonate of [wherein R ¹ and R ² represent the above] with cyanamide, and the method includes 2 containing water and an organic solvent immiscible with water. It consists of carrying out the reaction in a phase system.

Details regarding R ¹ or R ² include, for example, methyl,
Ethyl or isopropyl group. Where R ¹ and R ² are combined to form an ethylene or propylene group, a preferred optional alkyl substituent is a methyl group.

An excellent PH value in the reaction is PH4-10, and a particularly good PH value is PH5-8.

Details of organic solvents that are immiscible with water include, for example, alkyl or dialkylbenzenes in which the alkyl group has 1 to 6 C atoms, toluene, xylene or ethylbenzene, or methylene chloride, ethyl acetate, ether, chloroform, chlorobenzene, n-butanol. Or isobutanol. A good, water-immiscible organic solvent is toluene.

The process may be carried out at temperatures of -15 to 60°C, preferably at temperatures of -5 to 25°C. A particularly preferred temperature is 5
~25℃.

The method may be carried out over a period of 5 minutes to 24 hours, preferably 5 minutes to 1 hour. Cyanamide may be used as the free base or as a salt, such as hydrochloride, hydrobromide, dihydrochloride or dihydrobromide. Dihydrochloride or dihydrobromide may be used as such in solid form, or hydrochloride, hydrobromide, dihydrochloride or dihydrobromide may be used in the form of an aqueous solution. Alternatively, any one of these salts may be prepared in situ in the reaction mixture.

The product can be isolated by separating the water-immiscible solvent from the aqueous phase and optionally subsequently extracting the aqueous phase with a further water-immiscible organic solvent. The product may be isolated by evaporation of the organic solvent to dryness, or the product may be precipitated by adding an organic solvent in which the product has very low solubility, such as petroleum ether or hexane. . This addition may optionally be carried out after reducing the volume of water-immiscible organic solvent. Precipitation of the product may be facilitated by cooling the solvent mixture to, for example, 0°C. If necessary, the product may be recrystallized from a solvent such as a mixture of methylene chloride and ether or a mixture of toluene and hexane.

According to another feature of the invention, the starting material of the formula is itself treated in situ with a suitable alcohol or diol in a two-phase system comprising cyanogen chloride or cyanogen bromide with water and a water-immiscible organic solvent. It can be manufactured by The reaction is preferably carried out in the presence of a base. When R ¹ and R ² are alkyl or phenyl groups, the cyanogen chloride or cyanogen bromide is preferably reacted with 2 or more molar equivalents of an alcohol of the formula R ¹ —OH in the presence of slightly more than 1 equivalent of a base. . When R ¹ and R ² are combined, cyanogen chloride or cyanogen bromide is reacted with one or more molar equivalents of diol in the presence of slightly more than one equivalent of base. The base used may be in the form of an alkoxide derived from the alcohol or diol used in the process of the second invention. When used in this manner, the required minimum amount of free alcohol or diol is reduced by an amount equal to the amount of alkoxide used. Alternatively, the base may be, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide or potassium hydroxide. The alcohol and/or base may be used in amounts significantly exceeding the above-mentioned minimum amounts. Thus, for example, if R ¹ and R ² are alkyl or phenyl groups, 2 to 10, preferably 3 to 4 molar equivalents of alcohol R ¹ --OH are used and >1.0 to 5, preferably 1.1 to 1.5 Equivalent amounts of base may be used. When R ¹ and R ² are combined, the number of molar equivalents of diols which may be used is from 1 to 5, preferably from 1.5 to 2. The base is preferably present in such an amount that in the process of the second invention the PH value of the reaction medium is between PH 11 and 15. The method according to the second invention has a temperature of −15 to
It may be carried out at 60°C, preferably between -5 and 25°C. Particularly advantageous temperatures are from 5 to 25°C. The water-immiscible organic solvent is preferably the same as that used in the first inventive process of the invention. Solvents that are unstable towards bases, such as ethyl acetate, cannot be used. If an alcoholic solvent is used, it must be the same alcohol or diol as that involved in the reaction. The method according to the second invention is 5
It can be carried out over a period of time from minutes to 24 hours, advantageously from 30 minutes to 10 hours.

At the end of the process according to the second invention, the PH value of the reaction mixture can be lowered by the addition of a strong mineral acid, such as hydrochloric acid or sulfuric acid, to a PH value in the superior range of the process according to the first invention. can.

The invention further provides a method for preparing compounds of the formula. The preparation of diethyl imide carbonate from cyanogen chloride by reaction with absolute ethanol and sodium ethoxide at -10°C is described in "Liebigs Annalen" [Vol. 287, p. 310 (1895)]. It is described in. By-products were formed when water was used or temperatures above 0°C were used. Isolation of the product is also difficult when water is used. It has now been found that the product can be obtained in high yield and in pure form by reaction of cyanogen chloride with a suitable alcohol or diol under aqueous conditions.

According to the invention, the formula: [In the formula, R ¹ and R ² are the same, and the number of C atoms is 1
-6 alkyl group or phenyl group, or
R ¹ and R ² are bonded and each has a C-atom number of 1 to
Forms an ethylene or propylene group optionally substituted with one or two alkyl groups of 3]
The preparation of disubstituted imidocarbonates is obtained, the process consisting of carrying out the reaction in a two-phase system containing water and a water-immiscible organic solvent.

The details and preferred conditions for the invention are the same as those detailed for preparing the compound of formula in the process according to the second invention.

Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Example 3 also describes a superior method.

Example 1 A concentrated aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (46 g) in water (35 ml). A measured amount of the solution (58.6 g, containing 27.1 g (0.677 mol) of sodium hydroxide) was diluted with water (20 ml) and the diluted solution was dissolved in methanol (54.2 g) containing 27.1 g (0.677 mol) of sodium hydroxide.
g, 1.69 mol) and toluene (90 ml).
Added with stirring at ~5°C. Toluene (25
A solution of cyanogen chloride (34.7 g, 0.564 mol) in ml) was added over 1 hour, maintaining the temperature of the reaction mixture between 0 and 5 °C;
The mixture was further stirred at 5°C for 2 hours. Then concentrated hydrochloric acid (a solution prepared by adding 36 g of HCl in 64 ml of water)
61.5g, equivalent to 22.2g (0.609 mol) of HCl) at 5℃
The PH value of the reaction mixture while maintaining the temperature below PH
7 (approximately 13
ml). Next, an aqueous solution of cyanamide (42.3 g of a solution prepared by dissolving 50 g of cyanamide in 50 ml of water,
Cyanamide (equivalent to 21.2 g (0.508 mol)) was added simultaneously with the remaining amount of acid. Then the temperature of the mixture is reduced to 1
The temperature was raised to 20°C over a period of time. Water (40ml) was added and the phases were separated when all the sodium chloride had dissolved. The aqueous phase was extracted with toluene (50 ml x 2) and the combined toluene solutions were washed with saturated aqueous sodium chloride (15 ml x 2) and evaporated to dimethyl (N-cyanoimide) carbonate (47.1 g,
73.3%) is obtained as a white solid. Alternatively, the product can be obtained by concentrating the combined toluene solution to approximately 30 ml.
and isolated by adding approximately 40 ml of hexane. The product was recrystallized from methylene chloride/ether (1:2 V/V) and had a melting point of 62-64°C.
It had “J.Org.Chem.” magazine, [Volume 11,
1524 (1974)], the melting point is 52~
It is 56℃.

Example 2 Cyanogen chloride (8.67 g; 0.141 mol) was dissolved in absolute ethanol (33 ml; 0.57 mol) with stirring. Toluene (37.5ml) was added and the solution was cooled to -10°C in an ice/salt bath. A solution of sodium hydroxide (11.24 g; 0.281 mol) in water (29 ml) was added over 1 hour while maintaining the temperature between -10 and -5°C. The reaction mixture was then stirred for an additional hour at -5°C. 36W/W% - Concentrated hydrochloric acid (23.0 g, 8.28 g HCl; equivalent to 0.227 mol) was added in small portions while maintaining the temperature at -5°C, and when half of the acid was added, water (4.7 A solution of cyanamide (4.74 g; 0.113 mol) in ml) was added simultaneously with the remaining amount of acid. The total addition time was 40 minutes and the final PH value was PH 6-7. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 30 minutes. The toluene phase was separated and the aqueous solution was extracted with ethyl acetate (50ml x 2). The organic solutions were combined, washed with water (25 ml x 3), dried (MgSO ₄ ) and evaporated to give diethyl (N-cyanoimide) carbonate (10.19) as a yellow oil.
g, 51%) was obtained. The infrared spectrum (liquid film) of the product was consistent with the description in "Chem. Ber." [vol. 100, p. 2604 (1967)].

Example 3 Toluene (300ml) and methanol (120g, 3.75
mol) mixture was stirred and cooled to 10-15°C. Sodium hydroxide (45.1
g; 1.13 mol) was added to the mixture while maintaining the temperature below 15°C. Cyanogen chloride (58.0 g, 0.94 mol) was then added to the reaction vessel at a temperature of 0 to 0.
Conductivity was maintained at a rate that maintained the temperature at 15°C. After the addition, the mixture was stirred for 2 hours while the temperature was allowed to drop to -10 to -5°C. Then add concentrated hydrochloric acid (to 64 ml of water)
Solution obtained by adding 36 g of HCl 19.0
g, HCl 6.8 g; equivalent to 0.19 mol) was added over a period of about 10 minutes, after which the pH value of the reaction mixture decreased from PH8 to
It was 9. Immediately add an aqueous solution of cyanamide (50 ml of water)
(63 g of solution obtained by dissolving 50 g of cyanamide in the solution, 31.5 g of cyanamide; equivalent to 0.75 mole)
Concentrated hydrochloric acid (72.5 g of solution made by adding 36 g of HCl to 64 ml of water, 26.0 g of HCl; equivalent to 0.71 mol)
was added over about 10 minutes while maintaining the reaction mixture at a temperature below 15°C. The pH value of the mixture at the end of the addition was approximately PH6. mix 20-25
℃ and stirred at this temperature for 1 hour. Water (120ml) was added to the reaction mixture to dissolve the sodium chloride and the phases were separated. The aqueous solution was further extracted with toluene (90ml x 2). The three toluene solutions were combined and washed with a solution of sodium chloride (14g) in water (41ml). Stir the toluene solution,
and diluted with cyclohexane (500ml) and stirred the mixture at -5 to 0°C. Dimethyl (N-cyanoimide) carbonate (58.1g, 54
%) were obtained as white crystals, which were washed with cyclohexane (100 ml) and dried in vacuo at 20°C.

Example 4 A concentrated aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (46g) in water (53ml). A measured amount of the solution (87.7 g, containing 40.8 g of sodium hydroxide; containing 1.02 mol) was diluted with water (29 ml), and the diluted solution was added to methanol (67.7 g; containing 1.02 mol).
2.11 mol) and toluene (125 ml).
It was added with stirring at 5°C. Then toluene (25
A solution of cyanogen chloride (32.5 g; 0.53 mol) in ml) was added while maintaining the reaction mixture at a temperature below 5°C. The mixture was stirred at 0-5°C for 1 hour, then water (50ml) was added and stirring continued for a further 2 hours at 0-5°C. Concentrated hydrochloric acid (in 64 ml of water)
96.4 g of solution prepared by adding 36 g of HCl,
34.7 g of HCl (corresponding to 0.95 mol) was added over 30 minutes while keeping the temperature below 5°C, followed by an aqueous solution of cyanamide (50 g of cyanamide in 50 ml of water).
40.7 g of a solution prepared by dissolving 20.4 g of cyanamide; corresponding to 0.49 mol) were added over 2 minutes at 2°C. The mixture was stirred at 20-25°C for 30 minutes and the phases were separated. Add toluene (50 ml) to the aqueous phase.
×2). The toluene solutions were combined, washed with saturated aqueous sodium chloride (15 ml x 2) and evaporated to give dimethyl (N-cyanoimido) carbonate (20.3 g, 33%) as a white solid.

Example 5 A concentrated aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (46g) in water (53ml). A measured amount of the solution (91.3 g, containing 42.4 g of sodium hydroxide; 1.06 mol) was diluted with water (30 ml) and the diluted solution was dissolved in methanol (70.4 g;
0 to 5 in a mixture of 2.2 mol) and toluene (125 ml)
It was added with stirring at °C. Then toluene (25
A solution of cyanogen chloride (33.8 g; 0.55 mol) in ml) was added while maintaining the reaction mixture at a temperature below 5°C. The mixture was stirred for 1 hour at 0-5°C, then water (50ml) was added and the mixture was stirred for a further 2 hours at 0-5°C. Concentrated hydrochloric acid (in 64 ml of water)
Solution prepared by adding 36g of HCl
53.0 g, HCl 19.1 g; equivalent to 0.52 mol) was added to reach a pH of 8 while maintaining the temperature at 0-5°C. An aqueous solution of cyanamide (42.4 g of a solution prepared by dissolving 50 g of cyanamide in 50 ml of water, 21.2 g of cyanamide; equivalent to 0.50 mol) was added rapidly, followed by further concentrated hydrochloric acid (47.2 g of a solution, 17.0 g of HCl).
g; equivalent to 0.47 mol) was added while maintaining the temperature between 0 and 5°C. The mixture was stirred for 30 minutes at 20-25°C and the phases were separated. The aqueous phase was mixed with toluene (50ml x
2). The toluene solutions were combined, washed with saturated aqueous sodium chloride solution (15 ml x 2) and evaporated to give dimethyl (N-cyanoimido) carbonate (27.8 g; 44%) as a white solid.

Example 6 A concentrated aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (46g) in water (53ml). A measured amount of the solution (70.5 g, containing 32.8 g of sodium hydroxide; containing 0.82 mol) was added to water (24 ml).
and dilute the diluted solution with methanol (54.4
g; 1.70 mol) and toluene (125 ml) at 0-5° C. with stirring. Toluene (45
A solution of cyanogen chloride (26.1 g; 0.42 mol) in ml) was added over 30 minutes, maintaining a temperature of 0-5°C, and the mixture was stirred at 0°C for 90 minutes. Water (50 ml) was then added, followed by concentrated hydrochloric acid (water).
Solution 41.0 made by adding 36g of HCl to 64ml
g, HCl 14.8 g; equivalent to 0.40 mol) were added at once. The temperature rose to 27°C and the PH value was PH8. Aqueous solution of cyanamide (solution prepared by dissolving 50 g of cyanamide in 50 ml of water 32.7
g, cyanamide 16.4 g; equivalent to 0.39 mol) and more concentrated hydrochloric acid (36.4 g solution, 13.1 g HCl;
0.36 mol) was simultaneously added to the mixture over 5 minutes. The temperature of the mixture rose to 38°C and the final PH value was PH6. Heat the mixture to 20-25℃
Stir for 30 minutes and separate the phases. The aqueous phase was washed with saturated aqueous sodium chloride solution (15ml x 2) and evaporated to give dimethyl (N-cyanoimido)carbonate (32.5g, 67%) as a white solid.

Example 7 A concentrated aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (46g) in water (53ml). A weighed amount of the solution (51.5 g, 23.9 g of sodium hydroxide; 0.60 mol) was added to methanol (56.9 g, 0.60 mol).
g; 1.78 mol) and toluene (150 ml).
Added over 12 minutes with stirring at 15-20°C.
The mixture was warmed to 40°C and then toluene (25ml)
A solution of cyanogen chloride (31.0 g; 0.50 mol) in
The addition was carried out over 40 minutes while maintaining the temperature of the mixture at 40-45°C. The mixture was cooled to 20°C and concentrated hydrochloric acid (10.3 g of a solution prepared by adding 36 g of HCl to 64 ml of water, 3.7 g of HCl; equivalent to 0.10 mol) was added to maintain the temperature of the mixture at 15-20°C. The mixture was added over a period of 14 minutes. The pH value at the end of the addition was PH7-8. Aqueous solution of cyanamide (cyanamide in 50 ml of water)
38.2g of solution prepared by dissolving 50g of cyanamide
19.1 g; equivalent to 0.45 mol) and concentrated hydrochloric acid (40.9 g solution, 14.7 g HCl; equivalent to 0.40 mol) were added over 3 minutes. PH value at the end of addition is PH5 ~
It was 6. Add water and heat the mixture at 20-25 °C for 30
Stir for a minute and separate the phases. The aqueous phase was extracted with toluene (50ml x 2), and the toluene solutions were combined.
Washing with saturated aqueous sodium chloride solution (25ml) and evaporation gave dimethyl (N-cyanoimido)carbonate (29.5g, 51%) as a white solid.

Claims (1)

[Claims] 1 Formula: [In the formula, R ¹ and R ² are the same, and the number of C atoms is 1
-6 alkyl group or phenyl group, or
R ¹ and R ² are bonded and each has a C-atom number of 1 to
Forms an ethylene or propylene group optionally substituted with one or two alkyl groups of 3]
A di-substituted (N-cyanoimide) carbonate with the formula: A method for producing by reacting a di-substituted imidocarbonate of [wherein R ¹ and R ² represent the above] with cyanamide, which comprises 2 containing water and an organic solvent that is immiscible with water for the reaction.
Di-substitution (N
-Production method of cyanoimide) carbonate. 2. The method according to claim 1, wherein R ¹ is a methyl or ethyl group. 3. The method according to claim 1 or 2, wherein the reaction mixture has a PH value of PH4 to 10. 4. The method according to claim 1 or 2, wherein the reaction mixture has a PH value of PH5 to 8. 5. The method according to any one of claims 1 to 4, wherein the temperature of the reaction mixture is -15 to 60°C. 6. The method according to any one of claims 1 to 4, wherein the temperature of the reaction mixture is 5 to 25°C. 7 Toluene is an organic solvent that does not mix with water.
A method according to any one of claims 1 to 6. 8 Formula: [In the formula, R ¹ and R ² are the same, and the number of C atoms is 1
-6 alkyl group or phenyl group, or
R ¹ and R ² are bonded and each has a C-atom number of 1 to
Forms an ethylene or propylene group optionally substituted with one or two alkyl groups of 3]
di-substituted (N-cyanoimide) carbonate,
First, cyanogen chloride or bromide is reacted with a suitable alcohol or diol, and then the formula: A method for producing cyanamide by adding cyanamide to a reaction mixture consisting of a di-substituted imidocarbonate [wherein R ¹ and R ² represent the above], wherein all the reactions are carried out using water and an organic solvent that is immiscible with water. A method for producing a di-substituted (N-cyanoimide) carbonate, which is carried out in a two-phase system containing. 9. The method of claim 8, wherein the reaction is carried out in the presence of a base in the preparation of the starting material of formula 9. 10. Process according to claim 9, wherein the base used is sodium hydroxide. 11. The method according to any one of claims 8 to 10, wherein the PH value of the reaction mixture in the preparation of the starting material of formula 11 is PH11 to 15. 12. Claims 8 to 11, wherein the water-immiscible organic solvent used in the preparation of the starting material of formula is the same as the solvent used in the preparation of the compound of formula from formula The method described in any one of the above. 13. The process according to any one of claims 8 to 12, wherein the temperature of the reaction mixture in the preparation of the starting material of formula 13 is between -15 and 60<0>C. 14. The process according to any one of claims 8 to 12, wherein the temperature of the reaction mixture in the preparation of the starting material of formula 14 is between 5 and 25<0>C.