Patent Grant
7148377
The invention relates to novel 4-alkoxy-cyclohexane-1-amino-carboxylic 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 can generally be obtained by the Bucherer-Bergs synthesis or by the Strecker synthesis, resulting in each case in different isomeric forms. Thus, using the conditions of the Bucherer-Bergs synthesis in the preparation of the substituted cyclic aminocarboxylic acids of the general formula (I)
give predominantly the isomer (I-a),
in which the radical R1 and the amino group are arranged cis to one another, whereas the conditions of the Strecker synthesis give predominantly the trans isomer (I-b)
(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 reacting a substituted cyclic ketone of the general formula (II)
in a solvent or solvent mixture with ammonium carbonate and an alkali metal cyanide, generally sodium cyanide or potassium cyanide, followed by isolation of the resulting hydantoin of the general formula (III)
Here, the hydantoins of the general formula (III) are usually obtained as mixtures of the cis isomers (III-a)
and trans isomers (III-b)
The hydantoins of the general formula (III) are subsequently hydrolysed by known methods, under acidic or alkaline conditions, to give the substituted cyclic aminocarboxylic acids 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 the substituted cyclic aminocarboxylic esters of the general formula (IV)
We have found novel compounds of the formulae (IV-a) and (IV-b)
in which
Preference is given to compounds of the formulae (IV-a) and (IV-b), in which
Particular preference is given to compounds of the formulae (IV-a) and (IV-b) in which
Some compounds (for example 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 formula (IV) as precursors.
For certain of these compounds disclosed, for example, in 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, a preparation with the use of substituted cyclic aminocarboxylic esters of the general formula (IV) in which the cis isomer (IV-a) is the only or at least the predominant isomer may be advantageous.
Solvents used for the Bucherer-Bergs reaction are, in general, approximately 50% strength aqueous methanol (J. Org. Chem. 53 (1988) 4069–4074) or approximately 50% strength aqueous ethanol (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 optimized Bucherer-Bergs reactions, too, the solvent used was aqueous ethanol (J. Heterocycl. Chem. 21 (1984) 1527–1531). A further solvent known for the Bucherer-Bergs reaction is N,N-dimethylformamide (Helv. Chim. Acta 67 (1984) 1291–1297). However, if these solvents are used for preparing the hydantoins of the general formula (III), unsatisfactory yields are obtained. Moreover, the isolated products are contaminated considerably by inorganic fractions. Additional purification operations result in products having compositions which vary considerably with respect to cis and trans isomers, so that a constant product quality cannot be ensured.
It has been found that compounds of the formula (III)
in which
in which
Surprisingly, by the process according to the invention, the compounds of the formula (III) can be obtained in high yield and purity and with a high and reproducible proportion of the cis isomer (III-a)
in which
In the general formulae (II), (III) and (III-a), the radical
Particularly preferably, R3 represents methyl, ethyl, n-propyl, n-butyl or i-butyl.
Very particularly preferably, R3 represents methyl.
Emphasis is given to the compound of the formula (III-a), in which R3 represents methyl.
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 this invention.
In the general formula (II-b), the variable R1 is as defined above.
Compounds of the formula (III) can be hydrolysed by known methods to give the compounds of the formula (I)
in which
Preferred alkali metal cyanides which can be used for preparing the compounds of the formula (III) are lithium cyanide, sodium cyanide and potassium cyanide; particular preference is given to sodium cyanide and potassium cyanide.
Based on the ketone, the amount of alkali metal cyanide or TMSCN is from 0.9 to 3 mol per mole of ketone. Preference is given to using amounts from 1 to 2.5 mol per mole of ketone; particular preference is given to amounts from 1.1 to 2 mol of alkali metal cyanide per mole of ketone.
The amount of ammonium carbonate is from 0.5 to 7 mol of ammonium carbonate per mole of ketone. Preference is given to using amounts from 0.8 to 5 mol per mole of ketone; particular preference is given to amounts from 1 to 5 mol of ammonium carbonate per mole of ketone.
The reaction temperature for the process according to the invention is from 20 to 100° C.; preference is given to a temperature range from 30 to 70° C.
It is also possible to carry out the reaction 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° C., preferably at a temperature of from 15 to 30° C.
In this manner, the desired hydantoins of the formula (III) are obtained in high yield and purity, with a reproducible isomer ratio.
The process according to the invention can be illustrated, for example, by the scheme below:
This invention also provides a process for preparing the compounds of the formula (III-a)
in which
in which
Particular preference is given to a process for preparing the compound of the formula (III-a), in which
Suitable for use as alkali metal cyanides are lithium cyanide, sodium cyanide or potassium cyanide; preference is given to sodium cyanide and potassium cyanide. Particular preference is given to sodium cyanide.
Based on the compound of the formula (II), the amount of alkali metal cyanide is from 0.9 to 3 mol per mole of the compound of the formula (II). Preference is given to amounts of from 0.9 to 2.5 mol per mole of the compound of the formula (II); particular preference is given to amounts of from 1 to 2 mol of alkali metal cyanide per mole of the compound of the formula (II).
At the same time, the amount of ammonium carbonate is from 0.8 to 2 mol of ammonium carbonate per mole of the compound of the formula (II). Preference is given to using amounts of from 1 to 1.8 mol per mole of the compound of the formula (II).
The amount of the solvent water is from 500 to 3000 ml of water per mole of the compound of the formula (II); preference is given to an amount of water of from 1000 to 2500 ml per mole of the compound of the formula (II).
The reaction temperature for the process according to the invention is from 20 to 100° C.; preference is given to a temperature range of from 30 to 70° C.
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° C., preferably at a temperature of from 0 to 20° C.
This invention also provides a process for isolating the compound of the formula (III-a),
in which
Based on the trans isomer of the formula (III-b) present in the mixture, the amount of ammonia is from 1 to 30 mol per mole of the trans isomer of the formula (III-b). Preference is given to amounts of from 4 to 20 mol per mole of the trans isomer of the formula (III-b); particular preference is given to amounts of from 6 to 15 mol of ammonia per mole of the trans isomer of the formula (III-b).
The amount of the solvent water is from 500 to 3000 ml of water per mole of the compound of the formula (III); preference is given to an amount of water of from 1000 to 2500 ml per mole of the compound of the formula (III).
The temperature for the process according to the invention is from 0 to 100° C.; preference is given to a temperature range of from 10 to 60° C.
The hydantoins of the general formula (III) can be hydrolysed by known methods to the amino acids of the general formula (I), which can then be esterified by known methods to give compounds of the formula (IV).
The present invention also provides substituted cyclic aminocarboxylic acids of the general formula (I)
in which
The substituted cyclic aminocarboxylic acids of the general formula (I) can be present either as mixtures of the cis isomers (I-a) and trans isomers (I-b), or as pure isomers.
The compounds of the formula (I) are novel and form part of the subject-matter of this invention.
Particular preference is given to compounds of the general formula (I) in which
Very particular preference is given to compounds of the general formula (I-a), in which
Substituted cyclic aminocarboxylic acids of the formula (I) or aminocarboxylic esters of the formula (IV) are intermediates in the preparation of other compounds which are used, for example, as active compounds in plant protection or as pharmaceutically active compounds.
Thus, for example, EP-A-596 298, WO 95/20572, EP-A-668 267, WO 95/26954, WO 96/25395, WO 96/35664, WO 97/02243, WO 97/01535, WO 97/36868, WO 98/05638 disclose that substituted cyclic aminocarboxylic acids are required for preparing substituted phenylketoenols which can be used as pesticides and herbicides.
The subject-matter of the invention is illustrated by the examples below, without limiting it in any way.
26.9 g [280 mmol] of ammonium carbonate and 5.88 g [120 mmol] of sodium cyanide are initially charged in 110 ml of water. Starting at room temperature, a solution of 7.7 g [60 mmol] of 4-methoxy-cyclohexanone in 110 ml of ethanol is added dropwise. The reaction mixture is stirred at 55–60° C. for 16 hours and then concentrated completely (according to HPLC, the cis/trans ratio is 66:34). The crude product is stirred with 100 ml of 50% strength aqueous ethanol for 1 hour, cooled to 0–5° C., stirred at 0–5° C. for 1 hour and filtered. The filter residue is dried, giving 12.07 g of a solid having a product content of 57.8% (HPLC, compared to standard), resulting in a yield of 58.7% of theory; the cis/trans ratio is 91:9. Elemental analysis shows a sodium content of 16%.
The procedure of Comparative Example 1 was repeated. Following work-up, a product having a cis/trans ratio of 80:20 was obtained.
134.6 g [1.4 mol] of ammonium carbonate and 29.4 g [0.6 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 16 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 57.88 g of a solid having a product content of 93.4% (HPLC, compared to standard), resulting in a yield of 90.9% of theory; the cis/trans ratio is 71:29. Elemental analysis shows a sodium content of 1.2%.
134.6 g [1.4 mol] of ammonium carbonate and 22.05 g [0.45 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 57.64 g of a solid having a product content of 93.7% (HPLC, compared to standard), resulting in a yield of 90.8% of theory; the cis/trans ratio is 72:28. Elemental analysis shows a sodium content of 1.3%.
134.6 g [1.4 mol] of ammonium carbonate and 16.17 g [0.33 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 61.02 g of a solid having a product content of 94.1% (HPLC, compared to standard), resulting in a yield of 96.5% of theory; the cis/trans ratio is 71:29.
The procedure of Example 3 is repeated. This gives 59.54 g of a solid having a product content of 93.6% (HPLC, compared to standard), resulting in a yield of 93.7% of theory; the cis/trans ratio is 71:29.
134.6 g [1.4 mol] of ammonium carbonate and 16.17 g [0.33 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours and then stirred at room temperature overnight. At room temperature the solid is filtered off with suction and dried. This gives 58.5 g of a solid having a product content of 95.4% (HPLC, compared to standard), resulting in a yield of 93.9% of theory; the cis/trans ratio is 71:29.
43.2 g [0.45 mol] of ammonium carbonate and 29.4 g [0.6 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 26.4 g of a solid, resulting in a yield of 44.4% of theory; the cis/trans ratio is >99.7:0.3.
Melting point: 267–268° C. (sublimation).
1H-NMR (400 MHz, 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.
34.6 g [0.36 mol] of ammonium carbonate and 29.4 g [0.6 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 18.8 g of a solid, resulting in a yield of 31.6% of theory; the cis/trans ratio is 99.4:0.6.
28.8 g [0.3 mol] of ammonium carbonate and 16.2 g [0.33 mol] of sodium cyanide are initially charged in 560 ml of water. Starting at room temperature, 38.5 g [0.3 mol] of 4-methoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 15.5 g of a solid, resulting in a yield of 26.1% of theory; the cis/trans ratio is 99.2:0.8.
13.5 g [140 mmol] of ammonium carbonate and 1.62 g [33 mmol] of sodium cyanide are initially charged in 56 ml of water. Starting at room temperature, 4.3 g [30 mmol] of 4-ethoxy-cyclohexanone are added dropwise. The reaction mixture is stirred at 55–60° C. for 4 hours, cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 5.55 g of a solid (78.8% of theory); the cis/trans ratio is 72:28.
1H-NMR (400 MHz, d-DMSO): δ=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)
which may be mentioned are:
R1═O—nC3H7 m.p.>250° C. cis/trans=87/13
R1═O—nC4H9 m.p.>250° C. cis/trans=85/15
R1═O—iC4H9 m.p.>250° C. cis/trans=51/49
In an autoclave, 19.8 g [0.1 mol] of 4-methoxycyclohexane-1-spiro-5′-hydantoin (cis/trans ratio 71:29), 4 g [0.1 mol] of sodium hydroxide and 400 ml of water are heated at 160° C. for 24 hours. With ice-cooling, the reaction mixture is adjusted to pH 3 using hydrochloric acid and concentrated substantially under reduced pressure. The remaining water is removed by azeotropic distillation with toluene. This gives 29.6 g of a solid.
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(sil.): m/e=302 (product (disilylated)—15), 200 (base peak, product (disilylated)—CO2SiMe3), 168 (200—MeOH).
In an autoclave, 7.9 g [40 mmol] of cis-4-methoxycyclohexane-1-spiro-5′-hydantoin, 160 ml of water and 1.6 g [40 mmol] of sodium hydroxide are heated at 160° C. for 24 hours. With ice-cooling, the reaction mixture is adjusted to pH 3 using hydrochloric acid and substantially concentrated under reduced pressure. The remaining water is removed by azeotropic distillation with toluene. This gives 11.2 g of a solid.
m.p.>400° C.
1H-NMR (400 MHz, d6-DMSO): δ=3.17 (m, 1H, CHOCH3), 3.22 (s, 3H, OCH3) ppm.
In an autoclave, 1 g [5 mmol] of trans-4-methoxycyclohexane-1-spiro-5′-hydantoin, 20 ml of water and 0.2 g [5 mmol] of sodium hydroxide are heated at 160° C. for 24 hours. With ice-cooling, the reaction mixture is adjusted to pH 3 using hydrochloric acid and substantially concentrated under reduced pressure. The remaining water is removed by azeotropic distillation with toluene.
This gives 0.8 g of a solid.
6.9 g [40 mmol] of cis-4-methoxycyclohexane-1-aminocarboxylic acid are suspended in 50 ml of anhydrous methanol. The mixture is briefly heated to reflux and then cooled to 0° C. At 0–5° C., 6.9 g [58 mmol] of thionyl chloride are added dropwise. The mixture is stirred at 0–5° C. for half an hour, then allowed to warm to room temperature, heated to 40° C. and stirred at 40° C. overnight. The reaction mixture is filtered, the filter residue is washed with 20 ml of methanol and the filtrate is concentrated. The residue is stirred with 50 ml of methyl tert-butyl ether and filtered off with suction, and the residue is dried. This gives 5.6 g of methyl cis-4-methoxy-cyclohexane-1-aminocarboxylate hydrochloride (63% of theory).
m.p. 298° C.
1H-NMR (400 MHz, 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.
In the same manner as described in Example 12, methyl trans-4-methoxycyclohexane-1-aminocarboxylate hydrochloride is prepared.
m.p. 173° C.
1H-NMR (400 MHz, d6-DMSO): δ=185–2.37 (4 m, 8H, CH2), 3.32 (s, 3H, CHOCH3), 3.50 (“d”, 1H, CHOCH3), 3.82 (s, 3H, OCH3), 8.94 (br, 3H, ⊕NH3) ppm.
Similarly to Example 15, the following amino acid esters of the formula (IV) are obtained
R1═O—C2H5 R2=Me m.p.>220° C.
R1═O—nC3H7 R2=Me m.p.>220° C.
R1═O—nC4H9 R2=Me m.p. 183° C.
R1═O—iC4H9 R2=Me m.p. 179° C.
R1═OMe R2=Et MS(silyl.): m/e=273 (M+)
R1═OMe R2=nBu 1H-NMR
1H-NMR (400 MHz, d-DMSO): δ=0.88–0.92 (t; 3 H), 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.
10.2 g of the compound of the formula (III) where R1═OR3, R3 being methyl (8-methoxy-1,3-diazaspiro[4.5]decane-2,4-dione; 97% pure, cis/trans ratio=75:25) are stirred at 55° C. in 86 ml of water and 9.8 g of 26% strength ammonia for 4 hours. The mixture is cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 5.37 g of a solid; the cis/trans ratio is 98.3:1.7.
Example 24 is repeated, except that the mixture is stirred at room temperature for 4 hours. This gives 5.03 g of a solid having a cis/trans ratio of 97.7:2.3.
10.2 g of the compound of the formula (III) where R1═OR3, R3 being methyl (8-methoxy-1,3-diazaspiro[4.5]decane-2,4-dione; 97% pure, cis/trans ratio=75:25) are stirred at 55° C. in 86 ml of water and 6.5 g of 26% strength ammonia for 4 hours. The mixture is cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 5.73 g of a solid; the cis/trans ratio is 97.3:2.7.
10.4 g of the compound of the formula (III) where R1═OR3, R3 being methyl (8-methoxy-1,3-diazaspiro[4.5]decane-2,4-dione; 95.3% pure, cis/trans ratio=98.2:1.8) are stirred at 55° C. in 17 ml of water and 0.69 g of 26% strength ammonia for 4 hours. The mixture is cooled to 0–5° C. and stirred at this temperature for 2 hours. The solid is filtered off with suction and dried. This gives 9.58 g of a solid; the cis/trans ratio is >99.7:0.3.
| Number | Date | Country | Kind |
|---|---|---|---|
| 100 32 587 | Jul 2000 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP01/07115 | 6/22/2001 | WO | 00 | 1/3/2003 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO02/02532 | 1/10/2002 | WO | A |
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| Number | Date | Country |
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| 9717092 | May 1997 | WO |
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| Number | Date | Country | |
|---|---|---|---|
| 20040039223 A1 | Feb 2004 | US |
