DE1543942C - Process for the preparation of 1 Oxa 2 methyl 3 carbonylarmno 4 tnia cyclohe xen (2) en - Google Patents

Description

The invention relates to a process for the production of hydrolyzed acid, which converts the acid into an acid halide of 1 - oxa - 2 - methyl - 3 - aminocarbonyl - 4 - thia and mag Amine of the general formula

/ R \

HN

in which R ¹ and R ^{3 are} identical or different and are hydrogen, fine aniirro group or dialkylamino group, remote alkyl, alkynyl, cycloalkyl, araikyl [ Al Alk

^ y, y, yyl ^ AyV [

Aryl, alkaryl groups or radicals of heterocyclic compounds ;; with one or more: Heteroatoms, such as nitrogen, oxygen, and / or sulfur, which are optionally substituted by hydroxyl, alkoxy, carboxyl, carbalkp, carboxamide, nitrile, mercapto, alkyl mercapto, halogen and / or nitro groups can be very substituted ^ where R ¹ and R ^{2 can} also be connected by an alkylene chain which can be interrupted by an oxygen or nitrogen atom, characterized in that one

a) an N-substituted a-chloro-acetic acid amide the general formula

20th

, R ¹

CRCOCHCICON

.30

in which R ¹ and R ^{2 have} the meaning given, reacts with 2-mercaptoethanol in a customary solvent in the presence of a base and cyclizes the intermediate product formed by elimination of water during acidification or

b) an α-chloro-acetic acid ester of the general formula

CH ₃ -CO-CH-COOR

40

■ egg. .

in which R is a low molecular weight alkyl group, with 2-mercaptoethanol in a conventional solvent Reacts in the presence of a base, the resulting intermediate product with acidification to, a Ester cyclizes, the ester to the corresponding

C-CH ₃
H ₂ = CCNR ¹ , + SQ ₂ Cl ₂ .

■ .-. ■ ^ ■■■■ y. Q: R2 .- ■■ ■ · ■■ Λ .-. ··. :

implements.

The compounds prepared according to the invention are not only useful as intermediates for the manufacture of other chemical compounds ^ s'onderiv they find practical use themselves as fungicide, bacetericide and for other purposes.

From J. Chem. Soc, 1959, pp. 2360 to 2363; the implementation of monochloroacetone with 1-thioethanol (2) is known. According to the invention, however, no halogenated ketone is used, but an acetoacetic acid derivative. Under the alkaline conditions used according to the invention, either cleavage of the acyl radical (—COCH ₃ ), so-called customary acid cleavage of the acetoacetic derivatives, or cleavage of the carboxyl radical, so-called customary ketone cleavage, is therefore to be expected in the usual manner with acetoacetic acid derivatives. In the case of the known ketone derivatives, however, this possibility does not exist, but it was surprisingly found that in the reaction occurring in the present case neither the expected ketone cleavage nor the expected acid cleavage occurs, but ring closure with formation of a 1-oxa-4-thia-cyclohexene - 2-derivative entrance. This implementation is completely surprising.

The first method, which is represented by the following reaction equations, is based on known ones a-chloro-acetoacetamides of the formula III, which by known methods, for. B. by chlorination the acetoacetamides of the formula II can be prepared with sulfuryl chloride in benzene. These a-chloro-acetoacetamides of the formula III are made basic with 2-mercaptoethanol of the formula IV Conditions implemented. The a-bromo-acetoacetamides can be used as starting compounds in the same way Find use. The reaction proceeds via two intermediate compounds V and VI, which neither need to be isolated.

The substituents given in the following formulas are explained in detail below.

-ΊΙ ■ - ^r '

C-CH ₃
- H — C — C — N — R ¹

', · ■■ ■ · Cl O R ²

II

III -

OH
CH ₂
CH ₂
SH
IY

H-III "OH O

CH ₂ C-CH ₃

CH ₂ C-C-N-R ¹

\ c / l Il I

_ -, ^ HQR ²

'• ■ ν

1 543 942 4th 3 ■: ■ CH ₃ ^:
/ Ο \ / ³ CH ₃ : (Y ΟΆ: H ₊ I I
\ / \ · -H \ C / \
^b C — Ν — R ¹
Il I * C — Ν — R ¹ 'JfII L ■ ·
OR ² ' Ό R ² -,

The reactions between the compounds of the formulas III and IV in the presence of a base, and although either an inorganic base, e.g. B. an alkali metal hydroxide, carbonate or bicarbonate, or an organic base, e.g. pyridine or N, N-dimethylaniline, proceeds easily at room temperature. The reaction is carried out in an inert solvent, e.g. B. water; Alcohol, such as methanol, Ethanol, butanol or propanol, or benzene, hexane, ether, acetone, pyridine or dioxane or a mixture of such solvents. To facilitate isolation of the product, a volatile solvent applied. The reaction is exothermic. To avoid a rise in temperature one of the reactants, in solution, gradually becomes the other, who is preferably also located in solution, are added. If necessary, it can be cooled from the outside will. In any case, however, it is not necessary to maintain any critical temperature range. The starting compounds can be used in equimolar amounts or, if appropriate, in excess will. If the base used is potassium hydroxide, then during the reaction it becomes potassium chloride educated. If the solvent is not water, this precipitates and can be filtered off. At this stage, the reaction mixture contains the intermediate of the formula V and / or the Intermediate of formula VI. Although the intermediates can be obtained by evaporation of the solvent, this is not necessary. The intermediate of Formula V readily cyclizes to the intermediate under mildly acidic conditions of formula VI; which in turn dehydrates easily to the final product of formula I. will. This is done by acidifying the solution z. B. with a small amount of an organic Acid such as p-toluenesulfonic acid, benzenesulfonic acid or p-chlorobenzenesulfonic acid or an inorganic one Acid such as hydrochloric acid. Dehydration is facilitated by warming, and in particular by heating under reflux to drive off the water formed as an azeotrope with benzene, from which the water can be separated off before refluxing back.

It is also possible to do the implementation in a single Carry out vessel. When the chlorination is complete, the hydrogen chloride and sulfur dioxide become blown out with air, and then the resulting suspension or solution of α-chloro-acetoacetamide of formula III in benzene directly with 2-mercaptoethanol, as stated above, 'treated. ■

In the second process according to the invention for the preparation of the new compounds of all-

b +. SO, .C1 ₂ , -

According to general formula I, the ring is formed first and then the amide group is introduced, as by the the following reaction equations. An alkylacetoacetate, such as the ethyl acetoacetate of the formula VII (or an equivalent compound such as any acetoacetate with a low molecular weight alkyl group with

1 to 4 carbon atoms), is chlorinated with sulfuryl chloride to form the known ethyl-a ^L chloroacetoacetate of the formula VIII. (Ice is advised that

20. for this purpose also other halogens, e.g. B. Brom: are suitable.) The ethyl-a-chloro-acetoacetate of the formula VIII is treated with the 2-mercaptoethanol of the formula IV in the presence of a base in a manner which is analogous to that described for the first process, resulting in the formation of two intermediates of formulas IX and X, which do not need to be isolated. Instead of this the intermediates are cyclized and acid to the compound of formula XI as in the first process dehydrated, advantageously by refluxing in a benzene solution, whereby the water is separated azeotropically. The ester of formula XI is then converted to the 1-oxa

2 - methyl - 4 - thia - cyclohexene (2) - 3 - carboxylic acid of the formula XII by briefly boiling with aqueous Alkali hydrolyzed. The acid of formula XII is made with the aid of thionyl chloride or an equivalent Halogenating agent converted to the acid chloride of formula XIII. The amide of formula I. is then from the compound of formula XIII obtained by adding an amine. The acid chloride of formula XIII reacts with any primary or secondary amine (also hydrazine or ammonia) without any restriction under Formation of the amide of the formula I. The acid chloride of the formula XIII and the amine react in a molar ratio of 1: 2, in which one mole of amine takes up the hydrogen chloride and the other mole the amide forms. Optionally, however, one mole of the amine together with one mole of an inorganic Base or organic tertiary base can be used with equally good results.

In the case of the first, the direct method of the invention, it is easier for side reactions to form. The yields of ^: Compounds of the formula I by this process can therefore be lower. The first process is particularly suitable when at least one of the substituents R ¹ and R ^{2 is} hydrogen. The second method is preferred when both substituents R ¹ and R ^{2 are} hydrocarbons or substituted hydrocarbons.

The following reaction equations represent that second procedure:

-VII ..,

CH ₃ COCHCOOc ₂ H ₅

Cl. .,

VIII

VIII + HSCH ₂ CH ₂ OH

IV

CH ₃ COCHCOOc ₂ H ₅
SCH ₂ CH ₂ OH
IX

y OH
^ CH ₃ COOC ₂ H ₅ X

H +

COOC ₂ H ₅
XI

Base _>
water

SOCl,,

COCl

XIII

HNR ¹ R ²

In the reaction equations, the substituents R ¹ and R ² denote hydrogen, NH ₂ or various monovalent organic groups, either a hydrocarbon group or an equivalent substituted hydrocarbon group.
. Preferred compounds which can be prepared according to the present invention are those in which R ^{1 is} hydrogen and R ^{2 has} one of the other meanings given, especially alkyl (especially butyl), aryl (especially phenyl), alkaryl (especially tolyl, preferably o-tolyl and m-tolyl) or cycloalkyl (especially cyclohexyl) or similar hydrocarbon groups with up to 12 carbon atoms.

The following examples serve to illustrate the invention in more detail.

B ei s ρ i e 1 1

1 - Oxa-2-methyl-3-carboxanilido ^: 4-thia- 'cyclohexene (2)

■ (Formal: R = C ₆ H ₅ , R '=. H) ■■
Method 1 (from acetoacetanilide)

Process step 1

Production of a-chloro-acetoacetanilide ,.
(Formula III: R = C ₆ H ₅ , R '= H)

To a stirred suspension of 150 g of acetoacetanilide (0.845 mol) and 1 liter of dry benzene, 72 ml (120 g) of sulfuryl chloride (0.890 mol) were added dropwise over the course of ₂ hours.

Stirring was continued for another half hour. The product was filtered (the filtrate used instead of dry benzene in a second batch gave a higher yield of α-chloroacetoacetanilide), washed with water and benzene and dried. Yield: 131 g corresponding to 73.5% of theory. Melting point: 136 to 138 ⁰ C (.. Naik, Trivedi and Mankad, J. Indian Chem Soc, 20, 365 [1943] Bu low and King, Ann, 439, 211 [1924]).

Step 2

Production of l-oxa ^ -methyl-S-carboxanilido-4-thia-cyclohexene (2)

(Formula I: R = C ₆ H ₅ , R = H)

To a stirred suspension of 63.5 g of a-chloroacetoacetanilide (0.3 mol) and 300 ml of dry benzene became a. Solution of 20.4 g of KOH, 22.2 ml

'6o (22.5 g) of 2-mercaptoethanol (0.3 mol) and 40 ml of methanol were added dropwise over the course of 2 hours, the temperature being kept below 30 ^° C. The mixture was stirred for a further hour and / the potassium chloride which precipitated out was filtered off and the filtrate was freed from the solvents by distillation. Benzene was added to the residue and then washed neutral with water. The benzene solution was mixed with 0.8 g of p-toluene

sulfonic acid acidified and refluxed using a Dean-Stark trap for collection of the water heated. 5 ml of water were collected (5.3 ml after calculation). The solution was with Washed water and separated the benzene. The residue solidified and became 95% ethanol recrystallized.

Yield: 45.8 g corresponding to 65% of theory. Melting point: 93 to 95 ° C.

Step 2

Procedure IA

(using sodium bicarbonate instead of potassium hydroxide)

To a stirred suspension of 42.3 g of a-chloroacetoacetanilide (0.2 mol) in 200 ml of benzene and 17 g of 2-mercaptoethanol was a solution of 22 g Sodium bicarbonate in 150 ml of water was added in portions over the course of an hour. The reaction mixture stirring was continued until all the solid constituents had gone into solution, which took Vz hour. The benzene layer was separated, washed with water, with 0.5 g of p-toluenesulfonic acid acidified and then heated to reflux, leaving 3.5 ml of water, which is obtained by azeotropic distillation were separated using a Dean-Stark trap. The reaction mixture was cooled, washed with water, the solvent separated off and the residue crystallized from methanol.

Yield: 27 g. Melting point: 93 to 94 ° C.

The mother liquors were brought to dryness, but the viscous oily residue was not wanted to crystallize. This residue was dissolved in benzene with aqueous sodium hydroxide and washed with water and: the benzene separated. The residue solidified quickly and crystallized out Methanol. ,. . . .

Yield: 8.5 g. Melting point: 92 to 93 ° C. Total yield: 35.5 g corresponding to 75% of theory.

Process [from ethyl acetoacetate (Formula VII)]
Process step 1

Production of ethyl-a-chloro-acetoacetate
(Formula VIII).

45

(1. A11 i h n, Ber., Bl. 567 [1878], 2. B 0 e h m e, W.R. Org. Syn. Vol. 33, 43 [1953])

To a stirred and cooled solution of 260 g of ethyl acetoacetate (2 mol) was added 270 g of sulfuryl chloride (2 mol) were added over the course of 3 hours, the temperature being kept between 0 and 5 ° C. The reaction mixture was left to stand overnight. The sulfur dioxide and the hydrogen chloride were withdrawn from a water jet pump. The remaining dark liquid was in vacuo distilled. After a small forerun, 300 g, corresponding to 91% of the theory of the liquid, get / which between 88 and 90 ° C / 16mmHg distilled. .

, Process step 2

Production of l-oxa-2-methyl-4-thiacyclohexene (2) -3-ethylcarboxylic acid ester,

(Formula XI)

A solution of 13.6 g of potassium hydroxide, 15.0 ml (15.6 g) of 2-mercaptoethanol and 30 ml of methanol were converted into a cooled and stirred solution of 33 g of ethyl α-chloroacetoacetate in the course of I ¹ I _{2 hours} (0.2 mol) and 200 ml of dry benzene, the temperature being kept below 30 ⁰ C _: was. The reaction mixture was _{stirred for a further V 2} hours, the potassium chloride formed was filtered off and the solvents were separated off. Benzene was then added to the residue, followed by washing with water. The benzene solution was acidified with p-toluenesulfonic acid and 3.4 ml of water (calculated amount 3.6 ml) was collected by azeotropic distillation using the Dean-Stark trap. The reaction mixture was cooled and washed with water, and then the benzene was separated off. The residue was distilled in a high vacuum and boiled at 107 to 110 ° C / mm Hg. The yield was 23 g, corresponding to 61.2% of theory. '

This compound was also made using sodium bicarbonate, such as Method IA, in place made of potassium hydroxide. Yield: 76% of theory.

Process step 3

Preparation of l-OXAE ^ -methyl-S-carboxy-4-thia-cyclohexene _(2):
(Formula XII)

A solution of 60 g of sodium hydroxide in 400 ml of water was added to a solution of 188 g of 1-oxa-2-methyl-4-thia-cyclohexene (2) -3-carboxylic acid ethyl ester in 50 ml of 95% ethanol. The reaction mixture was refluxed until the two layers were homogeneous. what took about ¹ _1/2 hours.

The solution was cooled, diluted with water and then acidified with dilute hydrochloric acid. The white precipitate was immediately filtered, washed with water and air dried. Yield: 134 g, corresponding to 84% of theory. The substance melted at 178-180 ⁰ C, after recrystallization from ethanol at 180 to 181 ° C.

Step 4

Production of l-Oxa ^ -methyl-S-carboxanilido-

4-thia-cyclohexene (2)
(Formal: R = C ₆ H ₅₁ R = H)

16 ml of thionyl chloride were added to a suspension of 32 g of l-oxa ^ -methyW-carboxy ^ -thia-cyclohexene (2) of the formula XII (0.2 mol) in 200 ml of chloroform and the reaction mixture under reflux heated. Hydrogen chloride and sulfur dioxide were evolved, and all solids went in solution within 2 hours. The excess thionyl chloride and the solvent were im Separated vacuum. Then a solution of 37.2 g of aniline in chloroform (it can also Benzene can be used) to the one dissolved in chloroform (benzene can also be used) The residue containing the compound of the formula XIII was added in portions. The educated Aniline hydrochloride was filtered off. The filtrate was washed with very dilute hydrochloric acid solution and then washed with water. The chloroform (or optionally benzene) was removed, leaving the residue immediately froze. The residue was recrystallized from 95% ethanol. the The yield was 38 g, corresponding to 80% of theory, melting point 93 to 94 ° C. ·

009 542/390

Example 2

1 -Oxa ^ -methyl-S-carboxymorpholido ^ -thiacyclohexene (2)

(Formula I: R ¹ and R ² together =

^V CH ₂ —CH ₂ '

This compound was obtained in 30% yield from the 1-oxa-2-methyl-4-thia-cyclohexene (2) -3-carboxylic acid chloride of the formula XIlI and morpholine prepared by the process 2 according to the invention. boiling point 170 ° C / 2 to 3 mm Hg.

ίο

left to stand at room temperature for 2 days and then heated for a further two hours. Well was dilute hydrochloric acid was added to the reaction mixture and the insolubles collected by filtration. The solids were treated with aqueous sodium bicarbonate and the bicarbonate-insolubles are separated by filtration. By acidifying the filtrate with dilute Hydrochloric acid and recrystallization

ίο of the precipitate formed from ethanol were g l-Oxa ^ -methyl-SNp-carboxycarboxanilido-4-thia-cyclohexene (2), corresponding to 47% of theory, based on l-Oxa ^ -methyl-S-carboxy ^ -thia- cyclohexene (2). Melting point 249 to 251 ^° C. (decomposition).

B e i s ρ i e 1 3

NjN-a ^ -ethylene-bis-Cl-oxa ^ -methyl-S-carboxamido-4-thia-cyclohexene (2))

(Formal: R ^ H ₅ R ¹ =

CH,

CONH · CH, CH,

20th

35

This compound was obtained in 40% yield from the l-oxa-2-methyl-4-thia-cyclohexene (2) -3-carboxylic acid chloride of the formula XIII and ethylenediamine by process 2 according to the invention. Melting point 168 ⁰ C.

Example 4

1 - Oxa ^ -methyl-S-p-carboxycarboxanilido ^ -thiacyclohexene (2)

\
-COOH

A solution of thionyl chloride 26 g (0.22 mol) in 50 ml of chloroform was added to 32 g of l-oxa-2-methyl-3 - carboxy -A- thiä - cyclohexen (2) of the formula XII (0.20 mol), suspended in 75 ml of chloroform, added and the mixture heated under reflux until a solution had resulted, which took about 2 hours. The solution was then evaporated in vacuo to remove the solvent from the unreacted thionyl chloride and the hydrogen chloride and sulfur dioxide which were formed in the course of the reaction. The remaining crude l-oxa-2-methyl-4-thia-cyclohexene (2) -3-carboxylic acid chloride of the formula XIII was dissolved in 100 ml of benzene and added to 120 g of p-aminobenzoic acid (0.88 mol), some of which was dissolved in a mixture of 300 ml of benzene and 200 ml of chloroform was dissolved. Since initially no noticeable reaction occurred, the reaction mixture was heated on a steam funnel for 1 hour,

Claims (1)

Claim: Process for the preparation of l-oxa-2-methyl-3-aminocarbonyl-4-thia-cyclohexene (2) en the general formula in which R ¹ and R ^{2 are} identical or different and are hydrogen, an amino group or dialkylamino group, also alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkaryl groups or radicals of heterocyclic compounds with one or more heteroatoms, such as nitrogen, oxygen and / or sulfur, which can optionally be substituted by hydroxyl, alkoxy, carboxyl, carbalkoxy, carboxamide, nitrile, mercapto, alkylmercapto, halogen and / or nitro groups, where R ¹ and R ² can also be connected by an alkylene chain which can be interrupted by an oxygen or nitrogen atom, characterized in that one a) an N-substituted a-chloro-acetic acid amide the general formula ^R \ CH3COCHCJCON 2 ^A in which R ¹ and R ^{2 have} the meaning given, are reacted with 2-mercaptoethanol in a customary solvent in the presence of a base and the intermediate product formed. cyclized by elimination of water during acidification or b) an α - chloro-acetic acid ester of the general formula CH ₃ - CO - CH - COOR Cl
in which R is a low molecular weight alkyl group 11 12 indicates, with 2-mercaptoethanol in a common ammonia or an amine of the general Reacts solvent in the presence of a base, formula j ^ i _s the resulting intermediate product under acidification / \ cyclized to an ester, the ester to the ent- '■ HN j speaking acid hydrolyzed, the acid in 5 ^ R ² ' Acid halide transferred and the halide reacted with.