CA1277988C - Process for producing n-acyl-2,3-dehydro-amino carboxylic esters - Google Patents
Process for producing n-acyl-2,3-dehydro-amino carboxylic estersInfo
- Publication number
- CA1277988C CA1277988C CA000503677A CA503677A CA1277988C CA 1277988 C CA1277988 C CA 1277988C CA 000503677 A CA000503677 A CA 000503677A CA 503677 A CA503677 A CA 503677A CA 1277988 C CA1277988 C CA 1277988C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/28—Halogen atoms
Abstract
ABSTRACT OF THE DISCLOSURE
N-acyl-2,3-dehydro-amino carboxylic esters having the general formula (I), wherein R1 represents a straight-chain or branched (C1-C4) alkyl radical, a phenyl radical or a benzyl radical, R2 re-presents hydrogen or a methyl radical, R3 represents hydro-gen, a straight-chain or branched (C1-C16)alkyl radical, a (C3-C8)cycloalkyl radical, a (C1-C6)alkyl mercapto radical, a phenyl mercapto radical or a methoxy-carbonyl-methyl mercapto radical and R4 represents a straight-chain or branched (C1-C16)alkyl radical or (C2-C16)alkenyl radical, either unsub-stituted or mono- or poly-substituted by halogen, a methoxy group or by an acetylthio group, an unsubstituted (C3-C8) cycloalkyl radical which may be mono- or poly-substituted by halogen or a methyl group, an unsubstituted phenyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (C1-C4)alkyl or alkoxy group or by a trifluoromethyl group, an unsubstituted cinnamyl radical, which may be mono- or poly-substituted heteroaryl radical which may be mono or poly-substituted by halogen, a (C1-C4)alkyl or alkoxy group or by a trifluoromethyl group, an aryl or heteroaryl methyl radical, an unsubstituted phenoxy methyl radical or phenyl-ethyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (C1-C4)alkyl group or by a trifluoromethyl group, or a 2-(2,2,2-dichloro-ethenyl)-3,3-dimethyl cyclopropyl radical are produced by reacting a 2-azido-carboxylic ester having the general formula (II) at a temperature of between 0 and 150°C in the presence of a perrhenate with a carboxylic acid halide having the general formula
N-acyl-2,3-dehydro-amino carboxylic esters having the general formula (I), wherein R1 represents a straight-chain or branched (C1-C4) alkyl radical, a phenyl radical or a benzyl radical, R2 re-presents hydrogen or a methyl radical, R3 represents hydro-gen, a straight-chain or branched (C1-C16)alkyl radical, a (C3-C8)cycloalkyl radical, a (C1-C6)alkyl mercapto radical, a phenyl mercapto radical or a methoxy-carbonyl-methyl mercapto radical and R4 represents a straight-chain or branched (C1-C16)alkyl radical or (C2-C16)alkenyl radical, either unsub-stituted or mono- or poly-substituted by halogen, a methoxy group or by an acetylthio group, an unsubstituted (C3-C8) cycloalkyl radical which may be mono- or poly-substituted by halogen or a methyl group, an unsubstituted phenyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (C1-C4)alkyl or alkoxy group or by a trifluoromethyl group, an unsubstituted cinnamyl radical, which may be mono- or poly-substituted heteroaryl radical which may be mono or poly-substituted by halogen, a (C1-C4)alkyl or alkoxy group or by a trifluoromethyl group, an aryl or heteroaryl methyl radical, an unsubstituted phenoxy methyl radical or phenyl-ethyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (C1-C4)alkyl group or by a trifluoromethyl group, or a 2-(2,2,2-dichloro-ethenyl)-3,3-dimethyl cyclopropyl radical are produced by reacting a 2-azido-carboxylic ester having the general formula (II) at a temperature of between 0 and 150°C in the presence of a perrhenate with a carboxylic acid halide having the general formula
Description
1~77988 The present invention ~elates to a p~ocess for producillg N-acyl.-2,3-dehydro-amino carboxylic esters having the ge~leral formula 1~ ,coo~l R~' ~ Nll - C R4 (I), o .
wherein Rl represents a straight-chain or branched (Cl-C4) alky]. radi.cal, a phenyl radical or a benzyl radical, ~2 re-preserll:s hydrogen or a methyl radical, R3 represents hydrogen, a stra;.ghl:.-chai.n or branched (Cl-C16)alkyl radical, a (C3-C~) cycloalkyl radi.cal, a (Cl-C6)alkoxy radi.cal, a phenoxy radical, a (C1-C~)alkyl mercapto radi.cal, a uhenyl mercapto radical or a methoxy-carbonyl-methyl mercapto radical and R represents a str:aight-chaitl or branched (C1-C16)alkyl radical OJ: (C2-C16) alkenyl .radical, either unsubst:ituted by halogen, a methoxy group 01. by an acet:yl-thio group, an unsubstituted (C3-C8) cycloalkyl ra~ical whi.ch may be mono- or poly-substituted by alogen or a methyl group, an unsubstituted phenyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (Cl-C4)alkyl or alkoxy group or by a trifluoromethyl group, an unsubstituted cinnamyl radical, which may be mono- or poly-substituted by halogen, an unsubstituted heteroaryl radical which may be mono- or poly-substi.tuted by halogen, a (Cl-C4) alkyl or alkoxy group or by a trifluoromethyl group, an aryl or heteroaryl methyl radi.cal or an unsubstituted phenoxy methyl radi.cal or phenyl-ethyl radical which may be mono- or poly-30 substituted by halogen, a nitro group, a (Cl-C4)alkyl group or by a trifluoromethyl groyp~ or a 2-(2',2'-dichloroethenyl)-3,3-di.methyl cyclopropyl radical.
. --7~388 The N-acyl-2,3-dehydro-amino carboxylic esters havirlg the gel~eral formula (I), as such or Oll saponification of the es~:er ~urlction, are effective inhibitors for the dipeptidase [E.C.3.4.13.11~ and thus valuable substances for maintajning the activity of ~ -lactam antibiotics, particularly those of the thienamycin group. They can also be used as intermediate pro-ducts for the production of the corresponding optically active 2-acyl-amino carboxylic estexs by asymmetric cataly-tic hydro-genation of the prochiral C-C double bonds. When required, the 2-acyl-amino carboxylic esters can then be saponified to the corresporldirlg optically active 2-acyl-amino carboxylic esters.
'rhe production of N-acetyl-2,3-dehydro-amino carboxy-lic ester by reactirlg the corresponding 2-azido-carboxylic esters wi~h a mixture of acetic acid anhydride and acetic acid in the L~resence of rhenium (VII) sulphide is disclosed in German Patent No. 3 140 227. However, this process does not permit the ~oduction of the N-acetyl compounds.
In the process according to the present invention a 2-azido-carboxylic ester having the general formula ~2 Cll - ~CH - CoO~l (II), wherein Rl, R2 and R3 have the Meanings specified hereinbefore, are reacted at a téhperature of between 0 and 150C in the pre-sence of a perrhena~e with a carboxylic acid halide having the general formula 3 o 1~ 4 - C` - H~ I
o ~ III ), 1'~7~79~38 wherei~ 4 llas the meanings specified hereinbefore and the ~lal rep~esents chlorine or brornine.
ln this manner all the N-acyl-2,3-dehydro-amino carboxylic estes can be readily produced in a single-stage process with good yields.
The perrhenate is preferably used in an amount of between 0.005 and 10 mole percent, particularly between 0.1 and 3 mole percent, relative to the amount of 2-azido-carboxylic ester having the general formula (II). Suitable perrhenates are for example, sodium, potassium or ammoniurn perrhenate or sub-stituted ammonium perrhenates such as tetraethyl, tetrabutyl, tetrabenzyl or tricapryl-methyl ammoniurn perrhenate.
Under certain conditions it is advantageous to carry out the reac-tion of the 2-azido-carboxylic ester having the general formula (lI) with the carboxylic acid halide having the general formula (III) in the additional presence of an acid amide, a lactam or of a substituted urea. These substances serving as activators are suitably used in at least an equimolar amount relative to the carboxylic acid halide having the general formula (III). Suitable acid amides are, for exmaple, dimethyl formamide, dimethyl acetamide or hexamethyl phosphoric triamide.
N-methyl pyrrolidone is preferred as loctam. Tetramethyl urea and N,N'-dimethyl-propylene urea are particularly sutiabe as substituted ureas.
The 2-azido-carboxylic esters having the general for-mula (II) and serving as starting materials can be produced according to the process described in Chem. Ber. 117, page 1497 to 1512 (1984) by reacting the corresponding 2-chloro-2-bromo carboxylic esters with an aqueous sodium azide solution in the 30 presence of a phase transfer catalyst. Examples of the 2-azido-carboxylic esters having the general formula (II) which can be reacted by means of the process according to the present inven-1~77988 tiOIl are the esters of 2-azido-propionic acid, -butyric acid, -3-methyl-butyric acid, -3-phenyl-propionic acid, -pentanoi.c acid, -4-methyl-pentanoic acid, -3-cyclopentyl-propionic acid, -3-cyclohexyl-propionic acid, -hexanoic acid, -heptanoic acid, -octanoic acid, -norlanoic acid, -decanoic acid, -hendecanoic acid, -dodecanic acid, tridecanoic, -tetradecanoic acid, -pentadecanoic acid, -hexadecanoic acid, -heptadecanoic acid, -octadecanoic acid, -nonadecanoic acid, -3-methyl-mercapto propionic acid, -3-methoxy-carbonyl-methyl-mercapto pro-10 pionic acid, -3-pherlyl-mercapto propionic acid or 3-phenoxy propionic acld.
The carboxylic acid halides having the general formula (J.II) can be produced by means of generally known processes from the basic carboxylic acids with chlorinating agents such as thionyl chloride, phosphorus trichlorie or phosgene or bromina-tion agents such as a mixture of red phosphorus and bromine or phosphorus tribromide. The acid chlorides are preferably applied as carboxylic acid halides having the general formula ,, (III). The carboxylic acid halides are suitably used in an 20 amount of 1.0 to 1.5 moles, perferably in an amount of 1.0 to 1.1 moles per mole of applied 2-azido-carboxylic acid having the general formula (II).
The process according to the present invention is preferably carri.ed out at a temperature of between 20 and 80C.
The reacti'on is carried out with advantage in an inert solvent. Suitable solvents are, for example, carboxylic alkyl estes, such as acetic ethyl ester, acetic propyl ester, acetic isopropyl ester, acetic butyl ester, propionic ethyl esters;
: acetonitrile, nitro-methane, tetrahydrofuran, dioxane or 30 d:imethoxy ethane. ~lowever, an excess of the acid amides, ~ lactams or substi-tuted u~eas mentioned above can also be applied : instead of an additional solvent.
wherein Rl represents a straight-chain or branched (Cl-C4) alky]. radi.cal, a phenyl radical or a benzyl radical, ~2 re-preserll:s hydrogen or a methyl radical, R3 represents hydrogen, a stra;.ghl:.-chai.n or branched (Cl-C16)alkyl radical, a (C3-C~) cycloalkyl radi.cal, a (Cl-C6)alkoxy radi.cal, a phenoxy radical, a (C1-C~)alkyl mercapto radi.cal, a uhenyl mercapto radical or a methoxy-carbonyl-methyl mercapto radical and R represents a str:aight-chaitl or branched (C1-C16)alkyl radical OJ: (C2-C16) alkenyl .radical, either unsubst:ituted by halogen, a methoxy group 01. by an acet:yl-thio group, an unsubstituted (C3-C8) cycloalkyl ra~ical whi.ch may be mono- or poly-substituted by alogen or a methyl group, an unsubstituted phenyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (Cl-C4)alkyl or alkoxy group or by a trifluoromethyl group, an unsubstituted cinnamyl radical, which may be mono- or poly-substituted by halogen, an unsubstituted heteroaryl radical which may be mono- or poly-substi.tuted by halogen, a (Cl-C4) alkyl or alkoxy group or by a trifluoromethyl group, an aryl or heteroaryl methyl radi.cal or an unsubstituted phenoxy methyl radi.cal or phenyl-ethyl radical which may be mono- or poly-30 substituted by halogen, a nitro group, a (Cl-C4)alkyl group or by a trifluoromethyl groyp~ or a 2-(2',2'-dichloroethenyl)-3,3-di.methyl cyclopropyl radical.
. --7~388 The N-acyl-2,3-dehydro-amino carboxylic esters havirlg the gel~eral formula (I), as such or Oll saponification of the es~:er ~urlction, are effective inhibitors for the dipeptidase [E.C.3.4.13.11~ and thus valuable substances for maintajning the activity of ~ -lactam antibiotics, particularly those of the thienamycin group. They can also be used as intermediate pro-ducts for the production of the corresponding optically active 2-acyl-amino carboxylic estexs by asymmetric cataly-tic hydro-genation of the prochiral C-C double bonds. When required, the 2-acyl-amino carboxylic esters can then be saponified to the corresporldirlg optically active 2-acyl-amino carboxylic esters.
'rhe production of N-acetyl-2,3-dehydro-amino carboxy-lic ester by reactirlg the corresponding 2-azido-carboxylic esters wi~h a mixture of acetic acid anhydride and acetic acid in the L~resence of rhenium (VII) sulphide is disclosed in German Patent No. 3 140 227. However, this process does not permit the ~oduction of the N-acetyl compounds.
In the process according to the present invention a 2-azido-carboxylic ester having the general formula ~2 Cll - ~CH - CoO~l (II), wherein Rl, R2 and R3 have the Meanings specified hereinbefore, are reacted at a téhperature of between 0 and 150C in the pre-sence of a perrhena~e with a carboxylic acid halide having the general formula 3 o 1~ 4 - C` - H~ I
o ~ III ), 1'~7~79~38 wherei~ 4 llas the meanings specified hereinbefore and the ~lal rep~esents chlorine or brornine.
ln this manner all the N-acyl-2,3-dehydro-amino carboxylic estes can be readily produced in a single-stage process with good yields.
The perrhenate is preferably used in an amount of between 0.005 and 10 mole percent, particularly between 0.1 and 3 mole percent, relative to the amount of 2-azido-carboxylic ester having the general formula (II). Suitable perrhenates are for example, sodium, potassium or ammoniurn perrhenate or sub-stituted ammonium perrhenates such as tetraethyl, tetrabutyl, tetrabenzyl or tricapryl-methyl ammoniurn perrhenate.
Under certain conditions it is advantageous to carry out the reac-tion of the 2-azido-carboxylic ester having the general formula (lI) with the carboxylic acid halide having the general formula (III) in the additional presence of an acid amide, a lactam or of a substituted urea. These substances serving as activators are suitably used in at least an equimolar amount relative to the carboxylic acid halide having the general formula (III). Suitable acid amides are, for exmaple, dimethyl formamide, dimethyl acetamide or hexamethyl phosphoric triamide.
N-methyl pyrrolidone is preferred as loctam. Tetramethyl urea and N,N'-dimethyl-propylene urea are particularly sutiabe as substituted ureas.
The 2-azido-carboxylic esters having the general for-mula (II) and serving as starting materials can be produced according to the process described in Chem. Ber. 117, page 1497 to 1512 (1984) by reacting the corresponding 2-chloro-2-bromo carboxylic esters with an aqueous sodium azide solution in the 30 presence of a phase transfer catalyst. Examples of the 2-azido-carboxylic esters having the general formula (II) which can be reacted by means of the process according to the present inven-1~77988 tiOIl are the esters of 2-azido-propionic acid, -butyric acid, -3-methyl-butyric acid, -3-phenyl-propionic acid, -pentanoi.c acid, -4-methyl-pentanoic acid, -3-cyclopentyl-propionic acid, -3-cyclohexyl-propionic acid, -hexanoic acid, -heptanoic acid, -octanoic acid, -norlanoic acid, -decanoic acid, -hendecanoic acid, -dodecanic acid, tridecanoic, -tetradecanoic acid, -pentadecanoic acid, -hexadecanoic acid, -heptadecanoic acid, -octadecanoic acid, -nonadecanoic acid, -3-methyl-mercapto propionic acid, -3-methoxy-carbonyl-methyl-mercapto pro-10 pionic acid, -3-pherlyl-mercapto propionic acid or 3-phenoxy propionic acld.
The carboxylic acid halides having the general formula (J.II) can be produced by means of generally known processes from the basic carboxylic acids with chlorinating agents such as thionyl chloride, phosphorus trichlorie or phosgene or bromina-tion agents such as a mixture of red phosphorus and bromine or phosphorus tribromide. The acid chlorides are preferably applied as carboxylic acid halides having the general formula ,, (III). The carboxylic acid halides are suitably used in an 20 amount of 1.0 to 1.5 moles, perferably in an amount of 1.0 to 1.1 moles per mole of applied 2-azido-carboxylic acid having the general formula (II).
The process according to the present invention is preferably carri.ed out at a temperature of between 20 and 80C.
The reacti'on is carried out with advantage in an inert solvent. Suitable solvents are, for example, carboxylic alkyl estes, such as acetic ethyl ester, acetic propyl ester, acetic isopropyl ester, acetic butyl ester, propionic ethyl esters;
: acetonitrile, nitro-methane, tetrahydrofuran, dioxane or 30 d:imethoxy ethane. ~lowever, an excess of the acid amides, ~ lactams or substi-tuted u~eas mentioned above can also be applied : instead of an additional solvent.
779t~8 To avoid losses in yield it can be expedient to carry out the reaction in the presence of a small amount of an inhibitor for radical polymerizations, for exa~ple, hydroquinone or hydroquinone monomethyl ether. Suitable amount for the application of these inhibitors are between 0.001 and 10 percent by weight, particularly between 0.1 and 3 percent by weight, relative to the 2-azido-carboxylic ester having the general formula (II).
'~, ' ' i In the case of 2-azido-carboxylic esters that are par-ticularly sensitive to acids it can be advantageous to carry out the reaction with the carboxylic acid halides having the general formula (III) in the additional presence of an acid acceptor, which is suitably applied in an amount equivalent to the carboxylic acid halide. Suitable acid acceptors are particu-larly the acetates or oxalates of sodium or potassium.
For example, the process according to the present in-vention can be so carried out that the 2-azido-carboxylic acid having the general formula (II) in an inert solvent is put into a reactor and that the perrhenate and, when required, the acti-vator and/or polymerization inhibitor are added to the solution, whexeupon the carboxylic acid halide having the general formula (III) is added. In the case of small mixtures the carboxylic acid halide can be added all at once but in the case of large mixtures it is more expedient to add, it slowly, for example, within 1 to 3 hour$.~ The carboxylic acid halide can be added in the pure form or as à solution in the inert solvent used. The rate of addition is suitably so selected that the generation of nitrogen can be kept properly under control.
., , When adding the carboxylic acid halide at room tem-perature the reaction temperature can be kept below approxi-mately 25C by water cool~ing. When operating without external cooling the reaction will sooner or later become exothermic.
~: -- 5 --" 1'~7'7~8 'l'he reaction temperature can then reacll the boiling temperature of t~le ;l~ert solvent -temporarily. In any case the reaction mixl:ure is stirred until the generation of gas is terlllirlated.
When required, the end of the reaction can also be determined IR-spectroscopically by the disappearance of the azide bands~
On terminating the reaction the solvent and, when required, the activator are removed, suitably under reduced pressure, for exa~iple, with a rotary evaporator. The residue is taken up in a readily volatile solvent, for example, acetic ethyl ester, acetic isopropyl ester or diethyl ether, shaken out with an aqueous sodium hydrogen carbonate solution and then rewashed with water. 'rhe organic phase dried over sodium sul-phate or magnesium sulphate is then again concentrated by eva-poratioll under reduced pressure, once more in a rotary evapora-tor. In many cases the remaining residue can be crystallized by addi.ng n-pentane. The crystals are then filtered with suction and dried under reduced pressure at a temperature of maximally .~ SOC.
When the residue is a non-crystallizing oil a further purification by distillation in high vacuum, for example, in a bulb tube, can be attempted. In many cases it can also be advantageous to purify the residue by chromatography on a silica gel column. E'or this purpose a mixture of acetic ethyl ester and a low-boiling petroleum ether in a ratio by volume of between 1:1 and l:9,lcan be used as eluate. On evaporating the eluate and removing the last solvent residue in high vacuum the analytically puxe N-acyl-2,3-dehydro-amino carboxylic esters are obtained.
I'he present invention will be explained in greater 30 detail by the l~xamples hereafter.
Fxample 1 13.7 mg (0.05 mmole) of sodium perrhenate, 715.7 mg (5 1~775~8 mmoles) of 2-azido~propanoic ethyl ester and 383.8 ~ng (5.25 nlmoles) of dimethyl formamide were dissolved in 5 ml of acetonitrile. 592.9 mg (5.25 mmoles) of chloro acetyl chloride were then added at room temperature while stirring vigorously.
- The reaction proceeded while homogeneously generating nitrogen within 5 to 6 hours. When the generation of gas was terminated the acetonitrile was removed under reduced pressure. The resi-due was taken up in ~cet:ic ethyl ester, spaken out with 10.5 ml of a 0.5 molar sodium-hydrogen-carbonate solution. The separa-ted organic phase was once more washed with water and dried over magnesium sulphate. On removing the drying agent the concentra-ted organic phase was chromatographed over sil~ca gel with a mixture of low-boiling petroleum ether alld acetic ethyl ester in the ratio by volume of 9:1 as the eluate.
On evaporating the eluate there remained 581.5 mg of analytically pure 2-chloro-methyl-carboxamido propenoic ethyl ester (i.e., 60.7% of the theoretical,yield) H ~ ~NH-C-CII Cl llloClN03(191~614) ~C %~ %N %Cl - computed: 43.88 , 5.26 7.31 18.50 obtained: ' 43.99 5.40 7.02 18.46 melting point: 63C
NMn~CDC13):
= 8,9 (s, lH) NH;
6,64 (s, lH) H-CI3=;
6~0 (d, lH) H-CH=;
.
~77988 4~37 (q, 21~) OC~2-:
(s, 2~ C~I2-Cl:
1~38 ppm (t, 3H)-CH3.
Il~ (KBr)~NIl = 3282 cm ~CO = 1716 cm 1679 c~~ .
Example 2 13.4 mg (0!.05 mmole) of ammonium perrhenate 715.7 mg (5 mmoles) of 2-azido-butanoic methyl ester and 383.8 mg (5.25 mmoles) of dimethyl formamide were dissolved in 5 ml of acetonitrile, whereupon 592.9 mg (5.25 mmoles) of chloroacetyl chloride weré added at room temperature while stirring vig-orously. The reaction mixture was stirred for 9 hours at room temperature, followed by further treatment analogously to that of Example 1. 845.6 mg (88.3% of the theoretical yield) of ~ analytically pure 2-chloro-methyl-carboxamido-2-butenoic methyl - ester were obtained.
-H3C~ ~ Nll-C-CH Cl It~ ~CO2C~l3 C7llloclNo3(l9l~6lq) %C %1l ~ %N ~Cl ; computed:43.88 5.26 7.31 18.50 obtained:43.75 5.23 7.19 18.37 melting point: 58.5 to 59C
.~
1'~77~
1 Il-NMI~ ( CDCl 3 ):
'~ = B,05 ~s, 1~) NH
6,95 ~q, l~ C~C~3)=;
4,19 (s, 2~) C~2Cl;
3,80 ~s, 3H) OCH3;
l,8 ppm ~d, 311) CH3-CH=.
IR (KBr)~'N11 = 3260 cm - ~CO = 1727 cm ' 1676 cm F ample 3 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 (g (50 mmoles) of 2-azido-butano.ic-n-butyl ester and 3.85 (52.6 mrnoles) of dimethyl formamide were dissolved in 50 ml of acetonitrile, whexeupon 5.93 g (52.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 30 minutes.
When the generation of gas was terminated the aceto-nitrile was removed under reduced pressure. The residue wastaken up in acetic ethyl ester, shaken out with lO0 ml of a 0.5 molar sodium-hydrogen-carbonate solution; the separated organic phase was once more washed with water and dried over sodium sul-phate. On removing the drying agent the concentrated organic phase was crystalliz,ed with n-pentane, filtered with suction and dried.
9.8 g (83.9~ of the theoretical yield) of analytically pure 2-chloro-methyl-carboxamido-2-butenoic-n-butyl ester were obtained.
_ g ~ 77~
C~13C~ c_ocll2c1~2cll3 ,IIN-~-cll2 Cl o CloHl6No3cl(233~69) ,~
. , %C ~H %N %Cl computed: 51.40 6.90 5.9915.17 obtained: 51.36 7.01 5.9815.20 mel-ting point: 53.5C
:
Il-NMI~ (CDC13/TMS): .
= 7,85 (s broad~ lH) NH;
6~8 (q, lll) -CH=;
4,15 (t, 2H) -C~OCH2-;
4,1 (s, 2H) -CH2dl;
1,8 ~d, 311) Cl13-CH=;
. 20 U~6 - 2~0 ppm (m, 7H) -CH2-CH2-CH3.
Example 4 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-butanoic-n-butyl este~ and 3.85 g (52.6 mmoles) of dimethyl;formamide were dissolved in 50 ml of aceto-nitrile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl : chloride were added at room temperature while stirring vig-, , orously. The exothermic reaction started immediately and was terminated within 20 minutes. The further treatment was like that i.n Example 3.
11.2 g (83.5~ of the theoretical yield) of analyti--- 10 -- ~ I
., , ~ . . ~ .
cally pure 2-dichloro-met:llyl-carboxamido-2-butenois n-butyl ester were obtained.
C1-13CII=~-C-OC~2c~l2c~2c~l3 ~N-C-CIIC12 O
, CloH15N03C12t268,14) %C %H %N ~Cl computed: 44.79 5.64 5.22 26.44 obtained: 44.75 5.81 5.20 25.16 meltirlg point: 58.5C
~CDCl3/TMS) = 7,85 (s b~d, lH) Nll;
6,BS (q, 1ll) -CH=;
'~, ' ' i In the case of 2-azido-carboxylic esters that are par-ticularly sensitive to acids it can be advantageous to carry out the reaction with the carboxylic acid halides having the general formula (III) in the additional presence of an acid acceptor, which is suitably applied in an amount equivalent to the carboxylic acid halide. Suitable acid acceptors are particu-larly the acetates or oxalates of sodium or potassium.
For example, the process according to the present in-vention can be so carried out that the 2-azido-carboxylic acid having the general formula (II) in an inert solvent is put into a reactor and that the perrhenate and, when required, the acti-vator and/or polymerization inhibitor are added to the solution, whexeupon the carboxylic acid halide having the general formula (III) is added. In the case of small mixtures the carboxylic acid halide can be added all at once but in the case of large mixtures it is more expedient to add, it slowly, for example, within 1 to 3 hour$.~ The carboxylic acid halide can be added in the pure form or as à solution in the inert solvent used. The rate of addition is suitably so selected that the generation of nitrogen can be kept properly under control.
., , When adding the carboxylic acid halide at room tem-perature the reaction temperature can be kept below approxi-mately 25C by water cool~ing. When operating without external cooling the reaction will sooner or later become exothermic.
~: -- 5 --" 1'~7'7~8 'l'he reaction temperature can then reacll the boiling temperature of t~le ;l~ert solvent -temporarily. In any case the reaction mixl:ure is stirred until the generation of gas is terlllirlated.
When required, the end of the reaction can also be determined IR-spectroscopically by the disappearance of the azide bands~
On terminating the reaction the solvent and, when required, the activator are removed, suitably under reduced pressure, for exa~iple, with a rotary evaporator. The residue is taken up in a readily volatile solvent, for example, acetic ethyl ester, acetic isopropyl ester or diethyl ether, shaken out with an aqueous sodium hydrogen carbonate solution and then rewashed with water. 'rhe organic phase dried over sodium sul-phate or magnesium sulphate is then again concentrated by eva-poratioll under reduced pressure, once more in a rotary evapora-tor. In many cases the remaining residue can be crystallized by addi.ng n-pentane. The crystals are then filtered with suction and dried under reduced pressure at a temperature of maximally .~ SOC.
When the residue is a non-crystallizing oil a further purification by distillation in high vacuum, for example, in a bulb tube, can be attempted. In many cases it can also be advantageous to purify the residue by chromatography on a silica gel column. E'or this purpose a mixture of acetic ethyl ester and a low-boiling petroleum ether in a ratio by volume of between 1:1 and l:9,lcan be used as eluate. On evaporating the eluate and removing the last solvent residue in high vacuum the analytically puxe N-acyl-2,3-dehydro-amino carboxylic esters are obtained.
I'he present invention will be explained in greater 30 detail by the l~xamples hereafter.
Fxample 1 13.7 mg (0.05 mmole) of sodium perrhenate, 715.7 mg (5 1~775~8 mmoles) of 2-azido~propanoic ethyl ester and 383.8 ~ng (5.25 nlmoles) of dimethyl formamide were dissolved in 5 ml of acetonitrile. 592.9 mg (5.25 mmoles) of chloro acetyl chloride were then added at room temperature while stirring vigorously.
- The reaction proceeded while homogeneously generating nitrogen within 5 to 6 hours. When the generation of gas was terminated the acetonitrile was removed under reduced pressure. The resi-due was taken up in ~cet:ic ethyl ester, spaken out with 10.5 ml of a 0.5 molar sodium-hydrogen-carbonate solution. The separa-ted organic phase was once more washed with water and dried over magnesium sulphate. On removing the drying agent the concentra-ted organic phase was chromatographed over sil~ca gel with a mixture of low-boiling petroleum ether alld acetic ethyl ester in the ratio by volume of 9:1 as the eluate.
On evaporating the eluate there remained 581.5 mg of analytically pure 2-chloro-methyl-carboxamido propenoic ethyl ester (i.e., 60.7% of the theoretical,yield) H ~ ~NH-C-CII Cl llloClN03(191~614) ~C %~ %N %Cl - computed: 43.88 , 5.26 7.31 18.50 obtained: ' 43.99 5.40 7.02 18.46 melting point: 63C
NMn~CDC13):
= 8,9 (s, lH) NH;
6,64 (s, lH) H-CI3=;
6~0 (d, lH) H-CH=;
.
~77988 4~37 (q, 21~) OC~2-:
(s, 2~ C~I2-Cl:
1~38 ppm (t, 3H)-CH3.
Il~ (KBr)~NIl = 3282 cm ~CO = 1716 cm 1679 c~~ .
Example 2 13.4 mg (0!.05 mmole) of ammonium perrhenate 715.7 mg (5 mmoles) of 2-azido-butanoic methyl ester and 383.8 mg (5.25 mmoles) of dimethyl formamide were dissolved in 5 ml of acetonitrile, whereupon 592.9 mg (5.25 mmoles) of chloroacetyl chloride weré added at room temperature while stirring vig-orously. The reaction mixture was stirred for 9 hours at room temperature, followed by further treatment analogously to that of Example 1. 845.6 mg (88.3% of the theoretical yield) of ~ analytically pure 2-chloro-methyl-carboxamido-2-butenoic methyl - ester were obtained.
-H3C~ ~ Nll-C-CH Cl It~ ~CO2C~l3 C7llloclNo3(l9l~6lq) %C %1l ~ %N ~Cl ; computed:43.88 5.26 7.31 18.50 obtained:43.75 5.23 7.19 18.37 melting point: 58.5 to 59C
.~
1'~77~
1 Il-NMI~ ( CDCl 3 ):
'~ = B,05 ~s, 1~) NH
6,95 ~q, l~ C~C~3)=;
4,19 (s, 2~) C~2Cl;
3,80 ~s, 3H) OCH3;
l,8 ppm ~d, 311) CH3-CH=.
IR (KBr)~'N11 = 3260 cm - ~CO = 1727 cm ' 1676 cm F ample 3 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 (g (50 mmoles) of 2-azido-butano.ic-n-butyl ester and 3.85 (52.6 mrnoles) of dimethyl formamide were dissolved in 50 ml of acetonitrile, whexeupon 5.93 g (52.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 30 minutes.
When the generation of gas was terminated the aceto-nitrile was removed under reduced pressure. The residue wastaken up in acetic ethyl ester, shaken out with lO0 ml of a 0.5 molar sodium-hydrogen-carbonate solution; the separated organic phase was once more washed with water and dried over sodium sul-phate. On removing the drying agent the concentrated organic phase was crystalliz,ed with n-pentane, filtered with suction and dried.
9.8 g (83.9~ of the theoretical yield) of analytically pure 2-chloro-methyl-carboxamido-2-butenoic-n-butyl ester were obtained.
_ g ~ 77~
C~13C~ c_ocll2c1~2cll3 ,IIN-~-cll2 Cl o CloHl6No3cl(233~69) ,~
. , %C ~H %N %Cl computed: 51.40 6.90 5.9915.17 obtained: 51.36 7.01 5.9815.20 mel-ting point: 53.5C
:
Il-NMI~ (CDC13/TMS): .
= 7,85 (s broad~ lH) NH;
6~8 (q, lll) -CH=;
4,15 (t, 2H) -C~OCH2-;
4,1 (s, 2H) -CH2dl;
1,8 ~d, 311) Cl13-CH=;
. 20 U~6 - 2~0 ppm (m, 7H) -CH2-CH2-CH3.
Example 4 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-butanoic-n-butyl este~ and 3.85 g (52.6 mmoles) of dimethyl;formamide were dissolved in 50 ml of aceto-nitrile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl : chloride were added at room temperature while stirring vig-, , orously. The exothermic reaction started immediately and was terminated within 20 minutes. The further treatment was like that i.n Example 3.
11.2 g (83.5~ of the theoretical yield) of analyti--- 10 -- ~ I
., , ~ . . ~ .
cally pure 2-dichloro-met:llyl-carboxamido-2-butenois n-butyl ester were obtained.
C1-13CII=~-C-OC~2c~l2c~2c~l3 ~N-C-CIIC12 O
, CloH15N03C12t268,14) %C %H %N ~Cl computed: 44.79 5.64 5.22 26.44 obtained: 44.75 5.81 5.20 25.16 meltirlg point: 58.5C
~CDCl3/TMS) = 7,85 (s b~d, lH) Nll;
6,BS (q, 1ll) -CH=;
5,95 (s, lli) -CIIC12;
4,1 (t, 21~) -COOCl~2-;
1,7S (~, 3~1) C~13-CI~=;
0~6 - l~B5 ppm ~m, 7H) -CH2-CH2-Cll3.
Example 5 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-butanoic-n-butyl ester, 50 mg (0.45 mmoles) of hydroquinone and 3.85 g (52.6 mmoles) of dimethyl formamide were dissolved in 50 ml of acetonitrile. At room temperature 14.4 g (52.3 mmoles) of hexadecanoic acid chloride were then 30 added while stirring vigorously. Within 1.5 hours the mixture reacted exothermically. ~'he crude product precipitated on cooling. It was filtered with suction and washed with water '1,'~7'7_3~8 uni.tl free from chloride.
1~.5 g (98.5~ of the theretical yield) of analyti-cal.ly pure 2-(pentadecyl-carbonyl-amino)-2-bu-tenoic-n-butyl ester were obtained.
CH3 C~=f-~-oc~2c~2c~2c~3 HN-~~ -CH2 - ~ C1~2 ) 1 3C~
CZ~45NO3(395,63) %C %H %N
computecl: 72.86 11.46 3.54 o~tai.rled: 72.86 11.76 3.18 melting point: 66 ko 69C
lH-NMII (CDC13/TMS):
~ = 6,9 (s broad, lH) Nl3;
4,1 (t, 21~) -COOCl~2-;
1,7S (~, 3~1) C~13-CI~=;
0~6 - l~B5 ppm ~m, 7H) -CH2-CH2-Cll3.
Example 5 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-butanoic-n-butyl ester, 50 mg (0.45 mmoles) of hydroquinone and 3.85 g (52.6 mmoles) of dimethyl formamide were dissolved in 50 ml of acetonitrile. At room temperature 14.4 g (52.3 mmoles) of hexadecanoic acid chloride were then 30 added while stirring vigorously. Within 1.5 hours the mixture reacted exothermically. ~'he crude product precipitated on cooling. It was filtered with suction and washed with water '1,'~7'7_3~8 uni.tl free from chloride.
1~.5 g (98.5~ of the theretical yield) of analyti-cal.ly pure 2-(pentadecyl-carbonyl-amino)-2-bu-tenoic-n-butyl ester were obtained.
CH3 C~=f-~-oc~2c~2c~2c~3 HN-~~ -CH2 - ~ C1~2 ) 1 3C~
CZ~45NO3(395,63) %C %H %N
computecl: 72.86 11.46 3.54 o~tai.rled: 72.86 11.76 3.18 melting point: 66 ko 69C
lH-NMII (CDC13/TMS):
~ = 6,9 (s broad, lH) Nl3;
6,75 (q, lH) -CH=;
4,1 (t, 2l1) -COOCH2;
2,25 (t, 2H) -COCH2-;
1,75 (d, 311) CH3-CH=;
0 55 - 1,G5 ppm (m~ 36H) -(CH2,)l3c~3; (CH2)3 3 . , ' .
_xample 6 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 30 mmoles) of 2-azido-pentanoic methyl ester, 50 mg (0.45 mmoles) of hydroquniorle and 3.85 ~ (52.6 mmoles) of dimethyl formamide were dissolved .in 50 ml of acetoni.tri.le, whereupon 10.6 g (52.3 ~ '~779~38 mmoles) of 10-hendecenoic acld chloride were added ~t room tem-peratllre while stirrillg vigorously. The mixture reacted exo-therlllically within 30 minutes and was then further processed analogously to Example 3.
The crude product thus obtained was distilled in high vacuum (0.06 mbar) at an instrumellt temperature of 200 to 250C
in the bulb tube.
11.5 g (77!.8~ of the theoretical yield) of analyti-cally pure 2-(decen-9-yl-carbonyl-amino)-2-pentanoic methyl ester were obtained.
CH C~ CH=C-C-OCH3 HN-lcl-cH2-~cH2)7cH CH2 ~C ~H ~N
computed: 69.129.89 4.74 20 obtained: 68.9110.16 4.36 melting point: 34 to 35C
-N~ (DMso/TMs~:
= 9,1 ~s, 1~1) NH;
6,3 (t, lH~) -CH=C0;
5.4 - 6~05 ~m, lH) -CH2-CH=CH2;
4,6 - 5~2 ~m, 2H) -CH=CH2;
3.6 (s, 3~1) -COOC~3;
1~65 - 2~5 (m, 6H) CH3CH2; -COCH2; -CH2=CH;
0~7 - 1,75 ppm (m, 1511) CH3; -(CH2)6.
b \
~;~77988 Exan~le 7 146.6 rng (0.05 mmole) of potassium perrhenate, 7.85 g (50 mmoles) of 2-aæido-pentarIoic methyl ester and S0 mg (0.45 mmoles) of hydroquinone were put into a reactor at 80C wi.th 25 ml of acetic ethyl ester. 5.93g (52.5 mmoles) of chloro acetyl chloride, di.ssolved in 25 ml of acetic ethyl ester, were then added dropwise within 30 minutes while stirring vigorously. The reacti.on mixture was kept at 80C for a total of 2.5 hours while sti.rri.ng vigorously, whereupon it was further processed as in Example 3.
4,1 (t, 2l1) -COOCH2;
2,25 (t, 2H) -COCH2-;
1,75 (d, 311) CH3-CH=;
0 55 - 1,G5 ppm (m~ 36H) -(CH2,)l3c~3; (CH2)3 3 . , ' .
_xample 6 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 30 mmoles) of 2-azido-pentanoic methyl ester, 50 mg (0.45 mmoles) of hydroquniorle and 3.85 ~ (52.6 mmoles) of dimethyl formamide were dissolved .in 50 ml of acetoni.tri.le, whereupon 10.6 g (52.3 ~ '~779~38 mmoles) of 10-hendecenoic acld chloride were added ~t room tem-peratllre while stirrillg vigorously. The mixture reacted exo-therlllically within 30 minutes and was then further processed analogously to Example 3.
The crude product thus obtained was distilled in high vacuum (0.06 mbar) at an instrumellt temperature of 200 to 250C
in the bulb tube.
11.5 g (77!.8~ of the theoretical yield) of analyti-cally pure 2-(decen-9-yl-carbonyl-amino)-2-pentanoic methyl ester were obtained.
CH C~ CH=C-C-OCH3 HN-lcl-cH2-~cH2)7cH CH2 ~C ~H ~N
computed: 69.129.89 4.74 20 obtained: 68.9110.16 4.36 melting point: 34 to 35C
-N~ (DMso/TMs~:
= 9,1 ~s, 1~1) NH;
6,3 (t, lH~) -CH=C0;
5.4 - 6~05 ~m, lH) -CH2-CH=CH2;
4,6 - 5~2 ~m, 2H) -CH=CH2;
3.6 (s, 3~1) -COOC~3;
1~65 - 2~5 (m, 6H) CH3CH2; -COCH2; -CH2=CH;
0~7 - 1,75 ppm (m, 1511) CH3; -(CH2)6.
b \
~;~77988 Exan~le 7 146.6 rng (0.05 mmole) of potassium perrhenate, 7.85 g (50 mmoles) of 2-aæido-pentarIoic methyl ester and S0 mg (0.45 mmoles) of hydroquinone were put into a reactor at 80C wi.th 25 ml of acetic ethyl ester. 5.93g (52.5 mmoles) of chloro acetyl chloride, di.ssolved in 25 ml of acetic ethyl ester, were then added dropwise within 30 minutes while stirring vigorously. The reacti.on mixture was kept at 80C for a total of 2.5 hours while sti.rri.ng vigorously, whereupon it was further processed as in Example 3.
7.0 g t68.1% of the theoretical yield~ of analyti-cally pure 2-chloro-methyl-carboxamido-2-pentenoic methyl ester wre obtaiI-led.
O
C113C112CII=C~-C-OC113 o C~ 2Cl(205,64) ..
%C %II %N ~Cl computed: 46.72 5.84 6.81 17.24 obtained: 46.89 5.81 6.80 17.31 melting ponint: 62C
; II-N~IR (CDC13/T~IS):
= 7~85 (s broad, llI) NII;
6~75 tt, lH) -CH=;
4,15 (s, 2H) -CH2Cl;
3,~ (s, 3~1) COOC113;
l~7 - 2~65 (m~ 2H) -CIi2-;
1,U5 ppm (t, 313) CI13-.
1~77988 }`xample 8 . . ~
138.5 mg (0.5 mmole) of sodium perrhenate, 7.85 g (50 mmoles) of 2-azido-pentanoic methyl ester and 50 mg (0.45 mmoles) of hydxoqujnone were put into a reacto~ with 25 ml of acetic ethyl ester at 80C. Within 30 minutes 7.75 g (52.5 mmoles) of dichloro acetyl chloride, dissolved in 25 ml of acetic el:hyl ester, were then added dropwise while stirring vigorously. The re~ction mixture was kept at 80C for a total of 3 hours while stirring vigorously and then further processed as in Example 3.
7.5 g (62.5~ of the theoretical yield) of analytically pure 2-dichloro-methyl-carboxamido-2-pentelloic me-thyl ester were obtained CH3cH2c~ c-c OC1~3 HN-ICl-CIIC12 o C81111N03C12(24'87) ~C ~H %N %Cl computed: 40.02 4.62 5.8329.53 obtained: 40.22 4.62 5.8229.65 melting point: 85C
-NM~ (cDcl3/TMs):
= 7.8 (s broad, lH) Nll;
68 (t, lll) -CH=;
6,05 (s, 111) CHC12;
3~5 (s, 311) COOC~13;
1,75 -~2.6 (m, 2H) -CH2-;
1~1 ppm (t, 311) CH3-.
~7~7~88 Example 9 134 mg (0.5 mmole) of ammonium perrhenate, 9.26 g (50 mmoles) o~ 2-azi.do-pentanoic isopropyl ester and 50 mg (0.45 mmoles) of hydroquinone were put into a reactor with 25 ml of acetic ethyl ester at 80C. Withi.n 45 minutes 5.93 g (52.5 mmoles) of chloro acetyl chloride, dissolved in 25 ml of acetic ethyl ester, were then added dropwise while stirring vigorously.
The reaction mixture was kept at 80C~or a total of 4 hours while stirring vigorously, whereupon it was further processed as in ~xample 3.
7.3 g (62.5 ~ of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-pentanoic isopropyl ester were o~tained.
Cfl3C112CII-f-C8-OCI~lC113 tHN-~ -C112Cl O
No3cl~233,69s) ,, ~C ~H %N %Cl computed: 51.39 6.90 5.99 15.17 obtained: 51.87 6.68 5.94 15.24 melting t~oint: 96C
: , = 7,85 (.s broad, 1ll) Nll;
6,65 (t, 11l) -Cll=;
4~7 - 5,65 (m, lH) - COOCII;
4,15 (s, lH) -CIIC12;
1,65 - 2~65 (m, 213) -CH2-;
1~3 (d, 6H) C-(CI13)2;
1,05 ppm ~, 311) Cl13-.
;
~L~717~8~
~xa~ le 10 134 mg (0.5 mmole) of ammonium perrhenate, 9.26 g (50 mmoles) of 2-azi.do-pentanoic isopropyl ester and 50 mg (0.45 mmoles) of hydroquinolle wele put into a reactor with 25 ml of acetic ethyl ester at 80C. Within 70 minutes 7.75 g (52.5 mmoles) of dichloro acetyl chloride, dissolved in 25 ml of ace1-.ic ethyl ester, were then added dropwise whi.le stirring vigorously. The reaction mixture was kept at 80C for a total oE 5 hours while stirring vigorously and then further processed as in r,xample 3.
10.6 g (79% of the theoretical yield) of analytically pure 2-clichloro-methyl-carboxamido-2-penta}loic isopropyl ester were obtai.ned.
Cll3CI12CII=IC-C-O ~ 3 I~N-C-CflCl 1~ 15 3cl2(268~l4) %C ~ N %Cl computed: 44.79 5.63 5.22 26.44 obtained: 45.25 5.50 5.20 26.38 melting point: 110Ç
Il-NMR ~CDC13/T~IS):
= 7,85 (s broad~ lH) Nll;
6,7 (t, 1ll) -Cl3=:
6~0 (s, 113) CHC12;
4~75 - 5~4 (m, 1ll) COOC~I;
1,8 - ~2,5.(lll, 211) -Cll2-;
1,3 (d, 611) -C-(CII ) ;
1~05 ~t, 3l3) Cl13-.
~77~t~8 E:xaml>le 11 134 mg (0.5 mmole) of ammmonium perrhenate, 7.85 g (50 mlnoles) of 2-azido-pentanoic methyl ester and 50 mg (0.45 mmole) of hyclroquinorle were put into a reactor with 25 ml of aceti.c ethyl este.r at 80C. Within 30 minutes 9.3 g (52.6 mmoles) of difluoro benzoyl chloride, dissolved in 25 ml of acetic ethyl ester, were then added dropwise. The reaction mixture was kept at 80C for a total!of 10 hours while stirring vigorously, whereuE)on it was further processed as in Example 3.
9.75 g ~72.4~ of the theoretical y.ield) of arlalytically pure 2-[2',6'-difluoro-phenyl)-carbonyl-amino]-2-pen~arloic methyl ester were obtained O
CH3cfl2cl~-c-c OC
HN-C~
F
Cl 2111 33NF2 ~ 269, ~s %C %H %N
computed: 57.19 4.86 5.20 obtained: 58.12 4.58 5.13 melting l~oint: 138.5C
, Il-N~ (CDC13/l'MS):
= 6~4 - 7~85 (m, 5H) aromat.-CH; -Cll= Nll;
3,8 (s, 3~1) COOCI13;
1,85 - 2,65 ~m, 2H) -C112-;
1,1 ppm ~t, 3H) C1l3-.
-`18 -`` 1~77~8~
I~'Yan1P I e 12 146.6 mg (0.5 mmole) of po~assium perrhenate, 9.26 g (5~ mmoles) of 2-azido-pentanoic isopropyl ester and 50 mg (0.45 mmoles) of hydroquinone were put into a reactor with 25 ml of acetic ethyl ester at 80C. Within 30 minutes 9.3 g (52.6 mmoles) of 2,6-difluoro benzoyl chloride, dissolved i.n 25 ml of acetic ester, were then added dropwise. The reaction mixture was kept, at 80C for a total of 10 hours while stirring vigor-ously, whereupon it was further processed as in Example 3.
10.9 g (73.3% of the theoretical yield) of analyti-cally pure 2-[(2'6'-difluoro-phenyl)-carbonyl-amino]-2-pentanoic isopropyl ester were obtained.
: Cll3CI~2CII=C-C-OC~ 3 ¦ F CH3 0,~
F
%C %H %N
co~nput:ed: 60.60 5.76 4.71 obt;ained: 61.14 5.50 4.66 meltirlg ~oint: 91C
H-NMI~ (CDC13/TMS):
= 6.45 - 7.9 (m, 5il)aromatic'~CH; -CH=; NH;
4~7 - 5,4 (m, 113) COOCH:
1~75 - 2,65 (m~ 2H) -CH2-;
1,3 (d, 611) C-(CI13)2;
1~1 pplll (t, 3y) C1i3.
~.f~ 88 Example_13 536 mg (19.9 mmoles) of ammollium perrhenat:e, 31.4 g (0.2 Inmole) of 2-azido-pentanoic methyl ester and 15.4 g (0.21 mmole) of dimethyl formamide were dissolved in 150 ml of acetonitrile, ~hereupon 25.3 g (0.21 mmole) of 3-methyl-butanoic acid chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically with-in 45 mirlutes, whereupon it was further processed as in Example 3.
30.2 g (70.8~ of the theoretical yield) of analyti-cally pure 2-[(2'-methyl-propyl)-carbonyl-amino]-2-pentanoic methyl ester wexe obtained.
Il Cli3C112Cll= ~C-c-ocll3~cH3 HN- -CH CH
2 ~C113 C111119N03t213'28) %C %1l ~N
comuuted: 61.95 8.98 6.57 obtained: 61.84 9.01 6.51 melting pOillt: 45 to 47C
H-NMR ~C~C13/TMS):
= 7,05 (s broad, .lH) Nll;
6,65 (t, 1ll1 -Cl~=;
3,75 (s, 3il) -COOCH3;
1,7 - 2,6 (m, 5H) -C112-C=; ~-CH2-CII-;
1~15 (s, 3~1) Cll3-C112;
1,0 ppm (d, 611) C~cll3.
~ ~77~
xample 14 . .=
134 mg (0.5 mmole) of ammonium perrh~nate, 7.85 g (50 mmoles) of 2-azido-pentanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and S0 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.5 g (52.3 mmoles) of 2-ethyl hexanoyl chloride were added at room tempera-ture while stirring vigorously. The reaction mixture was sti~red for 120 hours, the exothermic reaction reaching a maxi-mal ternperature of 80C.
The further processing was analogous to that of Example 3. 'rhe crude product thus obtained was distilled in high vacuum (0.06 mbar) at an instrument tempe,rature of 180 to 210C in the bulb tube.
7.0 g (54.8% of the theoretical yield) of 2-[(1'-ethyle~rle-pentyl)-carborlyl-amino]-2-pentenoic methyl ester were obta:ined .
' C113Cfl2C~ C-C-ocH3 3N-~ cEl-cll2cl32cH2c~l3 10 25 03~255,36) ~ %C %H %N
computed: 65.85 9.87 5.48 obtained: ~ 65.11 10.31 5.52 i-NMI~ (C~C13/~'MS):
~= 6,85 (s brad' lli) NH;
6~55 (t, 1ll) -C~3=;
~,7 (s, 3ll) -COOCI~3;
0~6 - 2~45 ppm (m~ 2011) Cll3C112-C=; -Clll-(CII2)3-C1l3.
C'12CI~3 1~77~t~B
llxample 15 __ ___.__ 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-az:ido-pentanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro~luinone wre dissolved in 50 ml of acetonitrile, whereupon 7.8 g (52.5 mmoles) of 2-methyl-2-ethyl-butanoic acid chloride were added at room temperature while stirring vigorously. The reaction mix-ture was stirred foi 120 hours, the exot4ermic reaction reaching a temperature of 80C. The further treatment was analogous to that of Exar.lple 1. The oily crude product thus obtained was distilled in high vacuum (0.06 mbar) at an instrument tem-perature of 100 to 150C in the bulb tube.
6.4 g (53% of the theoretical yield) of 2-[(1'-methyl-l'-ethyl-propyl)-carbonyl-amino]-2-pentanoic methyl ester were obtained.
C133C132cl3=f- -OCll3 I HN_C_C_CH2CH3 3 ' C131123NO3(241~33) %C 9~H 96N
comput:ed: 64.709.,61 5.80 obtaitled: ' 63.7010.16 6.25 -N~I~ (cDCl3/TMs):
= 7,15 (s broac~, lH) Nll;
6~65 (t, lH) -CH=;
3,75 (s, 311) -COOC133;
0,65 - 2,35 ppm (~, 1813) C113C132-C=; -C-(CH2C133)2.
.~
77~38 ExamL)le 16 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-azido-pen-tanoic methyl ester, 50 mg (0.45 mmole) of hydroquinone and 3.85 g (52.6 mmoles) of dimethyl formamide were dissolved in 50 ml of acetic ethyl ester. 8.5 g (52.9 mmoles) of thiophene-2-acetic acid chloride were then added dropwise at roo~n temperature while stirring vigorously. Within 30 minu-tes the mixture reacted!exothermically.
When the generation of gas was terminated the reaction mix-ture was diluted with 50 ml of acetic ethyl ester, shaken out with a 0.5 ~lolar sodium hydrogen carbona-te solution and the organic pllase was once more washed with water and dried over sodium sulE~hate. On removing the drying agent the concentrated organic phase was crystallized with n-pentane.
12.1 g (95.5% of the theoretical yield) of analyti-cally pure 2-(thenyl-carbonyl-amino)-2-pentanoic methyl es~er were obtained.
~, O
Cl33c~l2c~3=f-c-ocl33 C12l~l5NO3S(253,26) ~C %1l %N %Cl computed: 56.91 5.97 5.53 12.63 obtained: 56.80 5.86 5.66 12.63 meltirlg point: 67 to 70C
~'~77~8 Il-NI~ (CDC13/TMS):
J` = G,B5 - 7,5 ~m~ 411) Nll; 1~;
G,65 (t, 111) Cll=;
3~9 (s, 211) COCE12;
3,75 (s, 31~) COOCH3;
1,65 - 2~55 (m, 2~ C112-;
1~05 ppm (t, 31~) CH3-.
!
Examp e 17 134 mg (0.5 mmoles) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-azido-pentanoic methyl ester, 50 mg (0.45 mmole) of hydro~uinone and 3.85 g (52.6 mmoles) of dirnethyl formamide were reacted Wit}l 9.5 g (52.6 mmoles) of 3-acetyl-thio-2-methyl-pro-piol~ic acicl chloricle analogously to Example 16.
On further E~rocessing as in Example 16 10.9 g (79.8%
of the theoretical yield) of analytically pure 2-[(1'-methyl-2' acetyl-thio-ethyl)-carboxamido]-2-pentanoic methyl ester were obtained .
o C113C112C~ C-C-OC113 O cll3 O
( 12lll9N04S(273,29) %C I g61~ ~6N 96Cl .,' ';
computed: 52.74 7.01 5.12 11.71 obtained: 52.46 7.01 5.22 11.56 rnelting pOillt: 56 to 58C
~'~775~
111-NM1~ ( CDC1 3/~rMs ~:
= 7,55 (s broad, 1~l) Nll;
6,65 (~, lli) Cl~=;
3,8 (s, 3~) COOC1~3, 3,1 (t, 21~) S-CII2~;
2,4 ~ ?-9 (m, lH) COCH;
2~35 (s, 3HJ COCH3, 1,8 - 2~4 (m, 2~3) ~CH2-;
1,25 (d, 3H) CH-CH3;
1,05 ppm (t, 3H) Cll3-CI12.
~xamp e 18 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-pentanoic isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro~uinone were dissolved in 50 ml of acetonitrile, whereupon 12.35 g (52.5 mmoles) of 2,6-dichloro cinnamic acid chloride are added at roorn temperature while stirring vigorously. The reaction mixture was stirred for 16 hours while the product precipitated. The residue was separated, washed with water until free from chloride and dried.
12.5 g (70.2% of the theoretical yield) of analyti-cally pure 2-[2'-(2,6-dichloro-phenyl)-vinyl-carbonyl-amino]-2-pentanoic isopropyl ester were obtained.
: '' O
' CH3cl~2cl~=c-e' H1-lCI-CH-CH
Cl 30C17~19NO3C12(356,27) \
~C %1l ~N%Cl computed: 57.31 5.37 3.53 19.90 obtained: 57.31 5.76 4.06 18.45 melt:ing point: 166C
', 1 Il-NMI~ ~CDC13/TMS):
,. ~
~ = 7,75 (d, lH) -COCH=;
6,B5 _! 7,5 (m, 4~) NH; ,aromatic CH;
6~65 (d, 113) -C=CH-;
6,55 (t, 1~l) C~12-C~I=;
4,65 - 5,3 (m, lH) COOCH-;
1,85 - 2,5 (m, 2H) -CH2-;
1,25 (d, 611) C-(CI13)2;
1,05 ppm (t, 311) CH3-.
E, ml~le__9 27.3 mg (0.1 mmole) of sodium perrhenate, 1.71 g (10 mmoles) of 2-azido-hexanoic methyl es-ter and 767.6 mg tlO.5 nmloles) of dimethyl formamide were dissolved in 1 ml of acetoni-trile, whereupon 1.19 g (10.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 30 minutes and was then further processed as in Example 3.
1.8109 y (82.4~ of theoretical yield) of analyti-cally ~ure 2-chloro-methyl carboxamido-2-hexenoic methyl ester were obtained.
'' ' O
3 2C~l2 ~C
, 11 . C02C113 :
C9~ clNo3(2l9~66B) %C ~H %N %Cl cornpu~ed: 49.21 6.42 6.38 16.14 obtained: 49.21 6.33 6.41 16.15 melting point: 63.5 to 64C
.~ lH-NMR (CDC13):
= 8,0 (s, lH) NH;
6,86 (t, lH)-CH2-CH=;
4~19 (s, 2H) C112Cl;
3,81 (s, 3H) OCH3;
2,18 ~q, 2H)-C1l2-CH=;
1,8 - 1,28 (m, 211) CH3-CH2-;
0~95 ppm (t, 3H) CH3-CH2.
ln(KBr) ~NII = 3255 cm 1, ~CO = 1722 cm 1, 1664 cm 1.
- Example 20 _.
134 Ing (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-hexanoic ethyl ester, 3. 85 g (52.6 mmoles) of dirnethyl formantide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 rnl of acetic isopropyl ester, whereupon 5.95 g (52. 6 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixtures reacted exothermically withln 40 minutes. The mixture was further pro-cessed as in Example 16.
O
C113C112CII=C~-C-OC113 o C~ 2Cl(205,64) ..
%C %II %N ~Cl computed: 46.72 5.84 6.81 17.24 obtained: 46.89 5.81 6.80 17.31 melting ponint: 62C
; II-N~IR (CDC13/T~IS):
= 7~85 (s broad, llI) NII;
6~75 tt, lH) -CH=;
4,15 (s, 2H) -CH2Cl;
3,~ (s, 3~1) COOC113;
l~7 - 2~65 (m~ 2H) -CIi2-;
1,U5 ppm (t, 313) CI13-.
1~77988 }`xample 8 . . ~
138.5 mg (0.5 mmole) of sodium perrhenate, 7.85 g (50 mmoles) of 2-azido-pentanoic methyl ester and 50 mg (0.45 mmoles) of hydxoqujnone were put into a reacto~ with 25 ml of acetic ethyl ester at 80C. Within 30 minutes 7.75 g (52.5 mmoles) of dichloro acetyl chloride, dissolved in 25 ml of acetic el:hyl ester, were then added dropwise while stirring vigorously. The re~ction mixture was kept at 80C for a total of 3 hours while stirring vigorously and then further processed as in Example 3.
7.5 g (62.5~ of the theoretical yield) of analytically pure 2-dichloro-methyl-carboxamido-2-pentelloic me-thyl ester were obtained CH3cH2c~ c-c OC1~3 HN-ICl-CIIC12 o C81111N03C12(24'87) ~C ~H %N %Cl computed: 40.02 4.62 5.8329.53 obtained: 40.22 4.62 5.8229.65 melting point: 85C
-NM~ (cDcl3/TMs):
= 7.8 (s broad, lH) Nll;
68 (t, lll) -CH=;
6,05 (s, 111) CHC12;
3~5 (s, 311) COOC~13;
1,75 -~2.6 (m, 2H) -CH2-;
1~1 ppm (t, 311) CH3-.
~7~7~88 Example 9 134 mg (0.5 mmole) of ammonium perrhenate, 9.26 g (50 mmoles) o~ 2-azi.do-pentanoic isopropyl ester and 50 mg (0.45 mmoles) of hydroquinone were put into a reactor with 25 ml of acetic ethyl ester at 80C. Withi.n 45 minutes 5.93 g (52.5 mmoles) of chloro acetyl chloride, dissolved in 25 ml of acetic ethyl ester, were then added dropwise while stirring vigorously.
The reaction mixture was kept at 80C~or a total of 4 hours while stirring vigorously, whereupon it was further processed as in ~xample 3.
7.3 g (62.5 ~ of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-pentanoic isopropyl ester were o~tained.
Cfl3C112CII-f-C8-OCI~lC113 tHN-~ -C112Cl O
No3cl~233,69s) ,, ~C ~H %N %Cl computed: 51.39 6.90 5.99 15.17 obtained: 51.87 6.68 5.94 15.24 melting t~oint: 96C
: , = 7,85 (.s broad, 1ll) Nll;
6,65 (t, 11l) -Cll=;
4~7 - 5,65 (m, lH) - COOCII;
4,15 (s, lH) -CIIC12;
1,65 - 2~65 (m, 213) -CH2-;
1~3 (d, 6H) C-(CI13)2;
1,05 ppm ~, 311) Cl13-.
;
~L~717~8~
~xa~ le 10 134 mg (0.5 mmole) of ammonium perrhenate, 9.26 g (50 mmoles) of 2-azi.do-pentanoic isopropyl ester and 50 mg (0.45 mmoles) of hydroquinolle wele put into a reactor with 25 ml of acetic ethyl ester at 80C. Within 70 minutes 7.75 g (52.5 mmoles) of dichloro acetyl chloride, dissolved in 25 ml of ace1-.ic ethyl ester, were then added dropwise whi.le stirring vigorously. The reaction mixture was kept at 80C for a total oE 5 hours while stirring vigorously and then further processed as in r,xample 3.
10.6 g (79% of the theoretical yield) of analytically pure 2-clichloro-methyl-carboxamido-2-penta}loic isopropyl ester were obtai.ned.
Cll3CI12CII=IC-C-O ~ 3 I~N-C-CflCl 1~ 15 3cl2(268~l4) %C ~ N %Cl computed: 44.79 5.63 5.22 26.44 obtained: 45.25 5.50 5.20 26.38 melting point: 110Ç
Il-NMR ~CDC13/T~IS):
= 7,85 (s broad~ lH) Nll;
6,7 (t, 1ll) -Cl3=:
6~0 (s, 113) CHC12;
4~75 - 5~4 (m, 1ll) COOC~I;
1,8 - ~2,5.(lll, 211) -Cll2-;
1,3 (d, 611) -C-(CII ) ;
1~05 ~t, 3l3) Cl13-.
~77~t~8 E:xaml>le 11 134 mg (0.5 mmole) of ammmonium perrhenate, 7.85 g (50 mlnoles) of 2-azido-pentanoic methyl ester and 50 mg (0.45 mmole) of hyclroquinorle were put into a reactor with 25 ml of aceti.c ethyl este.r at 80C. Within 30 minutes 9.3 g (52.6 mmoles) of difluoro benzoyl chloride, dissolved in 25 ml of acetic ethyl ester, were then added dropwise. The reaction mixture was kept at 80C for a total!of 10 hours while stirring vigorously, whereuE)on it was further processed as in Example 3.
9.75 g ~72.4~ of the theoretical y.ield) of arlalytically pure 2-[2',6'-difluoro-phenyl)-carbonyl-amino]-2-pen~arloic methyl ester were obtained O
CH3cfl2cl~-c-c OC
HN-C~
F
Cl 2111 33NF2 ~ 269, ~s %C %H %N
computed: 57.19 4.86 5.20 obtained: 58.12 4.58 5.13 melting l~oint: 138.5C
, Il-N~ (CDC13/l'MS):
= 6~4 - 7~85 (m, 5H) aromat.-CH; -Cll= Nll;
3,8 (s, 3~1) COOCI13;
1,85 - 2,65 ~m, 2H) -C112-;
1,1 ppm ~t, 3H) C1l3-.
-`18 -`` 1~77~8~
I~'Yan1P I e 12 146.6 mg (0.5 mmole) of po~assium perrhenate, 9.26 g (5~ mmoles) of 2-azido-pentanoic isopropyl ester and 50 mg (0.45 mmoles) of hydroquinone were put into a reactor with 25 ml of acetic ethyl ester at 80C. Within 30 minutes 9.3 g (52.6 mmoles) of 2,6-difluoro benzoyl chloride, dissolved i.n 25 ml of acetic ester, were then added dropwise. The reaction mixture was kept, at 80C for a total of 10 hours while stirring vigor-ously, whereupon it was further processed as in Example 3.
10.9 g (73.3% of the theoretical yield) of analyti-cally pure 2-[(2'6'-difluoro-phenyl)-carbonyl-amino]-2-pentanoic isopropyl ester were obtained.
: Cll3CI~2CII=C-C-OC~ 3 ¦ F CH3 0,~
F
%C %H %N
co~nput:ed: 60.60 5.76 4.71 obt;ained: 61.14 5.50 4.66 meltirlg ~oint: 91C
H-NMI~ (CDC13/TMS):
= 6.45 - 7.9 (m, 5il)aromatic'~CH; -CH=; NH;
4~7 - 5,4 (m, 113) COOCH:
1~75 - 2,65 (m~ 2H) -CH2-;
1,3 (d, 611) C-(CI13)2;
1~1 pplll (t, 3y) C1i3.
~.f~ 88 Example_13 536 mg (19.9 mmoles) of ammollium perrhenat:e, 31.4 g (0.2 Inmole) of 2-azido-pentanoic methyl ester and 15.4 g (0.21 mmole) of dimethyl formamide were dissolved in 150 ml of acetonitrile, ~hereupon 25.3 g (0.21 mmole) of 3-methyl-butanoic acid chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically with-in 45 mirlutes, whereupon it was further processed as in Example 3.
30.2 g (70.8~ of the theoretical yield) of analyti-cally pure 2-[(2'-methyl-propyl)-carbonyl-amino]-2-pentanoic methyl ester wexe obtained.
Il Cli3C112Cll= ~C-c-ocll3~cH3 HN- -CH CH
2 ~C113 C111119N03t213'28) %C %1l ~N
comuuted: 61.95 8.98 6.57 obtained: 61.84 9.01 6.51 melting pOillt: 45 to 47C
H-NMR ~C~C13/TMS):
= 7,05 (s broad, .lH) Nll;
6,65 (t, 1ll1 -Cl~=;
3,75 (s, 3il) -COOCH3;
1,7 - 2,6 (m, 5H) -C112-C=; ~-CH2-CII-;
1~15 (s, 3~1) Cll3-C112;
1,0 ppm (d, 611) C~cll3.
~ ~77~
xample 14 . .=
134 mg (0.5 mmole) of ammonium perrh~nate, 7.85 g (50 mmoles) of 2-azido-pentanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and S0 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.5 g (52.3 mmoles) of 2-ethyl hexanoyl chloride were added at room tempera-ture while stirring vigorously. The reaction mixture was sti~red for 120 hours, the exothermic reaction reaching a maxi-mal ternperature of 80C.
The further processing was analogous to that of Example 3. 'rhe crude product thus obtained was distilled in high vacuum (0.06 mbar) at an instrument tempe,rature of 180 to 210C in the bulb tube.
7.0 g (54.8% of the theoretical yield) of 2-[(1'-ethyle~rle-pentyl)-carborlyl-amino]-2-pentenoic methyl ester were obta:ined .
' C113Cfl2C~ C-C-ocH3 3N-~ cEl-cll2cl32cH2c~l3 10 25 03~255,36) ~ %C %H %N
computed: 65.85 9.87 5.48 obtained: ~ 65.11 10.31 5.52 i-NMI~ (C~C13/~'MS):
~= 6,85 (s brad' lli) NH;
6~55 (t, 1ll) -C~3=;
~,7 (s, 3ll) -COOCI~3;
0~6 - 2~45 ppm (m~ 2011) Cll3C112-C=; -Clll-(CII2)3-C1l3.
C'12CI~3 1~77~t~B
llxample 15 __ ___.__ 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-az:ido-pentanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro~luinone wre dissolved in 50 ml of acetonitrile, whereupon 7.8 g (52.5 mmoles) of 2-methyl-2-ethyl-butanoic acid chloride were added at room temperature while stirring vigorously. The reaction mix-ture was stirred foi 120 hours, the exot4ermic reaction reaching a temperature of 80C. The further treatment was analogous to that of Exar.lple 1. The oily crude product thus obtained was distilled in high vacuum (0.06 mbar) at an instrument tem-perature of 100 to 150C in the bulb tube.
6.4 g (53% of the theoretical yield) of 2-[(1'-methyl-l'-ethyl-propyl)-carbonyl-amino]-2-pentanoic methyl ester were obtained.
C133C132cl3=f- -OCll3 I HN_C_C_CH2CH3 3 ' C131123NO3(241~33) %C 9~H 96N
comput:ed: 64.709.,61 5.80 obtaitled: ' 63.7010.16 6.25 -N~I~ (cDCl3/TMs):
= 7,15 (s broac~, lH) Nll;
6~65 (t, lH) -CH=;
3,75 (s, 311) -COOC133;
0,65 - 2,35 ppm (~, 1813) C113C132-C=; -C-(CH2C133)2.
.~
77~38 ExamL)le 16 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-azido-pen-tanoic methyl ester, 50 mg (0.45 mmole) of hydroquinone and 3.85 g (52.6 mmoles) of dimethyl formamide were dissolved in 50 ml of acetic ethyl ester. 8.5 g (52.9 mmoles) of thiophene-2-acetic acid chloride were then added dropwise at roo~n temperature while stirring vigorously. Within 30 minu-tes the mixture reacted!exothermically.
When the generation of gas was terminated the reaction mix-ture was diluted with 50 ml of acetic ethyl ester, shaken out with a 0.5 ~lolar sodium hydrogen carbona-te solution and the organic pllase was once more washed with water and dried over sodium sulE~hate. On removing the drying agent the concentrated organic phase was crystallized with n-pentane.
12.1 g (95.5% of the theoretical yield) of analyti-cally pure 2-(thenyl-carbonyl-amino)-2-pentanoic methyl es~er were obtained.
~, O
Cl33c~l2c~3=f-c-ocl33 C12l~l5NO3S(253,26) ~C %1l %N %Cl computed: 56.91 5.97 5.53 12.63 obtained: 56.80 5.86 5.66 12.63 meltirlg point: 67 to 70C
~'~77~8 Il-NI~ (CDC13/TMS):
J` = G,B5 - 7,5 ~m~ 411) Nll; 1~;
G,65 (t, 111) Cll=;
3~9 (s, 211) COCE12;
3,75 (s, 31~) COOCH3;
1,65 - 2~55 (m, 2~ C112-;
1~05 ppm (t, 31~) CH3-.
!
Examp e 17 134 mg (0.5 mmoles) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-azido-pentanoic methyl ester, 50 mg (0.45 mmole) of hydro~uinone and 3.85 g (52.6 mmoles) of dirnethyl formamide were reacted Wit}l 9.5 g (52.6 mmoles) of 3-acetyl-thio-2-methyl-pro-piol~ic acicl chloricle analogously to Example 16.
On further E~rocessing as in Example 16 10.9 g (79.8%
of the theoretical yield) of analytically pure 2-[(1'-methyl-2' acetyl-thio-ethyl)-carboxamido]-2-pentanoic methyl ester were obtained .
o C113C112C~ C-C-OC113 O cll3 O
( 12lll9N04S(273,29) %C I g61~ ~6N 96Cl .,' ';
computed: 52.74 7.01 5.12 11.71 obtained: 52.46 7.01 5.22 11.56 rnelting pOillt: 56 to 58C
~'~775~
111-NM1~ ( CDC1 3/~rMs ~:
= 7,55 (s broad, 1~l) Nll;
6,65 (~, lli) Cl~=;
3,8 (s, 3~) COOC1~3, 3,1 (t, 21~) S-CII2~;
2,4 ~ ?-9 (m, lH) COCH;
2~35 (s, 3HJ COCH3, 1,8 - 2~4 (m, 2~3) ~CH2-;
1,25 (d, 3H) CH-CH3;
1,05 ppm (t, 3H) Cll3-CI12.
~xamp e 18 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-pentanoic isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro~uinone were dissolved in 50 ml of acetonitrile, whereupon 12.35 g (52.5 mmoles) of 2,6-dichloro cinnamic acid chloride are added at roorn temperature while stirring vigorously. The reaction mixture was stirred for 16 hours while the product precipitated. The residue was separated, washed with water until free from chloride and dried.
12.5 g (70.2% of the theoretical yield) of analyti-cally pure 2-[2'-(2,6-dichloro-phenyl)-vinyl-carbonyl-amino]-2-pentanoic isopropyl ester were obtained.
: '' O
' CH3cl~2cl~=c-e' H1-lCI-CH-CH
Cl 30C17~19NO3C12(356,27) \
~C %1l ~N%Cl computed: 57.31 5.37 3.53 19.90 obtained: 57.31 5.76 4.06 18.45 melt:ing point: 166C
', 1 Il-NMI~ ~CDC13/TMS):
,. ~
~ = 7,75 (d, lH) -COCH=;
6,B5 _! 7,5 (m, 4~) NH; ,aromatic CH;
6~65 (d, 113) -C=CH-;
6,55 (t, 1~l) C~12-C~I=;
4,65 - 5,3 (m, lH) COOCH-;
1,85 - 2,5 (m, 2H) -CH2-;
1,25 (d, 611) C-(CI13)2;
1,05 ppm (t, 311) CH3-.
E, ml~le__9 27.3 mg (0.1 mmole) of sodium perrhenate, 1.71 g (10 mmoles) of 2-azido-hexanoic methyl es-ter and 767.6 mg tlO.5 nmloles) of dimethyl formamide were dissolved in 1 ml of acetoni-trile, whereupon 1.19 g (10.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 30 minutes and was then further processed as in Example 3.
1.8109 y (82.4~ of theoretical yield) of analyti-cally ~ure 2-chloro-methyl carboxamido-2-hexenoic methyl ester were obtained.
'' ' O
3 2C~l2 ~C
, 11 . C02C113 :
C9~ clNo3(2l9~66B) %C ~H %N %Cl cornpu~ed: 49.21 6.42 6.38 16.14 obtained: 49.21 6.33 6.41 16.15 melting point: 63.5 to 64C
.~ lH-NMR (CDC13):
= 8,0 (s, lH) NH;
6,86 (t, lH)-CH2-CH=;
4~19 (s, 2H) C112Cl;
3,81 (s, 3H) OCH3;
2,18 ~q, 2H)-C1l2-CH=;
1,8 - 1,28 (m, 211) CH3-CH2-;
0~95 ppm (t, 3H) CH3-CH2.
ln(KBr) ~NII = 3255 cm 1, ~CO = 1722 cm 1, 1664 cm 1.
- Example 20 _.
134 Ing (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-hexanoic ethyl ester, 3. 85 g (52.6 mmoles) of dirnethyl formantide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 rnl of acetic isopropyl ester, whereupon 5.95 g (52. 6 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixtures reacted exothermically withln 40 minutes. The mixture was further pro-cessed as in Example 16.
8.7 9 (74.,4% of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-hexenoic ethyl ester were obtainecl.
" C11 3C11 2C~1 2C~=f -l-oc~l 2cll 3 HN-I~-c1~2cl Clolll6No3cl(233~69) .
~'~775~
%C ~1l %N ~Cl comput:ed: 51.40 6.90 6.0 15.17 obtained: 51.56 6.83 6.06 15.23 meltillg point: 49 to 49.5C
N~ (cDcl3/TMs) = 7,9 (s ~roaa, lH) NH;
6,75 (t, lH) -CH=;
4,2 (q, 211) -CH2Cl;
1.8 - 2~4 (m~ 2EI) -C112-CH=;
1~2 - 1.8 ~m, 2H) CH3-CH2-;
1,3 (t, 311) COOC~12Ci~3;
0~9 ppm (t, 3H) CH3-CH2.
Exam~le 21 a) 134 mg (O.S mmole) of a~mnonium perrhenate, 9.25 g (50 mmoles) of 2-azido-hexanoic ethyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmole) of hydroquinone were put into a reactor with 50 ml of acetonitrile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 20 minutes. It was further processed as in Examule 3.
~ 10.1 g (75.3% of the theoretical yield) of analyti-- cally pure 2-dichlor4-methyl-carboxamido-2-hexenoic ethyl ester were obtained.
b) 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-hexanoic ethyl ester, 6.1 g (52.5 mmoles) of tetramethyl urea and 50 mg of hydroquinone were reacted with 7.75 g (52.5 mmoles) of dichloro acetyl chloride analogously to a).
" C11 3C11 2C~1 2C~=f -l-oc~l 2cll 3 HN-I~-c1~2cl Clolll6No3cl(233~69) .
~'~775~
%C ~1l %N ~Cl comput:ed: 51.40 6.90 6.0 15.17 obtained: 51.56 6.83 6.06 15.23 meltillg point: 49 to 49.5C
N~ (cDcl3/TMs) = 7,9 (s ~roaa, lH) NH;
6,75 (t, lH) -CH=;
4,2 (q, 211) -CH2Cl;
1.8 - 2~4 (m~ 2EI) -C112-CH=;
1~2 - 1.8 ~m, 2H) CH3-CH2-;
1,3 (t, 311) COOC~12Ci~3;
0~9 ppm (t, 3H) CH3-CH2.
Exam~le 21 a) 134 mg (O.S mmole) of a~mnonium perrhenate, 9.25 g (50 mmoles) of 2-azido-hexanoic ethyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmole) of hydroquinone were put into a reactor with 50 ml of acetonitrile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 20 minutes. It was further processed as in Examule 3.
~ 10.1 g (75.3% of the theoretical yield) of analyti-- cally pure 2-dichlor4-methyl-carboxamido-2-hexenoic ethyl ester were obtained.
b) 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 mmoles) of 2-azido-hexanoic ethyl ester, 6.1 g (52.5 mmoles) of tetramethyl urea and 50 mg of hydroquinone were reacted with 7.75 g (52.5 mmoles) of dichloro acetyl chloride analogously to a).
9.4 g (70.1% of the theoretical yield) of analyti-,_ '1,~7798~ ' cally r)ure 2-dichloro-methyl-carboxamido-2-hexenoic ethyl ester were obtained.
c) 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 Inllloles) of 2-azido-hexanoic ethyl ester, 9.4 g (52.5 mmoles) of N,N,N',N', N', N" of hexamethyl phosphoric acid triamide and 50 mg (0.45 mmole) of hydroquinone were reacted with 7.75 g (52.5 mmoles) of dichloro acetyl chloride analogously to a).
7.3 g (54.!5% of the theoretical yield) of analyti-cally pure 2-dichloro-methyl-carboxamido-2-hexenoic ethyl ester 10 were obtained.
CH3cl~2cl~2cll=c~ -C-OCH2ClH3 HN-C~CHC12 O
clol~l5No3cl2(268l14) 96C 96EI 96N ~6Cl computed: 44.79 5.64 5.2226.44 obtained: 44.61 5.30 5.2026.31 melting point: 75C
H-NMII (CDC13/TMS) = 7~9~ (s b~ad~ lH) NH;
6,8 ~t, lHJ -CH=;
6,05 (s, 11~) -C~C12;
4~25 (q, 2H) COOC112-;
1,9 - 2,4 (m, 211) -C112-CII=;
1,2 - 1,85 (m~ 211) C113-C112-;
1,35 (t, 31~) -CO0C132CE~3;
0~95 ppm~(t, 3H) CH.~-CH2.
~ 77~8f~
Example 22 134 mg (0.5 mmole) of ammonium perrhenate, 9.95 g (49.9 mllloles) o~ 2-azido-octanoic methyl ester, 3.85 g (52.5 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro-qui.none were dissolved in 50 ml of acetonitrile, whereupon 5.95 g (52.6 mmoles) of chloro acetyl chloride are added at room temperature while stirri.ng vigorously. The mi.xture ,reacted exothermically wlth~n 25 minut,es. It'was further processed as in F,xample 3.
10.8 g (87.3% of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-octenoic m~thyl ester we~e obt:ained.
C113C~12C112C~12C~2C~ C-C-OC~13 N-lC-Cll2C
C~ 8No3cl(247~72) %C ~}l %N %Cl computed: 53.33 7.32 5.65 14.31 obtai.ned: 53.29 7.41 5.52 14.27 melting point: 52.5C
Il-NMI~ ( CDCl 3/TMS):
= 7,85 (s bLoad, lll~ NH;
6~8 (t, 1ll) -Cll=;
4~2 (s, 2~) -c~2Cl;
3~85 (s, 31~) -COOCI-~3;
2~2 (dt, 2ll) -Cl12CII=;
0 65 - 1~85 ppm (m, 911) CH3CII2C1l2C 2 ~2~77988 Example 23 246 mg (0.5 mmole) of tetra-n-butyl ammonium perrhenate, 9.95 g (49.9 mmoles) of 2-azido-octanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupoll 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room ~erat ~ while stirring vigor-ously. The mixtuL~e!immediately reacted exothermically. The further treatment was like that in Example 3.
10.4 g (73.85~ of the theoretical yield) of analyti-cally pure 2-dichloro-rnethyl-carboxamido-2-octenoic methyl ester were obtained.
Cl13C~2C~l2cll2cll2cll=f-c-ocil3 o , .
Cll11l7NO3Cl2(282,17) %C ~ Cl computed: 46.826.07 4.9625.15 obtained: 46.886.22 4.8724.63 meltitlg point: 57C
, , , i , lll-NMR (CVC13/TMS):
.
= 7,8 (s broad,, lH) NH;
6~75 (t, lH) -CH=;
5,95 (s, 1ll! -C~IC12;
3,8 (s, 3H) -COOCH3;
2,15 (dt, 2H)~ -Cll2-CII;
0,55 - 1,75 ppm (m~ 91l) CH3C1l2CH2CH2~-1~7988 Exalr~le 24 . .
246 mg (0.5 mmole) of tetra-n-butyl ammonium perrhen~te, 11.35 g (49.9 mmole) of 2-azido-octanoic isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of acetic ethyl estex, whereupon 5.95 g (52.6 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 1 hour.
It was further treated as in Example 16. 10.5 g (76.3% of the . 10 theoretical yield) o~ analytically pure 2-chloro-methyl-car-.(: boxamido-2-octenoic isopropyl ester were obtained.
C~3CH2CI~2CI~2C~I2C~1 f C ~ C113 IIN-ICl-Cl~2C
, O
3l~22NO2C1(275,78) i~:
;~ %C %H %N ~Cl computed: 56.628.04 5.079 12.85 obtained: 56.558.32 5.00 12.83 - mel~.ing point: 55C
~' Il-N~ ( CDCl 3/TMS):
= 7~85 (s b~oad; lH) NH;
: 6,7 (t, 113) -Cll=;
5~35 - 4,7 (m, lH) -COOCII-;
4,1 (s, 2~l) -C1~2Cl;
2,1S (dt, 211) -CH2-CH=;
~,.: 30 1~35 (d, 6H) -CH-(CH3)2;
,,, 0,5 - 1,8 ppm (m, 913) CH3CH2CH2C~12--.. ...
. ~, :
t77988 L~`xamE~le 25 _ ___,_ __ _ 246 nlg (0.5 mmole) of tetra-n-butyl-ammonium per,r-llenate, 11.35 g (49.9 mmoles) of 2-azido-octanoi,c i.soproE~yl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmolé) of hydroquinone were dissolved in 50 ml of ace-toni-t~ile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stir.ring vig-orously. The reaction mixture was stirred for 18 hours a-t room ternperal..ure and was then further treated as in Example 3.
12.3 g (79.3~ of the theoretical yield) of analy-tically pure 2-dichloro-methyl-carboxamido-2-octanoic iso-propyl ester we.re obtained.
O
3 2 2 2 2CEI C C OC~
' Cl3ll2lNo3cl2(3lo~22) .
%C ~H %N ~Cl cornpuled: 50.33 6.82 4.51 22.85 obtained: 50.11 6.96 4.50 22.77 meltirlg point: 88C
-NMI~ (cDcl3/TMs):
= 7,9,5 (,S br3ad, 11l) NH;
6~8 (t, 1ll) -Cll=;
6,05 (s, 1ll) -CIIC12;
5,4 - 4,7 (m, 1ll) -COOCII-;
2,15 (dt, 2H) -Cll2-CH=;
1,35 (d, 611) -Cll-(CH3)2;
0 6 - 1~8 ppm (m, 9ll) Cll3CII2C 2 2 .
," - 33 -xaml~le 26 134 mg (0.5 mmole) of ammonium perrhenate, 9.85 g (49.9 mmole) of 2-azido-3-cycloperltyl propionic met~lyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinolle were dissolved in 50 ml of acetonitrile, whereupon 59.3 g (52.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The re-action mixture was !stirred for 13 hours at room temperature and then fuxther treated as in Example 3.
6.9 g (56.3% of t:he theoretical yield of analytically pure 2-chloro-methyl-carboxamido-3-cyclopentyl propenoic methyl ester were obtained.
~ CII=C- -OCE~
HN-f-CH Cl o C~ l6No3cl~245~7l) ~C %H ~N ~Cl computed: 53.77 6.56 5.70 14.43 o~tained: 53.61 6.63 5.29 14.78 melting ~oint: 65.5C
lH-NMR ~CDC13/l'MS):
., I
~= 7,8 ~,sb ~ d, lH) Nll;
~ 6,7 ~d, lH) -CH=;
4,15 Is, 211) -CH2Cl;
~: 3,8 (s, 3H) COOCH3;
2,15 - 3,1 (s breit, 113) C,CH;
1,0 - 2.2 ppm ~m, 8ll) H ~ il 1'~77988 ~_amL~le 27 134 mg (0.5 mmole) of ammonium perrhenat:e, 9.85 g (4~.~ mmole) of 2-azi.do-3-cyclopentyl-propionic metllyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg of (0.45 mmole) of hdyr~quinone were dissolved in 50 ml of acetonitri.le, whereupon 7.75 y (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stirring viyorously. The re-action was stirred.for 15 hours a~ room cemperature and then further processed as in Example 3.
10.9 g (77.9% of the theoretical yield) of analyti-10 cally pure 2-dichlor-metllyl-3-cyclopentyl-propenoj.c methyl ester we~e obta.ined.
/~ U
~CEE= ~C-C-OCH3 EIN-C-CHCl z ~ O
Clllll5No3cl2l28o~l5) ~C %H %N %Cl 20 computed: 47.16 5.40 5.00 25.31 obtained: 47.06 5.32 4.98 25.00 melting point: 85 t.o 86C
NMI~ (CDC13/TMS):
= 7,75 (s broad~ lH) Nll;
6,75 (~d, lH) -CH=;
6,0 (s, lH) -CHC12;
3, 8 ( s, 311 ) COOCIE3;
2,25 - 3,0 (s breit, 1ll) CC,CH;
0,9 - 2,2 ppm (m, 8H) EI~EI --- 3s --Hixalnt~le 28 ~ ~77988 134 mg (0.5 mmole) of ammonium per,rhenate, 11.25 g (4~.9 mMoles) of 2-a~ido-3-cyclopentyl propionic isopropyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 5U mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitri.le, whereupon 5.93 g (52.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vig-orously. The Mixture reacted exother~ically within 30 minutes.
The mixture was fur~her processed as in Example 3.
c) 134 mg (0.5 mmole) of ammonium perrhenate, 9.25 g (50 Inllloles) of 2-azido-hexanoic ethyl ester, 9.4 g (52.5 mmoles) of N,N,N',N', N', N" of hexamethyl phosphoric acid triamide and 50 mg (0.45 mmole) of hydroquinone were reacted with 7.75 g (52.5 mmoles) of dichloro acetyl chloride analogously to a).
7.3 g (54.!5% of the theoretical yield) of analyti-cally pure 2-dichloro-methyl-carboxamido-2-hexenoic ethyl ester 10 were obtained.
CH3cl~2cl~2cll=c~ -C-OCH2ClH3 HN-C~CHC12 O
clol~l5No3cl2(268l14) 96C 96EI 96N ~6Cl computed: 44.79 5.64 5.2226.44 obtained: 44.61 5.30 5.2026.31 melting point: 75C
H-NMII (CDC13/TMS) = 7~9~ (s b~ad~ lH) NH;
6,8 ~t, lHJ -CH=;
6,05 (s, 11~) -C~C12;
4~25 (q, 2H) COOC112-;
1,9 - 2,4 (m, 211) -C112-CII=;
1,2 - 1,85 (m~ 211) C113-C112-;
1,35 (t, 31~) -CO0C132CE~3;
0~95 ppm~(t, 3H) CH.~-CH2.
~ 77~8f~
Example 22 134 mg (0.5 mmole) of ammonium perrhenate, 9.95 g (49.9 mllloles) o~ 2-azido-octanoic methyl ester, 3.85 g (52.5 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro-qui.none were dissolved in 50 ml of acetonitrile, whereupon 5.95 g (52.6 mmoles) of chloro acetyl chloride are added at room temperature while stirri.ng vigorously. The mi.xture ,reacted exothermically wlth~n 25 minut,es. It'was further processed as in F,xample 3.
10.8 g (87.3% of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-octenoic m~thyl ester we~e obt:ained.
C113C~12C112C~12C~2C~ C-C-OC~13 N-lC-Cll2C
C~ 8No3cl(247~72) %C ~}l %N %Cl computed: 53.33 7.32 5.65 14.31 obtai.ned: 53.29 7.41 5.52 14.27 melting point: 52.5C
Il-NMI~ ( CDCl 3/TMS):
= 7,85 (s bLoad, lll~ NH;
6~8 (t, 1ll) -Cll=;
4~2 (s, 2~) -c~2Cl;
3~85 (s, 31~) -COOCI-~3;
2~2 (dt, 2ll) -Cl12CII=;
0 65 - 1~85 ppm (m, 911) CH3CII2C1l2C 2 ~2~77988 Example 23 246 mg (0.5 mmole) of tetra-n-butyl ammonium perrhenate, 9.95 g (49.9 mmoles) of 2-azido-octanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupoll 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room ~erat ~ while stirring vigor-ously. The mixtuL~e!immediately reacted exothermically. The further treatment was like that in Example 3.
10.4 g (73.85~ of the theoretical yield) of analyti-cally pure 2-dichloro-rnethyl-carboxamido-2-octenoic methyl ester were obtained.
Cl13C~2C~l2cll2cll2cll=f-c-ocil3 o , .
Cll11l7NO3Cl2(282,17) %C ~ Cl computed: 46.826.07 4.9625.15 obtained: 46.886.22 4.8724.63 meltitlg point: 57C
, , , i , lll-NMR (CVC13/TMS):
.
= 7,8 (s broad,, lH) NH;
6~75 (t, lH) -CH=;
5,95 (s, 1ll! -C~IC12;
3,8 (s, 3H) -COOCH3;
2,15 (dt, 2H)~ -Cll2-CII;
0,55 - 1,75 ppm (m~ 91l) CH3C1l2CH2CH2~-1~7988 Exalr~le 24 . .
246 mg (0.5 mmole) of tetra-n-butyl ammonium perrhen~te, 11.35 g (49.9 mmole) of 2-azido-octanoic isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of acetic ethyl estex, whereupon 5.95 g (52.6 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 1 hour.
It was further treated as in Example 16. 10.5 g (76.3% of the . 10 theoretical yield) o~ analytically pure 2-chloro-methyl-car-.(: boxamido-2-octenoic isopropyl ester were obtained.
C~3CH2CI~2CI~2C~I2C~1 f C ~ C113 IIN-ICl-Cl~2C
, O
3l~22NO2C1(275,78) i~:
;~ %C %H %N ~Cl computed: 56.628.04 5.079 12.85 obtained: 56.558.32 5.00 12.83 - mel~.ing point: 55C
~' Il-N~ ( CDCl 3/TMS):
= 7~85 (s b~oad; lH) NH;
: 6,7 (t, 113) -Cll=;
5~35 - 4,7 (m, lH) -COOCII-;
4,1 (s, 2~l) -C1~2Cl;
2,1S (dt, 211) -CH2-CH=;
~,.: 30 1~35 (d, 6H) -CH-(CH3)2;
,,, 0,5 - 1,8 ppm (m, 913) CH3CH2CH2C~12--.. ...
. ~, :
t77988 L~`xamE~le 25 _ ___,_ __ _ 246 nlg (0.5 mmole) of tetra-n-butyl-ammonium per,r-llenate, 11.35 g (49.9 mmoles) of 2-azido-octanoi,c i.soproE~yl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmolé) of hydroquinone were dissolved in 50 ml of ace-toni-t~ile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stir.ring vig-orously. The reaction mixture was stirred for 18 hours a-t room ternperal..ure and was then further treated as in Example 3.
12.3 g (79.3~ of the theoretical yield) of analy-tically pure 2-dichloro-methyl-carboxamido-2-octanoic iso-propyl ester we.re obtained.
O
3 2 2 2 2CEI C C OC~
' Cl3ll2lNo3cl2(3lo~22) .
%C ~H %N ~Cl cornpuled: 50.33 6.82 4.51 22.85 obtained: 50.11 6.96 4.50 22.77 meltirlg point: 88C
-NMI~ (cDcl3/TMs):
= 7,9,5 (,S br3ad, 11l) NH;
6~8 (t, 1ll) -Cll=;
6,05 (s, 1ll) -CIIC12;
5,4 - 4,7 (m, 1ll) -COOCII-;
2,15 (dt, 2H) -Cll2-CH=;
1,35 (d, 611) -Cll-(CH3)2;
0 6 - 1~8 ppm (m, 9ll) Cll3CII2C 2 2 .
," - 33 -xaml~le 26 134 mg (0.5 mmole) of ammonium perrhenate, 9.85 g (49.9 mmole) of 2-azido-3-cycloperltyl propionic met~lyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinolle were dissolved in 50 ml of acetonitrile, whereupon 59.3 g (52.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigorously. The re-action mixture was !stirred for 13 hours at room temperature and then fuxther treated as in Example 3.
6.9 g (56.3% of t:he theoretical yield of analytically pure 2-chloro-methyl-carboxamido-3-cyclopentyl propenoic methyl ester were obtained.
~ CII=C- -OCE~
HN-f-CH Cl o C~ l6No3cl~245~7l) ~C %H ~N ~Cl computed: 53.77 6.56 5.70 14.43 o~tained: 53.61 6.63 5.29 14.78 melting ~oint: 65.5C
lH-NMR ~CDC13/l'MS):
., I
~= 7,8 ~,sb ~ d, lH) Nll;
~ 6,7 ~d, lH) -CH=;
4,15 Is, 211) -CH2Cl;
~: 3,8 (s, 3H) COOCH3;
2,15 - 3,1 (s breit, 113) C,CH;
1,0 - 2.2 ppm ~m, 8ll) H ~ il 1'~77988 ~_amL~le 27 134 mg (0.5 mmole) of ammonium perrhenat:e, 9.85 g (4~.~ mmole) of 2-azi.do-3-cyclopentyl-propionic metllyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg of (0.45 mmole) of hdyr~quinone were dissolved in 50 ml of acetonitri.le, whereupon 7.75 y (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stirring viyorously. The re-action was stirred.for 15 hours a~ room cemperature and then further processed as in Example 3.
10.9 g (77.9% of the theoretical yield) of analyti-10 cally pure 2-dichlor-metllyl-3-cyclopentyl-propenoj.c methyl ester we~e obta.ined.
/~ U
~CEE= ~C-C-OCH3 EIN-C-CHCl z ~ O
Clllll5No3cl2l28o~l5) ~C %H %N %Cl 20 computed: 47.16 5.40 5.00 25.31 obtained: 47.06 5.32 4.98 25.00 melting point: 85 t.o 86C
NMI~ (CDC13/TMS):
= 7,75 (s broad~ lH) Nll;
6,75 (~d, lH) -CH=;
6,0 (s, lH) -CHC12;
3, 8 ( s, 311 ) COOCIE3;
2,25 - 3,0 (s breit, 1ll) CC,CH;
0,9 - 2,2 ppm (m, 8H) EI~EI --- 3s --Hixalnt~le 28 ~ ~77988 134 mg (0.5 mmole) of ammonium per,rhenate, 11.25 g (4~.9 mMoles) of 2-a~ido-3-cyclopentyl propionic isopropyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 5U mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitri.le, whereupon 5.93 g (52.5 mmoles) of chloro acetyl chloride were added at room temperature while stirring vig-orously. The Mixture reacted exother~ically within 30 minutes.
The mixture was fur~her processed as in Example 3.
11.2 g (81.8% of the theoretical yield) of analytically pure 2-chloro-methyl-carboxamido-3-cyclopentyl propenoic isopropyl ester were obtained.
O- Cll=f-C-OCII '3 HN- lC~ -C112C
O
13~l2oNo3cl~273~76) ~C %H %N %Cl com~uted: 57.04 7.36 5.12 12.95 obtained: 57.04 7.71 5.15 13.01 ~:: melting point: 72C
tl-NMn '(CDC13/~'MS):
= 7,75 ~s broad, 111) NH;
' 6,65 (d, 111) -CH=;
4,7 - 5,35 (m, 111) COOCH;
: 4.15 (s, 211) -CH2Cl; -C
2.25 - 3.0 (s.breit, lH) c`CII;
- 2,15 (m, 811)11t_t~H
1~
1,30 ppm (b, 6tl) COOC'cl'l3.
7'7988 xam~le_29 134 mg (0.5 mmole) of ammonium perrhenate, 11.25 g (49.9 mmoles) of 2-azido-3-cyclopentyl propionic iso~ropyl ester, 3.85 g (52.g mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupoll 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stirring vigor-ously. The mixture!reacted exo~hermically within 45 minutes.
The mixture was further processed as in Example 3.
8.7 g (56.6~ of the theoretical yield) of analyti-cally l~ure 2-dichloro-methyl carboxatnido-3-cyclopentyl-propenoic isopropyl ester were obtained.
O- CH=T-C--C"
HN-~-cllcl ?
: o C131ll9NO3C12(308,205) %C %H %N ~Cl comput.ed: 50.66 6.21 4.54 23.00 s obtai.ned: 50.82 6.26 4.63 22.79 melting point: 99C
, 1 Il-N~ (CDC13/l'~lS):
.
J= 7,85 (s brad , lH) Nll;
6~75 (d, lH) -Cll=;
6.05 (s, 1l~) CIIC12;
4,7 - 5,4 ~m, lH) COOCII;
2,25 - 2~95 (s breit; 1ll) cC`CH;
2~2 (n~, 8l~)~H ~ 1l;
1,35 ppm (d, 6H) COOC~cll3.
, :: ::
.
~ ~7~7988 Lxa~ le 30 134 mg (0.5 mmole) of ammoni.um perrhella~e, 10.55 g (50 mmoles) of 2-azido-3-cyclohexyl-propionic me-thyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmole) of hydroclulnone were dissolved in 50 ml of acetic-n-pxopyl ester, whereupon 5.93 g (52.5 mmoles) of chlo~o acetyl chloride were added at room temperature while stirring vigorously. After one hour ~he reactio~ miY~ture was maximally exothermical and was then further processed as in Example 16.
10 10.3 g (79.3~ of the theoretical yield) of analyti-cally pure 2-chloro-methyl carboxamido-3-cyclopentyl propenoic methyl ester were obtained.
o -C-OC~3 ~N-ICI-CH2C
O
C12~N03Cl(259~73) %C %11 %N %Cl comEJuted: 55.49 6.995.39 13.65 obtained: 55.39 7.284.75 13.83 meltillg pOillt: 117 to 118C
; ' Il-NM~ (~DC13/T~ISJ:
= 7,7 (s broad,~ 1 H) N)3;
6.6 (d, lH) -CH=;
4,15 (s, 211) -CH2Cl;
3,85 (s, 311) COOCH3;
0,75 - 2,6 ppm (m, 1113) ~ .
- 3~ -7798~
I~'xaml~le 31 134 mg (0.5 mmoles) of ammollium perrhellate, 10.55 g (50 mmoles) of 2-azido-3-cyclohexyl propionic methyl ester, 3.85 g (52.6 rnmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro(luinone were dissolved in 50 ml of acetonitrile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl chloride wer~ added at room -cemperature while stirring vigorously. The reaction mixture was stirred!for 16 hours at ~oom temperature and was then further processed as in Example 16.
11.7 g ( 79.5% of the theore-tical yield) of analyti-cally pure 2-dichloro-methyl-carboxamido-3-cyclohexyl propenoic methyl ester were obtained.
o acll=~c-c_Oc~l3 ~IN-C-CIIC 1 12l3l7No3cl2~294ll8J
%C ~H %N %Cl computed: 48.99 5.82 4.76 24.10 obtalrled: 48.95 5.91 4.70 24.06 melting point: 98C
1ll-N~ (CDC13/T~S):
= 7,65 (s bL~ad~ 111) N13;
6,65 (d, 111) -Cll=;
5,95 (s, 111) -C}12Cl;
3,8 (s, 311) COOC113;
1,9 - 2,65 (s breit, 111)C`C-H;
0"7 - 2rQ pplll ~m, 1013)~3337~11 .
'79~8 _Y~ mple 32 13.7 mg (0.05 mMole) of sodium perrhenate, 715.7 my (S
mmoles) of 2-azido-hutanoic rnethyl ester and 383.8 Ing (5.25 mmoles) of dimethyl formamide were dissolved in 5 ml of acetoIIitrile, whereupon 1.195 g (5.25 mmoles) of 2-(2',2'-dichloro-etheIlyl)-3,3-dimethyl-cyclopxopane carboxylic acid chloride were added at room temperature while stirring vigor-ously. The reaction mix-ture was stir~ed for 30 hours at room temperat:ure, whereupon it was further treated as in Example l.
1.31 g (85.6~6 of the theoretical yield) of analyti-cally pure 2-[2'-(2,2-dichloro-ethenyl)-3',3'-dimettlyl]-cyclo-p~oL)a~ -carboxamido-2-hexelloic methyl ester were obtained.
H /CO2CfI3 113C NII-ICl ~CII=CC12 I~3C CIJ3 C13II17C12NO3~306,189) %C %H 96~1 %Cl compuled: 51.00 5.60 4.57 23.16 obtained: 50.79 5.66 4.29 23.11 meltiIly point: 109 to 109.5C
Il - NMII (CDC13) ~= 7,32 (s, lII) Nll; IR ~rNII = 3320 cm, 6,8 (q, lII) li-C(CII3)=; ~rcO = 1720 cm, 6,42 (d, lII) II-C=CCL2; 1658 cm 3,77 (s, 311) OC113;
1,76 (~3, 3II)IJ3C-C~I=;
1,28 (s, 311) ~ \\7 1,25 ppln (5~ 3~)J~t3c~cIl3 ~'~77~
I`xa~ )le 33 _ _ _ _ _ _ 13.7 mg (0.05 nImole) of so~i.um perrhenate, 856 mg (5 mI;loles) of 2-azido-hexanoic methyl ester and 383.8 I~Iy (5.25 mmoles) of ~i.methyl formamide were dissolved in O.S ~ll of acei-oIli.tri]e whereupon 1.1945 g (5.25 mmoles) of 2-(2'-2'-dichl.oro-ethenyl)-3~3'-dimethyl-cyclopropane carboxylic acid chloride we.re added at room 'ernpe-rature whi.le sti.rring vigor-ously, The reaction mixture was kept for 15 hours at room ternL~erature and then further treated as in Example 1.
1.40 g (83.8% of the theoretical yield) of analyti-cally pure 2-[2'-(2,2-dichloxo-ethenyl)--3'-3'-dimethyl]-cycloproparle-carbox~mido-2-hexelloic methyl ester were ob-tained.
Il ~ C02C113 C=C 11 1]
CII3CI12C1l2 NII-C ~ ~ CI3=CC12 O ~'~
~13C Cil3.
lslJ2lcl2No3~334~243) %C %~I %N %Cl comL~uted: 53.90 6.33 4.19 21.21 obtained: 53.62 6.51 3.98 2~.. 44 melt~ g L~oint: 105 to 106C
I3-N~ CDC13) = 6,97 (s, 113) NII; IR ~NI3 = 3300 cm G,73 (t, 113) -CII2-CII=; ~CO = 1715 cm 1, 6,43 (d, lII) I3-C=CC12; 1655 cm 3~8 (s, 3II) OCII3;
2 38 - 0,77 (m, 9I3) CII3CII2CI32;
1~3 (s, 311) 1~27 ppn~ (s~ 3II)J ~13C/~C~33 l~7~7~8~
I:xaml~le 34 13.7 Ing (0.05 mmole) of sodium perrhenate, 1.0261 y (S
n:moles) of 2-azido-3--phellyl propanoic rnethyl ester and 383.8 mg (5.25 mnloles) of di.nlethyl formamide were dissolved in 5 ml of acel:onitrile, ~hereupon 592.9 rng (5.25 mmoles) oE chloro acetyl chlorLdewere added while stirring vigorously. The reactiorl mixture was stirred for 7 hours at room temperature and then fur:ther processed as in rxarnple 1.
1.1657 g (91.9% of -the theoretical yield) of analyti-cally I~ure 2-chloro-methyl carboxamido-3-phenyl propenoic methyl esle~ ~/ere obtained.
6115~ N~l_C_ ~C=C
Il 2CH3 No3(253~6g5) ~C %H ~N %Cl compu~ed: 56.82 4 77 5.52 13.98 obtai.ncd: 56.90 4.83 5.38 13.93 mel~:ing point: 113.5 to 114C
-N~ (C~C13) (m, 511) aromat~C -Cll Nll ~ 3235 cm 4,09 (s, 2H) Cll2Cl; CO 1617 cm 1 3,~2 ~plll (s, 311) Cll3.
- 4~ -77~
k'xample~ 35 _ _ _ _ 13.7 mg (().05 mmole) of sodium perrhenat~, 1.()261 mg (S mllloles) ol 2-azjdo-3-pherlyl pro~anoic rme~h~l estel- and 383.8 ng (5.25 mrnoles) of dimethyl formamide were dissolved in 5 ml of acel:onitrile, whereupon 1.1945 g (5.25 mmoles) of 2-(2',2'-di-chloro-ethenyl)-3,3-dimethyl cyclopropane carboxylic acid chloride were added at room temperature while stirring vigor-ously. The reaction~mixture was stirred for 15 hours at roorm ~empcrature and then further processed as in Example 1. 1.7136 g (93.1 ~ of the theoretical yield) o~ analytically pure 2-[2'-(2,2-dichloro-ethellyl)-3',3'-dimethyl]-cycloproparle-carboxamido-3-phenyl propenoic methyl ester were obtained.
~C02C1~3 C=C 11 11 C61~5 \NII-C~CII=CC12 ~:l8lll9cl2No3(368~26) ~C ~l %N %Cl comput:ed: 58.71 5.20 3.8019.25 obtain~d: 58.61 5.12 3.8419.27 melting point: 127 to 128C
Il-NMI~ ( CI)Cl 3 ~:
~= 7,65 - 7,15 (m, Sll) aromabC-C~l=; lR ~NII = 3270 e~
6,35 (d, 111) -Cll=CC12;~CO = 1720 cm , 3,85 (s, 311) OC113;1635 em 1.
1,25 (s, 3H) 1,23 pum (s, 311~ ~
1~3 ~113 ~ t7'7988 I~'xan~)le 3 fi 27.3 mg (O.l mmole) of sodi.um ~er~henate al1d 1.57 g (10 mrnoles) o:E 2-azido-3-methyl-butanoic methyl estex we~e put i l~tO a reactor with 5 ml of acetic ethyl ester at 80C, where-UpOIl ~ g (10.5 mmoles) of chloro acetyl chloride, dissolved in 5 Inl of acetic ethyl ester, were added dropwise within 20 m.inu~es while stirring vigorously. 'rhe reaction mi.xture was then ]ce1~t at 80C for 3 hours while stirring vigorously ar1d then further processed as in Example l.
l.97 g (95.8~ of the theoretical yield) of analyti-cally ~Jure 2-chl.oro-methyl-carboxamido-3-methyl-2-butenoic metllyl esl~e~ we~e obtained.
3\C C/ 2 3 C133/ NH-Ii_CH2C
C~ 2ClN03 (205,641) ZO %C %~1 %~ %Cl com)uted: 46.73 5.88 6.81 17.24 obtained: 46.76 S.79 6.75 l7.34 mell:.ing pOillt: 106C
IJ-NMI~ ( CDCl ~
cS = 7,83 (s, 111) N13; I~ `rN}1 = 3275 cm 4,17 (s, 211) C132Cl; ~CO = 1719 cm, 3,8 (s, 311) OC113; 1660 cm 2,22 (d, 313) 113C~_ ;
`N
1,89 ~pln ~s, 311)~113c~ `N.
-- 4* --7'7'~
I'.XCIIII~ 37 13~ g (~.5 mmole) of am~loni,um perrhe~ e, ~.s5 g (49.9 nlmol(-~s) (~ a%:i~lo-3-mel~ y] butarl~ic e~:tlyl es~,er, 4.6 g (52.8 Mmoles) of butanoic ethyl esteI, 416 g (52.8 ~moles) of diemthyl acetam:ide and 5~ Illg ~ O . 45 mmoles~ of hydroquinone were put into a react:oi- with 50 ml of acetonitrile, whereupon 5.95 g (52.6 Mmoles) of chloro acetyl chloride were added at rool~ ter,peratue while stir ing vigorously. The mixture reacted exothermically witllin 15 minutes.
The further treatment was analogous to that of Example 3.
9.35 g (85.3% of the theoretical yie]d) of analyti-cally pure 2-chloro-Methyl-carboxamido-3-methyl-2-butenoic ethyl ester were obtained.
C113 q ' ~c=c-c-oc~l2cl~3 Cll ~IN-C-CI~ 2C 1 Cglll~NO3Cl(219~67) %C%1l ~N %Cl computed: 49.21 6.42 6.38 16.14 obl:ained: 49.11 6.52 6.31 16.29 melting pOillt: 117CC
lI-NMIi(CDC13 /TMS ):
~= 7,7 (s kroad, lH) N)l;
4,15 (q, 211) COOCI12-;
4,1 (s, Zll) -C112Cl;
2,2 Is, 3Ji) Cl~3-C=;
1,~5 (s, 311) C113-C=;
1,25 U~ (t, 311) COOCII2CI13.
1,~77988 ~ rll~l~ 3~
____ _ ._ 134 Ing (O.S mmole) of ammollium perrhenate, ~.55 g (4~.'3 Inl;loles) of 2-a~ido-3-methyl hulanoic etllyl ester, 3.~5 g (52.6 r,lrlloles) of dimethyl formamide and 50 mg (0.45 mlnoles) of hydroquinol-le we~e E)ut into a reactor with 50 ml of acetonitrile, whereu~on 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at ~oorn temperature. The mixture reacted exothermically witll:irl 40 minutes. ,It was further processed as in Example 3.
9.8 g (77.3~ of ~he theoretical yield) of analyti-cally pul-e 2-dichloro-methyl-carhoxamido-3-methyl-2-butenoic ethyl est:er were obtained.
Cl3 O
3\ \ 11 ~C= IC-C-OC112C113 C113 llN-l CEIC 2 13 3 2~ 54,11) ~C ~l-l %N ~Cl col~lputed: 42.54 5.16 5.51 27.90 ohtailled: 42.20 5.19 5.44 27.58 meltirlg point: 145C
1ll-N~]I~ (CDC13/'l'MS) ~= 7~8 (s broad, 111) Nll;
S,95 (s, 1l~) CIIC12;
4,2 (q, 211) COOC~l2;
2,25 (s, 3~ ) C113-C=;
1,9 (s, 311) C113-C=;
1~25 ppm (t, 3~1) COOC1l2Cll3.
- 4~ -as ~a~ple 3~
_ __.__ :l34 ~g (0.5 mmole) of amlnorlium perrhellat~, 8.55 g (49.'~ lnoles) of 2-azi,do-3-methyl-butarloic ethyl e~ter, 3.85 g (52.6 mmoles) of dlmethyl formamide and 50 mg ~0.45 mmoles) of hydroquinone were put into a reactor with 50 ml of acetonitrile, whereuE>on 6.45 g (52.4 mmoles) of acetyl bromide were added at xoom terll~erature while stirring vigorously. The reaction mi,xture was stirred,for 3 hours while'a maximal reaction tem-perature of 35C was reached. The reaction mixture was further processed as in Example 3.
4.8 g (51.9~ of the theoretical yield) of analyti, cally ~ure N-acetyl-2,3-dehydro-valine ethyl ester were obl:ainecl.
!
C~13 1l ~ C=~-C-OC~12C~13 C~l3 1IN-IC-C~13 ~9lll5NO3(l~5~22) ,' 20 %C ~H %N
comput:ed: 58.36 8.16 7.56 obt,ained, 57.71 7.88 7.52 melting point: 77C
NMI~ (CDC13/TMS):
~= 7,9 (s broad, lH) NH;
4,15 (q, 211) -COOC132-;
2,1 ~s, 311) COC~13;
2,05 (s, 3~1) C~13-C=;
1~ (s, 311)~C113-C=;
1,2 pplll (t, 3~1) -COOC112-C~13.
7~7<~8 l~Xc~ f.~ 40 _. _ _ __ 134 In~] (0.5 mmole) of amlllo~ m perrhenate, ~.55 g (49.9 mmoles) of 2-azido-3-me-thyl-hutanoic ethyl ester, 3.85 g (r,2.6 nl~lo:Les) of dimethyl formamide and 50 mg (0.45 mmole) of hydro(lu:inolle were put illtO a reac-tor with 50 ml with acetoni-tri]e, whereupon 5.7 g (52.5 mmoles) of methoxy acetic acid chloxjde ~ere added a~ room tem~era-tu.re while stirri.rl~ vigorox-ously. 'rhe reacti.on mixture was stirred for 70 hours at room temperatul-e an~ then further processed as in ~.xample 3. The crude u~oduce thus obtained was distilled in vacuo (0.4 mbar).
6.0 g (55.8% of the theoretical yield) of analy-~ically pure N-methoxy-acetyl-2,3-dehydro-valine ethyl ester were vb~a:illcd .
C1~3~ ~C
C=C - -OCH 2CH 3 CH 3 IIN - ICl -CH 2OCH 3 - 20 C101117N4 ( 215 ~ 25 ) %C ~H ~N
compute~: 55.80 7.96 6.51 obtailled: 55.87 8.60 6.64 meltin~ point: 112 to 114C
1 Il-N~ ( CDCl 3/l'MS ):
J = 7,65 (s broad~ 111) NH;
4, 2 ( q, 211 ) -COOC112-;
3,95 (s, 211) C0-C~12-0;
3,45 (s, 311) -OC~13;
2,15 (s, 311) Cll3~C=;
1,~5 ~s, 311) C113~C=;
1, 25 ppm ( t, 311 ) -COOC112-C113 .
-- 4~ --7~7988 Example 41 __ __ 134 mg (0.5 mmole) o ammonium perrhellate, 8.55 g (4~.9 l~moles) of 2-azido-3-methyl-butalloic methyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmole) of hydroc~ui.none were put into a reac-tor with 50 ml of acetonitrile, whereupoll 6.35 g (52.6 mmoles) of 3-methyl-butanoic acid chlori.de wexe added at room temperature while stirri.ng vigor-ously. ~rhe reaction mixture was stirred for 9 hours at room temperature and then furthex processed as in Example 3.
6.5 g (57.3~ of the theoretical yield) of analytically pUI e 2-[2'-methyl-propyl)-carbonyl-amillo]-3-methyl-2-butenoic ehl:yl ester were obtained.
Cll3 O
~C=j-C-oc~l2clJ3 3 ,CI~
IIN-~C-CII2CII 3 C~13 12 21N3(227,30) ~C ~H ~N
computed: 63.41 9.31 6.16 obta.ined: 64.00 10.18 6.25 melt:ing pOillt: 123 to 125C
; 30 ~ 77 NI`11~ (CDC13/1MS) = G,8 (s broad, 111) NH;
4,2 (q, 211) -C00C112-;
1,7 - 2~4 (m, 311) C0C!12-C13;
2,2 (s, 311) C113-C=;
1,9 (s, 3}1) C113-C=;
1,3 (t, 311) C113-C~I2;
1, 05 ppm ( d, 611) -C_ccl33.
r.xam~le 42 134 mg (0.5 mmole) of ammonium perrhellai:e, 8.55 g (49.9 mliloles) of 2-a~ido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 I,lmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro~luillorle were put into a reactor with 50 rml of acetoni.trile, whe1eupon 7.4 g (5~.5 mmoles) of 4-chloro-blltanoic acid chloride were added at room temperatur-e while stirri.ng vigorously. The reacti.otl mixture was sitrred fo~ 10 hours at roorn temperature ancl then furthe processe~ as in rJxample 3.
~.4 g (67.9% of the theoretical yield) of analyti-ca].].y pure 2-[(3'-chloro-pr.opyl)-carbonyl-amino]-3-1llethyl-2-bulerloi.c e-thyl es1:er were obtained.
C113~ 0 C=;C-c_0cH CH
113 I~N -BC- CHzcll2cl~ Cl N3 C 1 ( 2 4 7 ~ 7 --5C)--~,7t7~S~
%C %1-1 ~N %CI
c(~r,~l-ul~ 53. 33 7 . 32 5. 65 14 . 31 o~ 5 3 . 3 6 7 . 6 4S . ~ 7 1 4 . 5 0 m~ g l-oin~ 0C
N~lII (CDC13/TI`IS):
= 7,1 (s broad~ ) Nll;
4,15 (q, 211) -COOCH2-;
3,6 (t, 2~1) -C~12Cl;
1,75 - 2,7 (1ll, 413) -COC132C132-;
2,15 (s, 311) C113-C=;
1,~5 (s, 3~1) C113-C=;
1,25 pL)m (t, 3f3) -COOC132-C113.
I~,xampJ e 4 3 134 ~Ig (O.S mmole) of aMmonium perrhenate, 8.55 g (49.9 nlmoles) of 2-azido-3-methyl-bu'canoic ethyl ester and 3.85 g (52.6 mmoles) of dimethyl formamide were ~issc-lved in 50 ml of acetic ethyl estex, whereuporl 9.2 g (52.5 mmoles) of 2-chloro-20 benzyol chlor:ide were added at room tempexature while stirringvigorously. The reaction mixture was stirred for 14 houxs at XOOIII temperature and then further processed as in Example 16.
7.1 g (50.5% of the theoretical yield) of analtyi-cally pure 2-[(2'-chloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
CIJ3 o ,, 3~=C-C-OC112C113 CI ~
Cl 14 16 3 ~281,74) 7~7~8~
%C ~1l %N %Cl computed: 59.68 5.72 4.97 12.58 obtained: 58.72 5.96 4.91 11.64 melting point: 86 to 89C
ll-N~I~ (CDCl 3/T~15 J:
~= 7~0 - 7,9 ~ , 5H) NH aromatic-CH;
4,2 (q, 213) COOC112;
2,2 (s, 311) CH3-C=;
1,95 (s, 3H) CH3-C=;
1125 ppJIl (t, 3H) COOC112CH3. -E,xample 44 -134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-bu-tanoic e-thyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone weLe added at room temperature while stirring vigorously. Tile reaction mixture was stirred for 14 hours at room temperature and then further processed as in F.xample 16.
10.2 g (72.5% the theoretical yield) of analytically pure 2-[(3'-chloro-phenyl)carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
CH3 ~ ~o C=C-C-OCH Cll ~IN - iC~ ~
Cl 14 lG 03cl(28l~74) 77~
~C %EI ~N %Cl computetl: 59.68 5.72 4.97 12.58 obtained: 59.52 5.78 4.89 12.32.
Illeltirlg pOillt: 120 to 122C
-N~ CDC 13/1~MS) = 7,0 - 8,1 ~m, 511) Nll; arom~tic-CH-4~15 ~q, 2H) coocl~2;
2,15 (s, 311) C113-C=;
1,~5 ~s, 31i) C113-C=;
,2~ ppm ~t, 3ll) COOCI12CII3.
E~xampl 4_ 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetic ethyl ester, whereu~on 9.2 g (52.5 mmoles) of 4-chloro-benzoyl chloride were added at room teml~erature while stirring vigorously. The reac-tion mixture was stirred for 14 hours at room temperature. The ~recipitated crude product was filtered with suction and washed unitl free from chloride.
11.1 g (78.9~ of the theoretical yield) of analyti-cally pure 2-[(4'-chloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
Cll3 O
,~ ,C=C-~'-OC~12C113 C 3 ¦ ~ Cl O
191116N3Ci(281,74) - 1~7~988 %C %H ~N ~Cl computed: 59.68 5.72 4.97 12.58 obtairled: 58.97 5.55 4.09 14.08 melting point: 124 to 124.5C
ll-N~ (C~C13/l'MS):
~= 7,1 - 8,25 (m, 511) N13; aroln~tic-CH;
4,2 (q, 2l1) ~OOCI~2;
2~2 (s, 313) Cl13-C=;
1,9 (s, 311) C~33-C=;
1,25 ~plll (t, 311) COOC1l2C1l3.
Exalllple 46 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinorle were dissolved in 50 ml of acetic ethyl ester, whereuporl 8.35 g (52.6 mmoles) of 2-fluoro-benzoyl chloride were added at room temperaturé while stirring vigorously. The reaction mixture was stirred for 14 hours at room temperature and then further processed as in Example 16.
9.0 g (68~ of the theoretical yield) of analytically pure 2-[(2'-fluoro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
CH3 o ~C=C-C-OCH CH
IIN-C~'~
o F
(~1411lGNo3F(265~285) ,7~a %C %H %N
com~uted: 63.38 6.08 5.28 obtaine(l: 63.06 6.04 5.23 melting point: 82.5C
ll-N~ (CDC13/TMS):
~ = 6~5 - 7,65 tlll, 511) Nl~; a~omatic-CH;
4,2 ~q, 21~) -COOC132-;
2~25 ~s, 311) C133-C=;
lt9 (S, 31~) C1~3-C=;
1~35 ppm (t, 31i) -COOC112C1~3.
I ample 47 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmole) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g ~52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquirlone were dissolved in 50 ml of acetonitrile, whereupon 8.35 g (52.6 mmoles) of 4-fluoro-benzoyl chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred at room temperature for 14 hours and then further processed as in Example 3.
9.3 g (70.2~ of the theoretical yield) of analytically pure 2-[(4'-fluoro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
C~i3 ~ o C=C-C-OCIl Cll HN-ICl ~ F
Cl4lll6No3Ft265~28s) ~ ~77~
Q~iC 2iH %N
compuled: 63.38 6.08 5.28 obtained: 62.94 6.15 5.11 melting point: 130 to 132C.
Nl`lR (cDcl3/TMs): H
~= 7~6 - 8,2 (m, 311) NH;~
6,7 - 7,3 (m, 211) C~
4~2 (q, 211) -COOC~2-:
2,15 (s, 311) C~13-C=;
1,85 (s, 311) -C~13-C=;
1,25 ppm ~t, 3~3) ~cOocll2-c~l3.
Example 48 134 mg (0.5 mmole) of a~mnonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 11.0 g (52.5 mmoles) of 2,4-dichloro-benzyl chloride were added at roorn temperature while stirring vigorously. The reaction mixture was stirred at room temperature for 14 hours and then further processed as in Exarnple 3.
9.3 g (58.996 of the theoretical yield) of analytically pure 2-~(2',4'-dichloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
Cil O
3\~'=C-~'-OCI~ Cll C141115N02C12(316,18) ........ . . . ..
.: . .. .: .
7~7~388 ~c ~H ~,N ~Cl comE)ute~: 53.18 4.78 4.43 22.43 obta~ cd: 52.22 4.80 4.41 20.73 melting point: 128.5 to 130C
N~ (cDCl3/l'Ms):
= 7,1 - 7,7 (m, 411) NH; aromatic-CH;
4,2 (q, 2fl) -COOCH2-;
2,2 (s, 311) C113-C=;
1,95 (s, 311) Cli3-C=;
1,3 p~lll (t, 31~ COOCII2-C~33.
l~xample 4_ 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 11.0 g (52.5 mmoles) of 3,4-dichloro-berlzyl chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 15 hours at room temperature and the further processed as in Examule 3.
10.5 g (6.5% of the theroetlcal yield) of analytically pure 2-[3',4'-dichloro-phenyl)-carbonyl-amirlo]-3-methyl-2-butenoic ethyl ester were obtained.
C~13 ~ 1l ~C=C-C-OC132C1~3 ~ C ~ Cl C141115N03C12(316~18) ~ ~7988 %c ~H ~N %Cl computed: 53.18 4.78 4.43 22.43 obtained: 53.40 4.86 4.36 22.11 melting point: 115 to 120C
~ ' Il-N;I~ (CDC13/TMS):
2 ~ 8,2 (m;, 4~3) Nll; aromatic-CH;
~,2 (q, 211) - COOC112-;
2,15 (s, 3~1) Cf33-C=;
1~9 (s, 313) C113-C=;
1~25 ppm (t, 311) -COOC112C}13.
~xanlple 50 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g ~49.9 mMole~) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mllloles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinorle were put into a reac~or with 50 ml of acetonitrile, whereupon 11.0 g ~52.5 mmoles) of 3.5-dichloro-benzoyl chloride wexe added at room ternperature while stirring vigorously. The reactiorl mixture was stirred for 15 hours at room temperature.
The precipi.tated crude product was fi.ltered with suction and wa~hed w.ith water until free from chloride.
12.3 g (77.9% oP the theoretical yield) of 2-[(3', 5'-dichloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
_ ., 3 ~ C C U-OCfl Cf3 3 3 ill-C
Cl4lll5No3cl2(3l6~l8) %C %H %N ~Cl computed: 53.18 4.78 4.43 22.43 obtailled: 50.44 4.88 3.91 21.12 melting point: 171C
ll-N~1~ (CDC13/TMS):
~= 7,15 - 7,85 (m, 411) Nll; aromati.c-CH;
4,2 (q, 211) - COOC1~2-:
2,2 (s, 311) C113-C=;
1,9 ~s, 311) C113-C=;
1,25 ppm ~t, 311) -COOC112-C113.
Example 51 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49 9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 9 (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroqui.none were put into a reactor with 50 ml of acetonitrile, whereupoll 12.6 g (52.6 mmoles) of 2,6-dichloro-phenoxy acetyl chloride were added at room temperature while stirring vigor-ously. The reaction mixture was stirred for 14 hours at room temperature. The precipitated crude product was filtered with SUCtiOtl and washed with water until free from chloride. 14.4 g (87.4~ of the theoretical yield) of analytically pure 2-. [(2',6'-dichloro-phenoxy)-acetyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
3 ~ ~
Cll ~ C l-C-c~J2c~l3 IIN-C-CII -O ~ Cl ~ Cl C15lll7NO3cl2(3~o~2lJ
779~8 %c %H %N %Cl comput:ed: 54.56 5.19 4.24 21.47 obtained: 50.24 5.12 4.12 20.30 melting point: 124 to 125C
ll-NI~ CL)C13/'l'MS):
Ct = 7,95 (s broad~ 1ll) NH;
6,65 - 7,5 (m~ 211) aromat'~-n Cll;
4,6 (s, 211) COCII2-O-;
4,2 ~q, 2119 COOC112;
2,2 (s, 311) C~12-C=;
1,9 (s, 311) CH3-C=;
1,25 pplll (t, 3ll) COOCII2C~13.
13xample 52 134 mg (O.S mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hdyroquinone were put into a react:or with 50 ml of acetonitrile, whereupon 11.3 g (52.5 mmoles) of 4.5-dichloro-thiophene-2-carboxylic acid chloride were added at room temperature. The reaction mixture was stirred at room temperature for 15 hours while a maximal exothermical reaction temperature of 45C was attained. The reaction mixture was then further treated as in Example 3.
11.6 g (72.196 of the theoretical yield) of analyti-cally pure 2-[2'-(4,5-dichloro-thienyl-carbonyl-amino]-3-methyl-butenoic ethyl ester were obtained.
. .
~'~77988 Cll o = ~ -C-oC112C1l3 13N-C ~ 1 O
12 12 3 2 (32Z,21) ~C ~H %N ~S ~Cl computed: 44.74 4.07 4.35 9.49 22.00 10 obtained: 43.16 4.20 3.60 9.49 21.65 melting pOillt: 9S to 98C
ll-N~IJ~ (CDC13/~MS) ~= 8,45 (s, 1ll) N~]
7,55 (s, 1l~) ll ~ Cl 4,2 (q, 211) -COOCH2-;
2,15 (s, 3~3) Cli3-C=;
1,9 (s, 311) Cl33-C=;
20 l,3 pplll (t, 31~) -COOCll2-Cl~3.
~xample 53 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g ~49.9 mmoles ) of 2~-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (G.45 mmoles) of hydroquinone were put illtO a reactor with 50 ml of acetoni-trile, whereupon 7.1 g (52.7 mmoles) of 2,2-dimethyl butanoic acld chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 35 hours at room temperature and theA further processed as in Example 3. In order to purify the crude product, it was distilled in vacuo (U.53 mbar) at llO to 150C in the bulb tube. The oil thus obtained was crystallized w:ith n-pentane.
8.8 g (73.1% of the theoretical yield) of analytically pure 2-[(l',l'-dimethyl propyl)-carbonyl-amino]-3-methyl-2-butenoic methyl ester were obtained.
C113 ~ 0 ~C=C-C-OC}1 CH
CI33 l ICl33 IIN-~C~ - I -C112C~33 o c~l3 12II23N3~291~33) ~C ~H %N
computed: 64.70 9.61 5.80 obtained; 64.8l 9.89 5.67 melting point: lO0 to 105C
1H-NMI~ ~CDC13/T~Is):
~= 6,85 (s hroa~ 111) Nll;
9,15 (q, lfl) -COOCII2:
2,15 (s, 311) Cl33-C=;
1,~ (s, 31I) Cl~3-C=;
0,65 - 1,85 ppIl~ (m, 1411) C-(CH3-C1~2C133; 0-C112CII3.
Example 54 13.7 mg (0.05 rnmole) of sodium perrhenate, 926 mg (5 mmoles) of 2-azido-3-methyl-butnaoic isopropyl ester and 383.8 mg (525 nm~oles) of dimethyl formamide were dissolved in 2.5 ml of acetonitrile, whereup~n 529 mg (5.25 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigor-779f~
ously. The reaction mixture was stirred for 7 hours at room tempera~ure and then further pl:ocessed as in Example 1.
1.0657 g (81.2% of the theoreti.cal yield) of analyti-cally pure 2-chloro-methyl-carboxamido-3-methyl-2-butenoic iso-propyl ester were obtained.
Cl13 ~ / CO2C~I~C113)2 ~ C=C~
C~13 N~
C'1UlllGC'1N03(233,695) %C %H %N %Cl computed: 51.40 6.90 5.99 15.17 obtained: 51.41 6.97 5.77 15.16 melting point: 126C
IIJ-NI~ CDC13):
1~' = 7,9 (s, 111) Nll; I~ ~NII = 3265 Clll 5,13 ( septet , 111 ) O-CII (C113)2 ~tco 17 ~,15 ~S, 211) C112Cl: 1663 clll 1.
2,2 (s, 31l) 1 3C-C=C~N:
(S~ 311~lll3c~ N
1,2g ppm (d, 611)-CH~C113)2.
Example 55 13.7 mg (0.05 nmloles) of sodium perrhenate, 1.17 g (5 mmoles) of 2-azido-3-methyl-butanoic benzyl ester and 383.8 mg (5.25 mrnoles) of dimeth~l formamide were dissolved in 1.5 ml of acetonitrile, whereupon 592.9 mg (5.25 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigo~-ously. '1'he reactio11 mixtu~e was stirred for 15 hours at room temp~rature and then further processed as in Example l.
l.32 g (97.7 % of the theoretical yield) of analy-tically pure 2-chloro-methyl-carboxamido-3-methyl-2-butneoic benzyl ester were obtained.
C~13 ~ ~ CO2Cl12 C6~15 ~C=C
C133~ N~ ~
O- Cll=f-C-OCII '3 HN- lC~ -C112C
O
13~l2oNo3cl~273~76) ~C %H %N %Cl com~uted: 57.04 7.36 5.12 12.95 obtained: 57.04 7.71 5.15 13.01 ~:: melting point: 72C
tl-NMn '(CDC13/~'MS):
= 7,75 ~s broad, 111) NH;
' 6,65 (d, 111) -CH=;
4,7 - 5,35 (m, 111) COOCH;
: 4.15 (s, 211) -CH2Cl; -C
2.25 - 3.0 (s.breit, lH) c`CII;
- 2,15 (m, 811)11t_t~H
1~
1,30 ppm (b, 6tl) COOC'cl'l3.
7'7988 xam~le_29 134 mg (0.5 mmole) of ammonium perrhenate, 11.25 g (49.9 mmoles) of 2-azido-3-cyclopentyl propionic iso~ropyl ester, 3.85 g (52.g mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupoll 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at room temperature while stirring vigor-ously. The mixture!reacted exo~hermically within 45 minutes.
The mixture was further processed as in Example 3.
8.7 g (56.6~ of the theoretical yield) of analyti-cally l~ure 2-dichloro-methyl carboxatnido-3-cyclopentyl-propenoic isopropyl ester were obtained.
O- CH=T-C--C"
HN-~-cllcl ?
: o C131ll9NO3C12(308,205) %C %H %N ~Cl comput.ed: 50.66 6.21 4.54 23.00 s obtai.ned: 50.82 6.26 4.63 22.79 melting point: 99C
, 1 Il-N~ (CDC13/l'~lS):
.
J= 7,85 (s brad , lH) Nll;
6~75 (d, lH) -Cll=;
6.05 (s, 1l~) CIIC12;
4,7 - 5,4 ~m, lH) COOCII;
2,25 - 2~95 (s breit; 1ll) cC`CH;
2~2 (n~, 8l~)~H ~ 1l;
1,35 ppm (d, 6H) COOC~cll3.
, :: ::
.
~ ~7~7988 Lxa~ le 30 134 mg (0.5 mmole) of ammoni.um perrhella~e, 10.55 g (50 mmoles) of 2-azido-3-cyclohexyl-propionic me-thyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmole) of hydroclulnone were dissolved in 50 ml of acetic-n-pxopyl ester, whereupon 5.93 g (52.5 mmoles) of chlo~o acetyl chloride were added at room temperature while stirring vigorously. After one hour ~he reactio~ miY~ture was maximally exothermical and was then further processed as in Example 16.
10 10.3 g (79.3~ of the theoretical yield) of analyti-cally pure 2-chloro-methyl carboxamido-3-cyclopentyl propenoic methyl ester were obtained.
o -C-OC~3 ~N-ICI-CH2C
O
C12~N03Cl(259~73) %C %11 %N %Cl comEJuted: 55.49 6.995.39 13.65 obtained: 55.39 7.284.75 13.83 meltillg pOillt: 117 to 118C
; ' Il-NM~ (~DC13/T~ISJ:
= 7,7 (s broad,~ 1 H) N)3;
6.6 (d, lH) -CH=;
4,15 (s, 211) -CH2Cl;
3,85 (s, 311) COOCH3;
0,75 - 2,6 ppm (m, 1113) ~ .
- 3~ -7798~
I~'xaml~le 31 134 mg (0.5 mmoles) of ammollium perrhellate, 10.55 g (50 mmoles) of 2-azido-3-cyclohexyl propionic methyl ester, 3.85 g (52.6 rnmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro(luinone were dissolved in 50 ml of acetonitrile, whereupon 7.75 g (52.5 mmoles) of dichloro acetyl chloride wer~ added at room -cemperature while stirring vigorously. The reaction mixture was stirred!for 16 hours at ~oom temperature and was then further processed as in Example 16.
11.7 g ( 79.5% of the theore-tical yield) of analyti-cally pure 2-dichloro-methyl-carboxamido-3-cyclohexyl propenoic methyl ester were obtained.
o acll=~c-c_Oc~l3 ~IN-C-CIIC 1 12l3l7No3cl2~294ll8J
%C ~H %N %Cl computed: 48.99 5.82 4.76 24.10 obtalrled: 48.95 5.91 4.70 24.06 melting point: 98C
1ll-N~ (CDC13/T~S):
= 7,65 (s bL~ad~ 111) N13;
6,65 (d, 111) -Cll=;
5,95 (s, 111) -C}12Cl;
3,8 (s, 311) COOC113;
1,9 - 2,65 (s breit, 111)C`C-H;
0"7 - 2rQ pplll ~m, 1013)~3337~11 .
'79~8 _Y~ mple 32 13.7 mg (0.05 mMole) of sodium perrhenate, 715.7 my (S
mmoles) of 2-azido-hutanoic rnethyl ester and 383.8 Ing (5.25 mmoles) of dimethyl formamide were dissolved in 5 ml of acetoIIitrile, whereupon 1.195 g (5.25 mmoles) of 2-(2',2'-dichloro-etheIlyl)-3,3-dimethyl-cyclopxopane carboxylic acid chloride were added at room temperature while stirring vigor-ously. The reaction mix-ture was stir~ed for 30 hours at room temperat:ure, whereupon it was further treated as in Example l.
1.31 g (85.6~6 of the theoretical yield) of analyti-cally pure 2-[2'-(2,2-dichloro-ethenyl)-3',3'-dimettlyl]-cyclo-p~oL)a~ -carboxamido-2-hexelloic methyl ester were obtained.
H /CO2CfI3 113C NII-ICl ~CII=CC12 I~3C CIJ3 C13II17C12NO3~306,189) %C %H 96~1 %Cl compuled: 51.00 5.60 4.57 23.16 obtained: 50.79 5.66 4.29 23.11 meltiIly point: 109 to 109.5C
Il - NMII (CDC13) ~= 7,32 (s, lII) Nll; IR ~rNII = 3320 cm, 6,8 (q, lII) li-C(CII3)=; ~rcO = 1720 cm, 6,42 (d, lII) II-C=CCL2; 1658 cm 3,77 (s, 311) OC113;
1,76 (~3, 3II)IJ3C-C~I=;
1,28 (s, 311) ~ \\7 1,25 ppln (5~ 3~)J~t3c~cIl3 ~'~77~
I`xa~ )le 33 _ _ _ _ _ _ 13.7 mg (0.05 nImole) of so~i.um perrhenate, 856 mg (5 mI;loles) of 2-azido-hexanoic methyl ester and 383.8 I~Iy (5.25 mmoles) of ~i.methyl formamide were dissolved in O.S ~ll of acei-oIli.tri]e whereupon 1.1945 g (5.25 mmoles) of 2-(2'-2'-dichl.oro-ethenyl)-3~3'-dimethyl-cyclopropane carboxylic acid chloride we.re added at room 'ernpe-rature whi.le sti.rring vigor-ously, The reaction mixture was kept for 15 hours at room ternL~erature and then further treated as in Example 1.
1.40 g (83.8% of the theoretical yield) of analyti-cally pure 2-[2'-(2,2-dichloxo-ethenyl)--3'-3'-dimethyl]-cycloproparle-carbox~mido-2-hexelloic methyl ester were ob-tained.
Il ~ C02C113 C=C 11 1]
CII3CI12C1l2 NII-C ~ ~ CI3=CC12 O ~'~
~13C Cil3.
lslJ2lcl2No3~334~243) %C %~I %N %Cl comL~uted: 53.90 6.33 4.19 21.21 obtained: 53.62 6.51 3.98 2~.. 44 melt~ g L~oint: 105 to 106C
I3-N~ CDC13) = 6,97 (s, 113) NII; IR ~NI3 = 3300 cm G,73 (t, 113) -CII2-CII=; ~CO = 1715 cm 1, 6,43 (d, lII) I3-C=CC12; 1655 cm 3~8 (s, 3II) OCII3;
2 38 - 0,77 (m, 9I3) CII3CII2CI32;
1~3 (s, 311) 1~27 ppn~ (s~ 3II)J ~13C/~C~33 l~7~7~8~
I:xaml~le 34 13.7 Ing (0.05 mmole) of sodium perrhenate, 1.0261 y (S
n:moles) of 2-azido-3--phellyl propanoic rnethyl ester and 383.8 mg (5.25 mnloles) of di.nlethyl formamide were dissolved in 5 ml of acel:onitrile, ~hereupon 592.9 rng (5.25 mmoles) oE chloro acetyl chlorLdewere added while stirring vigorously. The reactiorl mixture was stirred for 7 hours at room temperature and then fur:ther processed as in rxarnple 1.
1.1657 g (91.9% of -the theoretical yield) of analyti-cally I~ure 2-chloro-methyl carboxamido-3-phenyl propenoic methyl esle~ ~/ere obtained.
6115~ N~l_C_ ~C=C
Il 2CH3 No3(253~6g5) ~C %H ~N %Cl compu~ed: 56.82 4 77 5.52 13.98 obtai.ncd: 56.90 4.83 5.38 13.93 mel~:ing point: 113.5 to 114C
-N~ (C~C13) (m, 511) aromat~C -Cll Nll ~ 3235 cm 4,09 (s, 2H) Cll2Cl; CO 1617 cm 1 3,~2 ~plll (s, 311) Cll3.
- 4~ -77~
k'xample~ 35 _ _ _ _ 13.7 mg (().05 mmole) of sodium perrhenat~, 1.()261 mg (S mllloles) ol 2-azjdo-3-pherlyl pro~anoic rme~h~l estel- and 383.8 ng (5.25 mrnoles) of dimethyl formamide were dissolved in 5 ml of acel:onitrile, whereupon 1.1945 g (5.25 mmoles) of 2-(2',2'-di-chloro-ethenyl)-3,3-dimethyl cyclopropane carboxylic acid chloride were added at room temperature while stirring vigor-ously. The reaction~mixture was stirred for 15 hours at roorm ~empcrature and then further processed as in Example 1. 1.7136 g (93.1 ~ of the theoretical yield) o~ analytically pure 2-[2'-(2,2-dichloro-ethellyl)-3',3'-dimethyl]-cycloproparle-carboxamido-3-phenyl propenoic methyl ester were obtained.
~C02C1~3 C=C 11 11 C61~5 \NII-C~CII=CC12 ~:l8lll9cl2No3(368~26) ~C ~l %N %Cl comput:ed: 58.71 5.20 3.8019.25 obtain~d: 58.61 5.12 3.8419.27 melting point: 127 to 128C
Il-NMI~ ( CI)Cl 3 ~:
~= 7,65 - 7,15 (m, Sll) aromabC-C~l=; lR ~NII = 3270 e~
6,35 (d, 111) -Cll=CC12;~CO = 1720 cm , 3,85 (s, 311) OC113;1635 em 1.
1,25 (s, 3H) 1,23 pum (s, 311~ ~
1~3 ~113 ~ t7'7988 I~'xan~)le 3 fi 27.3 mg (O.l mmole) of sodi.um ~er~henate al1d 1.57 g (10 mrnoles) o:E 2-azido-3-methyl-butanoic methyl estex we~e put i l~tO a reactor with 5 ml of acetic ethyl ester at 80C, where-UpOIl ~ g (10.5 mmoles) of chloro acetyl chloride, dissolved in 5 Inl of acetic ethyl ester, were added dropwise within 20 m.inu~es while stirring vigorously. 'rhe reaction mi.xture was then ]ce1~t at 80C for 3 hours while stirring vigorously ar1d then further processed as in Example l.
l.97 g (95.8~ of the theoretical yield) of analyti-cally ~Jure 2-chl.oro-methyl-carboxamido-3-methyl-2-butenoic metllyl esl~e~ we~e obtained.
3\C C/ 2 3 C133/ NH-Ii_CH2C
C~ 2ClN03 (205,641) ZO %C %~1 %~ %Cl com)uted: 46.73 5.88 6.81 17.24 obtained: 46.76 S.79 6.75 l7.34 mell:.ing pOillt: 106C
IJ-NMI~ ( CDCl ~
cS = 7,83 (s, 111) N13; I~ `rN}1 = 3275 cm 4,17 (s, 211) C132Cl; ~CO = 1719 cm, 3,8 (s, 311) OC113; 1660 cm 2,22 (d, 313) 113C~_ ;
`N
1,89 ~pln ~s, 311)~113c~ `N.
-- 4* --7'7'~
I'.XCIIII~ 37 13~ g (~.5 mmole) of am~loni,um perrhe~ e, ~.s5 g (49.9 nlmol(-~s) (~ a%:i~lo-3-mel~ y] butarl~ic e~:tlyl es~,er, 4.6 g (52.8 Mmoles) of butanoic ethyl esteI, 416 g (52.8 ~moles) of diemthyl acetam:ide and 5~ Illg ~ O . 45 mmoles~ of hydroquinone were put into a react:oi- with 50 ml of acetonitrile, whereupon 5.95 g (52.6 Mmoles) of chloro acetyl chloride were added at rool~ ter,peratue while stir ing vigorously. The mixture reacted exothermically witllin 15 minutes.
The further treatment was analogous to that of Example 3.
9.35 g (85.3% of the theoretical yie]d) of analyti-cally pure 2-chloro-Methyl-carboxamido-3-methyl-2-butenoic ethyl ester were obtained.
C113 q ' ~c=c-c-oc~l2cl~3 Cll ~IN-C-CI~ 2C 1 Cglll~NO3Cl(219~67) %C%1l ~N %Cl computed: 49.21 6.42 6.38 16.14 obl:ained: 49.11 6.52 6.31 16.29 melting pOillt: 117CC
lI-NMIi(CDC13 /TMS ):
~= 7,7 (s kroad, lH) N)l;
4,15 (q, 211) COOCI12-;
4,1 (s, Zll) -C112Cl;
2,2 Is, 3Ji) Cl~3-C=;
1,~5 (s, 311) C113-C=;
1,25 U~ (t, 311) COOCII2CI13.
1,~77988 ~ rll~l~ 3~
____ _ ._ 134 Ing (O.S mmole) of ammollium perrhenate, ~.55 g (4~.'3 Inl;loles) of 2-a~ido-3-methyl hulanoic etllyl ester, 3.~5 g (52.6 r,lrlloles) of dimethyl formamide and 50 mg (0.45 mlnoles) of hydroquinol-le we~e E)ut into a reactor with 50 ml of acetonitrile, whereu~on 7.75 g (52.5 mmoles) of dichloro acetyl chloride were added at ~oorn temperature. The mixture reacted exothermically witll:irl 40 minutes. ,It was further processed as in Example 3.
9.8 g (77.3~ of ~he theoretical yield) of analyti-cally pul-e 2-dichloro-methyl-carhoxamido-3-methyl-2-butenoic ethyl est:er were obtained.
Cl3 O
3\ \ 11 ~C= IC-C-OC112C113 C113 llN-l CEIC 2 13 3 2~ 54,11) ~C ~l-l %N ~Cl col~lputed: 42.54 5.16 5.51 27.90 ohtailled: 42.20 5.19 5.44 27.58 meltirlg point: 145C
1ll-N~]I~ (CDC13/'l'MS) ~= 7~8 (s broad, 111) Nll;
S,95 (s, 1l~) CIIC12;
4,2 (q, 211) COOC~l2;
2,25 (s, 3~ ) C113-C=;
1,9 (s, 311) C113-C=;
1~25 ppm (t, 3~1) COOC1l2Cll3.
- 4~ -as ~a~ple 3~
_ __.__ :l34 ~g (0.5 mmole) of amlnorlium perrhellat~, 8.55 g (49.'~ lnoles) of 2-azi,do-3-methyl-butarloic ethyl e~ter, 3.85 g (52.6 mmoles) of dlmethyl formamide and 50 mg ~0.45 mmoles) of hydroquinone were put into a reactor with 50 ml of acetonitrile, whereuE>on 6.45 g (52.4 mmoles) of acetyl bromide were added at xoom terll~erature while stirring vigorously. The reaction mi,xture was stirred,for 3 hours while'a maximal reaction tem-perature of 35C was reached. The reaction mixture was further processed as in Example 3.
4.8 g (51.9~ of the theoretical yield) of analyti, cally ~ure N-acetyl-2,3-dehydro-valine ethyl ester were obl:ainecl.
!
C~13 1l ~ C=~-C-OC~12C~13 C~l3 1IN-IC-C~13 ~9lll5NO3(l~5~22) ,' 20 %C ~H %N
comput:ed: 58.36 8.16 7.56 obt,ained, 57.71 7.88 7.52 melting point: 77C
NMI~ (CDC13/TMS):
~= 7,9 (s broad, lH) NH;
4,15 (q, 211) -COOC132-;
2,1 ~s, 311) COC~13;
2,05 (s, 3~1) C~13-C=;
1~ (s, 311)~C113-C=;
1,2 pplll (t, 3~1) -COOC112-C~13.
7~7<~8 l~Xc~ f.~ 40 _. _ _ __ 134 In~] (0.5 mmole) of amlllo~ m perrhenate, ~.55 g (49.9 mmoles) of 2-azido-3-me-thyl-hutanoic ethyl ester, 3.85 g (r,2.6 nl~lo:Les) of dimethyl formamide and 50 mg (0.45 mmole) of hydro(lu:inolle were put illtO a reac-tor with 50 ml with acetoni-tri]e, whereupon 5.7 g (52.5 mmoles) of methoxy acetic acid chloxjde ~ere added a~ room tem~era-tu.re while stirri.rl~ vigorox-ously. 'rhe reacti.on mixture was stirred for 70 hours at room temperatul-e an~ then further processed as in ~.xample 3. The crude u~oduce thus obtained was distilled in vacuo (0.4 mbar).
6.0 g (55.8% of the theoretical yield) of analy-~ically pure N-methoxy-acetyl-2,3-dehydro-valine ethyl ester were vb~a:illcd .
C1~3~ ~C
C=C - -OCH 2CH 3 CH 3 IIN - ICl -CH 2OCH 3 - 20 C101117N4 ( 215 ~ 25 ) %C ~H ~N
compute~: 55.80 7.96 6.51 obtailled: 55.87 8.60 6.64 meltin~ point: 112 to 114C
1 Il-N~ ( CDCl 3/l'MS ):
J = 7,65 (s broad~ 111) NH;
4, 2 ( q, 211 ) -COOC112-;
3,95 (s, 211) C0-C~12-0;
3,45 (s, 311) -OC~13;
2,15 (s, 311) Cll3~C=;
1,~5 ~s, 311) C113~C=;
1, 25 ppm ( t, 311 ) -COOC112-C113 .
-- 4~ --7~7988 Example 41 __ __ 134 mg (0.5 mmole) o ammonium perrhellate, 8.55 g (4~.9 l~moles) of 2-azido-3-methyl-butalloic methyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmole) of hydroc~ui.none were put into a reac-tor with 50 ml of acetonitrile, whereupoll 6.35 g (52.6 mmoles) of 3-methyl-butanoic acid chlori.de wexe added at room temperature while stirri.ng vigor-ously. ~rhe reaction mixture was stirred for 9 hours at room temperature and then furthex processed as in Example 3.
6.5 g (57.3~ of the theoretical yield) of analytically pUI e 2-[2'-methyl-propyl)-carbonyl-amillo]-3-methyl-2-butenoic ehl:yl ester were obtained.
Cll3 O
~C=j-C-oc~l2clJ3 3 ,CI~
IIN-~C-CII2CII 3 C~13 12 21N3(227,30) ~C ~H ~N
computed: 63.41 9.31 6.16 obta.ined: 64.00 10.18 6.25 melt:ing pOillt: 123 to 125C
; 30 ~ 77 NI`11~ (CDC13/1MS) = G,8 (s broad, 111) NH;
4,2 (q, 211) -C00C112-;
1,7 - 2~4 (m, 311) C0C!12-C13;
2,2 (s, 311) C113-C=;
1,9 (s, 3}1) C113-C=;
1,3 (t, 311) C113-C~I2;
1, 05 ppm ( d, 611) -C_ccl33.
r.xam~le 42 134 mg (0.5 mmole) of ammonium perrhellai:e, 8.55 g (49.9 mliloles) of 2-a~ido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 I,lmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydro~luillorle were put into a reactor with 50 rml of acetoni.trile, whe1eupon 7.4 g (5~.5 mmoles) of 4-chloro-blltanoic acid chloride were added at room temperatur-e while stirri.ng vigorously. The reacti.otl mixture was sitrred fo~ 10 hours at roorn temperature ancl then furthe processe~ as in rJxample 3.
~.4 g (67.9% of the theoretical yield) of analyti-ca].].y pure 2-[(3'-chloro-pr.opyl)-carbonyl-amino]-3-1llethyl-2-bulerloi.c e-thyl es1:er were obtained.
C113~ 0 C=;C-c_0cH CH
113 I~N -BC- CHzcll2cl~ Cl N3 C 1 ( 2 4 7 ~ 7 --5C)--~,7t7~S~
%C %1-1 ~N %CI
c(~r,~l-ul~ 53. 33 7 . 32 5. 65 14 . 31 o~ 5 3 . 3 6 7 . 6 4S . ~ 7 1 4 . 5 0 m~ g l-oin~ 0C
N~lII (CDC13/TI`IS):
= 7,1 (s broad~ ) Nll;
4,15 (q, 211) -COOCH2-;
3,6 (t, 2~1) -C~12Cl;
1,75 - 2,7 (1ll, 413) -COC132C132-;
2,15 (s, 311) C113-C=;
1,~5 (s, 3~1) C113-C=;
1,25 pL)m (t, 3f3) -COOC132-C113.
I~,xampJ e 4 3 134 ~Ig (O.S mmole) of aMmonium perrhenate, 8.55 g (49.9 nlmoles) of 2-azido-3-methyl-bu'canoic ethyl ester and 3.85 g (52.6 mmoles) of dimethyl formamide were ~issc-lved in 50 ml of acetic ethyl estex, whereuporl 9.2 g (52.5 mmoles) of 2-chloro-20 benzyol chlor:ide were added at room tempexature while stirringvigorously. The reaction mixture was stirred for 14 houxs at XOOIII temperature and then further processed as in Example 16.
7.1 g (50.5% of the theoretical yield) of analtyi-cally pure 2-[(2'-chloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
CIJ3 o ,, 3~=C-C-OC112C113 CI ~
Cl 14 16 3 ~281,74) 7~7~8~
%C ~1l %N %Cl computed: 59.68 5.72 4.97 12.58 obtained: 58.72 5.96 4.91 11.64 melting point: 86 to 89C
ll-N~I~ (CDCl 3/T~15 J:
~= 7~0 - 7,9 ~ , 5H) NH aromatic-CH;
4,2 (q, 213) COOC112;
2,2 (s, 311) CH3-C=;
1,95 (s, 3H) CH3-C=;
1125 ppJIl (t, 3H) COOC112CH3. -E,xample 44 -134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-bu-tanoic e-thyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone weLe added at room temperature while stirring vigorously. Tile reaction mixture was stirred for 14 hours at room temperature and then further processed as in F.xample 16.
10.2 g (72.5% the theoretical yield) of analytically pure 2-[(3'-chloro-phenyl)carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
CH3 ~ ~o C=C-C-OCH Cll ~IN - iC~ ~
Cl 14 lG 03cl(28l~74) 77~
~C %EI ~N %Cl computetl: 59.68 5.72 4.97 12.58 obtained: 59.52 5.78 4.89 12.32.
Illeltirlg pOillt: 120 to 122C
-N~ CDC 13/1~MS) = 7,0 - 8,1 ~m, 511) Nll; arom~tic-CH-4~15 ~q, 2H) coocl~2;
2,15 (s, 311) C113-C=;
1,~5 ~s, 31i) C113-C=;
,2~ ppm ~t, 3ll) COOCI12CII3.
E~xampl 4_ 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetic ethyl ester, whereu~on 9.2 g (52.5 mmoles) of 4-chloro-benzoyl chloride were added at room teml~erature while stirring vigorously. The reac-tion mixture was stirred for 14 hours at room temperature. The ~recipitated crude product was filtered with suction and washed unitl free from chloride.
11.1 g (78.9~ of the theoretical yield) of analyti-cally pure 2-[(4'-chloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
Cll3 O
,~ ,C=C-~'-OC~12C113 C 3 ¦ ~ Cl O
191116N3Ci(281,74) - 1~7~988 %C %H ~N ~Cl computed: 59.68 5.72 4.97 12.58 obtairled: 58.97 5.55 4.09 14.08 melting point: 124 to 124.5C
ll-N~ (C~C13/l'MS):
~= 7,1 - 8,25 (m, 511) N13; aroln~tic-CH;
4,2 (q, 2l1) ~OOCI~2;
2~2 (s, 313) Cl13-C=;
1,9 (s, 311) C~33-C=;
1,25 ~plll (t, 311) COOC1l2C1l3.
Exalllple 46 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinorle were dissolved in 50 ml of acetic ethyl ester, whereuporl 8.35 g (52.6 mmoles) of 2-fluoro-benzoyl chloride were added at room temperaturé while stirring vigorously. The reaction mixture was stirred for 14 hours at room temperature and then further processed as in Example 16.
9.0 g (68~ of the theoretical yield) of analytically pure 2-[(2'-fluoro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
CH3 o ~C=C-C-OCH CH
IIN-C~'~
o F
(~1411lGNo3F(265~285) ,7~a %C %H %N
com~uted: 63.38 6.08 5.28 obtaine(l: 63.06 6.04 5.23 melting point: 82.5C
ll-N~ (CDC13/TMS):
~ = 6~5 - 7,65 tlll, 511) Nl~; a~omatic-CH;
4,2 ~q, 21~) -COOC132-;
2~25 ~s, 311) C133-C=;
lt9 (S, 31~) C1~3-C=;
1~35 ppm (t, 31i) -COOC112C1~3.
I ample 47 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmole) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g ~52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquirlone were dissolved in 50 ml of acetonitrile, whereupon 8.35 g (52.6 mmoles) of 4-fluoro-benzoyl chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred at room temperature for 14 hours and then further processed as in Example 3.
9.3 g (70.2~ of the theoretical yield) of analytically pure 2-[(4'-fluoro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
C~i3 ~ o C=C-C-OCIl Cll HN-ICl ~ F
Cl4lll6No3Ft265~28s) ~ ~77~
Q~iC 2iH %N
compuled: 63.38 6.08 5.28 obtained: 62.94 6.15 5.11 melting point: 130 to 132C.
Nl`lR (cDcl3/TMs): H
~= 7~6 - 8,2 (m, 311) NH;~
6,7 - 7,3 (m, 211) C~
4~2 (q, 211) -COOC~2-:
2,15 (s, 311) C~13-C=;
1,85 (s, 311) -C~13-C=;
1,25 ppm ~t, 3~3) ~cOocll2-c~l3.
Example 48 134 mg (0.5 mmole) of a~mnonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of di.methyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 11.0 g (52.5 mmoles) of 2,4-dichloro-benzyl chloride were added at roorn temperature while stirring vigorously. The reaction mixture was stirred at room temperature for 14 hours and then further processed as in Exarnple 3.
9.3 g (58.996 of the theoretical yield) of analytically pure 2-~(2',4'-dichloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
Cil O
3\~'=C-~'-OCI~ Cll C141115N02C12(316,18) ........ . . . ..
.: . .. .: .
7~7~388 ~c ~H ~,N ~Cl comE)ute~: 53.18 4.78 4.43 22.43 obta~ cd: 52.22 4.80 4.41 20.73 melting point: 128.5 to 130C
N~ (cDCl3/l'Ms):
= 7,1 - 7,7 (m, 411) NH; aromatic-CH;
4,2 (q, 2fl) -COOCH2-;
2,2 (s, 311) C113-C=;
1,95 (s, 311) Cli3-C=;
1,3 p~lll (t, 31~ COOCII2-C~33.
l~xample 4_ 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 11.0 g (52.5 mmoles) of 3,4-dichloro-berlzyl chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 15 hours at room temperature and the further processed as in Examule 3.
10.5 g (6.5% of the theroetlcal yield) of analytically pure 2-[3',4'-dichloro-phenyl)-carbonyl-amirlo]-3-methyl-2-butenoic ethyl ester were obtained.
C~13 ~ 1l ~C=C-C-OC132C1~3 ~ C ~ Cl C141115N03C12(316~18) ~ ~7988 %c ~H ~N %Cl computed: 53.18 4.78 4.43 22.43 obtained: 53.40 4.86 4.36 22.11 melting point: 115 to 120C
~ ' Il-N;I~ (CDC13/TMS):
2 ~ 8,2 (m;, 4~3) Nll; aromatic-CH;
~,2 (q, 211) - COOC112-;
2,15 (s, 3~1) Cf33-C=;
1~9 (s, 313) C113-C=;
1~25 ppm (t, 311) -COOC112C}13.
~xanlple 50 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g ~49.9 mMole~) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mllloles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinorle were put into a reac~or with 50 ml of acetonitrile, whereupon 11.0 g ~52.5 mmoles) of 3.5-dichloro-benzoyl chloride wexe added at room ternperature while stirring vigorously. The reactiorl mixture was stirred for 15 hours at room temperature.
The precipi.tated crude product was fi.ltered with suction and wa~hed w.ith water until free from chloride.
12.3 g (77.9% oP the theoretical yield) of 2-[(3', 5'-dichloro-phenyl)-carbonyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
_ ., 3 ~ C C U-OCfl Cf3 3 3 ill-C
Cl4lll5No3cl2(3l6~l8) %C %H %N ~Cl computed: 53.18 4.78 4.43 22.43 obtailled: 50.44 4.88 3.91 21.12 melting point: 171C
ll-N~1~ (CDC13/TMS):
~= 7,15 - 7,85 (m, 411) Nll; aromati.c-CH;
4,2 (q, 211) - COOC1~2-:
2,2 (s, 311) C113-C=;
1,9 ~s, 311) C113-C=;
1,25 ppm ~t, 311) -COOC112-C113.
Example 51 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g (49 9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 9 (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroqui.none were put into a reactor with 50 ml of acetonitrile, whereupoll 12.6 g (52.6 mmoles) of 2,6-dichloro-phenoxy acetyl chloride were added at room temperature while stirring vigor-ously. The reaction mixture was stirred for 14 hours at room temperature. The precipitated crude product was filtered with SUCtiOtl and washed with water until free from chloride. 14.4 g (87.4~ of the theoretical yield) of analytically pure 2-. [(2',6'-dichloro-phenoxy)-acetyl-amino]-3-methyl-2-butenoic ethyl ester were obtained.
3 ~ ~
Cll ~ C l-C-c~J2c~l3 IIN-C-CII -O ~ Cl ~ Cl C15lll7NO3cl2(3~o~2lJ
779~8 %c %H %N %Cl comput:ed: 54.56 5.19 4.24 21.47 obtained: 50.24 5.12 4.12 20.30 melting point: 124 to 125C
ll-NI~ CL)C13/'l'MS):
Ct = 7,95 (s broad~ 1ll) NH;
6,65 - 7,5 (m~ 211) aromat'~-n Cll;
4,6 (s, 211) COCII2-O-;
4,2 ~q, 2119 COOC112;
2,2 (s, 311) C~12-C=;
1,9 (s, 311) CH3-C=;
1,25 pplll (t, 3ll) COOCII2C~13.
13xample 52 134 mg (O.S mmole) of ammonium perrhenate, 8.55 g (49.9 mmoles) of 2-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hdyroquinone were put into a react:or with 50 ml of acetonitrile, whereupon 11.3 g (52.5 mmoles) of 4.5-dichloro-thiophene-2-carboxylic acid chloride were added at room temperature. The reaction mixture was stirred at room temperature for 15 hours while a maximal exothermical reaction temperature of 45C was attained. The reaction mixture was then further treated as in Example 3.
11.6 g (72.196 of the theoretical yield) of analyti-cally pure 2-[2'-(4,5-dichloro-thienyl-carbonyl-amino]-3-methyl-butenoic ethyl ester were obtained.
. .
~'~77988 Cll o = ~ -C-oC112C1l3 13N-C ~ 1 O
12 12 3 2 (32Z,21) ~C ~H %N ~S ~Cl computed: 44.74 4.07 4.35 9.49 22.00 10 obtained: 43.16 4.20 3.60 9.49 21.65 melting pOillt: 9S to 98C
ll-N~IJ~ (CDC13/~MS) ~= 8,45 (s, 1ll) N~]
7,55 (s, 1l~) ll ~ Cl 4,2 (q, 211) -COOCH2-;
2,15 (s, 3~3) Cli3-C=;
1,9 (s, 311) Cl33-C=;
20 l,3 pplll (t, 31~) -COOCll2-Cl~3.
~xample 53 134 mg (0.5 mmole) of ammonium perrhenate, 8.55 g ~49.9 mmoles ) of 2~-azido-3-methyl-butanoic ethyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (G.45 mmoles) of hydroquinone were put illtO a reactor with 50 ml of acetoni-trile, whereupon 7.1 g (52.7 mmoles) of 2,2-dimethyl butanoic acld chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 35 hours at room temperature and theA further processed as in Example 3. In order to purify the crude product, it was distilled in vacuo (U.53 mbar) at llO to 150C in the bulb tube. The oil thus obtained was crystallized w:ith n-pentane.
8.8 g (73.1% of the theoretical yield) of analytically pure 2-[(l',l'-dimethyl propyl)-carbonyl-amino]-3-methyl-2-butenoic methyl ester were obtained.
C113 ~ 0 ~C=C-C-OC}1 CH
CI33 l ICl33 IIN-~C~ - I -C112C~33 o c~l3 12II23N3~291~33) ~C ~H %N
computed: 64.70 9.61 5.80 obtained; 64.8l 9.89 5.67 melting point: lO0 to 105C
1H-NMI~ ~CDC13/T~Is):
~= 6,85 (s hroa~ 111) Nll;
9,15 (q, lfl) -COOCII2:
2,15 (s, 311) Cl33-C=;
1,~ (s, 31I) Cl~3-C=;
0,65 - 1,85 ppIl~ (m, 1411) C-(CH3-C1~2C133; 0-C112CII3.
Example 54 13.7 mg (0.05 rnmole) of sodium perrhenate, 926 mg (5 mmoles) of 2-azido-3-methyl-butnaoic isopropyl ester and 383.8 mg (525 nm~oles) of dimethyl formamide were dissolved in 2.5 ml of acetonitrile, whereup~n 529 mg (5.25 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigor-779f~
ously. The reaction mixture was stirred for 7 hours at room tempera~ure and then further pl:ocessed as in Example 1.
1.0657 g (81.2% of the theoreti.cal yield) of analyti-cally pure 2-chloro-methyl-carboxamido-3-methyl-2-butenoic iso-propyl ester were obtained.
Cl13 ~ / CO2C~I~C113)2 ~ C=C~
C~13 N~
C'1UlllGC'1N03(233,695) %C %H %N %Cl computed: 51.40 6.90 5.99 15.17 obtained: 51.41 6.97 5.77 15.16 melting point: 126C
IIJ-NI~ CDC13):
1~' = 7,9 (s, 111) Nll; I~ ~NII = 3265 Clll 5,13 ( septet , 111 ) O-CII (C113)2 ~tco 17 ~,15 ~S, 211) C112Cl: 1663 clll 1.
2,2 (s, 31l) 1 3C-C=C~N:
(S~ 311~lll3c~ N
1,2g ppm (d, 611)-CH~C113)2.
Example 55 13.7 mg (0.05 nmloles) of sodium perrhenate, 1.17 g (5 mmoles) of 2-azido-3-methyl-butanoic benzyl ester and 383.8 mg (5.25 mrnoles) of dimeth~l formamide were dissolved in 1.5 ml of acetonitrile, whereupon 592.9 mg (5.25 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigo~-ously. '1'he reactio11 mixtu~e was stirred for 15 hours at room temp~rature and then further processed as in Example l.
l.32 g (97.7 % of the theoretical yield) of analy-tically pure 2-chloro-methyl-carboxamido-3-methyl-2-butneoic benzyl ester were obtained.
C~13 ~ ~ CO2Cl12 C6~15 ~C=C
C133~ N~ ~
14 16 3(281,739) %C %H ~N ~Cl computed:59.68 5.72 4.97 12.58 obtained:59.75 5.64 4.77 12.60 melting point: 122 to 122.5C
Il-N~ ( C~Cl3):
~= 7~76 (s, l11) N11;I1~ ~N11 = 3255 c1n 7~4 ~s, 5ll)aJ~o~a~ic-~cHc; ~C0 = 1705 Clll 5,25 (s, 211) -O-C~12-;1660 c 4,l3 (s, 2H) -C112Cl;
2,24 (d, 311) 3 C=C~N;
1,9 ppln (s, 311) 113C' `N
r;t7988 Example 56 13.7 mg (0.05 rnmole) of sodiwn perrhenate, 1.0961 g (5 mmoles) of 2-azido-3-methyl-butanoic phenyl ester and 383.8 mg (5.25 mmoles) o~ dimethyl formamide were dissolved in 1.5 ml of acetonitrile, whereupon 592.9 mg (5.25 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigor-ously. The reaction mixture was stirred for 15 hours at room temperature and then further processed as in Example 1.
1.24 g (92.6~ of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-3-methyl butenoic phenyl ester were obtained.
Cll3 ~ ~ Co2-c6l~5 Cll-- -C~
3 N~ -CII2Cl Cl3lll4clNo3(267~7l2) ~C ~H %N %C1 cornputed: 58.32 5.27 5.23 13.24 obtained: 58.34 5.20 4.96 13.42 melting poi-lt: 126C
-N~ ( CDC13) ;,1 (m, 511) aromab'~ v'NIl _ 1724 ~
2,29 (d, 311)113C'C=~N;
1,98 pplll (s, 3l~ C~=~ -\
77~&~
Ex~mple 57 27.3 mg (0.1 mmole) of sodiudm perrhenate and 1.57 g (10 mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with S ml of acetic ethyl ester at 80C, where-upon 1.55 g (10.5 mmoles) of dichloro acetyl chloride were added dropwise within 45 minutes while stirring vigorously. The reac-tion mixture was kept at 80C for a total of 3 hours while stir-ring vigorously and thereafter it was further processed as in 13xample 1.
2.27 g (94.7% of the theoretical yield) of analyti-cally puxe 2-dichloro-methyl-carboxamido-3-methyl-2-butenoic methyl ester were obtained.
cll3~ ~C02C~13 ~C=C\
C~13~ , 2 O , ;
C~Hllcl2No3(24o~o86) %C%H ~N %Cl computed: 40.04 4.64 5.83 29.53 obtained: 39.93 4.51 5.78 29.72 melting pOillt: 118C
~ .
Il-NMI~ ( CDCl 3 ):
~= 7,75 (i5, 111) Nll;IR ~NII = 3265 c~
6~05 (s, 1ll) CIIC12; ~CO = 1722 clll 1, 3,79 (s, 3IJ) OC~13; ' 1670 c 2,26 (d, 311)~ 3C~=~N;
1~9 pplll (s, 3H)Il C~=~N-77~388 Example 58 27.3 mg (0.1 mmole) of sodi.um perrhenate and 1.57 g (10 mmoles) of 2-azido-3-methyl butanoic methyl ester were put :into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 1.48 g (10.5 mmoles) of benzoyl chloride were added drop-wise within 15 minutes while stirring vigorously. The reaction mixture was kept at 80C for a total of 5 hours while stirring vigorously and was then further processed as in Example 1.
2.0877 g (89.5% of the theoretical yield) of analy-tically pure 2-phenyl-carboxamido-3-methyl-2-butenoic methyl ester were obtained.
C113~ ~C z 3 ,.
CH3 NH-~C-C6115 C13lllSNO3(233~267) %C %H %N
computed: 66.94 6.48 6.00 obtained: 66.96 6.59 6.01 melting point: 132C
' NMn ~CDC13):
~ = 7,91 - 7,29 (m, SH) aroma~iC~cH=; IR ~NI~ = 3280 cm 1, : 3,72 ~s, 3H) OCH3;~CO = 1725 cm 1, 2,18 (d, 3ll) 3~=~ ;lG43 cm 1.
l~B9 ppln (s, 31l)Cll3~ ~N-`
Example 59 27.3 mg (O.l mmole) of sodium perrhenate and 1.57 g (10 mlnoles) of 2-azido-3-methyl-butenoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon l.lO g (lO.5 mmoles) of cyclop~opane carboxylic acid chlori,de, dissolved in 5 ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80C for a total of 4 hours while stirring vigorously and was then further processed as in Example 10 1.
l.74 g (88.3% of the theoretical yield) of analyti-cally pure 2-cycloyropyl-carboxamido-3-methyl-2-butenoic methyl e6t e:~ we~e obtaisled.
cl,3 ~C2C113 ~C=C~
cll3 Nll~ / H
O ~
C~5N03 ( 19 7 ~ 2 3 4 ) %C %H %N
computed: 60.90 7.67 7.lO
obtained: 60.65 7.53 7.05 melting point: 150C
Il-NMI~ ~ CVCl 3):
~= 7,13 (s, 111) Nll; I~ ~N~ = 3270 cm 3,74 (s, 311) OC~13; ~CO = 1719 c~
2,11 ~s, 3ll)C113~ ; , 1644 cm 1.
~N
1,84 (s, 31l)c~ N;
1~6~ - 0,6 pplll (1ll; 5ll) ~ ll H
~ ~7~88 Ixample 60 27.3 mg (0.1 mmole) of sodium perrhenate, 1.57 g (10 mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with 5 ml fo acetic ethyl ester at 80C, whereupon 1.25 g (10.5 mmoles) of l-methyl-cyclopropane carboxylic acid chloride, dissolved in 5 ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80C for a total of 4 hours while stirring vigorously and was then further processed as in ~xample 10 1.
19.5 g (92.4% of the theoretical yield) of analyti-cally pure 2-[(1'-methyl-cyclopropyl)-carboxamido]-3-methyl-2-butenoic methyl ester were obtained.
3~ C C ~ 2 3 C~ 7N03(211~261) %C %H %N
computed: 62.54 8.11 6.63 obtained: 62.34 7.97 6.71 melting pOillt: 73.5C
ll-NMI~ ( C~C13):
~= 6,97 (s, 1ll) NH ll~ ~NII = 3325 c~
3,77 (s, 311) 0C113; ~CO = 1717 cm 1, 2,16 (s, 3ll)Cll3 ; 1645 cln 1,B4 (s~ 311)Cl~ N ;
1,43 (s, 311) C113; ~l 2,0 - 0,5 ppm (m, 41l) ~ '~77988 Example 61 27.3 mg (O.l mmole) of sodium perrhenate and 1.57 g (lO mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 1.97 g (lO.S mmoles) of 2,2-dichloro-l-methyl-cyclopropane carboxylic acid chloride, dissolved in S ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80 C for a total of 4 hours while stirring vigorously and was then further processed as in Exa~ple l.
2.61 g (93.l~ of the theoretical yield) of analyti-cally pure 2-[(2',2'-dichloro-l'-methyl)-cyclopropyl-carbox-amido]-3-methyl-2-butenoic methyl ester were obtained.
Il 11 ll lS 2 O3(280,151) ~C %~1 ~N ~Cl computed: 47.16 5.40 5.00 25.31 obtained: 47.05 5.45 4.88 25.35 melting point: 104C
Il-NMI~ ( CDCl 3 ):
d = 7,31 (s, 1~1) N~l; IR rN11 = 3280 cm 3,71 (s, 311) OCH3; ~CO = 1721 cm 1, 2,25 (d, l11) V~11 ; 1650 cm 2,18 (s, 311) C113~= ;
1~86 ~5~ 3H) C113- ~';
1,66 (s, 311) C~13;
1,39 ppm (d, lH) Exam_ e 62 27.3 m~ (0.1 mmole) of sodium perrhena-te and 1.57 g (10 mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 2.39 g (10.5 mmoles) of 2-(2',2'-dichloro-ethenyl)-3,3-dimethyl-cyclopropane carboxylic acid chloride, dissolved in 5 ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80C for a tol:al of 4 hours while stirring vigorusly and then further processed as in Example 1.
3.08 g (96.3% of the theoretical yield of analyti-cally pure 2-[2'-(2,2-dichloro-ethenyl)-3',3'-dimethyl]-cyclopropyl-carboxamido-3-methyl-2-butenoic methyl ester were obtailled.
C~l33~=c~C2C~13 1~
C~J3 ~NH-C Ik,l Cll=CC12 1~3C C1~3 C~ 9cl 2No3 ~ 3 2o ~ 2 l 6 ) %C %H %N %Cl computed: 52.51 5.98 4.37 22.14 obtained: 52.29 6.13 4.25 22.40 melting point: 151.5 to 152.5C
ll-NMI~ (CDC13):
~= G,69 ~s, 11l) Nll; Il~ ~)'Nll = 3345 cm 1, 6,46 (d, lH) -Cll=CC12; ~rcO = 17()0 Cln 3,76 (s, 3ll) OC1l3; , 1665 cm 2,16 (s, ill) ~13C`=~N;
1,85 ~s, 3l~) H3~ ~N;
1,29 (s, 3l~) l ~
1,27 ppm ~s, 3H~ l13C CH3 ~77~88 Exam~le 63 -245 mg (0.5 mmole) of tetra-n-butyl ammonium perr11et1ate, 7.85 g (50 mmole) of 2-a~ido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidine and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 9.75 g (52.5 mmoles) of 4-nitro-benzoyl chlor,i~e were added at room temperature while stirring vigor-ously. The reaction mixture was stirred for 14 hours at room temperature and then further treated as in Example 3.
8.9 g (64.0~ of the theoretical yield) of analytically pure 2-[(4'-nitrophenyl)-carbonyl-amino]-3-methyl-2-butenoic methyl ester were obtained.
C~1 c=c -1 -OCI~
o ~ 2 13 l4N2os(27B~27) %C %H %N
computed: 56.ll 5.07 lO.07 obtai,ned: 55.84 5.13 9.21 melting point: 122C
-NM~ ~CDC13/T~1S):
= 8,9 - 7,6 (m, SH) N11; ar~mat:iC Cll=, 3,75 (s, 311) COOC113;
2,15 (s, 31~) C113-;
1,9 pp111 ~s, 3,11) C113-.
Ixample 64 246 mg (0.5 mmole) of tetra-n-butyl ammonium perr-~;:7798~3 `
henate, 7.95 g (50 mmoles) of 2-azido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of ace-tonitrile, whe~eupon 11.05 g (52.5 mmoles) of 2,6-dichloro-isonicotinic acid chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 15 minutes while the crude product precipitated. The crude product was filtered with suction and washed with water until it was free from chloride.
8.9 g (58.7% of the theoretical yield) of analytically pure 2-(2',6'-dichloro-isonicotinoyl)-amino]-3-methyl-2-butenoic ethyl ester were obtained.
3~C=C-I-OCf~
c~3~ l Cl o~Cl Cl2lll2N2o3cl2~3o3~l5 t %C %H %N %Cl computed: 47.54 4.00 9.24 23.40 obtained: 47.50 3.84 8.39 22.69 melti.ng point: 186 to 187C
, ll-NMI~ (DMSO-J6/TMS):
~= 10,1 ~s broad, 111) NH;
7,95 (s, 211) aro~a~:iC CH
3,6 Is, 311) -COOC113;
2,1 Is, 311) C113-;
l~n5 pp~ 8, 31~) C113-.
1'~77988 _~ample 65 24G mg (0.5 mmole) of tetra-n-bu-tyl arnmonium perrhen-ate, 9.25 (50 mmoles) of 2-azido-butanoic-n-butyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon ll.05 g (52.5 mmoles) of 2,6-dichloro-isonicotinic acid chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 15 minutes. It was furlher processed as in Example 3.
ll.8 g (71.25% of the theoretical yield) oE analyti-cally pure 2-[(2',6'-dichloro-isonicotinoyl-alnir1o]-2-butenoic-~-bulyl ester were obtained.
o C1~3-C11=C-C-OC11 (Cll J C
Cl Il ~Cl Cl4lll6N2o3cl2(33l~2o) %C ~H %N %Cl computed: 50.77 4.87 8.46 21.40 obtained: 50.82 4.65 8.08 20.0l melt.ing point: 123 to 124C
l1-NMI~ (CDC13/T~lS):
~= 8,05 (s broad- ll1) Nl~;
7,65 (s, 21i) aromatic C~l;
G,9 (q, lll) -Cll=;
~,lS (t, 211) -COOC112-;
1,75 (d, 311) C113-;
U 55 - 2~0 pp~ 711) -C1l2cll2 C 3 ~ ~ ~7~988 Example 66 27~3 mg (0.1 mmole) of sodium perrhenat:e and 2.05 g (10 mmoles) of 2-azido-3-phenyl-p~opanoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 1.95 g (10.5 mmoles) of 2-bromo-butanoic acid chloride, dissolved in 5 ml of acetic ethyl ester, were added dropwise withirl 40 rninutes while stirring vigorously.
The recation mixture was kept at 80C for a total of 3 hours while stirring vigorously and was then further processed as in E~xample 1.
2.23 g (68.2% of the theoretical yield) of analyti-cally pure 2-[(2'-bromopropyl)-carboxamido]-3-phenyl propenoic methyl ester were obtained.
I~C=C~COOCf~3 fl5C6 Nll-nc-cl-l-cll2-cl~3 o Br Cl 41~1 6BrNo3 ( 326 ~ l 95 ) %C %H %N %Br computed: 51.55 4.94 4.29 24.50 obtained: 51.49 4.87 4.30 24.27 melting point: 115C
ll-NMI~ ( Cl)C13 ):
d`= 7,80 (s, 1ll) Nfl; lrNll = 3210 cm 7, 6 3 - 7, 25 ( m, 5H ) a~Omal:iC~C~I=; ~CO
4,38 (t, llJ) -CllBr-; . 1661 cm 3,~6 (s, 311) OC~13;
2,4 - 1,95 (m, 2fJ) -C112-C113;
1, 1 1 pplll ( t, 3~1 ) -ClJ2-Cfl3 .
~"~77988 ~xample 67 2.46 mg (0.5 mmole) of tetra-n-butyl ammonium perrhen-ate, 9.25 g (50 mmoles) of 2-azido-butanoic-n-butyl ester, 5.2 g (52.5 mmoles) of N-~nethyl pyrrolidone and 50 mg (0.45 mmole) of hyd~oquinone were dissolved in 50 ml of acetonitrile, whereupon 10.7 g (52.3 mmoles) of l-naphthyl acetyl chloride were added at room temperature while stirring vigorously. The reaction mix-ture was stirred for 20 hours at room tempexature and then further processed as in Example 3.
10.3 g (62.8~ of the theoretical yield) of analyti-cally pure 2-(1'-naphthyl-acetyl-amino)-2-butenoic-n-butyl ester were obtained.
~1` ~
~C=~C-C-OcH2c1~2cH2c~3 3 11N~7~C~12 0~
:':
C2oll23NO3(325,41) %C %H %N
computed: 73.82 7.12 4.30 obtained: 73.10 7.10 4.24 melting point: 101 to 102C
ll-NM~ (CDC13/TMS):
~= 7,1 - 8,2 ~ m, 7H) aromatic-CH;
6,8 (s broad, 111) Nll;
6,6 (q, 111) Cll3-CII=;
4,05 (s, 211) COC112-;
3~95 (t, 211) COOC~12-;
1,65 (d, 311) C113-C=;
0,5 - 1~7 ppl; (m, 711) -CH2CH2cll3-Example 68 1~77988 2.46 mg (0.5 mmole) of tetra-n-butyl ammonium perrhen-at~, 50 mg of hydroquinone and 6.85 g (52.5 mmoles) of furan-2-carboxylic acid chloride were put into a reactor at 80C with 25 ml of acetic ethyl ester saturated with hydrogen chloride, whereupon 7.85 g ~50 mmoles) of 2-aæido-3-methyl-butanoic methyl ester, dissolved in 25 ml of acetic ethyl ester, were added dropwise while stirring vigorously. After a reaction time of 4 hours the generation of gas was terminated. The reaction mix-ture was then further processed as in Example 16.
7.4 g (66.3% of the theoretical yield) of analytically pure 2-furyl-carbonyl-ami.no-3-methyl-2-butenoic methyl ester we~e obtained.
C113 ~
C=C-C-OCII
C113''' Ill-C
11 13N4 ~223,23) %C ~H %N
computed: 59.19 5.87 6.27 obtained: 59.36 5.35 6.29 melt:ing point: 95 to 98C
Il-N~ (CDC13/TMS):
= 7,55 (s broad~ lH) Nll;
7,35 - 7,5 (m, lH)~
7,0 - 7,15 (m, lH)~
6,2 - 6,6 (m, 1~
3,65 (s, 311) COOC113;
2,2 (s, 311) C~3-C=;
1,9 ppm (s, 3~1~ C113-C=.
,77988 l~xample 69 2.46 mg (0.5 mmole) of tetra-n-butyl-ammonium perrhen-ate, 7.~s g (50 ~moles) of 2-azido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmole) of hydroqui~one were dissolved in 50 ml of acetoni-'crile, whereupon 9.55 g (52.5 mmoles) of trichloro-acetyl chloride were added at room temperature while stirring vigor-ously. Within 20 minutes the reaction mixture reacted exother-mically. It was then further processed as in Example 3.
7.9 g (57.6~ of the theoretical yleld) of analyti-cally pure 2-trichloromethyl-carboxarnido-3-methyl-2-butenoic met:hyJ ester were obtained.
3~ c=c_ll-I ~Cl IIN-C-IC-Cl O Cl 8~l1oNo3cl3(274~5o) ~C %H ~N ~Cl computed: 35.00 3.67 5.10 38.75 obtained: 33.99 3.61 4.83 39.80 ll-NMI~ (C~Cl3/TMS) ~e 7,85 (s broad, ll1) N11;
3,7 (s, 3H) COOCH3;
2,25 (s, 31~) C113-;
l,85 ppm (s, 3H) C113.
~xample 70 2.46 mg (0.5 mmole) of tetra-n-butyl-ammonium perr-hena1:e, 9.25 g (50 mmoles) of Z-azido-butanoic-n-butyl ester, 5.2 g (52.5 mmoles) of ~-methyl pyrrolidone and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, 77g88 whereupon 9.55 g (52.5 mmoles) of trichloro-ace-tyl chloride were added at room temperature while stirr.ing vigorously. The reac-tion mi.xture was sitrred for 16 hours at ~oom temperature and then further processed as in Example 3. The crude product thus obtai.ned was distilled in high vacuum (0.013 mbar) at an instru-ment temperature of 150 to 190C in the bulb tube.
9.5 g (62.7% of the theoretical yield) of analytically pure 2-trichloromethyl-carboxamido-2-butenoic-n-butyl ester were obtained.
Il~ p =f-C-OC'l2CH2CH2CH3 HN-~ C-C
O Cl Clolll4N03C13~302,59) ~C ~H %N ~Cl computed: 39.69 4.66 4.63 35.15 obtained: 39.11 4.67 4.06 32.77 Il-NM~ (CDC13/T~IS):
~= 8,05 (8 broad~ 111) Nll;
6,9 (q, 11~) -C~l=;
4,15 (t, 211) COOC~12-;
1,75 (d, 313) CH3-C=;
0,65 - 1,75 pptn (m, 7H) -C112C112CH3.
7ssa ' ~xample 71 134 mg (0.5 mmole) of aluminum perrhenate, 7.85 g ~50 mmoles) of 2-azido-3-methyl-but.anoic acld methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 rnmole) of hydroquinor~e we~e dissolved in 50 ml of acetic ethyl ester, whereupon 8.5 g (52 mmoles) of caprylic acid chloride were added at room temperature while stirring vigorously. The mixture ~eacted exot.hermically within 10 minutes and was then further processed as in Example 16.
9.5 g (74.4~ of the theoretical yield) of analytically pure 2-he~tyl-carboxamido-3-1nethyl-2-butenoic methyl ester were obl:aillcd.
3~ C=c~u-Oc113 C113 1IN-C-~C~l2)6cl~3 Cl~lll5o3N(255l36) ~C ~H %N
computed: 65.85 9.87 5.48 obtained: 65.79 9.92 5.30 melting point: 71C
NMI~ 13/'rMS):
S= 6,6 (s b~ad, 111) NH;
3,65 (s, 311) -COOC113;
1,9 - 2,45 (m, 2H) -COC112-;
2,1 (s, 311) C~13-C=;
! ~ 1,75 (s, 311) C113 C=
1~25 (s, 1011) -(C112)5=;
0,~ pplll (t, 3~1) C112-C113-7~7988 ~xample 72 134 mg (0.5 mmole) of ammonium perrhenate, 7,85 g (50 mmoles) of 2-azido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmoles) of hydroquinone were put into a reactor with 50 ml of acetic acid ethyl ester, whereupon 9.0 g (52.7 mmoles) of phenoxy acetic acid chloride were added at room temperature while stirring vig-orously. The mixture reacted exothermically within 30 minutes and was then further processed as in Example 16.
9.0 g (68.4~ of the -theoretical yield) of analytically pure 2-phenoxy-acety-amino-3-methyl-2-butenoic methyl ester were obtained.
3~C=
e ~
Cl4lll7o4N(263~3) %C ~H %N
computed: 63.86 6.51 5.32 obtained: 63.71 6.48 5.21 melting point: 79C
H-N~ cDcl3/TMs):
S= 7,65 (s broad, 111) Nll;
6,65 - 7,55 ~m, 5ll)aroma~ic CH;
4,6 (s, 211) -COC112-;
3,7 (s, 311) COOC~13;
2,25 (s, 311) C113-;
1,~5 p~ (8, 311) C1~3-.
\
~xample 73 ~ ~7~988 246 mg (0.5 mmole) of tetra-n-butyl ammonium perrhenate, 15.5 g (49.7 mmoles) of Z-azido-hexadecanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl py~rolidone and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 25 ml of acetic acid ethyl acid and 25 ml of acetonitrile, whereupon 5.9 g (52.3 `
mmoles) of chloro acetyl chlo~ide were added at room temperature while stirring vigorously. The mixture reacted exothermically within 30 minutes. It was further processed as in Example 3.
11.5 g (62.3~ of the theo~etical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-hexadecenoic methyl ester were obtained.
Cl13~Cll2)l2cHFl-c-Ocll3 I~N-~i-C191134N03Cl(359,94) %C %H %N %Cl computed: 63.40 9.52 3.89 9.85 obtained: 63.38 9.51 3.84 9.86 melting point: 74 to 75C
Il-N~ ( CDCI 3/l'MS ):
= 7,75 (s broad, lH) NH;
6,75 It, Il~) -Cl~=;
4,1 (s, 2l1~ -CH~Cl;
3 , 75 (s, 311 ) -COOCt~3;
1,7 - 2,5 (Il~, 2ll) -Cl~2-Cl~=-1,25 (s, 2211) -~Cl~2)ll-;
3 ' Example 74 246 mg (0.5 mole) of tetra-n-butyl ammonium perrhen-ate, 9.25 g (49.9 mmoles) of 2-azido-pentanoic acid isopropyl ester, 3.85 (52.6 mmoles) of dimethyl formamide and 50 ml (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 11.8 g (52.5 mmoles) of 2-[4'-(2-methyl-propyl)-phenyl-propionic acid chloride were added at room temperature while stirring vigorously. The reaction mixture was then stirred for 15 hours at room temperature, whereupon it was further treated as in Example 3.
10.0 g (58.0% of the theoretical yield) of analy-tically pure 2-~2'-[4-(2'-methyl~propyl)-phenyl]-propionyl-amido~-2-pentenoic isopropyl ester were obtained.
ClliC112CII~-C-Ocll(c113)2 ~C~13 HN- lC~ - ~CII ~CH2CII
C211131N03~345'48) %C~H ~N
computed: 73.00 9.04 4.05 obtained: 73.21 9.11 4.21 melting point: 80 to 83C
1 Il-N~ c~cl3/~ ls):
= 6,9 - 7,3 (1~, 411) -Cll= a~omatic; 1 15 ~d, 61~) -COO ~
6,65 ~s broad~ 111) NH; ~C113 6,45 ~t, 111) -C112-CII=;O,g5 ~t, 3~1) C113-C~12;
4,6 - 5,25 (m, 111) COOCII-;~C~l 3,G5 ~q, 111) COCII-;0,85 ppm (d, 6H) -~1 2,4 (d, 211) ~ C112-;
1,G5 - 2,2 ~m, 311) -C~12-CII= -ICII;
1,45 ~, 311) Cl~-C~13;
~xample 75 246 mg (0.5 mmole) of tetra-n-butyl-ammonium perr-henate, 11.25 g (50 mmoles) of 2-azido-3-cyclopentyl propionic acid isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl for-mamide, and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 9.5 g (52.6 mrnoles) of 3-acetyl-thio-2-methyl propionic acid chloride were added at room temperature. The mixture reacted exothermically within 30 minutes and was then further treated as in ~xample 3.
9.6 g (56.2~ of the theoretical yield) of analytically ~ure 2-~(1'-methyl-2'-acetyl-thio)-ethyl-carboxamido]-3-cyclo-pentyl-propenoic isopropyl ester were obtained.
6 C=IC-g-OC~I 3 IIN-Icl - ~C13-C132-S-c_cH3 O CH3 o Cl7ll27No4s~341~41) %C ~H ~N ~S
computed: 59.81 7.97 4.10 9.37 obtained: 59.55 8.22 4.12 9.94 melting point: 63 to 65C
II-N~ CDC13/'~'MS):
= 6,95 (s broad~ lII) NII;
6,6 (d, 1~3) -Cll=;
4,7 - 5,4 ~ In~ ) -COOCIl-;
2,15 - 3,5 (JII, 411) COI 11-;
2,3 (s, 311) COCI33;
l,3 - 2~25 ~m, 913) ~
1,25 ppln (d, 6I3) -C(CI33)2.
7~98~3 Example 76 246 mg (0.5 mmole) of tetra-n-butyl ammonium perr-heante, 11.25 g (50 mmoles) of 2-azido-3-cyclopentyl-propionic acid isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl fora-mide, and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.5 g (52.3 mmoles) of dip-ropyl acetic acid chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 16 hours at room temperature and then further treated as in Example 3.
9.2 g (56.9% of the theoretical yield) of analytically pure 2-[(1'-propyl-butyl)-carbonyl-amino]-3-cyclopentyl-proE~ionic isopropyl ester were obtained.
CII=C-~-OCH 3 IlN-uc-cl~(cll2cll2c1l3)2 O
~19Il33No3(323~48) %C %H %N
computed: 70.55 10.28 4.33 obtained: 70.02 10.59 4.33 melting point: 148.2C
E~l(cvcl3/T~ls) ~= 6,8 (s broad, lII) NEI;
6,55 (d, lII) -CII=;
4,8 - 5,3 ~ , lII) COOCII-;
0~G5 - 2,8 (m~ 28II) -CII~CII2CII2CII ) ;
1,25 E~ l (d, 61I)~-C(CII3)2.
~;~7~798t3 ExamE~le 77 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 (50 mm~les) of 2-azido pentanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.5 (52.3 mmoles) of dipropyl acetic acid chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 120 hours and a maximal reaction temperature of 80C
was attained. On further processing the reaction mixture as in l~xample 3, 7.0 g (54.8 ~ of the theoretical yield) of analyti-cal ly pure 2-[(1'-propyl-butyl)-carbonyl-amino]-2-perltenoic methyl ester were obtained:
cll3cll2c~ C-C-Oc113 IIN- ICl -Cll ~ CH2C112CH3 ) 2 C~ 5NO3 ~ 255~36) %C %H 96N
computed: 65.85 9.87 5.48 obtained: 64.85 10.18 5.26 melting point: 132C
NMI~ (CDCl 3/lrMs ):
~= G,9 ~s broad, lH) NIJ;
; 6,65 (t, 1111 -CH=;
3,75 (6, 311) COOC113;
1,85 - 2,5 ~In~ 211) -C112-CII=;
0,6 - 1~8 ppm (m, 1811) C113-C112; -Cll-(C112C112C 3)2 Example 78 ~.27798~3 246 mg (0.5 mmole) of tetra-n-butyl ammonium perr-herlat:e, 7.85 (50 mmoles) of 2- az1do-3-methyl-butanoic acid methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 moles) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.75 g (52.5 mmoles) of cinnamic acid chloride were added at room temperature while stirring vigor-ously. The reactiorl mixture was then stirred for 14 hours, the maximal reaction temperature being 40C. The reaction mixture was then further processed as in Example 3 and 9.3 g ~7.17~6 of the theoretical yield) of analytically pure 2-[(2'-phenyl-vinyl)-carbonyl-amino]-3-methyl-2-butenoic methyl ester were obtained.
3 C=C-C-OCII
cll3 ilN-ICl-Cl~=C
C15ll17N3(259'31) %C %H %N
computed: 69.48 6.48 5.40 obtairled: 67.44 6.61 5.41 melti.llg point: 138 to 1414C
111-NMI~ ( CDC1 3/TMS ):
c~= 7,1 - 7,6 (m~ 61l)aromati~ CII; Nll;
7,6 ~d, 1ll) -CO-C~I=;
6,5 (d, 1ll) -C=CII-;
3,7 (s, 3~1) COOC1l3:
2,15 (s, 3ll) Cll3-C=;
1,~5 PUIII (s, ~3ll) C113-C=.
~X77988 Example 79 .
134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-azido-pentanoic acid methyl ester, 50 mg (0.45 mmole) of hdyroquinone and 3.85 g (52.6 mmoles) of dimethyl for-mamide were dissolved in 50 ml of acetic ethyl ester, whereupon 12.0 g (52.02 mmoles) of 3,4,5-trimethoxy-benzoyl chloride were added dropwise at room temperature while stirring vigorously.
The reaction mixture was stirred for 240 hours at room tempera-ture and then further processed as in Example 16.
8.7g g (54.1~ of the theoretical yield) of 2-[(3', 4',5'-trimethoxy-phenyl)-carbonyl-amino]-2-pentenoic methyl e~ter were obtained.
C113CH2CH=C-C-OCH3 OC~I3 I ~ 3 o OCE13 C16ll21NO6~323,35) ~C ~fl %N
computed: 59.43 6.55 4.33 obtained: 59.21 6.75 3.70 melting point: 137 to 140C
;
1 Il-NMR ( CDC 1 3/TMS ):
~= 7,65 (s bxoad, lH) Nll;
7,05 ~s, 2H)a~o~aticCII=;
6,7 ~t~ 1ll) CII=C;
3,85 ~s, 3ll) COOCII3;
l,B - 2,55 ~m~ 2H) -Cll2-;
1,05 pp~ ~t, 311) C113-.
i
Il-N~ ( C~Cl3):
~= 7~76 (s, l11) N11;I1~ ~N11 = 3255 c1n 7~4 ~s, 5ll)aJ~o~a~ic-~cHc; ~C0 = 1705 Clll 5,25 (s, 211) -O-C~12-;1660 c 4,l3 (s, 2H) -C112Cl;
2,24 (d, 311) 3 C=C~N;
1,9 ppln (s, 311) 113C' `N
r;t7988 Example 56 13.7 mg (0.05 rnmole) of sodiwn perrhenate, 1.0961 g (5 mmoles) of 2-azido-3-methyl-butanoic phenyl ester and 383.8 mg (5.25 mmoles) o~ dimethyl formamide were dissolved in 1.5 ml of acetonitrile, whereupon 592.9 mg (5.25 mmoles) of chloro acetyl chloride were added at room temperature while stirring vigor-ously. The reaction mixture was stirred for 15 hours at room temperature and then further processed as in Example 1.
1.24 g (92.6~ of the theoretical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-3-methyl butenoic phenyl ester were obtained.
Cll3 ~ ~ Co2-c6l~5 Cll-- -C~
3 N~ -CII2Cl Cl3lll4clNo3(267~7l2) ~C ~H %N %C1 cornputed: 58.32 5.27 5.23 13.24 obtained: 58.34 5.20 4.96 13.42 melting poi-lt: 126C
-N~ ( CDC13) ;,1 (m, 511) aromab'~ v'NIl _ 1724 ~
2,29 (d, 311)113C'C=~N;
1,98 pplll (s, 3l~ C~=~ -\
77~&~
Ex~mple 57 27.3 mg (0.1 mmole) of sodiudm perrhenate and 1.57 g (10 mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with S ml of acetic ethyl ester at 80C, where-upon 1.55 g (10.5 mmoles) of dichloro acetyl chloride were added dropwise within 45 minutes while stirring vigorously. The reac-tion mixture was kept at 80C for a total of 3 hours while stir-ring vigorously and thereafter it was further processed as in 13xample 1.
2.27 g (94.7% of the theoretical yield) of analyti-cally puxe 2-dichloro-methyl-carboxamido-3-methyl-2-butenoic methyl ester were obtained.
cll3~ ~C02C~13 ~C=C\
C~13~ , 2 O , ;
C~Hllcl2No3(24o~o86) %C%H ~N %Cl computed: 40.04 4.64 5.83 29.53 obtained: 39.93 4.51 5.78 29.72 melting pOillt: 118C
~ .
Il-NMI~ ( CDCl 3 ):
~= 7,75 (i5, 111) Nll;IR ~NII = 3265 c~
6~05 (s, 1ll) CIIC12; ~CO = 1722 clll 1, 3,79 (s, 3IJ) OC~13; ' 1670 c 2,26 (d, 311)~ 3C~=~N;
1~9 pplll (s, 3H)Il C~=~N-77~388 Example 58 27.3 mg (0.1 mmole) of sodi.um perrhenate and 1.57 g (10 mmoles) of 2-azido-3-methyl butanoic methyl ester were put :into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 1.48 g (10.5 mmoles) of benzoyl chloride were added drop-wise within 15 minutes while stirring vigorously. The reaction mixture was kept at 80C for a total of 5 hours while stirring vigorously and was then further processed as in Example 1.
2.0877 g (89.5% of the theoretical yield) of analy-tically pure 2-phenyl-carboxamido-3-methyl-2-butenoic methyl ester were obtained.
C113~ ~C z 3 ,.
CH3 NH-~C-C6115 C13lllSNO3(233~267) %C %H %N
computed: 66.94 6.48 6.00 obtained: 66.96 6.59 6.01 melting point: 132C
' NMn ~CDC13):
~ = 7,91 - 7,29 (m, SH) aroma~iC~cH=; IR ~NI~ = 3280 cm 1, : 3,72 ~s, 3H) OCH3;~CO = 1725 cm 1, 2,18 (d, 3ll) 3~=~ ;lG43 cm 1.
l~B9 ppln (s, 31l)Cll3~ ~N-`
Example 59 27.3 mg (O.l mmole) of sodium perrhenate and 1.57 g (10 mlnoles) of 2-azido-3-methyl-butenoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon l.lO g (lO.5 mmoles) of cyclop~opane carboxylic acid chlori,de, dissolved in 5 ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80C for a total of 4 hours while stirring vigorously and was then further processed as in Example 10 1.
l.74 g (88.3% of the theoretical yield) of analyti-cally pure 2-cycloyropyl-carboxamido-3-methyl-2-butenoic methyl e6t e:~ we~e obtaisled.
cl,3 ~C2C113 ~C=C~
cll3 Nll~ / H
O ~
C~5N03 ( 19 7 ~ 2 3 4 ) %C %H %N
computed: 60.90 7.67 7.lO
obtained: 60.65 7.53 7.05 melting point: 150C
Il-NMI~ ~ CVCl 3):
~= 7,13 (s, 111) Nll; I~ ~N~ = 3270 cm 3,74 (s, 311) OC~13; ~CO = 1719 c~
2,11 ~s, 3ll)C113~ ; , 1644 cm 1.
~N
1,84 (s, 31l)c~ N;
1~6~ - 0,6 pplll (1ll; 5ll) ~ ll H
~ ~7~88 Ixample 60 27.3 mg (0.1 mmole) of sodium perrhenate, 1.57 g (10 mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with 5 ml fo acetic ethyl ester at 80C, whereupon 1.25 g (10.5 mmoles) of l-methyl-cyclopropane carboxylic acid chloride, dissolved in 5 ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80C for a total of 4 hours while stirring vigorously and was then further processed as in ~xample 10 1.
19.5 g (92.4% of the theoretical yield) of analyti-cally pure 2-[(1'-methyl-cyclopropyl)-carboxamido]-3-methyl-2-butenoic methyl ester were obtained.
3~ C C ~ 2 3 C~ 7N03(211~261) %C %H %N
computed: 62.54 8.11 6.63 obtained: 62.34 7.97 6.71 melting pOillt: 73.5C
ll-NMI~ ( C~C13):
~= 6,97 (s, 1ll) NH ll~ ~NII = 3325 c~
3,77 (s, 311) 0C113; ~CO = 1717 cm 1, 2,16 (s, 3ll)Cll3 ; 1645 cln 1,B4 (s~ 311)Cl~ N ;
1,43 (s, 311) C113; ~l 2,0 - 0,5 ppm (m, 41l) ~ '~77988 Example 61 27.3 mg (O.l mmole) of sodium perrhenate and 1.57 g (lO mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 1.97 g (lO.S mmoles) of 2,2-dichloro-l-methyl-cyclopropane carboxylic acid chloride, dissolved in S ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80 C for a total of 4 hours while stirring vigorously and was then further processed as in Exa~ple l.
2.61 g (93.l~ of the theoretical yield) of analyti-cally pure 2-[(2',2'-dichloro-l'-methyl)-cyclopropyl-carbox-amido]-3-methyl-2-butenoic methyl ester were obtained.
Il 11 ll lS 2 O3(280,151) ~C %~1 ~N ~Cl computed: 47.16 5.40 5.00 25.31 obtained: 47.05 5.45 4.88 25.35 melting point: 104C
Il-NMI~ ( CDCl 3 ):
d = 7,31 (s, 1~1) N~l; IR rN11 = 3280 cm 3,71 (s, 311) OCH3; ~CO = 1721 cm 1, 2,25 (d, l11) V~11 ; 1650 cm 2,18 (s, 311) C113~= ;
1~86 ~5~ 3H) C113- ~';
1,66 (s, 311) C~13;
1,39 ppm (d, lH) Exam_ e 62 27.3 m~ (0.1 mmole) of sodium perrhena-te and 1.57 g (10 mmoles) of 2-azido-3-methyl-butanoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 2.39 g (10.5 mmoles) of 2-(2',2'-dichloro-ethenyl)-3,3-dimethyl-cyclopropane carboxylic acid chloride, dissolved in 5 ml of acetic ethyl ester, were added dropwise within 30 minutes while stirring vigorously. The reaction mixture was kept at 80C for a tol:al of 4 hours while stirring vigorusly and then further processed as in Example 1.
3.08 g (96.3% of the theoretical yield of analyti-cally pure 2-[2'-(2,2-dichloro-ethenyl)-3',3'-dimethyl]-cyclopropyl-carboxamido-3-methyl-2-butenoic methyl ester were obtailled.
C~l33~=c~C2C~13 1~
C~J3 ~NH-C Ik,l Cll=CC12 1~3C C1~3 C~ 9cl 2No3 ~ 3 2o ~ 2 l 6 ) %C %H %N %Cl computed: 52.51 5.98 4.37 22.14 obtained: 52.29 6.13 4.25 22.40 melting point: 151.5 to 152.5C
ll-NMI~ (CDC13):
~= G,69 ~s, 11l) Nll; Il~ ~)'Nll = 3345 cm 1, 6,46 (d, lH) -Cll=CC12; ~rcO = 17()0 Cln 3,76 (s, 3ll) OC1l3; , 1665 cm 2,16 (s, ill) ~13C`=~N;
1,85 ~s, 3l~) H3~ ~N;
1,29 (s, 3l~) l ~
1,27 ppm ~s, 3H~ l13C CH3 ~77~88 Exam~le 63 -245 mg (0.5 mmole) of tetra-n-butyl ammonium perr11et1ate, 7.85 g (50 mmole) of 2-a~ido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidine and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 9.75 g (52.5 mmoles) of 4-nitro-benzoyl chlor,i~e were added at room temperature while stirring vigor-ously. The reaction mixture was stirred for 14 hours at room temperature and then further treated as in Example 3.
8.9 g (64.0~ of the theoretical yield) of analytically pure 2-[(4'-nitrophenyl)-carbonyl-amino]-3-methyl-2-butenoic methyl ester were obtained.
C~1 c=c -1 -OCI~
o ~ 2 13 l4N2os(27B~27) %C %H %N
computed: 56.ll 5.07 lO.07 obtai,ned: 55.84 5.13 9.21 melting point: 122C
-NM~ ~CDC13/T~1S):
= 8,9 - 7,6 (m, SH) N11; ar~mat:iC Cll=, 3,75 (s, 311) COOC113;
2,15 (s, 31~) C113-;
1,9 pp111 ~s, 3,11) C113-.
Ixample 64 246 mg (0.5 mmole) of tetra-n-butyl ammonium perr-~;:7798~3 `
henate, 7.95 g (50 mmoles) of 2-azido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of ace-tonitrile, whe~eupon 11.05 g (52.5 mmoles) of 2,6-dichloro-isonicotinic acid chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 15 minutes while the crude product precipitated. The crude product was filtered with suction and washed with water until it was free from chloride.
8.9 g (58.7% of the theoretical yield) of analytically pure 2-(2',6'-dichloro-isonicotinoyl)-amino]-3-methyl-2-butenoic ethyl ester were obtained.
3~C=C-I-OCf~
c~3~ l Cl o~Cl Cl2lll2N2o3cl2~3o3~l5 t %C %H %N %Cl computed: 47.54 4.00 9.24 23.40 obtained: 47.50 3.84 8.39 22.69 melti.ng point: 186 to 187C
, ll-NMI~ (DMSO-J6/TMS):
~= 10,1 ~s broad, 111) NH;
7,95 (s, 211) aro~a~:iC CH
3,6 Is, 311) -COOC113;
2,1 Is, 311) C113-;
l~n5 pp~ 8, 31~) C113-.
1'~77988 _~ample 65 24G mg (0.5 mmole) of tetra-n-bu-tyl arnmonium perrhen-ate, 9.25 (50 mmoles) of 2-azido-butanoic-n-butyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon ll.05 g (52.5 mmoles) of 2,6-dichloro-isonicotinic acid chloride were added at room temperature while stirring vigorously. The mixture reacted exothermically within 15 minutes. It was furlher processed as in Example 3.
ll.8 g (71.25% of the theoretical yield) oE analyti-cally pure 2-[(2',6'-dichloro-isonicotinoyl-alnir1o]-2-butenoic-~-bulyl ester were obtained.
o C1~3-C11=C-C-OC11 (Cll J C
Cl Il ~Cl Cl4lll6N2o3cl2(33l~2o) %C ~H %N %Cl computed: 50.77 4.87 8.46 21.40 obtained: 50.82 4.65 8.08 20.0l melt.ing point: 123 to 124C
l1-NMI~ (CDC13/T~lS):
~= 8,05 (s broad- ll1) Nl~;
7,65 (s, 21i) aromatic C~l;
G,9 (q, lll) -Cll=;
~,lS (t, 211) -COOC112-;
1,75 (d, 311) C113-;
U 55 - 2~0 pp~ 711) -C1l2cll2 C 3 ~ ~ ~7~988 Example 66 27~3 mg (0.1 mmole) of sodium perrhenat:e and 2.05 g (10 mmoles) of 2-azido-3-phenyl-p~opanoic methyl ester were put into a reactor with 5 ml of acetic ethyl ester at 80C, where-upon 1.95 g (10.5 mmoles) of 2-bromo-butanoic acid chloride, dissolved in 5 ml of acetic ethyl ester, were added dropwise withirl 40 rninutes while stirring vigorously.
The recation mixture was kept at 80C for a total of 3 hours while stirring vigorously and was then further processed as in E~xample 1.
2.23 g (68.2% of the theoretical yield) of analyti-cally pure 2-[(2'-bromopropyl)-carboxamido]-3-phenyl propenoic methyl ester were obtained.
I~C=C~COOCf~3 fl5C6 Nll-nc-cl-l-cll2-cl~3 o Br Cl 41~1 6BrNo3 ( 326 ~ l 95 ) %C %H %N %Br computed: 51.55 4.94 4.29 24.50 obtained: 51.49 4.87 4.30 24.27 melting point: 115C
ll-NMI~ ( Cl)C13 ):
d`= 7,80 (s, 1ll) Nfl; lrNll = 3210 cm 7, 6 3 - 7, 25 ( m, 5H ) a~Omal:iC~C~I=; ~CO
4,38 (t, llJ) -CllBr-; . 1661 cm 3,~6 (s, 311) OC~13;
2,4 - 1,95 (m, 2fJ) -C112-C113;
1, 1 1 pplll ( t, 3~1 ) -ClJ2-Cfl3 .
~"~77988 ~xample 67 2.46 mg (0.5 mmole) of tetra-n-butyl ammonium perrhen-ate, 9.25 g (50 mmoles) of 2-azido-butanoic-n-butyl ester, 5.2 g (52.5 mmoles) of N-~nethyl pyrrolidone and 50 mg (0.45 mmole) of hyd~oquinone were dissolved in 50 ml of acetonitrile, whereupon 10.7 g (52.3 mmoles) of l-naphthyl acetyl chloride were added at room temperature while stirring vigorously. The reaction mix-ture was stirred for 20 hours at room tempexature and then further processed as in Example 3.
10.3 g (62.8~ of the theoretical yield) of analyti-cally pure 2-(1'-naphthyl-acetyl-amino)-2-butenoic-n-butyl ester were obtained.
~1` ~
~C=~C-C-OcH2c1~2cH2c~3 3 11N~7~C~12 0~
:':
C2oll23NO3(325,41) %C %H %N
computed: 73.82 7.12 4.30 obtained: 73.10 7.10 4.24 melting point: 101 to 102C
ll-NM~ (CDC13/TMS):
~= 7,1 - 8,2 ~ m, 7H) aromatic-CH;
6,8 (s broad, 111) Nll;
6,6 (q, 111) Cll3-CII=;
4,05 (s, 211) COC112-;
3~95 (t, 211) COOC~12-;
1,65 (d, 311) C113-C=;
0,5 - 1~7 ppl; (m, 711) -CH2CH2cll3-Example 68 1~77988 2.46 mg (0.5 mmole) of tetra-n-butyl ammonium perrhen-at~, 50 mg of hydroquinone and 6.85 g (52.5 mmoles) of furan-2-carboxylic acid chloride were put into a reactor at 80C with 25 ml of acetic ethyl ester saturated with hydrogen chloride, whereupon 7.85 g ~50 mmoles) of 2-aæido-3-methyl-butanoic methyl ester, dissolved in 25 ml of acetic ethyl ester, were added dropwise while stirring vigorously. After a reaction time of 4 hours the generation of gas was terminated. The reaction mix-ture was then further processed as in Example 16.
7.4 g (66.3% of the theoretical yield) of analytically pure 2-furyl-carbonyl-ami.no-3-methyl-2-butenoic methyl ester we~e obtained.
C113 ~
C=C-C-OCII
C113''' Ill-C
11 13N4 ~223,23) %C ~H %N
computed: 59.19 5.87 6.27 obtained: 59.36 5.35 6.29 melt:ing point: 95 to 98C
Il-N~ (CDC13/TMS):
= 7,55 (s broad~ lH) Nll;
7,35 - 7,5 (m, lH)~
7,0 - 7,15 (m, lH)~
6,2 - 6,6 (m, 1~
3,65 (s, 311) COOC113;
2,2 (s, 311) C~3-C=;
1,9 ppm (s, 3~1~ C113-C=.
,77988 l~xample 69 2.46 mg (0.5 mmole) of tetra-n-butyl-ammonium perrhen-ate, 7.~s g (50 ~moles) of 2-azido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmole) of hydroqui~one were dissolved in 50 ml of acetoni-'crile, whereupon 9.55 g (52.5 mmoles) of trichloro-acetyl chloride were added at room temperature while stirring vigor-ously. Within 20 minutes the reaction mixture reacted exother-mically. It was then further processed as in Example 3.
7.9 g (57.6~ of the theoretical yleld) of analyti-cally pure 2-trichloromethyl-carboxarnido-3-methyl-2-butenoic met:hyJ ester were obtained.
3~ c=c_ll-I ~Cl IIN-C-IC-Cl O Cl 8~l1oNo3cl3(274~5o) ~C %H ~N ~Cl computed: 35.00 3.67 5.10 38.75 obtained: 33.99 3.61 4.83 39.80 ll-NMI~ (C~Cl3/TMS) ~e 7,85 (s broad, ll1) N11;
3,7 (s, 3H) COOCH3;
2,25 (s, 31~) C113-;
l,85 ppm (s, 3H) C113.
~xample 70 2.46 mg (0.5 mmole) of tetra-n-butyl-ammonium perr-hena1:e, 9.25 g (50 mmoles) of Z-azido-butanoic-n-butyl ester, 5.2 g (52.5 mmoles) of ~-methyl pyrrolidone and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, 77g88 whereupon 9.55 g (52.5 mmoles) of trichloro-ace-tyl chloride were added at room temperature while stirr.ing vigorously. The reac-tion mi.xture was sitrred for 16 hours at ~oom temperature and then further processed as in Example 3. The crude product thus obtai.ned was distilled in high vacuum (0.013 mbar) at an instru-ment temperature of 150 to 190C in the bulb tube.
9.5 g (62.7% of the theoretical yield) of analytically pure 2-trichloromethyl-carboxamido-2-butenoic-n-butyl ester were obtained.
Il~ p =f-C-OC'l2CH2CH2CH3 HN-~ C-C
O Cl Clolll4N03C13~302,59) ~C ~H %N ~Cl computed: 39.69 4.66 4.63 35.15 obtained: 39.11 4.67 4.06 32.77 Il-NM~ (CDC13/T~IS):
~= 8,05 (8 broad~ 111) Nll;
6,9 (q, 11~) -C~l=;
4,15 (t, 211) COOC~12-;
1,75 (d, 313) CH3-C=;
0,65 - 1,75 pptn (m, 7H) -C112C112CH3.
7ssa ' ~xample 71 134 mg (0.5 mmole) of aluminum perrhenate, 7.85 g ~50 mmoles) of 2-azido-3-methyl-but.anoic acld methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 rnmole) of hydroquinor~e we~e dissolved in 50 ml of acetic ethyl ester, whereupon 8.5 g (52 mmoles) of caprylic acid chloride were added at room temperature while stirring vigorously. The mixture ~eacted exot.hermically within 10 minutes and was then further processed as in Example 16.
9.5 g (74.4~ of the theoretical yield) of analytically pure 2-he~tyl-carboxamido-3-1nethyl-2-butenoic methyl ester were obl:aillcd.
3~ C=c~u-Oc113 C113 1IN-C-~C~l2)6cl~3 Cl~lll5o3N(255l36) ~C ~H %N
computed: 65.85 9.87 5.48 obtained: 65.79 9.92 5.30 melting point: 71C
NMI~ 13/'rMS):
S= 6,6 (s b~ad, 111) NH;
3,65 (s, 311) -COOC113;
1,9 - 2,45 (m, 2H) -COC112-;
2,1 (s, 311) C~13-C=;
! ~ 1,75 (s, 311) C113 C=
1~25 (s, 1011) -(C112)5=;
0,~ pplll (t, 3~1) C112-C113-7~7988 ~xample 72 134 mg (0.5 mmole) of ammonium perrhenate, 7,85 g (50 mmoles) of 2-azido-3-methyl-butanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 mmoles) of hydroquinone were put into a reactor with 50 ml of acetic acid ethyl ester, whereupon 9.0 g (52.7 mmoles) of phenoxy acetic acid chloride were added at room temperature while stirring vig-orously. The mixture reacted exothermically within 30 minutes and was then further processed as in Example 16.
9.0 g (68.4~ of the -theoretical yield) of analytically pure 2-phenoxy-acety-amino-3-methyl-2-butenoic methyl ester were obtained.
3~C=
e ~
Cl4lll7o4N(263~3) %C ~H %N
computed: 63.86 6.51 5.32 obtained: 63.71 6.48 5.21 melting point: 79C
H-N~ cDcl3/TMs):
S= 7,65 (s broad, 111) Nll;
6,65 - 7,55 ~m, 5ll)aroma~ic CH;
4,6 (s, 211) -COC112-;
3,7 (s, 311) COOC~13;
2,25 (s, 311) C113-;
1,~5 p~ (8, 311) C1~3-.
\
~xample 73 ~ ~7~988 246 mg (0.5 mmole) of tetra-n-butyl ammonium perrhenate, 15.5 g (49.7 mmoles) of Z-azido-hexadecanoic methyl ester, 5.2 g (52.5 mmoles) of N-methyl py~rolidone and 50 mg (0.45 mmoles) of hydroquinone were dissolved in 25 ml of acetic acid ethyl acid and 25 ml of acetonitrile, whereupon 5.9 g (52.3 `
mmoles) of chloro acetyl chlo~ide were added at room temperature while stirring vigorously. The mixture reacted exothermically within 30 minutes. It was further processed as in Example 3.
11.5 g (62.3~ of the theo~etical yield) of analyti-cally pure 2-chloro-methyl-carboxamido-2-hexadecenoic methyl ester were obtained.
Cl13~Cll2)l2cHFl-c-Ocll3 I~N-~i-C191134N03Cl(359,94) %C %H %N %Cl computed: 63.40 9.52 3.89 9.85 obtained: 63.38 9.51 3.84 9.86 melting point: 74 to 75C
Il-N~ ( CDCI 3/l'MS ):
= 7,75 (s broad, lH) NH;
6,75 It, Il~) -Cl~=;
4,1 (s, 2l1~ -CH~Cl;
3 , 75 (s, 311 ) -COOCt~3;
1,7 - 2,5 (Il~, 2ll) -Cl~2-Cl~=-1,25 (s, 2211) -~Cl~2)ll-;
3 ' Example 74 246 mg (0.5 mole) of tetra-n-butyl ammonium perrhen-ate, 9.25 g (49.9 mmoles) of 2-azido-pentanoic acid isopropyl ester, 3.85 (52.6 mmoles) of dimethyl formamide and 50 ml (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 11.8 g (52.5 mmoles) of 2-[4'-(2-methyl-propyl)-phenyl-propionic acid chloride were added at room temperature while stirring vigorously. The reaction mixture was then stirred for 15 hours at room temperature, whereupon it was further treated as in Example 3.
10.0 g (58.0% of the theoretical yield) of analy-tically pure 2-~2'-[4-(2'-methyl~propyl)-phenyl]-propionyl-amido~-2-pentenoic isopropyl ester were obtained.
ClliC112CII~-C-Ocll(c113)2 ~C~13 HN- lC~ - ~CII ~CH2CII
C211131N03~345'48) %C~H ~N
computed: 73.00 9.04 4.05 obtained: 73.21 9.11 4.21 melting point: 80 to 83C
1 Il-N~ c~cl3/~ ls):
= 6,9 - 7,3 (1~, 411) -Cll= a~omatic; 1 15 ~d, 61~) -COO ~
6,65 ~s broad~ 111) NH; ~C113 6,45 ~t, 111) -C112-CII=;O,g5 ~t, 3~1) C113-C~12;
4,6 - 5,25 (m, 111) COOCII-;~C~l 3,G5 ~q, 111) COCII-;0,85 ppm (d, 6H) -~1 2,4 (d, 211) ~ C112-;
1,G5 - 2,2 ~m, 311) -C~12-CII= -ICII;
1,45 ~, 311) Cl~-C~13;
~xample 75 246 mg (0.5 mmole) of tetra-n-butyl-ammonium perr-henate, 11.25 g (50 mmoles) of 2-azido-3-cyclopentyl propionic acid isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl for-mamide, and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 9.5 g (52.6 mrnoles) of 3-acetyl-thio-2-methyl propionic acid chloride were added at room temperature. The mixture reacted exothermically within 30 minutes and was then further treated as in ~xample 3.
9.6 g (56.2~ of the theoretical yield) of analytically ~ure 2-~(1'-methyl-2'-acetyl-thio)-ethyl-carboxamido]-3-cyclo-pentyl-propenoic isopropyl ester were obtained.
6 C=IC-g-OC~I 3 IIN-Icl - ~C13-C132-S-c_cH3 O CH3 o Cl7ll27No4s~341~41) %C ~H ~N ~S
computed: 59.81 7.97 4.10 9.37 obtained: 59.55 8.22 4.12 9.94 melting point: 63 to 65C
II-N~ CDC13/'~'MS):
= 6,95 (s broad~ lII) NII;
6,6 (d, 1~3) -Cll=;
4,7 - 5,4 ~ In~ ) -COOCIl-;
2,15 - 3,5 (JII, 411) COI 11-;
2,3 (s, 311) COCI33;
l,3 - 2~25 ~m, 913) ~
1,25 ppln (d, 6I3) -C(CI33)2.
7~98~3 Example 76 246 mg (0.5 mmole) of tetra-n-butyl ammonium perr-heante, 11.25 g (50 mmoles) of 2-azido-3-cyclopentyl-propionic acid isopropyl ester, 3.85 g (52.6 mmoles) of dimethyl fora-mide, and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.5 g (52.3 mmoles) of dip-ropyl acetic acid chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 16 hours at room temperature and then further treated as in Example 3.
9.2 g (56.9% of the theoretical yield) of analytically pure 2-[(1'-propyl-butyl)-carbonyl-amino]-3-cyclopentyl-proE~ionic isopropyl ester were obtained.
CII=C-~-OCH 3 IlN-uc-cl~(cll2cll2c1l3)2 O
~19Il33No3(323~48) %C %H %N
computed: 70.55 10.28 4.33 obtained: 70.02 10.59 4.33 melting point: 148.2C
E~l(cvcl3/T~ls) ~= 6,8 (s broad, lII) NEI;
6,55 (d, lII) -CII=;
4,8 - 5,3 ~ , lII) COOCII-;
0~G5 - 2,8 (m~ 28II) -CII~CII2CII2CII ) ;
1,25 E~ l (d, 61I)~-C(CII3)2.
~;~7~798t3 ExamE~le 77 134 mg (0.5 mmole) of ammonium perrhenate, 7.85 (50 mm~les) of 2-azido pentanoic methyl ester, 3.85 g (52.6 mmoles) of dimethyl formamide and 50 mg (0.45 mmole) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.5 (52.3 mmoles) of dipropyl acetic acid chloride were added at room temperature while stirring vigorously. The reaction mixture was stirred for 120 hours and a maximal reaction temperature of 80C
was attained. On further processing the reaction mixture as in l~xample 3, 7.0 g (54.8 ~ of the theoretical yield) of analyti-cal ly pure 2-[(1'-propyl-butyl)-carbonyl-amino]-2-perltenoic methyl ester were obtained:
cll3cll2c~ C-C-Oc113 IIN- ICl -Cll ~ CH2C112CH3 ) 2 C~ 5NO3 ~ 255~36) %C %H 96N
computed: 65.85 9.87 5.48 obtained: 64.85 10.18 5.26 melting point: 132C
NMI~ (CDCl 3/lrMs ):
~= G,9 ~s broad, lH) NIJ;
; 6,65 (t, 1111 -CH=;
3,75 (6, 311) COOC113;
1,85 - 2,5 ~In~ 211) -C112-CII=;
0,6 - 1~8 ppm (m, 1811) C113-C112; -Cll-(C112C112C 3)2 Example 78 ~.27798~3 246 mg (0.5 mmole) of tetra-n-butyl ammonium perr-herlat:e, 7.85 (50 mmoles) of 2- az1do-3-methyl-butanoic acid methyl ester, 5.2 g (52.5 mmoles) of N-methyl pyrrolidone and 50 mg (0.45 moles) of hydroquinone were dissolved in 50 ml of acetonitrile, whereupon 8.75 g (52.5 mmoles) of cinnamic acid chloride were added at room temperature while stirring vigor-ously. The reactiorl mixture was then stirred for 14 hours, the maximal reaction temperature being 40C. The reaction mixture was then further processed as in Example 3 and 9.3 g ~7.17~6 of the theoretical yield) of analytically pure 2-[(2'-phenyl-vinyl)-carbonyl-amino]-3-methyl-2-butenoic methyl ester were obtained.
3 C=C-C-OCII
cll3 ilN-ICl-Cl~=C
C15ll17N3(259'31) %C %H %N
computed: 69.48 6.48 5.40 obtairled: 67.44 6.61 5.41 melti.llg point: 138 to 1414C
111-NMI~ ( CDC1 3/TMS ):
c~= 7,1 - 7,6 (m~ 61l)aromati~ CII; Nll;
7,6 ~d, 1ll) -CO-C~I=;
6,5 (d, 1ll) -C=CII-;
3,7 (s, 3~1) COOC1l3:
2,15 (s, 3ll) Cll3-C=;
1,~5 PUIII (s, ~3ll) C113-C=.
~X77988 Example 79 .
134 mg (0.5 mmole) of ammonium perrhenate, 7.85 g (50 mmoles) of 2-azido-pentanoic acid methyl ester, 50 mg (0.45 mmole) of hdyroquinone and 3.85 g (52.6 mmoles) of dimethyl for-mamide were dissolved in 50 ml of acetic ethyl ester, whereupon 12.0 g (52.02 mmoles) of 3,4,5-trimethoxy-benzoyl chloride were added dropwise at room temperature while stirring vigorously.
The reaction mixture was stirred for 240 hours at room tempera-ture and then further processed as in Example 16.
8.7g g (54.1~ of the theoretical yield) of 2-[(3', 4',5'-trimethoxy-phenyl)-carbonyl-amino]-2-pentenoic methyl e~ter were obtained.
C113CH2CH=C-C-OCH3 OC~I3 I ~ 3 o OCE13 C16ll21NO6~323,35) ~C ~fl %N
computed: 59.43 6.55 4.33 obtained: 59.21 6.75 3.70 melting point: 137 to 140C
;
1 Il-NMR ( CDC 1 3/TMS ):
~= 7,65 (s bxoad, lH) Nll;
7,05 ~s, 2H)a~o~aticCII=;
6,7 ~t~ 1ll) CII=C;
3,85 ~s, 3ll) COOCII3;
l,B - 2,55 ~m~ 2H) -Cll2-;
1,05 pp~ ~t, 311) C113-.
i
Claims (20)
1. A process for producing N-acyl-2,3-dehydro-amino carboxylic esters having the general formula (I), wherein R1 represents a straight-chain or branched (C1-C4) alkyl radical, a phenyl radical or a benzyl radical, R2 represents hydrogen or a methyl radical, R3 represents hydrogen, .alpha. straight-chain or branched (C1-C16)alkyl radical, a (C3-C8) cycloalkyl radical, a (C1-C6)alkoxy radical, a phenoxy radical, a (C1-C6)alkyl mercapto radical, a phenyl mercapto radical or a methoxy-carbonyl-methyl mercapto radical and R4 represents a straight-chain or branched (C1-C16)alkyl radical or (C2-C16) alkenyl radical, either unsubstituted or mono- or poly-sub-stituted by halogen, a methoxy group or by an acetyl-thio group, an unsubstituted (C3-C8)cycloalkyl radical which may be mono- or poly-substituted by halogen or a methyl group, an unsubstituted phenyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (C1-C4)alkyl or alkoxy group or by a trifluoromethyl group, an unsubstituted cinnamyl radical, which may be mono- or poly-substituted by halogen, an unsubstituted heteroaryl radical which may be mono- or poly-substituted by halogen, a (C1-C4)alkyl or alkoxy group or by a trifluoromethyl group, an aryl or heteroaryl methyl radical, an unsubstituted phenoxy methyl radical or phenyl-ethyl radical which may be mono- or poly-substituted by halogen, a nitro group, a (C1-C4)alkyl group or by a trifluoromethyl group, or a 2-(2',
2'-dichloro-ethenyl)-3,3-dimethyl cyclopropyl radical in which a 2-azido-carboxylic ester having the general formula (II), wherein R1, R2, and R3 have the meaning define above, is reacted at a temperature of between 0 and 150°C in the presence of a perrhenate wlth a carboxylic acid halide having the general formula (III), wherein R4 has the meaning defined above and Hal represents chlorine or bromide.
2. A process according to claim 1, in which the perrhenate is used in an amount of between 0.005 and 10 mole percent relative to the amount of 2-azido-carboxylic ester having the formula (II).
2. A process according to claim 1, in which the perrhenate is used in an amount of between 0.005 and 10 mole percent relative to the amount of 2-azido-carboxylic ester having the formula (II).
3. A process according to claim 1, in which the reaction is carried out in the additional presence of an acid amide, a lactam or of a substituted urea.
4. A process according to claim 3, in which the perrhenate is present in an amount between 0.005 and 10 mole percent relative to the 2-azido carboxylic ester of formula II.
5. A process according to claim 1, 2 or 3, in which the perrhenate is present in an amount between 0.1 and 3 mole percent relative to the 2-azido carboxylic ester of formula II.
6. A process according to claim 1, 2 or 3, in which the perrhenate is selected from sodium, potassium or ammonium perrhenate.
7. A process according to claim 1, 2 or 3, in which the perrhenate is selected from tetraethyl, tetrabutyl, tetra-benzyl or tricapryl-methyl ammonium perrhenate.
8. A process according to claim 4, in which the acid amide, lactam or substituted urea is present in an equimolar amount relative to the carboxylic acid halide.
9. A process according to claim 8, in which the amide is selected from dimethyl formamide, dimethyl acetamide or hexamethyl phosphoric triamide.
10. A process according to claim 8, in which the lactam is pyrrolidone.
11. A process according to claim 8, in which the urea is selected from tetramethyl urea and N,N'-dimethyl-propylene urea.
12. A process according to claim 1, 2 or 3, in which the 2-azido-carboxylic esters having the general formula II are produced by reacting the corresponding 2-chloro-2-bromo car-boxylic esters with an aqueous sodium azide solution in the presence of a phase transfer catalyst.
13. A process according to claim 1, 2 or 3, in which the ester of formula II is selected from esters of 2-azido-propionic acid, -butyric acid, -3-methyl-butyric acid, -3-phenyl-propionic acid, -pentanoic acid, -4-methyl-pentanoic acid, -3-cyclopentyl-propionic acid, -3-cyclohexyl-propionic acid, -hexanoic acid, -heptanoic acid, -octanoic acid, -nonanoic acid, -decanoic acid, -hendecanoic acid, -dodecanoic acid, -tridecanoic acid, -tetradecanoic acid, -pentadecanoic acid, -hexadecanoic acid, -heptadecanoic acid, -octadecanoic acid, -nonadecanoic acid, -3-methyl-mercapto propionic acid, -3-methoxy-carbonyl-methyl-mercapto propionic acid, -3-phenyl-mercapto propionic acid or 3-phenoxy propionic acid.
14. A process according to claim 1, 2 or 3, in which the temperature is between 20 and 80°C.
15. A process according to claim 1, 2 or 3, in which the reaction is effected in an inert solvent.
16. A process according to claim 1, 2 or 3, in which the reaction is effected in an inert solvent and selected from carboxylic alkyl esters, acetonitrile, nitro-methane, tetra-hydroufuran dioxane or dimethoxy ethane.
17. A process according to claim 1, in which the reaction is effected in the presence of 0.001 to 10 percent by weight of a radical polymerization inhibitor relative to the ester of formula II.
18. A process according to claim 1, in which the reaction is effected in the presence of 0.1 to 3 percent by weight of a radical polymerization inhibitor relative to the ester of formula II.
19. A process according to claim 17 or 18 in which the inhibitor is selected from hydroquinone or hydroquinone monomethyl ether.
20. A process according to claim 1, 2 or 3, in which the reaction is effected in the presence of an acid acceptor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3508564.9 | 1985-03-11 | ||
| DE19853508564 DE3508564A1 (en) | 1985-03-11 | 1985-03-11 | METHOD FOR PRODUCING N-ACYL-2, 3-DEHYDROAMINOCARBONIC ACID ESTERS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1277988C true CA1277988C (en) | 1990-12-18 |
Family
ID=6264801
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000503677A Expired - Lifetime CA1277988C (en) | 1985-03-11 | 1986-03-10 | Process for producing n-acyl-2,3-dehydro-amino carboxylic esters |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0195201B1 (en) |
| JP (1) | JPS61212546A (en) |
| AT (1) | ATE53008T1 (en) |
| CA (1) | CA1277988C (en) |
| DE (2) | DE3508564A1 (en) |
| ES (1) | ES8706107A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5559268A (en) * | 1994-11-17 | 1996-09-24 | E. I. Du Pont De Nemours And Company | Process for the efficient preparation of N-substituted dehydroamino acid esters |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH16708A (en) * | 1978-07-24 | 1984-01-20 | Merck & Co Inc | Z-2-acylamino-3-monosubstituted propenoates |
| DE3140227C1 (en) * | 1981-10-09 | 1982-12-16 | Degussa Ag, 6000 Frankfurt | Process for the preparation of N-acetyl-2,3-dehydro-aminocarboxylic acid esters |
-
1985
- 1985-03-11 DE DE19853508564 patent/DE3508564A1/en active Granted
-
1986
- 1986-01-27 AT AT86101048T patent/ATE53008T1/en not_active IP Right Cessation
- 1986-01-27 DE DE8686101048T patent/DE3671431D1/en not_active Expired - Lifetime
- 1986-01-27 EP EP86101048A patent/EP0195201B1/en not_active Expired - Lifetime
- 1986-03-10 CA CA000503677A patent/CA1277988C/en not_active Expired - Lifetime
- 1986-03-10 ES ES552839A patent/ES8706107A1/en not_active Expired
- 1986-03-11 JP JP61051616A patent/JPS61212546A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ATE53008T1 (en) | 1990-06-15 |
| DE3508564A1 (en) | 1986-09-11 |
| EP0195201A3 (en) | 1988-01-13 |
| ES552839A0 (en) | 1987-06-01 |
| EP0195201B1 (en) | 1990-05-23 |
| DE3508564C2 (en) | 1988-02-18 |
| DE3671431D1 (en) | 1990-06-28 |
| EP0195201A2 (en) | 1986-09-24 |
| ES8706107A1 (en) | 1987-06-01 |
| JPS61212546A (en) | 1986-09-20 |
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