HK1057897B - 4-alkoxy cyclohexane-1 amino carboxylic acid esters and method for the production thereof - Google Patents

Description

4-alkoxy-cyclohexane-1-amino-carboxylic acid esters and method for the production thereof

The present invention relates to novel 4-alkoxy-cyclohexane-1-amino-carboxylic acid esters, to intermediates and processes for their preparation, and to their use as intermediates in the synthesis of insecticidal, acaricidal and herbicidal compounds or pharmaceutically active compounds.

Substituted cyclic aminocarboxylic acids are generally obtained by Bucherer-Bergs synthesis or by Strecker synthesis, in each case giving rise to different isomeric forms. Thus, Bucherer-Bergs synthesis conditions were used to prepare substituted cyclic aminocarboxylic acids of the general formula (I)

The isomer (I-a) is produced mainly:

(I-a) cis

Wherein the radical R¹In cis alignment with the amino group, while Strecker synthesis conditions produce predominantly the trans isomer (I-b):

(I-b) trans

(J.Chem.Soc.1961，4372-4379；Chem.Pharm.Bull.21(1973)685-691；Chem.Pharm.Bull.21(1973)2460-2465；Can.J.Chem.53(1975)3339-3350)。

The Bucherer-Bergs reaction is generally carried out by substituted cyclic ketones of the general formula (II)

By reaction with ammonium carbonate and an alkali metal cyanide, generally sodium cyanide or potassium cyanide, in a solvent or solvent mixture, and then isolating the hydantoin of the general formula (III) obtained,

of these, the hydantoin of the formula (III) is usually present as the cis-isomer (III-a)

With the trans isomer (III-b)

Is obtained as a mixture.

The hydantoin of the general formula (III) is then hydrolyzed by known methods under acidic or basic conditions to give the substituted cyclic aminocarboxylic acid of the general formula (I).

The substituted cyclic aminocarboxylic acids of the general formula (I) can then be esterified by known methods of organic chemistry to give substituted cyclic aminocarboxylic acid esters of the general formula (IV)

We have found novel compounds of the formulae (IV-a) and (IV-b)

And

wherein

R¹Represents OR³，

R²Represents an alkyl group, and

R³represents an alkyl group.

Preferred are compounds of the formulae (IV-a) and (IV-b), in which

R¹Represents OR³，

R²Represents C₁-C₆-alkyl, and

R³represents C₁-C₄-an alkyl group.

Particularly preferred are compounds of the formulae (IV-a) and (IV-b), in which

R¹Represents OR³，

R²Represents methyl, ethyl, n-propyl or n-butyl, and

R³represents methyl, ethyl, n-propyl, n-butyl or isobutyl.

Certain compounds (e.g. from EP-A-596298; WO 95/20572; EP-A-668267; WO 95/26954; WO 96/25395; WO 96/35664; WO 97/02243; WO 97/01535; WO 97/36868; WO 98/05638) require substituted cyclic aminocarboxylic esters of the general formulｃA (IV) as precursors.

For example EP-A-596298; WO 95/20572; EP-A-668267; WO 95/26954; WO 96/25395; WO 96/35664; WO 97/02243; WO 97/01535; WO 97/36868; some of the compounds disclosed in WO 98/05638 may advantageously be prepared from substituted cyclic aminocarboxylic acid esters of the general formula (IV) in which the cis-isomer (IV-a) is the sole or at least the major isomer.

The solvent used in the Bucherer-Bergs reaction is typically an aqueous methanol solution of approximately 50% concentration (J.org.chem.53(1988)4069-4074) or an aqueous ethanol solution of approximately 50% concentration (J.chem.Soc.1961, 4372-4379; chem.pharm.Bull.21(1973) 685-691; chem.pharm.Bull.21(1973) 2460-2465; Can.J.chem.53(1975) 3339-3350; Can.J.chem.57(1979) 1456-1461). In the optimized Bucherer-Bergs reaction, the solvent used is also aqueous ethanol (J.heterocyclic. chem.21(1984) 1527-1531). Other solvents known for use in the Bucherer-Bergs reaction are N, N-dimethylformamide (Helv. Chim. acta 67(1984) 1291-1297). However, if these solvents are used to prepare hydantoins of the general formula (III), unsatisfactory yields are obtained. Furthermore, the resulting isolated product is significantly contaminated with inorganic fractions. Additional purification operations produce products whose composition varies significantly with respect to the cis and trans isomers, so that constant product quality cannot be ensured.

Compounds of formula (III) have been found

Wherein R is¹As is defined above, the first and second parts,

by means of compounds of the formula (II)

Wherein R is¹As previously defined

With ammonium carbonate and an alkali metal cyanide or trimethylsilyl cyanide (TMSCN) in solvent water.

Surprisingly, by the process according to the invention, the compounds of the formula (III) can be obtained in high yields and purities with a reproducibly high proportion of the cis isomer (III-a)

Wherein

R¹Represents OR³，

R³Represents an alkyl group.

In the general formulae (II), (III) and (III-a), the radical R¹Represents OR³Wherein R is³Preferably represents C₁-C₄An alkyl group.

Particularly preferably, R³Represents methyl, ethyl, n-propyl, n-butyl or isobutyl.

Very particularly preferably, R³Represents a methyl group.

Is emphasized wherein R³A compound of formula (III-a) representing a methyl group.

The compounds of the formula (III) and the isomers of the formulae (III-a) and (III-b) are novel and form part of the subject matter of the invention.

In the general formula (III-b), the variable R¹As previously defined.

The compounds of formula (III) can be hydrolysed by known methods to give compounds of formula (I)

Wherein

R¹As previously defined

Followed by esterification by known methods to give the compound of formula (IV).

Preferred alkali metal cyanides useful in preparing the compounds of formula (III) are lithium cyanide, sodium cyanide and potassium cyanide; particularly preferred are sodium cyanide and potassium cyanide.

The alkali metal cyanide or TMSCN is used in an amount of 0.9 to 3mol/mol of ketone, based on the ketone. Preferably in an amount of 1 to 2.5mol/mol ketone; particularly preferred amounts are from 1.1 to 2mol of alkali metal cyanide per mol of ketone.

The amount of ammonium carbonate used is from 0.5 to 7mol ammonium carbonate per mol of ketone. Preferably in an amount of 0.8 to 5mol/mol ketone; particularly preferred amounts are from 1 to 5mol of ammonium carbonate per mol of ketone.

The reaction temperature of the method is 20 to 100 ℃; the preferred temperature range is 30 to 70 ℃.

The reaction may also be carried out under elevated or reduced pressure.

The reaction product is isolated in a simple manner by filtering the reaction mixture and drying the filter residue. The filtration is carried out at a temperature of from 0 to 40 ℃, preferably at a temperature of from 15 to 30 ℃.

In this way, the desired hydantoin of formula (III) is obtained in high yield and purity with reproducible isomer ratios.

The process of the invention can be illustrated, for example, by the following equation:

the invention also provides a preparation method of the compound of the formula (III-a)

Wherein

R¹As is defined above, the first and second parts,

characterized in that a compound of formula (II)

Wherein R is¹As previously defined

With alkali metal cyanide and ammonium carbonate in water.

Particularly preferred is a process for the preparation of a compound of the formula (III-a), in which

R¹Represents OR³，

Wherein

R³Represents a methyl group, and a salt thereof,

it is characterized in that 4-methoxycyclohexanone is reacted with alkali metal cyanide and ammonium carbonate in water.

Suitable as alkali metal cyanides are lithium cyanide, sodium cyanide or potassium cyanide; preferred are sodium cyanide and potassium cyanide. Sodium cyanide is particularly preferred.

The alkali metal cyanide is used in an amount of 0.9 to 3mol per mol of compound of the formula (I), based on the compound of the formula (II). Preferably in an amount of 0.9 to 2.5mol/mol of compound of formula (II); particularly preferred amounts are from 1 to 2mol of alkali metal cyanide per mol of compound of the formula (II).

Meanwhile, ammonium carbonate is used in an amount of 0.8 to 2mol of ammonium carbonate per mol of the compound of formula (II). Preference is given to using amounts of from 1 to 1.8mol per mol of compound of the formula (II).

The amount of solvent water is 500 to 3000ml water per mol of compound of formula (II); preferably, the amount of water is from 1000 to 2500ml/mol of compound of formula (II).

The reaction temperature of the method is 20 to 100 ℃; the preferred temperature range is 30 to 70 ℃.

The reaction product is isolated in a simple manner by filtering the reaction mixture and drying the filter residue. The filtration is carried out at a temperature of from 0 to 40 ℃, preferably at a temperature of from 0 to 20 ℃.

The invention also provides a method for isolating a compound of formula (III-a),

wherein

R¹As is defined above, the first and second parts,

characterized in that the compound of formula (III) (cis/trans mixture (III-a)/(III-b)) is treated with aqueous ammonia and the solid which has not yet dissolved is isolated in a known manner.

The amount of ammonia is from 1 to 30mol per mol of trans-isomer of the formula (III-b), based on the trans-isomer of the formula (III-b) present in the mixture. Preferably in an amount of from 4 to 20mol per mol of the trans isomer of the formula (III-b); particularly preferred amounts are from 6 to 15mol of ammonia per mol of trans isomer of the formula (III-b).

The amount of solvent water is 500 to 3000ml of water per mol of compound of formula (III); preferably, the amount of water is from 1000 to 2500ml/mol of compound of formula (III).

The temperature of the method is 0 to 100 ℃; the preferred temperature range is 10 to 60 ℃.

The hydantoins of the general formula (III) can be hydrolyzed by known methods to amino acids of the general formula (I) and then esterified by known methods to give compounds of the formula (IV).

The invention also provides substituted cyclic aminocarboxylic acids of the general formula (I)

Wherein

R¹Represents OR³，

Wherein

R³Represents alkyl, preferably C₁-C₄-an alkyl group.

The substituted cyclic aminocarboxylic acids of the general formula (I) can be present as a mixture of the cis-isomer (I-a) and the trans-isomer (I-b) or as pure isomers.

The compounds of formula (I) are novel and form part of the subject-matter of the present invention.

Particularly preferred are compounds of the formula (I), in which

R¹Represents OR³，

Wherein

R³Represents methyl or ethyl.

Very particular preference is given to compounds of the formula (I-a), in which

R¹Represents OR³，

Wherein

R³Represents methyl or ethyl.

Substituted cyclic aminocarboxylic acids of the formula (I) or aminocarboxylic acid esters of the formula (IV) are intermediates for the preparation of further compounds, for example for use as active compounds in plant protection or as pharmaceutically active compounds.

For example, EP-A-596298, WO 95/20572, EP-A-668267, WO95/26954, WO 96/25395, WO 96/35664, WO 97/02243, WO 97/01535, WO 97/36868, WO 98/05638 disclose the preparation of substituted cyclic aminocarboxylic acids which are required for substituted phenylketoenols to be useful as pesticides and herbicides.

The subject-matter of the invention is illustrated by the following examples, which in no way limit the invention in any way.

Preparation examples

Comparative example 1

26.9g [280mmol ] ammonium carbonate and 5.88g [120mmol ] sodium cyanide are added to 110ml of water. A solution of 7.7g [60mmol ] of 4-methoxy-cyclohexanone in 110ml of ethanol is added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 16 h and then completely concentrated (by HPLC, cis/trans ratio 66: 34). The crude product was stirred with 100ml of 50% strength aqueous ethanol solution for 1 hour, cooled to 0-5 ℃, stirred at 0-5 ℃ for 1 hour, and filtered. The filter residue was dried to give 12.07g of a solid with a product content of 57.8% (HPLC, compare to standard), resulting in a yield of 58.7% of theory; the cis/trans ratio is 91: 9. Elemental analysis showed a sodium content of 16%.

Comparative example 2

The procedure of comparative example 1 was repeated. After completion, a product with a cis/trans ratio of 80: 20 was obtained.

Example 1

134.6g [1.4mol ] ammonium carbonate and 29.4g [0.6mol ] sodium cyanide are added to 560ml of water. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 16 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 57.88g of a solid with a product content of 93.4% (HPLC, comparison with standard) were obtained, resulting in a yield of 90.9% of theory; the cis/trans ratio is 71: 29. Elemental analysis showed a sodium content of 1.2%.

Example 2

134.6g [1.4mol ] ammonium carbonate and 22.05g [0.45mol ] sodium cyanide are added to 560ml of water. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 57.64g of a solid with a product content of 93.7% (HPLC, comparison with standard) were obtained, resulting in a yield of 90.8% of theory; the cis/trans ratio is 72: 28. Elemental analysis showed a sodium content of 1.3%.

Example 3

134.6g [1.4mol ] ammonium carbonate and 16.17g [0.33mol ] sodium cyanide are added to 560ml of water. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 61.02g of a solid with a product content of 94.1% (HPLC, comparison with standard) were obtained, resulting in a yield of 96.5% of theory; the cis/trans ratio is 71: 29.

Example 4

The procedure of example 3 was repeated. 59.54g of a solid with a product content of 93.6% (HPLC, comparison with standard) were obtained, resulting in a yield of 93.7% of theory; the cis/trans ratio is 71: 29.

Example 5

134.6g [1.4mol ] ammonium carbonate and 16.17g [0.33mol ] sodium cyanide are added to 560ml of water. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours and then at room temperature overnight. The solid was filtered off with suction at room temperature and dried. 58.5g of a solid with a product content of 95.4% (HPLC, comparison with standard) are obtained, resulting in a yield of 93.9% of theory; the cis/trans ratio is 71: 29.

Example 6

To 560ml of water were added 43.2g [0.45mol ] ammonium carbonate and 29.4g [0.6mol ] sodium cyanide. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 26.4g of solid are obtained, resulting in a yield of 44.4% of theory; the cis/trans ratio is more than 99.7: 0.3.

Melting point: 267-.

¹H-NMR(400MHz，d-DMSO)：δ＝1,38-1,48(m；2H)，1,57-1,68(m；4H)，1,91-1,95(m；2H)，3,14-3,17(m；1H)，3,23(s；3H)，8,37(s；1H)ppm。

Example 7

To 560ml of water were added 34.6g [0.36mol ] ammonium carbonate and 29.4g [0.6mol ] sodium cyanide. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 18.8g of solid are obtained, resulting in a yield of 31.6% of theory; the cis/trans ratio is 99.4: 0.6.

Example 8

28.8g [0.3mol ] ammonium carbonate and 16.2g [0.33mol ] sodium cyanide are added to 560ml of water. 38.5g [0.3mol ] 4-methoxy-cyclohexanone were added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 15.5g of solid are obtained, resulting in a yield of 26.1% of theory; the cis/trans ratio is 99.2: 0.8.

Example 9

13.5g [140mmol ] ammonium carbonate and 1.62g [33mmol ] sodium cyanide are added to 56ml of water. 4.3g [30mmol ] 4-methoxy-cyclohexanone are added dropwise, starting at room temperature. The reaction mixture was stirred at 55-60 ℃ for 4 hours, cooled to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 5.55g of a solid (78.8% of theory) are obtained; the cis/trans ratio is 72: 28.

¹H-NMR (400MHz, d-DMSO): δ is 1,09 (t; 3H, cis), 1,12 (t; 3H, trans), 1,3-1,48 (m; 2H, cis + trans), 1,57-1,64 (m; 4H, cis + trans), 1,77-1,95 (m; 2H, cis + trans), 3,25-3,3 (m; 1H, cis + trans), 3,40 (q; 2H, trans), 3,45 (q; 2H, cis), 8,40(s, br; 1H, cis + trans) ppm.

Further examples of the formula (III)

Mention may be made of:

example 10：R¹＝O-ⁿC₃H₇m.p. > 250 ℃ cis/trans-87/13

Example 11：R¹＝O-ⁿC₄H₉m.p. > 250 ℃ cis/trans-85/15

Example 12：R¹＝O-ⁱC₄H₉m.p. > 250 ℃ cis/trans-51/49

Example 13

In an autoclave, 19.8g [0.1mol ] 4-methoxycyclohexane-1-spiro-5' -hydantoin (cis/trans ratio 71: 29), 4g [0.1mol ] sodium hydroxide and 400ml water were heated at 160 ℃ for 24 hours. The reaction mixture was adjusted to pH 3 with hydrochloric acid under ice-cooling, and then concentrated under reduced pressure. The remaining water was removed by azeotropic distillation with toluene. 29.6g of a solid were obtained.

According to GC/MS (after silylation), 3.7% of starting material and 89.3% of 4-methoxycyclohexane-1-amino-carboxylic acid are present; the cis/trans ratio is 70: 30.

GC/MS (silylation): m/e ═ 302 (product (disilylated) -15), 200 (base peak, product (disilylated) -CO₂SiMe₃)，168(200-MeOH)。

Example 14

In an autoclave, 7.9g [40mmol ] cis-4-methoxycyclohexane-1-spiro-5' -hydantoin, 160ml water and 1.6g [40mmol ] sodium hydroxide were heated at 160 ℃ for 24 hours. The reaction mixture was adjusted to pH 3 with hydrochloric acid under ice-cooling, and then concentrated under reduced pressure. The remaining water was removed by azeotropic distillation with toluene. 11.2g of a solid was obtained. m.p. > 400 ℃.

¹H-NMR(400MHz，d₆-DMSO)：δ＝3,17(m，1H，CHOCH₃)，3,22(s，3H，OCH₃)ppm。

Example 15

1g [5mmol ] trans-4-methoxycyclohexane-1-spiro-5' -hydantoin, 20ml water and 0.2g [5mmol ] sodium hydroxide were heated at 160 ℃ for 24 hours in an autoclave. The reaction mixture was adjusted to pH 3 with hydrochloric acid under ice-cooling, and then concentrated under reduced pressure. The remaining water was removed by azeotropic distillation with toluene. 0.8g of a solid was obtained.

Example 16

6.9g [40mmol ] cis-4-methoxycyclohexane-1-aminocarboxylic acid were suspended in 50ml of anhydrous methanol. The mixture was briefly heated to reflux and then cooled to 0 ℃. 6.9g of [58mmol ] thionyl chloride are added dropwise at 0-5 ℃. The mixture was stirred at 0-5 ℃ for half an hour, then allowed to warm to room temperature, heated to 40 ℃ and stirred at 40 ℃ overnight. The reaction mixture was filtered, and the filter residue was washed with 20ml of methanol, and the filtrate was concentrated. The residue is stirred with 50ml of methyl tert-butyl ether, filtered off with suction and the filter residue is dried. 5.6g of cis-4-methoxy-cyclohexane-1-aminocarboxylic acid methyl ester hydrochloride (63% of theory) are obtained. m.p.298 ℃.

¹H-NMR(400MHz，d-DMSO)：δ＝1,64-1,80(m；4H)，1,88-1,96(m；4H)，3,23(s；3H)，3,29-3,32(m；1H)，3,76(s；3H)，8,67(s，br；3H)ppm。

Example 17

In the same manner as in example 12, trans-4-methoxycyclohexane-1-aminocarboxylic acid methyl ester hydrochloride was prepared.

m.p.173℃。

¹H-NMR(400MHz，d₆-DMSO)：δ＝185-2,37(4m，8H，CH₂)，3,32(s，3H，CHOCH₃)，3,50(″d″，1H，CHOCH₃)，3,82(s，3H，OCH₃)，8,94(br，3H，^NH₃)ppm。

Analogously to example 15, the following amino acid ester of formula (IV) is obtained:

example 18:R¹＝O-C₂H₅ R²＝Me m.p.＞220℃

example 19:R¹＝O-ⁿC₃H₇ R²＝Me m.p.＞220℃

example 20:R¹＝O-ⁿC₄H₉ R²＝Me m.p.183℃

example 21:R¹＝O-ⁱC₄H₉ R²＝Me m.p.179℃

example 22:R¹＝OMe R²et MS (silylated): 273 (M/e)⁺)

Example 23:R¹＝OMe R²＝ⁿBu ¹H-NMR

¹H-NMR(400MHz，d-DMSO)：δ＝0,88-0,92(t；3H)，1,32-1,41(m；2H)，1,57-1,68(m；2H)，1,69-2,1(m；10H)，3,23(s；3H)，3,27-3,31(m；1H)，4,14-4,18(m；2H)，8,77(s，br；3H)ppm。

example 24

Mixing 10.2g of the compound in which R is¹＝OR³、R³A compound of formula (III) which is methyl (8-methoxy-1, 3-diazaspiro [4.5 ]]Decane-2, 4-dione; purity 97%, cis/trans ratio 75: 25) was stirred at 55 ℃ in 86ml of water and 9.8g of 26% strength ammonia for 4 hours. The mixture was allowed to cool to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 5.37g of a solid are obtained; the cis/trans ratio was 98.3: 1.7.

Example 25

Example 24 was repeated, but the mixture was stirred at room temperature for 4 hours. 5.03g of a solid having a cis/trans ratio of 97.7: 2.3 were obtained.

Example 26

Mixing 10.2g of the compound in which R is¹＝OR³、R³A compound of formula (III) which is methyl (8-methoxy-1, 3-diazaspiro [4.5 ]]Decane-2, 4-dione; purity 97%, cis/trans ratio 75: 25) was stirred in 86ml of water and 6.5g of 26% strength ammonia at 55 ℃ for 4 hours. The mixture was allowed to cool to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 5.73g of a solid are obtained; the cis/trans ratio was 97.3: 2.7.

Example 27

Mixing 10.4g of the compound in which R is¹＝OR³、R³A compound of formula (III) which is methyl (8-methoxy-1, 3-diazaspiro [4.5 ]]Decane-2, 4-dione; purity 95.3%, cis/trans 98.2: 1.8) was stirred at 55 ℃ for 4 hours in 17ml of water and 0.69g of 26% strength ammonia. The mixture was allowed to cool to 0-5 ℃ and stirred at this temperature for 2 hours. The solid was filtered off with suction and dried. 9.58g of a solid are obtained; cis/trans ratio of99.7∶0.3。

Claims (3)

1. Compounds of the formulae (IV-a) and (IV-b),

and

wherein

R¹Represents OR³，

R²Represents methyl, ethyl, n-propyl or n-butyl, and

R³representsMethyl, ethyl, n-propyl, n-butyl or isobutyl.

2. A compound of the general formula (I),

wherein

R¹Represents OR³，

Wherein

R³Represents C₁-C₄-an alkyl group.

3. A compound of formula (I) according to claim 2,

wherein

R¹Represents OR³，

Wherein

R³Represents methyl or ethyl.