JPS63126856A - Manufacture of di-substituted imidocarbonate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to a method for producing useful chemical intermediates.

West German patent application no. cyanoimide)
It is described that it is manufactured using carbonate.

Other histamine H-2 antagonists, Belgian patent no. 866
No. 155 and European Patent Publication No. 0003640,
710006286 and 0006679, as well as for example British patent dX13!1
The materials described in No. 8169 and No. 1,597,456 can also be produced using the same intermediate materials. The preparation of dimethyl (N-cyanoimido) carbonate from dimethyl (N-cyanoimido)zothiocarbonate is described in "Journal of Organic Chemistry (J, Org.

chem, )' (Vol. 69, p. 1522 (197
4 years)]. The preparation of diethyl (N-cyanoimir)-carbonate by reacting diethyl imir-carnabonate with cyazamide in a non-aqueous solvent at 0°C has been described in Chem. 100 volumes,
26043f, 1967].

By the way, dispatch jljj (Special Application No. 7021/1982: t
According to the invention of JP-A-55-100655), the above-mentioned compound can be produced in high yield and in a pure form by reacting the corresponding imidocarbonate and 7-anamide under aqueous conditions. According to the formula: [wherein R and R2 are the same and are an alkyl group having 1 to 6 carbon atoms or a phenyl group, or R1 and R2
are bonded to each alkyl group having 1 to 6 C atoms 1
Forming an ethylene or propylene group which may be di-substituted by 1 or 2 (N-cyanoimide)
A method is obtained for producing carbonate by reacting a dirt-transformed imi-P carbonate of the formula: [wherein R5 and R2 are as defined above] with a 7-anamide, which method comprises water and immiscible with water. It consists of carrying out the reaction in a two-phase system containing an organic solvent.

Particulars regarding R' or R2 are, for example, methyl, ethyl or isopropyl groups. When R and R2 are combined to form an ethylene or propylene group, a preferred optional alkyl substituent is a methyl group.

An excellent value for the reaction is between pH 4 and 10, and an especially excellent 9-value is F! 45-8.

For details on organic solvents that are immiscible with water, for example, the alkyl group is C
- alkyl or dialkylbenzenes having 1 to 6 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 a temperature of -15 to 60<0>C, preferably at a temperature of -5 to 25<0>C. A particularly preferred temperature is 5 to 250°C.

The process may be carried out over a period of 5 minutes to 24 hours, preferably 15 minutes to 1 hour. Cyanamide may be used as the free base or as eg hydrochloride, hydrobromide, dihydrochloride or dihydrobromide. Zohy P lochloride or dihydrobromide may be used as such in solid form, or hydrochlori P1 hydrobromide, dihydrochloride or dihydrobromide may be used in the form of a water bath liquid. 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 evaporated and dried and isolated, or the product has a very low M's character with a very low produce +! Precipitation may also be effected by adding an A4 agent such as petroleum ether or hexane. This addition may optionally take place after reducing the volume of the water-immiscible organic bath agent. 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 claimed invention, the starting material of formula (1) itself can be prepared in situ by mixing cyanogen chloride or cyanogen bromide with a suitable alcohol in a two-phase system comprising water and an organic solvent which is immiscible with water. Alternatively, it has been found that it can be produced by treatment with a diol. The reaction is preferably carried out in the presence of a base. When R1 and R2 are alkyl or phenyl groups, the cyanogen chloride or beautified cyanogen preferably has more than 2 molar equivalents of the formula: R
React with 1-OH alcohol. When R1 and R2 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 alkoxy P derived from the alcohol or diol used in the process of the second derivative 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. Alcohols and/or bases may be used in amounts significantly exceeding the above-mentioned minimum amounts. Thus, for example, if HA and R2 are alkyl or phenyl groups, 2 to 10, preferably 6 to 4 molar equivalents of alcohol R1
-OH and from /1.0 to 5, preferably from 1.1 to
1.5 equivalents of salt 4 may be used. When R and R2 are bonded, the number of diol groups which may be used is from 1 to 5, preferably from 1.5 to 2. The base is preferably present in the process of the 24th patent application such that the pH value of the reaction medium is between -11 and 15. The method according to the invention for the second meal is carried out at a temperature of -15 to 60 °C, preferably -15 to 2 °C.
It may be carried out at 5°C. Particularly advantageous temperatures are 5-25°C
It is. Organic solvents that are immiscible with water are advantageously used in the first patent application.
It is the same as that used in the method according to the invention of the examiner.

A base-unstable mortar, such as ethyl acetate, cannot be used. If an alcoholic mash is used, it must be the same alcohol or diol as that involved in the reaction. The process according to the second invention of the subsidiary application can be carried out over a period of 5 minutes to 24 hours, preferably 60 minutes to 10 hours.

Part 2 of the sub-application! At the end of the process according to the first invention of the application, the β value of the reaction mixture is reduced by the addition of a strong mineral acid, such as hydrochloric acid or sulfuric acid, to a β value in the superior range of the process according to the invention of the first patent application. can do.

According to the present invention, there is further provided a method for producing the compound of formula (1). Absolute ethanol and sodium ethoxy P and -10
The preparation of diethyl imide carbonate from cyanogen chloride by reaction at 1.
7, 310-member (1895)].

By-products are formed when water is used or temperatures above 0°C are used. Isolation of the product is also an option 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 present invention, the formula: [wherein R1 and R2 are the same and are an alkyl group having 1 to 6 carbon atoms or a phenyl group, or R1 and R2
are bonded to each alkyl group having 1 to 6 C atoms 1
forming ethyl-V or propylene-1ii, which may be substituted by It consists of what is done in a two-phase system.

The detailed and preferred conditions for the invention are the same as those detailed for preparing the compound of formula (1) 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 Add concentrated sodium hydroxide aqueous solution to sodium hydroxide (46,
! i') was prepared by dissolving it in water (!1511/). 1irt'jk of the solution (containing 58,6,F, 27,1 ! IC 0,677 mol) of sodium hydroxide) was diluted with water (20117), and the diluted solution was diluted with methanol (54,2,9 , 1,69 mol) and toluene (S>017) at 0-5° C. with stirring. Cyanogen chloride (34!/) in toluene (25++!/)
, 7L O, 564 mol) was added over ti hours, maintaining the temperature of the reaction mixture t'' at 0-5°C, and the mixture was then stirred for a further 2 hours at 0-5°C. Hydrogen acid (solution #61.5.9 prepared by adding HCl 561 to water 64'ILl, HCl22-2
;9 (corresponding to 0-609 mol)) was added while maintaining the temperature below t-5° C. until the β value of the reaction mixture decreased to pH 7 (approximately 16 d of acid added). Next, cyanamide water sg (a solution prepared by bathing 50 g of cyanamide in 50 d of water 42.5.!ii', cyanamide r21.
2. ! i' (corresponding to 0,508 mol)) was added simultaneously with the remaining amount of acid. The temperature of the mixture was then raised to 20°C over a period of 1 hour. Water (40m7) was added and the phases were separated when all the sodium chloride had dissolved. The aqueous phase was extracted with toluene (50×2) and the combined toluene was washed with saturated aqueous sodium chloride (151/×2) and evaporated to dimethyl (N-cyanoimir)carpone) (47,1 , 9,73,3%) was obtained as a white solid. Alternatively, the product was isolated by concentrating the combined toluene baths to about 50,111 ml and adding about 4 Qa/h of hexane. The product was recrystallized from methylene chloride/ether (1:2 V/V) and had a melting point of 62-
It had a temperature of 64°C. @J, Org, Chem,” magazine,
The melting point reported in [Vol. 11, p. 1524 (1974)] is 52-56°C.

Example 2 Cyanogen chloride (8.67 g: 0.141 mol) was stirred into absolute ethanol (331!/: 0.577 mol). Add toluene (57,51111>,
The solution was then cooled to -10°C in an ice/salt bath. Water (2
Sodium hydroxide (11,24,9:
Solution f of 0.281 mol) was added over 1 hour while maintaining the temperature at -10 to -5°C. The reaction mixture was then stirred for an additional hour at -5°C. 36W/W%-concentrated hydrochloric acid (25,011, HCl 8.289: 0.2
(equivalent to 27 mol) was added little by little while maintaining the temperature at -5°C, and when half a ton of acid was added, water (equivalent to 4,7 mol)
cyanamide (4,74, P: 0.11) in II/)
3 mol) solution was added simultaneously with the acid IAt. The total addition time was 40 minutes, and the final β value was PH6-7.
Met. Remove the cooling bath and add the reaction mixture t-60
Allowed to rise to room temperature over a period of minutes.

The toluene phase was separated and the aqueous solution was diluted with ethyl acetate (5Qa
/X 2 ). Combine the organic solutions and add water (251
12/X3), dried with MgSO4), and evaporated to give dimethyl (N-cyanoimide) as a yellow oil.
Carbonay) (10,19,51151%) was obtained. The infrared spectrum (liquid film) of the product is °Chem, B
er, vol. c100, p. 2604 (1967)].

Example 6 Toluene (300m) and methanol (1201,5,7
5 mol) was stirred and cooled to 10-15°C. Sodium hydroxide (45,
A solution of 1 g: 1.13 mol) was added to the mixture while maintaining the temperature below the i s'ct. Then cyanogen chloride (58,0&.

0.94 mol) was passed into the reaction vessel at such a rate that the temperature was maintained between 0 and 15°C. The addition@mixture was stirred for 2 hours, during which time the temperature was lowered to -10 to -5<0>C. Then the bath obtained by adding concentrated chlorinated water $rR (water 64 vertically HCl 36,!i'*19.09, HCl 6
．． B I : equivalent to 0.19 mol) was added over a period of about 10 minutes, after which the β value of the reaction mixture was P) (8 to
It was 9. Immediately make a solution of cyanamide (a solution obtained by dissolving 50 g of cyanamide in 50 g of water)
6g, cyanamide 31. ! Hydrochloric acid (corresponding to M: 0.75 mol) is prepared by adding HCl 36 and !i' to 64 mol of water to produce a bath solution of 72.5 L HCl 26.09
; equivalent to 0.71 mol) of the reaction mixture
The addition was carried out over approximately 10 minutes while maintaining the temperature below 0C. The beta value of the mixture at the end of the addition was approximately -6. The mixture was warmed to 20-25°C and stirred at this temperature for 1 hour. Water (120ml) was added to the reaction mixture to bathe the sodium chloride and the phases were separated. The water bath solution was further extracted with toluene (90×2). Combine the six toluene solutions and add sodium chloride (14 ml) in water (41 ml).
，! Washed with solution i'). The toluene solution was stirred and diluted with cyclohexane (500 FILt) and the mixture was stirred at t--5-0<0>C. Filter and dimethyl (N
-cyanoimide) carbonate (58,1, F, 54%
) was obtained as white crystals, which was mixed with cyclohexane (1
00m) and dried in vacuo at 20°C.

Example 4 A concentrated aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (4611) in water (511/).

A measured amount of the solution (87.7 g.

Sodium hydroxide (containing 40.8 &: 1.02 mol) was diluted with water (29 Fll/), and the diluted solution was mixed with methanol (67,711: 2.11 mol) and toluene (1
25 m) was added to the mixture with stirring from 0 to 5'0. Then cyanogen chloride (52
, 511: 0.53 mol) in the reaction mixture t-
The addition was made while maintaining the temperature below 5°C. Mixture from 0 to
Stirring was continued for 1 hour at 5°C, then water (50111/) was added and stirring was continued for a further 2 hours at 0-5°C. - Hydrochloric acid (corresponding to 96.41.Hcz34.7 g of bath solution prepared by adding 361 HCl to 64 d of water: 0.95 mol) is added over a period of 60 minutes while maintaining the temperature below 5°C. , then a cyanamide water bath solution (5 Qm of water/
40.7 g of a solution prepared by dissolving cyanamide 50.9 in cyanamide 20.4 & : 0.49
molar equivalent) was added over 2 minutes at 2°C. The mixture was stirred at 20-25°C for 60 minutes and the phases were separated.

The aqueous phase was extracted with toluene (50m+7X2). Combine the toluene solutions and add saturated sodium chloride water m*<15m/
X2) and evaporation to give dimethyl (N-cyanoimido) carbonate (20,3, 33% Fl) as a white solid.

Example 5 Concentrated Hydroxide An aqueous solution of IJ cum was prepared by dispersing 46 Jl of sodium hydroxide in water (5M).

Weighed the child's bath solution (91.3 g, sodium hydroxide 4
2.49: containing 1.06 mol) with water (30 m/) and the diluted solution with methanol (70.4 g;
2.2 mol) and toluene (12511!7) with stirring at 0-5°C. Then toluene (2
Cyanogen chloride (33,8F; 0.55 in 5+R1)
mol) of bath liquid 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 (501111) was added and the mixture was further stirred for 2 hours.
Stir for hours 0-5"0. Hydrochloric acid (64 mL water)
A solution prepared by adding HCl 569 to t'' 53.0,!i!, HCtl 9.111:
(equivalent to 0.52 mol) 1 - p) (8) was added while maintaining the temperature between 0 and 5 °C.Cyanamide water bath g (water 5
゜ is prepared by mixing cyanamide so, pts in 9 solutions 42.4 &, cyanamide 21,2, @
: equivalent to 0.50 mol) and then further hydrochloric acid (bath solution 47.211.Hcz 17.0
&: equivalent to 0.47 mol) was added while maintaining the temperature at 0-5°C. The mixture was stirred for 60 minutes at 20-25°C and the phases were separated. The aqueous phase was replaced with toluene (501117X
2). Combine the toluene solutions and saturated chloride)
Washed in a 13 um water bath (15ffi/X 2) and evaporated to dimethyl (N-cyanoimide) carbonate) (
27,8, li': 44%) was obtained as a white solid.

Example 6 An aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (46,F) in water (53m). A measured amount of the solution (70.5 g 1 containing 0.82 mol of sodium hydroxide) was added to water (24 m
), and the diluted bath solution was diluted with methanol (54,4,
It was added to a mixture of f; 1,70 mo, A/) and toluene (1251/) while stirring at 0-5''C.Toluene (
cyanogen chloride (26,111: 0.4
A solution of 2 mol) was added over 60 minutes while maintaining a temperature of 0-5°C and the mixture was stirred for 90 minutes with t-o ”c. Water (50 m) was then added and subsequently hydrogen chloride rR ( Produced by adding water 64xdVCHC1561/9 bath g41.Og, Hct 14-81: 0.
40 mol) were added at once. The temperature rose to 27°C and the -I value was -8. Aqueous solution of cyanamide (solution prepared by dissolving 50.9 t of cyanamide in 50 IILt of water, 52.79 t of cyanamide, 16.9 t of cyanamide)
4 & : equivalent to 0.59 mol) and more concentrated hydrochloric acid (bath solution 56.49, HCtl 3.1, @ :0
．． 667 l) was simultaneously added to the mixture over 5 minutes. The temperature of the mixture rose to 68°C and the final β value was PH6. Mixture t-6 at 20-25 °C
Stir for 0 min and separate the phases. The aqueous phase was washed with saturated aqueous sodium chloride solution (15ij x 2) and evaporated to give dimethyl(N-7anoimiP)carbonate (62,
5L (67%) was obtained as a white solid.

Example 7 A concentrated sodium hydroxide water bath solution was prepared by dissolving sodium hydroxide (46N) in water (53m). Weighed children's weight (51,57, sodium hydroxide 25.
9.9 ; 0.60 mol) in methanol (56,9 &
; 1.78 mol) and toluene (150 ml) over 12 minutes with stirring at 15-20"0. Mixture f: warmed to 40°C and then added toluene (2
cyanogen chloride (51,0,!i': 0.
50 mol) of #enemy, the temperature of the mixture is 40-45 ° OK
Add over 40 minutes while maintaining. Mixture at 20℃
cooled to
10.3 g of solution prepared by adding 69, HCl 5
．． 7&: equivalent to 0.10 mol) was added over 14 minutes while maintaining the temperature of the t-mixture at 15-20°C.

The β value at the end of the addition was -7 to 8. Aqueous solution of cyanamide (solution 5B prepared by dissolving cyanamide 5ON in 5C1l of water, 21.19.1 g of cyanamide: 0.
45 mol) and concentrated chlorinated water"Jg acid (bath solution 40.9
1. acz i 4.71; equivalent to 0.40 mol)
was added over 6 minutes.

Claims (1)

[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. ▼II [In the formula, R^1 and R^2 are the same and represent an alkyl group having 1 to 6 C atoms or a phenyl group. or R^
1 and R^2 are combined to form an ethylene group or a propylene group, each of which may be substituted with one or two alkyl groups having 1 to 3 C-atoms], to cyanogen chloride. or by reacting cyanogen bromide with a suitable alcohol or diol, characterized in that the reaction is carried out in a two-phase system containing water and a water-immiscible organic solvent.
Method for producing di-substituted imidocarbonate