CA1184177A - N-chloro-carbonyl-amino carboxylic esters, process for producing same and its use - Google Patents
N-chloro-carbonyl-amino carboxylic esters, process for producing same and its useInfo
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- CA1184177A CA1184177A CA000411699A CA411699A CA1184177A CA 1184177 A CA1184177 A CA 1184177A CA 000411699 A CA000411699 A CA 000411699A CA 411699 A CA411699 A CA 411699A CA 1184177 A CA1184177 A CA 1184177A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides N-chloro-carbonyl-amino carboxylic esters having the general formula
The present invention provides N-chloro-carbonyl-amino carboxylic esters having the general formula
Description
The present invention relates to N-chloro-carbonyl-amino carboxylic esters which are useful for producing active substances of the hydantoin type or of the urea type,.
particularly for plant protective agents.
The esters of the present invention have the general formula (R / C - R )1 5 1 4 CH - COOR lI) (R - C \ R ~ ~ CH2)m N
O ~ \Cl whe.rein X = -CH2- or -S-, Rl represents a straight-chain or branched alkyl radical containing up to 4 carbon atoms, R , R
and R4, independently of each other, each represents hydrogen or a methyl radical, R5 represents hydrogen, an alkyl radical, which is either unsubstituted or substituted by substituents stable against phosgene, or an aromatic or heteroaromatic radi-cal, which is either unsu~stituted or substituted by substi-tuents stable against phosgene, or R4 and R5 together repre-sent an alkylene radical containing 4 to 5 carbon atoms and 1, m and n, independently of each other, each represents 0, 1 or 2 with the stipulation that the sum of 1, m and n is mini-mally 1 and maxirnally 3 and for the case that 1 = 2, R2 and R can only represent hydrogen.
The esters of formula I may be produced in accordance with the present invention by a process in which an amino-carboxylic ester having the general formula (R3 - C R2) X CH - COOR
(R5 - C ~ R ) ~ CH2~m (II) N
wherein X, R , R , R , R , R , 1, m and n have the meanings defined he.reinbeforej or its hydrohalide is reacted in a solvent, which is inert with respect to phosgene, at a tempera-ture between -30 to +100C with 1 to 10 times the molar amount of phosgene.
The N-chloro-carbonyl-amino carboxylic esters having the general formula (I) can be further processed in a simple manner to conventional active substances. Thus, for example, with primary amines they form active substances of the hydan-1~ toin type and with secondary amines they form active substancesof the urea type~
Therefore, the present invention also provides for the use of the N-chloro-carbo~yl-amino carboxylic esters hav-iny the genPral formula (I~ for producing active substances, particularly plant protective agents.
Amongst the N-chloro-carbonyl-amino carboxylic esters having the formula (I) those for which n=1 and the radical R
has one of the following meanings are particularly important:
hydrogen; unsubstituted, straight-chain or branched alkyl radi-cal, particularly containiny 1 to 16 carbon atoms, such asmethyi, ethyl, n-propyl, i-propyl, n~butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-hendecyl, n-tridecyl, n-pentadecyl or n-hexadecyl; alkyl radical substituted with substituents stable a~ainst pnosgene, such as phenyl methyl, (l'-phenyl)ethyl, (2'-methyl-mercapto)-ethyl or (2'-ethyl-mercapto~-ethyl; unsubstituted aromatic or heteroaromatic radical, such as phenyl, naphthyl, 2'--furyl, 2'-thienyl or 3'-thien~l; aromatic or heteroaromatic radical substituted with substituents stable against phosyene such as 2'-fluoro phenyl, 3'-fluoro phenyl, 4'~fluoro phenyl~ 2'-chloro phenyl, 3'-chloro phenyl, 4'--chloro phenyl, 3',4'-dichloro pheny.l, 3',5'-dichloro phenyl, 2',4'-dichloro phenyl, 2',6'-dichloro phenyl, 2',5'-dichloro phenyl, 2'-nitro-phenyl, 3'-nitro phenyl, ~'-nitro-phenyl, 2'-methoxy phenyl, 3'-methoxy phenyl, 4'-methoxy phenyl, 4'-ethoxy phenyl, 4'-propoxy phenyl, 4'-bu~oxy phenyl, 3',9'-dimethoxy phenyl, piperonyl-(31,~'-methylene-dioxo-phenyl), 3'-phenoxy phenyl, 4'-phenoxy phenyl, 2'-methyl phenyl, 3'-methyl phenyl, 4'-methyl phenyl, 4'-tert.-butyl phenyl, 4'-n-pentyl phenyl, 2'-trifluoro-methyl phenyl, 3'-triCluoro-methyl phenyl, 4'-trifluoro-methyl phenyl, 5'-chloro-2'-thienyl, 57-bromo-2'-thienyl, 4'-bromo-2'-thienyl, 5'-ni-tro-2'-thienyl or 5'-nitro-2'-furyl.
The reaction of the amino carboxylic es~er having the general formula (II) with phosgene is preferably carried out at a temperature between -20 and ~80C.
Examples of solvents which are inert with respect to phosgene are hydrocarbons such as hexane or toluene; chloro hydrocarbons such as methylene chloride, chloroform or 1,2-dichloro ethane; ethers such as methyl-tert.-butyl ether or dioxane; or carboxylic esters such as acetic ethyl ester, acetic propyl ester or propionic methyl ester.
0 If the amino carboxylic esters having the general formula (II) have an asymmetry centre, they can be applied as pure enantiomers or as racemaies.
Under the reaction conditions defined the optical configuration is maintained in the reaction with ~he phosgene.
The amino carboxylic esters having the general for-mula (II) can be produced by means of conventional esterifica-tion methods from the free amino carboxylic acids on which they are based. Some of the free amino carboxylic acids are naturally occurring amino carboxylic acids, such as azetidine carboxylic acid or prolinej and some are produced cornmercially, such as pipecolinic acid or isonipecotine acid~ Insofar as synthetic amino carboxylic acids are concerned -they can be ~- 3 produced from naturally occurring or commercial amino carbox-ylic acids, amino carboxylic acid derivatives or first stages of amino carboxylic acid by simple reactions, for example, by condensation o~ suitable non-cyclic amino carboxylic acids with suitable aldehydes or ketones.
The reaction of the amino carboxylic esters having the general formula (II~ with phosgene is suitably so carried out that the phosgene is dissolved in the solvent selected and the amino carboxylic ester is then added. The amino car-boxylic esters can be used in the pure form or in the form of the crude reaction products from the dehydrohalogenation of the corresponding hydrohalides with ammonia.
As an alternative, the hydrohalides of the amino carboxylic esters having the general formula (II) can also be used directl~. In this case it is expedient to dissolve or suspend the hydrohalide in the solvent selected and to add the phosgene to the $olution or suspension.
Depending on the amino carboxylic ester having the general formula (II) the reaction requires a reaction time between 1 and 50 hours. In any case the reaction must be con-tinued until initially present suspensions or material precip itated thereafter have gone completely in solution.
The further treatment is so carried out that the solvent and the excess phosgene are first drawn off, when re-quired under reduced pressure. The recovered materials can be used again directly. I~ the N-chloro-carbonyl-amino carbox-ylic acid is volatile, then the remaining residue can be dis-tilled for further purification, when required under reduced pressure.
When the N-chloro-carbonyl amino carbox~lic ester Eormed has a higher molecular weight (this is generally the case when the ring carrying the chloro-carbonyl group has 6 ring members and/or carries aromatic or heteroaromatic substi-tuents) it frequently can no longer be distilled without de-composition. In these cases a further purification can be carried out in that the residue remaining after the removal of both the solvent and the excess phosgene is taken up in new solvent and subjected to clarification with active carbon.
After fil~ration the filtrate is freed from solven~ at reduced pressure and an oil which crystallizes under certain conditions is obtained.
When the N-chloro-carbonyl-amino carboxylic ester is optically active, its optical purity can be tested, for example, in that a sample is subjected to hydrolysis, the liberated amino acid is isolated and its rotational value is determined.
It is found that the original optical con~iguration has remain-ed unchanged.
The N-chloro-carbonyl-amino carboxylic esters having the general formula (I) can be reacted with the most varied primary and secondary amines to form active substances of the hydantoin or urea t~pe, which are known per se, for example, from the British Patent 1,S03,244~ This reaction is carried out in the presence of an acid acceptor, for example~ pyridine or triethyl amine, in at least equimolar amounts. It can b~
carried out in the absence of additional solvents or in a suit~
able solvent, for example, in dioxane or toluene. The reaction temperature can be between approximately 20C and the reflux temperature of the reaction mixture~ The desired hydantoin or urea derivatives are obtained in high yields within relative-ly short reaction times of e~g., ~ to 5 hours.
The invention will be explained in greater detail by means of the Examples hereafter.
Example 1 _ 1.2 moles (181.9 g~ of L-azetidine-carboxylic (2)-methyl ester ~HCl are suspended in 800 ml of chloroform and saturated with ammonia gas while stirring and cooling. The precipitated ammonium chloride is drawn off by suction and the filtrate is concentrated by evaporation in vacuo. The residue is added dropwise to a solution of 200 ml of phosgene in 400 ml of chloroform at 0C within 2 hours while stirring. The reac-tion mixture is then stirred for 12 hours at roo~ temperature.
After evaporating the solvent and the excess phosgene the resi-due is distilled in vacuo. At 100 to 105C and at a pressure of 1.3 m bars 137.5 g (64.5~) of L-N-chloro-carbonyl~azetidine carboxylic methyl ester pass over.
Computed (%)Obtained~%) C6H8ClNO3 C 40.58 39.82 (177.59) H 4.54 4.49 Cl 19.9620.03 N 7.89 8.23 H-NMR (CDC13):~ = 4.85 (mc, lH) CH - COOCH3, 4.33 (mc, 2H) CH2- NCOCl, 3.85 (s, 3H) COOCH3, 3~3 - 1.9 ppm(m,2H) CH2 - CH - COOCH3.
IR (liquid capillary) : 1740 cm Example 2 5O0 moles (828.1 g~ of L-proline methyl e~ter ~HCl are converted with amrnonia into the rree ester according to Example 1. The crude proline methyl ester is added dropwise to a solution of 1000 ml of phosgene in 2000 ml of chloroform at 0C within 45 minutes while stirring. Stirring is continued for a further hour at this temperature and for a further 12 hours at room temperature. Ater evaporating the chloroform a.~
and the excess phosgene the residue is distilled in vacuo.
896.1 g (93.5%) of L-N-chloro-carbonyl-proline methyl ester having a boiling point of 90 to 95C at 0.012 m bar are obtain-ed~
Computed (%)Obtained (~) C7HloCl NO3 C 43~88 44.16 (19lj62) H 5,26 5.46 Cl 1~.5017,93 N 7.31 7~38 H-NMR (CDC13): ~= 4.53 (mc,lH) - CH -COOCH3, 3.97 - 3.53 (m, 2H) - N - COCl, 3.87; 3.83 (s, 3H) - COOCH3,
particularly for plant protective agents.
The esters of the present invention have the general formula (R / C - R )1 5 1 4 CH - COOR lI) (R - C \ R ~ ~ CH2)m N
O ~ \Cl whe.rein X = -CH2- or -S-, Rl represents a straight-chain or branched alkyl radical containing up to 4 carbon atoms, R , R
and R4, independently of each other, each represents hydrogen or a methyl radical, R5 represents hydrogen, an alkyl radical, which is either unsubstituted or substituted by substituents stable against phosgene, or an aromatic or heteroaromatic radi-cal, which is either unsu~stituted or substituted by substi-tuents stable against phosgene, or R4 and R5 together repre-sent an alkylene radical containing 4 to 5 carbon atoms and 1, m and n, independently of each other, each represents 0, 1 or 2 with the stipulation that the sum of 1, m and n is mini-mally 1 and maxirnally 3 and for the case that 1 = 2, R2 and R can only represent hydrogen.
The esters of formula I may be produced in accordance with the present invention by a process in which an amino-carboxylic ester having the general formula (R3 - C R2) X CH - COOR
(R5 - C ~ R ) ~ CH2~m (II) N
wherein X, R , R , R , R , R , 1, m and n have the meanings defined he.reinbeforej or its hydrohalide is reacted in a solvent, which is inert with respect to phosgene, at a tempera-ture between -30 to +100C with 1 to 10 times the molar amount of phosgene.
The N-chloro-carbonyl-amino carboxylic esters having the general formula (I) can be further processed in a simple manner to conventional active substances. Thus, for example, with primary amines they form active substances of the hydan-1~ toin type and with secondary amines they form active substancesof the urea type~
Therefore, the present invention also provides for the use of the N-chloro-carbo~yl-amino carboxylic esters hav-iny the genPral formula (I~ for producing active substances, particularly plant protective agents.
Amongst the N-chloro-carbonyl-amino carboxylic esters having the formula (I) those for which n=1 and the radical R
has one of the following meanings are particularly important:
hydrogen; unsubstituted, straight-chain or branched alkyl radi-cal, particularly containiny 1 to 16 carbon atoms, such asmethyi, ethyl, n-propyl, i-propyl, n~butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-hendecyl, n-tridecyl, n-pentadecyl or n-hexadecyl; alkyl radical substituted with substituents stable a~ainst pnosgene, such as phenyl methyl, (l'-phenyl)ethyl, (2'-methyl-mercapto)-ethyl or (2'-ethyl-mercapto~-ethyl; unsubstituted aromatic or heteroaromatic radical, such as phenyl, naphthyl, 2'--furyl, 2'-thienyl or 3'-thien~l; aromatic or heteroaromatic radical substituted with substituents stable against phosyene such as 2'-fluoro phenyl, 3'-fluoro phenyl, 4'~fluoro phenyl~ 2'-chloro phenyl, 3'-chloro phenyl, 4'--chloro phenyl, 3',4'-dichloro pheny.l, 3',5'-dichloro phenyl, 2',4'-dichloro phenyl, 2',6'-dichloro phenyl, 2',5'-dichloro phenyl, 2'-nitro-phenyl, 3'-nitro phenyl, ~'-nitro-phenyl, 2'-methoxy phenyl, 3'-methoxy phenyl, 4'-methoxy phenyl, 4'-ethoxy phenyl, 4'-propoxy phenyl, 4'-bu~oxy phenyl, 3',9'-dimethoxy phenyl, piperonyl-(31,~'-methylene-dioxo-phenyl), 3'-phenoxy phenyl, 4'-phenoxy phenyl, 2'-methyl phenyl, 3'-methyl phenyl, 4'-methyl phenyl, 4'-tert.-butyl phenyl, 4'-n-pentyl phenyl, 2'-trifluoro-methyl phenyl, 3'-triCluoro-methyl phenyl, 4'-trifluoro-methyl phenyl, 5'-chloro-2'-thienyl, 57-bromo-2'-thienyl, 4'-bromo-2'-thienyl, 5'-ni-tro-2'-thienyl or 5'-nitro-2'-furyl.
The reaction of the amino carboxylic es~er having the general formula (II) with phosgene is preferably carried out at a temperature between -20 and ~80C.
Examples of solvents which are inert with respect to phosgene are hydrocarbons such as hexane or toluene; chloro hydrocarbons such as methylene chloride, chloroform or 1,2-dichloro ethane; ethers such as methyl-tert.-butyl ether or dioxane; or carboxylic esters such as acetic ethyl ester, acetic propyl ester or propionic methyl ester.
0 If the amino carboxylic esters having the general formula (II) have an asymmetry centre, they can be applied as pure enantiomers or as racemaies.
Under the reaction conditions defined the optical configuration is maintained in the reaction with ~he phosgene.
The amino carboxylic esters having the general for-mula (II) can be produced by means of conventional esterifica-tion methods from the free amino carboxylic acids on which they are based. Some of the free amino carboxylic acids are naturally occurring amino carboxylic acids, such as azetidine carboxylic acid or prolinej and some are produced cornmercially, such as pipecolinic acid or isonipecotine acid~ Insofar as synthetic amino carboxylic acids are concerned -they can be ~- 3 produced from naturally occurring or commercial amino carbox-ylic acids, amino carboxylic acid derivatives or first stages of amino carboxylic acid by simple reactions, for example, by condensation o~ suitable non-cyclic amino carboxylic acids with suitable aldehydes or ketones.
The reaction of the amino carboxylic esters having the general formula (II~ with phosgene is suitably so carried out that the phosgene is dissolved in the solvent selected and the amino carboxylic ester is then added. The amino car-boxylic esters can be used in the pure form or in the form of the crude reaction products from the dehydrohalogenation of the corresponding hydrohalides with ammonia.
As an alternative, the hydrohalides of the amino carboxylic esters having the general formula (II) can also be used directl~. In this case it is expedient to dissolve or suspend the hydrohalide in the solvent selected and to add the phosgene to the $olution or suspension.
Depending on the amino carboxylic ester having the general formula (II) the reaction requires a reaction time between 1 and 50 hours. In any case the reaction must be con-tinued until initially present suspensions or material precip itated thereafter have gone completely in solution.
The further treatment is so carried out that the solvent and the excess phosgene are first drawn off, when re-quired under reduced pressure. The recovered materials can be used again directly. I~ the N-chloro-carbonyl-amino carbox-ylic acid is volatile, then the remaining residue can be dis-tilled for further purification, when required under reduced pressure.
When the N-chloro-carbonyl amino carbox~lic ester Eormed has a higher molecular weight (this is generally the case when the ring carrying the chloro-carbonyl group has 6 ring members and/or carries aromatic or heteroaromatic substi-tuents) it frequently can no longer be distilled without de-composition. In these cases a further purification can be carried out in that the residue remaining after the removal of both the solvent and the excess phosgene is taken up in new solvent and subjected to clarification with active carbon.
After fil~ration the filtrate is freed from solven~ at reduced pressure and an oil which crystallizes under certain conditions is obtained.
When the N-chloro-carbonyl-amino carboxylic ester is optically active, its optical purity can be tested, for example, in that a sample is subjected to hydrolysis, the liberated amino acid is isolated and its rotational value is determined.
It is found that the original optical con~iguration has remain-ed unchanged.
The N-chloro-carbonyl-amino carboxylic esters having the general formula (I) can be reacted with the most varied primary and secondary amines to form active substances of the hydantoin or urea t~pe, which are known per se, for example, from the British Patent 1,S03,244~ This reaction is carried out in the presence of an acid acceptor, for example~ pyridine or triethyl amine, in at least equimolar amounts. It can b~
carried out in the absence of additional solvents or in a suit~
able solvent, for example, in dioxane or toluene. The reaction temperature can be between approximately 20C and the reflux temperature of the reaction mixture~ The desired hydantoin or urea derivatives are obtained in high yields within relative-ly short reaction times of e~g., ~ to 5 hours.
The invention will be explained in greater detail by means of the Examples hereafter.
Example 1 _ 1.2 moles (181.9 g~ of L-azetidine-carboxylic (2)-methyl ester ~HCl are suspended in 800 ml of chloroform and saturated with ammonia gas while stirring and cooling. The precipitated ammonium chloride is drawn off by suction and the filtrate is concentrated by evaporation in vacuo. The residue is added dropwise to a solution of 200 ml of phosgene in 400 ml of chloroform at 0C within 2 hours while stirring. The reac-tion mixture is then stirred for 12 hours at roo~ temperature.
After evaporating the solvent and the excess phosgene the resi-due is distilled in vacuo. At 100 to 105C and at a pressure of 1.3 m bars 137.5 g (64.5~) of L-N-chloro-carbonyl~azetidine carboxylic methyl ester pass over.
Computed (%)Obtained~%) C6H8ClNO3 C 40.58 39.82 (177.59) H 4.54 4.49 Cl 19.9620.03 N 7.89 8.23 H-NMR (CDC13):~ = 4.85 (mc, lH) CH - COOCH3, 4.33 (mc, 2H) CH2- NCOCl, 3.85 (s, 3H) COOCH3, 3~3 - 1.9 ppm(m,2H) CH2 - CH - COOCH3.
IR (liquid capillary) : 1740 cm Example 2 5O0 moles (828.1 g~ of L-proline methyl e~ter ~HCl are converted with amrnonia into the rree ester according to Example 1. The crude proline methyl ester is added dropwise to a solution of 1000 ml of phosgene in 2000 ml of chloroform at 0C within 45 minutes while stirring. Stirring is continued for a further hour at this temperature and for a further 12 hours at room temperature. Ater evaporating the chloroform a.~
and the excess phosgene the residue is distilled in vacuo.
896.1 g (93.5%) of L-N-chloro-carbonyl-proline methyl ester having a boiling point of 90 to 95C at 0.012 m bar are obtain-ed~
Computed (%)Obtained (~) C7HloCl NO3 C 43~88 44.16 (19lj62) H 5,26 5.46 Cl 1~.5017,93 N 7.31 7~38 H-NMR (CDC13): ~= 4.53 (mc,lH) - CH -COOCH3, 3.97 - 3.53 (m, 2H) - N - COCl, 3.87; 3.83 (s, 3H) - COOCH3,
2.19 ppm (mc,4H) - CH2 C 2 IR (liquid capillary) : 1735 cm 1.
Example 3 1.0 mole (165.6 g) of L-proline methyl ester ~HCl are dissolved in 500 ml of chloroform and 200 ml of phosgene and added dropwise to the solution, which has been cooled to 5 C, within 30 minutes while stirring. Stirring is continued for 12 hours at 5C and for a~further 5 hour-s at room temperature and then for 24 hours at 40C. The excess phosgene is kept in -the reaction space by correspondingly cooling. After processing as in Example 2 and distillation 168.0 g (87.7%) of L-N-chloro-carbonyl-proline methyl ester having a boiling point of 90 to 95 C at 0.013 m bar are obtained.
Example 4 19.1 y (0.1 mole) of N-chloro-carbonyl-proline methyl ester, 11.0 g oE triekhyl amine and 10.7 g (0.1 mole) of 4-methyl aniline are heated in 100 ml of dioxane for 4 hours to _ ~ _ 90 C while stirring intensely. After cooling the reaction mixture it is poured on 500 ml of ice water while stirring in-tensely. The fine-crystalline precipitate thus formed is filtered with suction and dried at 50C and 13 m bars. 21.4 g (93%) of 1,5-trimethylene-3-(4'-fluoro-phenyl)-hydantoin having a melting point of 161 to 162C are obtained.
Example 5 19.1 g (0.1 mole) of N-chloro-carbonyl-proline methyl ester, 8.2 g of pyridine and 11.1 g (0.1 mole) of 4-fluoro aniline are heated in 200 ml of toluene for 5 hours with reflux.
After completion of the reaction the toluene is drawn off on a rotary evaporator and the residue is poured on 500 ml of ice water while stirring vigorously. After filtering with suction and drying at 50C and 13 m bars 20.6 g (88%) of 1,5-trimethylene-
Example 3 1.0 mole (165.6 g) of L-proline methyl ester ~HCl are dissolved in 500 ml of chloroform and 200 ml of phosgene and added dropwise to the solution, which has been cooled to 5 C, within 30 minutes while stirring. Stirring is continued for 12 hours at 5C and for a~further 5 hour-s at room temperature and then for 24 hours at 40C. The excess phosgene is kept in -the reaction space by correspondingly cooling. After processing as in Example 2 and distillation 168.0 g (87.7%) of L-N-chloro-carbonyl-proline methyl ester having a boiling point of 90 to 95 C at 0.013 m bar are obtained.
Example 4 19.1 y (0.1 mole) of N-chloro-carbonyl-proline methyl ester, 11.0 g oE triekhyl amine and 10.7 g (0.1 mole) of 4-methyl aniline are heated in 100 ml of dioxane for 4 hours to _ ~ _ 90 C while stirring intensely. After cooling the reaction mixture it is poured on 500 ml of ice water while stirring in-tensely. The fine-crystalline precipitate thus formed is filtered with suction and dried at 50C and 13 m bars. 21.4 g (93%) of 1,5-trimethylene-3-(4'-fluoro-phenyl)-hydantoin having a melting point of 161 to 162C are obtained.
Example 5 19.1 g (0.1 mole) of N-chloro-carbonyl-proline methyl ester, 8.2 g of pyridine and 11.1 g (0.1 mole) of 4-fluoro aniline are heated in 200 ml of toluene for 5 hours with reflux.
After completion of the reaction the toluene is drawn off on a rotary evaporator and the residue is poured on 500 ml of ice water while stirring vigorously. After filtering with suction and drying at 50C and 13 m bars 20.6 g (88%) of 1,5-trimethylene-
3-(4-fluoro-phenyl~-hydantoin having a melting point of 143 to 146C are obtained.
Example 6 19.1 g (0.1 mole) of N-chloro-carbonyl-proline methyl ester, 8.5 g of pyridine and 16.2 g (0.1 mole) of 3,4-dichloro aniline are reacted as in Example 5. After fur-ther treatment 24.7 g (86.5%) of 1,5-trimethylene-3-(3',4'-dichloro-phenyl) hydantoin having a melting point of 141 to 145C are obtained.
Example 7 19.1 g (0.2 mole) of N-chloro-carbonyl-proline methyl ester and 16.2 g (0.1 mole~ of 3,5-dichloro aniline are heated in 100 ml of pyridine for 5 hours with reflux while stirring vigorously. After removing the pyxidine under reduced pressure and pouring the residue on 500 ml of ice wa-ter as in Example 5 25.3 g (89~ of 1,5-trimethylene-3-(3',5'-dichloro-phenyl) hydantoin are obtained~
Example 8 After converting 1.0 mole ~179.65 g) of L-proline-methyl ester HCl into the free ester it is reacted with phos-gene as in Example 2. After further processingl 196.4 g (95.5%) of L-N-chloro-carbonyl-proline ethyl ester having a boiling point of 90C at 0.Q013 m bar are obtained.
Computed (%) Obtained (%) 8 12 3 C 46,73 46.80 (205,64) H 5.88 6.03 Cl 17,24 17.20 N 6.81 7!21 ; H-NMR ~CDC13): ~= 4 47 (mc,lH) CH - COOC2H5,
Example 6 19.1 g (0.1 mole) of N-chloro-carbonyl-proline methyl ester, 8.5 g of pyridine and 16.2 g (0.1 mole) of 3,4-dichloro aniline are reacted as in Example 5. After fur-ther treatment 24.7 g (86.5%) of 1,5-trimethylene-3-(3',4'-dichloro-phenyl) hydantoin having a melting point of 141 to 145C are obtained.
Example 7 19.1 g (0.2 mole) of N-chloro-carbonyl-proline methyl ester and 16.2 g (0.1 mole~ of 3,5-dichloro aniline are heated in 100 ml of pyridine for 5 hours with reflux while stirring vigorously. After removing the pyxidine under reduced pressure and pouring the residue on 500 ml of ice wa-ter as in Example 5 25.3 g (89~ of 1,5-trimethylene-3-(3',5'-dichloro-phenyl) hydantoin are obtained~
Example 8 After converting 1.0 mole ~179.65 g) of L-proline-methyl ester HCl into the free ester it is reacted with phos-gene as in Example 2. After further processingl 196.4 g (95.5%) of L-N-chloro-carbonyl-proline ethyl ester having a boiling point of 90C at 0.Q013 m bar are obtained.
Computed (%) Obtained (%) 8 12 3 C 46,73 46.80 (205,64) H 5.88 6.03 Cl 17,24 17.20 N 6.81 7!21 ; H-NMR ~CDC13): ~= 4 47 (mc,lH) CH - COOC2H5,
4.27; 423 (q, I=7Hz; 2H) COOCH2CH3, 3.75 (mc,2H) CH2-NCOCl, 2.13 (mC~4H) CH2 - 2' 1.33 ppm (~,I=7Hz; 3H) COOCH2CH2-I~ (liquid capillary) ~ 1740 cm Example 9 0.5 mole (71.6 g) of D,L-pipecoline methyl ester are added dropwise at -10C within 30 minutes to a solution of 100 ml of phosgene in 400 ml of chloroform. The reaction mix-ture is then stirred for 12 hours at room temperature. After evaporating the solvent and the excess phosgene the residue obtained is subjected to clarification with active carbon.
After ~iltering and evaporating the solvent 100.9 g (98.1~) of D,L-N-chloro-carbonyl-pipecoline methyl ester are obtained as an oil.
~ Computed (~ Obtained (%~
C8H12Cl NO8 C 46.7246,90 (205.641 H 5~88 600~
Cl 17.24 17.15 _ g _ Computed (~) Obtained (%) N 6.81 7.17 IR (liquid capillary~ : 1735 cm Example 10 2Q.6 g ~0.1 mole) of N-chloro-carbonyl-pipecoline methyl ester, 11.1 g (0.1 mole) of 3-fluoro aniline are heated in 150 ml of pyridine for 4 hours to the boiling tem-perature while stirring vigorously. After comple~ion-of the reaction the excess solvent is evaporated under reduced pressure and the remaining residue is poured on 500 ml of ice water while stirr-ing vigorously. The precipitated crystalline substance is filtered with suction, washed with ice water and dried at 50C
and 13 m bars in a drying cabinet until constancy of weight is obtained.
20.8 g (84%) o 1,5-tetramethylene-3-~3'-fluoro-phenyl~-hydantoin having a melting point of 116 to 119 C are thus obtained.
Example 11 20.6 g (0.1 mole) of N-chloro-carbonyl~pipecoline methyl ester and 10.7 g (0.1 mole) of 4-methyl-aniline are reacted according to Example 10.
After further treatment 21.6 g (88.5%) of 1,5-tetra-methyl-3-(4'-methyl-phenyllhydantoin having a melting point of 185 to 188C are obtained.
Example 12 0.77 mole 1138.4 gl of isonipecotine methyl ester ~
HCl are converted with ammonia into the free base as in Example 1. The free ester is then added dropwise to a solution of 150 ml of phosgene in 400 ml o~ chloroform within an hour.
The reaction temperature is -5C. The solution is then stirred for 12 hours at room temperature. After further treatment and distillation 157.8 g (99.6%1 o~ N-chloro-carbonyl-isoni-pecotine methyl ester having a boiling point of 120C at 0.65 m bar are obtained.
Computed (%) Obtained (%) C8 12C NO3 C46.72 46.61 (205~64) H5.88 5.80 Cl17.2417.35 N6.81 6.84 IR (KBr - moulding) : 1720 cm ~-NM~ (CDC13) : ~ = 5 2 - 4.4 (m,3H) CH-COOCH3, S-CH2-N, 3.85; 3.80 (s,3H) COOCH3, 3-6 - 3-1 ppm (m,~H) CH2-CH-COOCH3.
H-NMR (CDC13~ : ~ = 4.35; 4.11 (m,2H) (CH2)2-NCOCl, 3.75 (s,3H) COOCH3, 3.6 - 2.9 (m,2H) (CH2)2-NCOCl, 2.65 (mc,lH) CH-COOCH3, 2 0 ppm (mc,4H) 2-CH2-.
Example 13 2.0 moles (367.3 g) of D,L-thiazolidine-carboxylic methyl ester (4) ~HCl are converted with ammonia into the free base as in Example 1. Said ester is then added dropwise to a solution of 4Q0 ml of phosgene in 800 ml of chloroform at -i0C within 30 minutes while stirring vigorously. The solution is then allowed to stand for 15 hours at room tempera-ture. After further treatment and distillation 403.0 g (96.1%) of D,L-N-chloro-carbonyl-thiazolidine carboxylic methyl ester(4~ having a hoiling point of 118 to 120C at 0.65 m bar are obtained.
Computed (%) Obtained ~%) C6H8ClNO3S C34.37 34.20 (20g.65) H3.84 3.81 N6.68 6.81 Cl16.91 16.~6 S15.-30 15.25 IR (KBr - molding) : 1730 cm^ .
Example 14 0.46 mole (74.2 g) of D,L-2-methyl-thiazolidine car-boxylic methyl ester (4) are reacted with 100 ml of phosgene in 400 ml of chloroform as in Example 9. After further treat-ment and distillation 84.5 g (82.1%) of D,L-3-chloro-carbonyl-2-methyl-thiazolidine carboxylic methyl ester (4) having a boiling point of 98 to 100C at 0.39 m bar are obtained.
Computed (%) Obtained (%) C7HloClNO3S C37.59 37.52 (223.68~ H4.51 4.60 2~ Cl15~85 15.61 N6.26 6.31 S14.33 14.17 IR (liquid capillary) : 1735 cm 1.
H-NMR (CDC13) : ~ = 5.65 - 4.65 (m,2H) CH-COOCH3 and S-CH2-N, 3.82 (s,3H) COOCH3, ; 3-6 - 3-2 (m,2H) CH2-CH-COOCH3, 1.65 ppm (mc,3H) CH-CH3.
Example 15 1.0 mole (211.7 g) of D,L-2,2-dimethyl-thiazolidine fl~
carboxylic methyl ester (4~ . HCl are converted with ammonia into the free ester as in Example 1. The free ester is then added drspwise to a solution of 200 ml of phosgene in 350 ml of chloroform at ~5C while stirring. The solution is then stirred for 12 hours at room temperature and further treated as in Example 9. 230.1 g (96.8%) of D,L-3-chloro-carbonyl-2-dimethyl thiazolidine carboxylic methyl ester are obtained as a colorless oil.
IR (liquid capillary) : 1740 cm H-NMR (CDC13) : ~ = 5.2 (mc,lH) CH-COOCH3, 4.85 (s,3H) COOCH3, 3.37 (mc,2H) S-CH2-N, 1.95; 1.85 ppm (s,6~) C(CH3)2.
Example 16 1.5 mole (386.6 g) of newly produced D,L-2-(p-chloro-phenyl)-thiazolidine carboxylic methyl ester (4) are dissolved in 300 ml of chloroform and added dropwise to a solu tion of 300 ml of phosgene in 500 ml of chloroEorm at 0 C.
The solution is stirred for 2 hours at 0C and allowed to stand for 12 hours at room temperature. The reaction mixture is then heated for 3 hours to 50C. The clear solution is concen-trated by evaporation under reduced pressure. The residue is taken up in 1 litre of chloroform, heated with active carbon for 1 hour with reflux, concentrated by evaporation and pre-cipitated by adding 200 ml of methyl-tert.-butyl ether.
390.5 g(81.3%) of D,L-3-chloro carbonyl-2-(p-chloro~
phenyl)-thiazolidine carboxylic methyl ester (4) having a melting point of 118 to 121C are obtained.
Computed (%) Obtained t%) Cl2Hllcl2NO3 C45~01 45.27 (32~.19) ~3.~6 3.50 Cl22.15 22,36 N4.38 4.81 S10.19 10.02 IR (KBr - molding) 1745 (shoulder), 172 cm 1.
H-NMR (CDC13) : ~ = 7.. 8 - 7.15 (m,4H) aromatic protons 6~23; 6.08 (s,lH) S-CH-N,
After ~iltering and evaporating the solvent 100.9 g (98.1~) of D,L-N-chloro-carbonyl-pipecoline methyl ester are obtained as an oil.
~ Computed (~ Obtained (%~
C8H12Cl NO8 C 46.7246,90 (205.641 H 5~88 600~
Cl 17.24 17.15 _ g _ Computed (~) Obtained (%) N 6.81 7.17 IR (liquid capillary~ : 1735 cm Example 10 2Q.6 g ~0.1 mole) of N-chloro-carbonyl-pipecoline methyl ester, 11.1 g (0.1 mole) of 3-fluoro aniline are heated in 150 ml of pyridine for 4 hours to the boiling tem-perature while stirring vigorously. After comple~ion-of the reaction the excess solvent is evaporated under reduced pressure and the remaining residue is poured on 500 ml of ice water while stirr-ing vigorously. The precipitated crystalline substance is filtered with suction, washed with ice water and dried at 50C
and 13 m bars in a drying cabinet until constancy of weight is obtained.
20.8 g (84%) o 1,5-tetramethylene-3-~3'-fluoro-phenyl~-hydantoin having a melting point of 116 to 119 C are thus obtained.
Example 11 20.6 g (0.1 mole) of N-chloro-carbonyl~pipecoline methyl ester and 10.7 g (0.1 mole) of 4-methyl-aniline are reacted according to Example 10.
After further treatment 21.6 g (88.5%) of 1,5-tetra-methyl-3-(4'-methyl-phenyllhydantoin having a melting point of 185 to 188C are obtained.
Example 12 0.77 mole 1138.4 gl of isonipecotine methyl ester ~
HCl are converted with ammonia into the free base as in Example 1. The free ester is then added dropwise to a solution of 150 ml of phosgene in 400 ml o~ chloroform within an hour.
The reaction temperature is -5C. The solution is then stirred for 12 hours at room temperature. After further treatment and distillation 157.8 g (99.6%1 o~ N-chloro-carbonyl-isoni-pecotine methyl ester having a boiling point of 120C at 0.65 m bar are obtained.
Computed (%) Obtained (%) C8 12C NO3 C46.72 46.61 (205~64) H5.88 5.80 Cl17.2417.35 N6.81 6.84 IR (KBr - moulding) : 1720 cm ~-NM~ (CDC13) : ~ = 5 2 - 4.4 (m,3H) CH-COOCH3, S-CH2-N, 3.85; 3.80 (s,3H) COOCH3, 3-6 - 3-1 ppm (m,~H) CH2-CH-COOCH3.
H-NMR (CDC13~ : ~ = 4.35; 4.11 (m,2H) (CH2)2-NCOCl, 3.75 (s,3H) COOCH3, 3.6 - 2.9 (m,2H) (CH2)2-NCOCl, 2.65 (mc,lH) CH-COOCH3, 2 0 ppm (mc,4H) 2-CH2-.
Example 13 2.0 moles (367.3 g) of D,L-thiazolidine-carboxylic methyl ester (4) ~HCl are converted with ammonia into the free base as in Example 1. Said ester is then added dropwise to a solution of 4Q0 ml of phosgene in 800 ml of chloroform at -i0C within 30 minutes while stirring vigorously. The solution is then allowed to stand for 15 hours at room tempera-ture. After further treatment and distillation 403.0 g (96.1%) of D,L-N-chloro-carbonyl-thiazolidine carboxylic methyl ester(4~ having a hoiling point of 118 to 120C at 0.65 m bar are obtained.
Computed (%) Obtained ~%) C6H8ClNO3S C34.37 34.20 (20g.65) H3.84 3.81 N6.68 6.81 Cl16.91 16.~6 S15.-30 15.25 IR (KBr - molding) : 1730 cm^ .
Example 14 0.46 mole (74.2 g) of D,L-2-methyl-thiazolidine car-boxylic methyl ester (4) are reacted with 100 ml of phosgene in 400 ml of chloroform as in Example 9. After further treat-ment and distillation 84.5 g (82.1%) of D,L-3-chloro-carbonyl-2-methyl-thiazolidine carboxylic methyl ester (4) having a boiling point of 98 to 100C at 0.39 m bar are obtained.
Computed (%) Obtained (%) C7HloClNO3S C37.59 37.52 (223.68~ H4.51 4.60 2~ Cl15~85 15.61 N6.26 6.31 S14.33 14.17 IR (liquid capillary) : 1735 cm 1.
H-NMR (CDC13) : ~ = 5.65 - 4.65 (m,2H) CH-COOCH3 and S-CH2-N, 3.82 (s,3H) COOCH3, ; 3-6 - 3-2 (m,2H) CH2-CH-COOCH3, 1.65 ppm (mc,3H) CH-CH3.
Example 15 1.0 mole (211.7 g) of D,L-2,2-dimethyl-thiazolidine fl~
carboxylic methyl ester (4~ . HCl are converted with ammonia into the free ester as in Example 1. The free ester is then added drspwise to a solution of 200 ml of phosgene in 350 ml of chloroform at ~5C while stirring. The solution is then stirred for 12 hours at room temperature and further treated as in Example 9. 230.1 g (96.8%) of D,L-3-chloro-carbonyl-2-dimethyl thiazolidine carboxylic methyl ester are obtained as a colorless oil.
IR (liquid capillary) : 1740 cm H-NMR (CDC13) : ~ = 5.2 (mc,lH) CH-COOCH3, 4.85 (s,3H) COOCH3, 3.37 (mc,2H) S-CH2-N, 1.95; 1.85 ppm (s,6~) C(CH3)2.
Example 16 1.5 mole (386.6 g) of newly produced D,L-2-(p-chloro-phenyl)-thiazolidine carboxylic methyl ester (4) are dissolved in 300 ml of chloroform and added dropwise to a solu tion of 300 ml of phosgene in 500 ml of chloroEorm at 0 C.
The solution is stirred for 2 hours at 0C and allowed to stand for 12 hours at room temperature. The reaction mixture is then heated for 3 hours to 50C. The clear solution is concen-trated by evaporation under reduced pressure. The residue is taken up in 1 litre of chloroform, heated with active carbon for 1 hour with reflux, concentrated by evaporation and pre-cipitated by adding 200 ml of methyl-tert.-butyl ether.
390.5 g(81.3%) of D,L-3-chloro carbonyl-2-(p-chloro~
phenyl)-thiazolidine carboxylic methyl ester (4) having a melting point of 118 to 121C are obtained.
Computed (%) Obtained t%) Cl2Hllcl2NO3 C45~01 45.27 (32~.19) ~3.~6 3.50 Cl22.15 22,36 N4.38 4.81 S10.19 10.02 IR (KBr - molding) 1745 (shoulder), 172 cm 1.
H-NMR (CDC13) : ~ = 7.. 8 - 7.15 (m,4H) aromatic protons 6~23; 6.08 (s,lH) S-CH-N,
5.05 (mc,lH) CH-COOCH3, 3.83 (s,3H) COOCH3, 3.4 ppm (mc,2H) CH2-CH-COOCH3.
Example 17 1.0 mole (211.7 g) of D-5.,5-dimethyl-thiozolid.ine-~rboxylic methyl ester ~ HCl are dehydrohalogenated and phos-genated as in Example 16. The vacuum distillation results in 202.0 g (85%) of D-3-chloro-carbonyl-5,5-dimethyl-thiazolidine carboxylic ester (4) having a boiling point of 117 at 0.65 m bar.
IR (liquid capillary) : 1735 cm H-NMR (CDC13) : ~ = 4.85 (S,lH) CH~COOCH3, 4.60 (mc,2H) S-CH2-N, 3.78 (S,3H) -COOCH3, . 1~6; 1.3 ppm (S,6H)-C(CH3)2.
~
1.0 mole (239.8 g~ of D-2,2,5,5-tetramethyl-thiazoli-dine carboxylic methyl ester ~4) are dehydrohalogenated and phosgenated as in Example 17. After further processin~ as in Example 16 256 ! 8 g (~6.6%) of D-3-chloro-carbonyl-2,2,5~5-tetra-methyl-thiazolidine carboxylic methyl ester ar~ obtained as an oil. Computed (%)Obtained (%) CloHl6clNo3 C45.19 45.51 (265,76) H6.07 6-24 Cl13.34 13.05 N5.27 5.34 S12.07 12.52 IR (liquid capillary) : 1735 cm H-NMR (CDC13) : ~ = 4.75 (s!lH) CH-COOCH3, 3.80 (s,3H) COOCH3, 1.95 (s,6H) -N-C(CH3)2-S-, 1.75; 1.4 ppm (s,6H) C(CH3)2.
Example 19 Q.2 mole (36.7 g) of D,L-thia~olidine-carboxylic methyl ester (2) ~HCl are dehydrohalogenated and phosgenated as in Example 14. After further treatment and distillation 39.8 g (94.9%) of D,L-3-chloro-carbonyl-thiazolidine carboxylic methyl ester~2) having a boiling point of 105 to 110 C at 0.0065 m bar are obtained.
Computed (%)Obtained (%) C6H8ClNO3S C34.37 34.87 (209~65) H3-84 3O90 N6.68 6.51 Cl16.91 16052 S15.30 15.15 IR ~liquid capillary) : 1735 cm 1.0 mole (197.7 g~ of D,L-tetrahydrothiazine (1,3)-carboxylic methyl ester -(4~ .HCl are dehydrohalogenated as in Example 1. The crude D,L-tetrahydrothiazine-(1,3)-carboxyliC
methyl ester is added dropwise to a solution of 180 ml of phosgene in 500 ml of chloroform at -5C within 45 minutes.
The solution is stirxed for 12 hours at room temperature and for a further 3 hours at 45C. The clear solution is concentrat-ed by evaporation and the residue is further treated as in Example 16.
223.5 g ~rvl00~) of D,L~3-chloro-carbonyl-tetrahydro-thiazine(l,3)-carboxylic methyl ester (4) are obtained.
IR (liquid capillary) : 1735 cm H-NMR ~CDC13) : ~ = 5~3 - 4~1 ~m,3H) CH-COOCH3 and , S-C~2-N~
3~85 (s,3H) COOCH3, 3.15 - 1.8 ppm (m,4H)-CH2~CH
Example 21 1~0 mole ~197.7 g~ of D,L-tetrahydrothiazine (1,4~
carboxylic methyl ester -(5) HCl are dehydrohalogenated and phsogenated as in Example 21. After processing as in Example 16, 21.9 g (99.2~ of D,L-4-chloro-carbonyl-tetrahydrothia-zine (1,4~-carboxylic methyl ester (5) are obtained.
IR (liquid capillary) : 1730 cm Computed (~) Obtained (%) 7 10 3 C 37.59 37.21 (223.68) H 4.51 4.36 Cl 15.8615~65 1~ -Computed (%~ Obtained (%) N 6.26 6.50 S 1~.33 14.01 i
Example 17 1.0 mole (211.7 g) of D-5.,5-dimethyl-thiozolid.ine-~rboxylic methyl ester ~ HCl are dehydrohalogenated and phos-genated as in Example 16. The vacuum distillation results in 202.0 g (85%) of D-3-chloro-carbonyl-5,5-dimethyl-thiazolidine carboxylic ester (4) having a boiling point of 117 at 0.65 m bar.
IR (liquid capillary) : 1735 cm H-NMR (CDC13) : ~ = 4.85 (S,lH) CH~COOCH3, 4.60 (mc,2H) S-CH2-N, 3.78 (S,3H) -COOCH3, . 1~6; 1.3 ppm (S,6H)-C(CH3)2.
~
1.0 mole (239.8 g~ of D-2,2,5,5-tetramethyl-thiazoli-dine carboxylic methyl ester ~4) are dehydrohalogenated and phosgenated as in Example 17. After further processin~ as in Example 16 256 ! 8 g (~6.6%) of D-3-chloro-carbonyl-2,2,5~5-tetra-methyl-thiazolidine carboxylic methyl ester ar~ obtained as an oil. Computed (%)Obtained (%) CloHl6clNo3 C45.19 45.51 (265,76) H6.07 6-24 Cl13.34 13.05 N5.27 5.34 S12.07 12.52 IR (liquid capillary) : 1735 cm H-NMR (CDC13) : ~ = 4.75 (s!lH) CH-COOCH3, 3.80 (s,3H) COOCH3, 1.95 (s,6H) -N-C(CH3)2-S-, 1.75; 1.4 ppm (s,6H) C(CH3)2.
Example 19 Q.2 mole (36.7 g) of D,L-thia~olidine-carboxylic methyl ester (2) ~HCl are dehydrohalogenated and phosgenated as in Example 14. After further treatment and distillation 39.8 g (94.9%) of D,L-3-chloro-carbonyl-thiazolidine carboxylic methyl ester~2) having a boiling point of 105 to 110 C at 0.0065 m bar are obtained.
Computed (%)Obtained (%) C6H8ClNO3S C34.37 34.87 (209~65) H3-84 3O90 N6.68 6.51 Cl16.91 16052 S15.30 15.15 IR ~liquid capillary) : 1735 cm 1.0 mole (197.7 g~ of D,L-tetrahydrothiazine (1,3)-carboxylic methyl ester -(4~ .HCl are dehydrohalogenated as in Example 1. The crude D,L-tetrahydrothiazine-(1,3)-carboxyliC
methyl ester is added dropwise to a solution of 180 ml of phosgene in 500 ml of chloroform at -5C within 45 minutes.
The solution is stirxed for 12 hours at room temperature and for a further 3 hours at 45C. The clear solution is concentrat-ed by evaporation and the residue is further treated as in Example 16.
223.5 g ~rvl00~) of D,L~3-chloro-carbonyl-tetrahydro-thiazine(l,3)-carboxylic methyl ester (4) are obtained.
IR (liquid capillary) : 1735 cm H-NMR ~CDC13) : ~ = 5~3 - 4~1 ~m,3H) CH-COOCH3 and , S-C~2-N~
3~85 (s,3H) COOCH3, 3.15 - 1.8 ppm (m,4H)-CH2~CH
Example 21 1~0 mole ~197.7 g~ of D,L-tetrahydrothiazine (1,4~
carboxylic methyl ester -(5) HCl are dehydrohalogenated and phsogenated as in Example 21. After processing as in Example 16, 21.9 g (99.2~ of D,L-4-chloro-carbonyl-tetrahydrothia-zine (1,4~-carboxylic methyl ester (5) are obtained.
IR (liquid capillary) : 1730 cm Computed (~) Obtained (%) 7 10 3 C 37.59 37.21 (223.68) H 4.51 4.36 Cl 15.8615~65 1~ -Computed (%~ Obtained (%) N 6.26 6.50 S 1~.33 14.01 i
Claims (28)
1. N-chloro-carbonyl-amino carboxylic esters having the general formula (I) wherein X = -CH2- or -S-, R1 represents a straight-chain or branched alkyl radical containing up to 4 carbon atoms, R2, R3 and R4, each independently represents hydrogen or a methyl radical, R5 represents hydrogen, an alkyl radical, which is either unsubstituted or substituted by substituents stable against phosgene, or an aromatic or heteroaromatic radical, which is either unsubstituted or substituted by substituents stable against phosgene, or R4 and R5 together represent an alkylene radical containing 4 to 5 carbon atoms and 1, m and n, independently of each other, each represents 0, 1 or 2 with the stipulation that the sum of 1, m and n is minimally 1 and maxi-mally 3 and for the case that 1 = 2, R2 and R3 can only repre-sent hydrogen.
2. An ester according to claim 1, in which n is 1 and R5 is selected from a unsubstituted straight chain alkyl group or such a group substituted with substituents stable against phosgene and a unsubstituted aromatic or heteroaromatic radical or such a radical substituted with substituents stable against phosgene.
3. An ester according to claim 2, in which the alkyl group has 1 to 16 carbon atoms.
4. An ester according to claim 1, in which n is 1 and R5 is methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-hendecyl, n-tridecyl, n-pentadecyl or n-hexadecyl.
5. An ester according to claim 1, in which n is 1 and R5 is phenyl methyl, (1'-phenyl)ethyl, (2'-methyl-mer-capto)-ethyl or (2'-ethyl-mercapto)-ethyl.
6. An ester according to claim 1, in which n is 1 and R5 is phenyl, naphthyl, 2'-furyl, 2'-thienyl or 3'-thienyl.
7. An ester according to claim 1, in which n is 1 and R5 is 2'-fluoro phenyl, 3'-tluoro phenyl, 4'-fluoro phenyl, 2'-chloro phenyl, 3'-chloro phenyl, 4'-chloro phenyl, 3',4'-dichloro phenyl, 3',5'-dichloro phenyl, 2',4'-dichloro phenyl, 2',6'-dichloro phenyl, 2',5'-dichloro phenyl, 2' nitro-phenyl, 3'-nitro-phenyl, 4'-nitro-phenyl, 2'-methoxy phenyl, 3'-methoxy-phenyl, 4'-methoxy-phenyl, 4'-ethoxy phenyl, 4'-propoxy phenyl, 4'-butoxy phenyl, 3',4'-dimethoxy phenyl, piperonyl-(3',4'-methylene-dioxo-phenyl), 3'-phenoxy phenyl, 4'-phenoxy phenyl, 2'-methyl phenyl, 3'-methyl phenyl, 4'-methyl phenyl, 4'-tert.-butyl phenyl, 4'-n-pentyl phenyl, 2'-trifluoro-methyl phenyl, 3'-trifluoro-methyl phenyl, 4'-trifluoro-methyl phenyl, 5'-chloro-2'-thienyl, 5'-bromo-2'-thienyl, 5'-nitro-2'-thienyl or 5'-nitro-2'-furyl.
8. L-N-chloro-carbonyl-azetidine carboxylic methyl ester.
9. L-N-chloro-carbonyl-proline methyl ester.
10. L-N-chloro-carbonyl-proline ethyl ester.
11. D,L-N-chloro-carbonyl-pipecoline methyl ester.
12. N-chloro-carbonyl-isonipecotine methyl ester.
13. D,L-N-chloro-carbonyl-thiazolidine carboxylic methyl ester (4).
14. D,L-3-chloro-carbonyl-2-methyl-thiazolidine carboxylic methyl ester (4).
15. D,L-3-chloro-carbonyl-2-dimethyl thiazolidine carboxylic methyl ester.
16. D,L-3 chloro-carbonyl-2-(p-chloro-phenyl)-thia-zolidine carboxylic methyl ester (4).
17. D-3-chloro-carbonyl-5,5-dimethyl-thiazolidine carboxylic ester (4).
18. D-3-chloro-carbonyl-2,2,5,5-tetramethyl-thiazoli-dine carboxylic methyl ester.
19. D,L-3-chloro-carbonyl-thiazolidine carboxylic methyl ester (2).
20. D,L-3-chloro-carbonyl-tetrahydrothiazine(1,3)-carboxylic methyl ester (4).
21. D,L-4-chloro-carbonyl-tetrahydrothiazine(1,4)-carboxylic methyl ester (5).
22. A process for producing N-chloro-carbonyl-amino-carboxylic esters having the general formula I given in claim 1, wherein X, R1, R2, R3, R4, R5, 1, m and n are as in claim 1, in which an amino-carboxylic ester having the general formula (II) wherein X, R1, R2, R3, R4, R5, 1, m and n have the meanings de-fined above, or its hydrohalide is reacted in a solvent, which is inert with respect to phosgene at a temperature between -30 and +100°C with 1 to 10 times the molar amount of phosgene.
23. A process according to claim 22, in which the temperature is from -20 to 480°C.
24. A process according to claim 22, in which the solvent is a hydrocarbon, chlorohydrocarbon, ether or carboxylic acid ester.
25. A process according to claim 22, 23 or 24, in which the phosgene is dissolved in the solvent and the ester of formula II then added.
26. A process according to claim 22, 23 or 24, in which the hydrohalide of the ester of formula II is suspended or dissolved in the solvent and the phosgene then added.
27. A process in which the N-chloro-carbonyl-amino-carboxylic ester having the general formula (I) given in claim 1, wherein X, R1, R2, R3, R4, R5, 1, m and n are as in claim 1, is reacted with a primary or secondary amine to produce a sub-stance of the hydantoin or urea type in the presence of an acid acceptor in a at least equimolar amount at a temperature be-tween 20°C and reflux temperature of the reaction mixture.
28. A process according to claim 27, in which the reaction is effected in an additional solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3137376.3 | 1981-09-19 | ||
| DE19813137376 DE3137376C2 (en) | 1981-09-19 | 1981-09-19 | Process for the preparation of 1,5-alkylene-3-aryl-hydantoin derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1184177A true CA1184177A (en) | 1985-03-19 |
Family
ID=6142161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000411699A Expired CA1184177A (en) | 1981-09-19 | 1982-09-17 | N-chloro-carbonyl-amino carboxylic esters, process for producing same and its use |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0075737A1 (en) |
| JP (2) | JPS5865266A (en) |
| CA (1) | CA1184177A (en) |
| DE (1) | DE3137376C2 (en) |
| ES (1) | ES515476A0 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60228954D1 (en) * | 2001-05-03 | 2008-10-30 | Galileo Lab Inc | Pyruvatderivate |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1493157A (en) * | 1965-09-10 | 1967-08-25 | Process for the preparation of hydrazine compounds | |
| DE2221770A1 (en) * | 1972-05-04 | 1973-11-15 | Bayer Ag | 1,2,5,6-tetrahydropyridines - prepd from corresp 1-benzyl tetrahydropyridines and phosgene |
| CA1076114A (en) * | 1975-02-10 | 1980-04-22 | Mitsubishi Chemical Industries Limited | 1,5-alkylene-3-aryl hydantoin derivatives |
| US4138242A (en) * | 1976-03-17 | 1979-02-06 | E. I. Du Pont De Nemours And Company | Novel 2-aryl-2,3,5,6,7,8-hexahydro-3-thioxoimidazo-[1,5-a-]pyridin-1(BaH)-ones as herbicides |
| BR7904156A (en) * | 1978-06-30 | 1980-03-25 | Mitsubishi Chem Ind | PROCESS FOR THE PREPARATION OF A COMPOUND 9- (3,5-DICLORO-FENIL) -PERHIDRO-IMIDAZO- (5,1-B) THIAZOLE, PROCESS TO COMBAT FUNGIC INFECTIONS ON PLANTS, AND FUNGICIDE COMPOSITION |
| GR78166B (en) * | 1981-05-04 | 1984-09-26 | Chinoin Gyogyszer Es Vegyeszet |
-
1981
- 1981-09-19 DE DE19813137376 patent/DE3137376C2/en not_active Expired
-
1982
- 1982-08-28 EP EP82107925A patent/EP0075737A1/en not_active Withdrawn
- 1982-09-03 ES ES515476A patent/ES515476A0/en active Granted
- 1982-09-17 JP JP16106382A patent/JPS5865266A/en active Granted
- 1982-09-17 CA CA000411699A patent/CA1184177A/en not_active Expired
-
1983
- 1983-09-16 JP JP16954283A patent/JPS5993068A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE3137376A1 (en) | 1983-05-05 |
| ES8306725A1 (en) | 1983-06-01 |
| EP0075737A1 (en) | 1983-04-06 |
| DE3137376C2 (en) | 1986-02-27 |
| JPH0341465B2 (en) | 1991-06-24 |
| ES515476A0 (en) | 1983-06-01 |
| JPS5993068A (en) | 1984-05-29 |
| JPS5865266A (en) | 1983-04-18 |
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