CA1077945A - Method for the direct manufacture of n-acyl derivatives of alpha-amino-gamma-keto acids and compounds thereof - Google Patents
Method for the direct manufacture of n-acyl derivatives of alpha-amino-gamma-keto acids and compounds thereofInfo
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- CA1077945A CA1077945A CA259,378A CA259378A CA1077945A CA 1077945 A CA1077945 A CA 1077945A CA 259378 A CA259378 A CA 259378A CA 1077945 A CA1077945 A CA 1077945A
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- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- 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
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- 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
- C07D307/66—Nitrogen atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the Disclosure A method is described for the direct preparation of N-acyl, e.g. acetyl or benzoyl, derivatives of alpha-amino-gamma-keto acids, which are new compounds. The method comprises adduct formation between a primary amide and glyoxylic acid or esters thereof and the subsequent reaction of the said adduct with 1, 3 dicarbonyl compounds in the presence of an acid catalyst. Examples of 1, 3 dicarbonyl compounds are 1, 3 diketones and beta-keto esters or methylene substituted compounds thereof. The N-acyl derivatives of alpha-amino-gamma-keto acids can be transformed directly into new compounds of nitrogen heterocyclic derivatives, which are interesting inter-mediate active compounds in the pharmacology industry.
Description
10779~5 The present invention relates to a new method for the direct manufacture of N - acyl derivatives of alpha - amino -gamma - keto acids. N - acyl derivatives of alpha - amino -gamma - keto acids are important compounds per se being natural occurring amino acids; they can easily be transformed into alpha - amino - gamma - hydroxy acids or into alpha, gamma-diamino acids. Another interesting reaction is their trans-formation into nitrogen - heterocyclic derivatives e.g. by treatment with hydrazine.
The known method for the preparation of alpha - amino -gamma - keto acids (described in Helv. Chimica Acta 35, 1952, 407) is based on the condensation of keto mono - bromides with sodium acetamino malon;c ester and a subsequent hydrolysis according to the following reactions :
R - CO - CH2Br + Na - C - NH - CO - CH3 I
2a N H2 Although a high yield is claimed to be obtained, the method has the drawback that the raw materials necessary are relatively expensive.
The synthesis of alpha - amino - gamma - hydroxy acids was recently reported (Liebigs Ann. Chem. 1973, 560-5) to be obtained by photochlorination and subsequent hydrolysis of amino acids such as leucine and isoleucine in strong aqueous ..~
.:' ~k -~r 1077~3~S
acids; yields of about 25~ are claimed to be obtained.
Besides the low yields obtained, this method involves complicated and expensive apparatus.
We have previously derived methods for the preparation of acyl derivatives of alpha - amino acids wherein an aromatic compound and an olefin with a definite formula respectively, is reacted with an adduct formed from a primary amide and glyoxylic acid or esters thereof.
It has now been found that N - acyl derivatives of alpha - amino - gamma - keto acids can be obtained in a similar manner using compounds containing active methylene groups, in the reaction with the same above adducts.
Thus, according to the invention there is provided a : method for the direct preparation of N-acyl derivatives of alpha-amino-gamma-keto acids of the formula ; R'CO
~ H-CH-COOH
X NHCOR
or RJ'vco_ ¢ wherein X is hydrogen or the group R"CO-1and wherein R' and R" may be the same or different and each represents an alkyl or aryl radical, and R is an alkyl, aryl, alkoxy or aryloxy radical; which comprises forming an adduct between a primary amide or primary carbamate of the formula wherein R is an alkyl, aryl, alkoxy or aryloxy radical, and glyocylic acid or an ester thereof and reacting the ; said adduct with a 1,3 dicarbonyl compound of the formula R'CO\
CH Z
y/
~ ~77~4S
wherein Y represents the group R"CO- or R"OCO-, R' and R"
may be the same or different and each represents an alkyl or aryl radical, and Z represents H when Y~is R"CO-, or Z
represents H or an alkyl group when Y is RAnOCO-.
The reaction involved between the adduct and 1, 3 diketones is a follows:
R'CO + HO - CH - COOH H R'CO\
/CH2 ¦ _ CH - CH - COOH
R"CO NH - COR R"CO NHCOR
Wherein: R' may be.equal or not equal to R", both being any alkyl or aryl such as CH3: C2H5, ,~ .
':
B
1~7~94S
-~henyl or their substituted derivatives, and R, is selected from among the aliphatic or aromatic radicals such as methyl, phenyl, benzyl, methoxy, ethoxy, butoxy etc.
Ihe reaction involved between the adduct and beta - ketoester is as follows :
R' CO 110 - CH - COOII R' CO-C112-CII-COOII
~ C~2 + I -- l I
R"O NII-COR Nl-lCOR
wherein: R', R" and R are the same as defined above.
R'CO - CH - ~1 COOII
The known method for the preparation of alpha - amino -gamma - keto acids (described in Helv. Chimica Acta 35, 1952, 407) is based on the condensation of keto mono - bromides with sodium acetamino malon;c ester and a subsequent hydrolysis according to the following reactions :
R - CO - CH2Br + Na - C - NH - CO - CH3 I
2a N H2 Although a high yield is claimed to be obtained, the method has the drawback that the raw materials necessary are relatively expensive.
The synthesis of alpha - amino - gamma - hydroxy acids was recently reported (Liebigs Ann. Chem. 1973, 560-5) to be obtained by photochlorination and subsequent hydrolysis of amino acids such as leucine and isoleucine in strong aqueous ..~
.:' ~k -~r 1077~3~S
acids; yields of about 25~ are claimed to be obtained.
Besides the low yields obtained, this method involves complicated and expensive apparatus.
We have previously derived methods for the preparation of acyl derivatives of alpha - amino acids wherein an aromatic compound and an olefin with a definite formula respectively, is reacted with an adduct formed from a primary amide and glyoxylic acid or esters thereof.
It has now been found that N - acyl derivatives of alpha - amino - gamma - keto acids can be obtained in a similar manner using compounds containing active methylene groups, in the reaction with the same above adducts.
Thus, according to the invention there is provided a : method for the direct preparation of N-acyl derivatives of alpha-amino-gamma-keto acids of the formula ; R'CO
~ H-CH-COOH
X NHCOR
or RJ'vco_ ¢ wherein X is hydrogen or the group R"CO-1and wherein R' and R" may be the same or different and each represents an alkyl or aryl radical, and R is an alkyl, aryl, alkoxy or aryloxy radical; which comprises forming an adduct between a primary amide or primary carbamate of the formula wherein R is an alkyl, aryl, alkoxy or aryloxy radical, and glyocylic acid or an ester thereof and reacting the ; said adduct with a 1,3 dicarbonyl compound of the formula R'CO\
CH Z
y/
~ ~77~4S
wherein Y represents the group R"CO- or R"OCO-, R' and R"
may be the same or different and each represents an alkyl or aryl radical, and Z represents H when Y~is R"CO-, or Z
represents H or an alkyl group when Y is RAnOCO-.
The reaction involved between the adduct and 1, 3 diketones is a follows:
R'CO + HO - CH - COOH H R'CO\
/CH2 ¦ _ CH - CH - COOH
R"CO NH - COR R"CO NHCOR
Wherein: R' may be.equal or not equal to R", both being any alkyl or aryl such as CH3: C2H5, ,~ .
':
B
1~7~94S
-~henyl or their substituted derivatives, and R, is selected from among the aliphatic or aromatic radicals such as methyl, phenyl, benzyl, methoxy, ethoxy, butoxy etc.
Ihe reaction involved between the adduct and beta - ketoester is as follows :
R' CO 110 - CH - COOII R' CO-C112-CII-COOII
~ C~2 + I -- l I
R"O NII-COR Nl-lCOR
wherein: R', R" and R are the same as defined above.
R'CO - CH - ~1 COOII
2 1 H2SO4 R' NHCOR ~ h (1) O ~ f Nll COR
(2) R' _ _ R'CO - C112 - CH - COO~I n ~HCOR Na B114 O ~ NH COR
(1) 0 In certain cases (e.g. using dibenzoyl methane) when strong acidic media such as concentrated sulfuric acid, is utilized as solvent, in the reaction between the adduct and tho 1, 3 diketone, one of the acyl groups R'CO or R"CO is removed during the reaction giving directly compounds of type (1).
~07'794S
:.
According to another enibodiment of the present invention, it is also possible to usc metnylene substituted beta - ~eto-esters in the reaction Witil the adduct, for exam~le ethyl alpha -methyl aceto-acetate reacts with hydroxyhippuric acid (in the prcsence of conc~ sulfuric acid) resulting in dimetnyl butenolide (~1 I C~-l ~ 3 O ~ ~ I~COPh \~
The dimethyl butenolide can be easily hydrogenated to butyrolactone ; C113 O ~ NllCOPh The butenolides (2) can also by themselves be catalytically hydrogenated to the corresponding butyrolactone (3~. The advantage : of this two-step transformation into the butyrolactone is that only one isomer is obtained in the catalytic hydrogenation whereas in the direct reduction of gamma keto-acids with Na BH4, a mixture of the isomeric lactones resulted.
According to another embodiment of the present invention, new compounds of N- acyl derivatives of alpha - amino - gamma -keto acids are described. These compounds are interesting 107~9~5 intermediate active compounds in the pharmacology - industry. Examples of such new compounds are:
N - benzoyl - 3, 5 dimethyl pyrazolylglycine, N - benzyloxy - carbonyl - 3, 5 - dimethyl pyrazolyl - 5 glycine; alpha - benzamido - beta - gamma - dimethyl alpha, beta, butenolide; alpha - benzyloxycarbonyl amino -beta - benzoyl levulinic acid; alpha - benz amido - gamma -oxovaleric acid; alpha - benzamido - beta - acetyl levulinic acid; alpha - benzyl-oxycarbonylamino - beta - acetyl levulinic acid; N - benzyl~oxycarbonyl - beta - beta -dibenzoylalanine ;
,:
, The term of primary amide as used in the present specification is meant to include the primary amides and primary carbamates such as: methyl, ethyl, butyl, benzyl etc.
. The method for the preparation of N - acyl derivatives of alpha - amino - gamma - keto acids according to the present invention, is very simply carried out and involves cheap starting raw materials such as glyoxylic acid, primary amides or carbamates and compounds containing active methylene ' groups.
.
The first step of the method is the adduct formation ,~ between glyoxylic acid or esters thereof and the primary - amides, adduct which can be considered as an amidoalkylating ' 25 reagent. The reaction involved is a simple additional reaction as follows :
- HO-CH-COOH
CHOCOOH.H O +
2 NH2COR ~ NHCOR
(Generally glyoxylic acid is encountered in the monohydrate form).
1077g45 Esters of glyoxylic acid will react in the same manner; no difficulties are encountered in this reaction wherein R represents a member which may be selected from among the aliphatic or aromatic radicals such as methyl, phenyl, benzyl, methoxy, ethoxy, butoxy etc.
The amidoalkylating reagent obtained reacts easily with the active methylene - containing compound, as shown in the reactions given above. The reactions are performed in the presence of an acid catalyst generally used in amidoalkylation. The preferred acidic catalyst is sulfuric acid, but any other acid catalyst utilized in amidoalkylation such as phosphoric acid, poly-phosphoric acid, formic acid, boron trifluoride, mixture of sulfuric acid and acetic acid may be successfully used. In some cases, the presence of an inert solvent is preferred; for instance in the case of benzyl carbamate, an adduct which is sensitive to strong acids (concentrated sulfuric acid), benzene and boron trifluoride etherate are utilized. A person skilled in the art will certainly know how to select the proper acidic catalyst in accordance with the reagents to be utilized. It was surprisingly found that the reaction of the glyoxylic acid derivatives with active methylene-containing compound, using a strong acid catalyst occur without any substantial side reaction or oxydation of the amidoalkylating reagent (adduct).
Active methylene-containing compounds are generally known to undergo alkylation reactions under basic conditions, but not under acidic conditions.
The method according to the present invention is very simple and, in addition to the use of cheap raw materials, the two reactions involved do not require any but normal conditions and standard equipment. The reaction between ~7 ~9~5 glyoxylic acid or its esters and tlle primary amide I~roceeds smoothly at ambient tem~erature and atmospheric pressure.
rne amide residue may be any aliphatic or aromatic group, all according to the acyl derivatives required to be produced.
; The reaction of the adduct with the active methylene-containing compound in the presence of an acidic catalyst also occurs smoothly at ambient temperature and atmospheric pressure without any substantial side reaction. Generally the ratio between the active methylene - containing compound and the adduct is 1 : 1 moles. A higher ratio of the active methylene - -containing compound may be used and is even desirable uy to ; about 4 moles to l mole of adduct, in order to reduce the reaction time and to increase the yield.
Another use of the N - acyl derivatives of alpha - amino -gamma - keto acid, is their direct transformation into nitrogen -heterocyclic derivatives e.g. pyrazolyglycine N ¦
HNI ~ CH-COOI-I
I NIICOR
Cl-13 wherein R may be phenyl or Ph CII20.
These derivatives are interesting intermediates active compounds in the pharmacology industry.
In order to further and fully illustrate the nature of this invention and the manner of practising it, the following examples ;; are presented for clearness of understanding only, and no limitation should be understood therefrom.
1~77~S
Bxan~ple 1 _ Preparation of alpha - benzamido - gamma - oxovaleric acid (alpha - benzamido levulinic acid) __ An amount of 1. 95 g. (0.01 mole) of alpha - hydroxy hippuric acid (prepared as described in U.S. application S.N. 634. 361 from benzamide, glyoxylic acid monohydrate and acetone) was dissolved in 10 mls of cold concentrated sulfuric acid. After that 4.64 g. (0.04 mole) of methyl acetoacetate were added upon cooliTIg. The mixture was stirred for 48 hours, poured into ice and extracted with ethyl acetate (three times with 100 mls). The ethyl acetate solution was extracted with a solution of 10% NaHC03, which upon acidificatlon, extraction ~ith ethyl acetate, evaporation of solvent and trituration with ether, yielded 1.11 g of alpha - benzamido - gamma ~ oxovaleric acid (44% yield) which had a mel~ing point of 138C. (from ethyl acetate - hexane). The heutral fraction, after removal of solvent and trituration with petroleum ether yielded methyl -alpha - benzamido - gamma - oxovalerate (1.06 g, 43.5% yield) with melting point 85-86C ~from hexane). Thus the overall yield ~ 20 is 87.5%.
:` :
By adding methanol prior to the reaction, it is possible to obtain the above ester as the only reaction product.
The alpha - benzamido - gamma - oxovaleric acid obtained could be easily transformed into the corresponding lactone. By dissolving the alpha - benzamido - gamma - oxovaleric acid in methanol and - reducing it with NaBH4,N - benzamido - gamma - valerolactone was obtained (as two diasteroisomers) with a yield of 92%. By several re-crystallization operations from ethyl acetate the less polar isomer was obtained in pure form, having a melting point of 139 C. Catalytic hydrogenation afforded the same lactone with a yield of 87%.
:
(2) R' _ _ R'CO - C112 - CH - COO~I n ~HCOR Na B114 O ~ NH COR
(1) 0 In certain cases (e.g. using dibenzoyl methane) when strong acidic media such as concentrated sulfuric acid, is utilized as solvent, in the reaction between the adduct and tho 1, 3 diketone, one of the acyl groups R'CO or R"CO is removed during the reaction giving directly compounds of type (1).
~07'794S
:.
According to another enibodiment of the present invention, it is also possible to usc metnylene substituted beta - ~eto-esters in the reaction Witil the adduct, for exam~le ethyl alpha -methyl aceto-acetate reacts with hydroxyhippuric acid (in the prcsence of conc~ sulfuric acid) resulting in dimetnyl butenolide (~1 I C~-l ~ 3 O ~ ~ I~COPh \~
The dimethyl butenolide can be easily hydrogenated to butyrolactone ; C113 O ~ NllCOPh The butenolides (2) can also by themselves be catalytically hydrogenated to the corresponding butyrolactone (3~. The advantage : of this two-step transformation into the butyrolactone is that only one isomer is obtained in the catalytic hydrogenation whereas in the direct reduction of gamma keto-acids with Na BH4, a mixture of the isomeric lactones resulted.
According to another embodiment of the present invention, new compounds of N- acyl derivatives of alpha - amino - gamma -keto acids are described. These compounds are interesting 107~9~5 intermediate active compounds in the pharmacology - industry. Examples of such new compounds are:
N - benzoyl - 3, 5 dimethyl pyrazolylglycine, N - benzyloxy - carbonyl - 3, 5 - dimethyl pyrazolyl - 5 glycine; alpha - benzamido - beta - gamma - dimethyl alpha, beta, butenolide; alpha - benzyloxycarbonyl amino -beta - benzoyl levulinic acid; alpha - benz amido - gamma -oxovaleric acid; alpha - benzamido - beta - acetyl levulinic acid; alpha - benzyl-oxycarbonylamino - beta - acetyl levulinic acid; N - benzyl~oxycarbonyl - beta - beta -dibenzoylalanine ;
,:
, The term of primary amide as used in the present specification is meant to include the primary amides and primary carbamates such as: methyl, ethyl, butyl, benzyl etc.
. The method for the preparation of N - acyl derivatives of alpha - amino - gamma - keto acids according to the present invention, is very simply carried out and involves cheap starting raw materials such as glyoxylic acid, primary amides or carbamates and compounds containing active methylene ' groups.
.
The first step of the method is the adduct formation ,~ between glyoxylic acid or esters thereof and the primary - amides, adduct which can be considered as an amidoalkylating ' 25 reagent. The reaction involved is a simple additional reaction as follows :
- HO-CH-COOH
CHOCOOH.H O +
2 NH2COR ~ NHCOR
(Generally glyoxylic acid is encountered in the monohydrate form).
1077g45 Esters of glyoxylic acid will react in the same manner; no difficulties are encountered in this reaction wherein R represents a member which may be selected from among the aliphatic or aromatic radicals such as methyl, phenyl, benzyl, methoxy, ethoxy, butoxy etc.
The amidoalkylating reagent obtained reacts easily with the active methylene - containing compound, as shown in the reactions given above. The reactions are performed in the presence of an acid catalyst generally used in amidoalkylation. The preferred acidic catalyst is sulfuric acid, but any other acid catalyst utilized in amidoalkylation such as phosphoric acid, poly-phosphoric acid, formic acid, boron trifluoride, mixture of sulfuric acid and acetic acid may be successfully used. In some cases, the presence of an inert solvent is preferred; for instance in the case of benzyl carbamate, an adduct which is sensitive to strong acids (concentrated sulfuric acid), benzene and boron trifluoride etherate are utilized. A person skilled in the art will certainly know how to select the proper acidic catalyst in accordance with the reagents to be utilized. It was surprisingly found that the reaction of the glyoxylic acid derivatives with active methylene-containing compound, using a strong acid catalyst occur without any substantial side reaction or oxydation of the amidoalkylating reagent (adduct).
Active methylene-containing compounds are generally known to undergo alkylation reactions under basic conditions, but not under acidic conditions.
The method according to the present invention is very simple and, in addition to the use of cheap raw materials, the two reactions involved do not require any but normal conditions and standard equipment. The reaction between ~7 ~9~5 glyoxylic acid or its esters and tlle primary amide I~roceeds smoothly at ambient tem~erature and atmospheric pressure.
rne amide residue may be any aliphatic or aromatic group, all according to the acyl derivatives required to be produced.
; The reaction of the adduct with the active methylene-containing compound in the presence of an acidic catalyst also occurs smoothly at ambient temperature and atmospheric pressure without any substantial side reaction. Generally the ratio between the active methylene - containing compound and the adduct is 1 : 1 moles. A higher ratio of the active methylene - -containing compound may be used and is even desirable uy to ; about 4 moles to l mole of adduct, in order to reduce the reaction time and to increase the yield.
Another use of the N - acyl derivatives of alpha - amino -gamma - keto acid, is their direct transformation into nitrogen -heterocyclic derivatives e.g. pyrazolyglycine N ¦
HNI ~ CH-COOI-I
I NIICOR
Cl-13 wherein R may be phenyl or Ph CII20.
These derivatives are interesting intermediates active compounds in the pharmacology industry.
In order to further and fully illustrate the nature of this invention and the manner of practising it, the following examples ;; are presented for clearness of understanding only, and no limitation should be understood therefrom.
1~77~S
Bxan~ple 1 _ Preparation of alpha - benzamido - gamma - oxovaleric acid (alpha - benzamido levulinic acid) __ An amount of 1. 95 g. (0.01 mole) of alpha - hydroxy hippuric acid (prepared as described in U.S. application S.N. 634. 361 from benzamide, glyoxylic acid monohydrate and acetone) was dissolved in 10 mls of cold concentrated sulfuric acid. After that 4.64 g. (0.04 mole) of methyl acetoacetate were added upon cooliTIg. The mixture was stirred for 48 hours, poured into ice and extracted with ethyl acetate (three times with 100 mls). The ethyl acetate solution was extracted with a solution of 10% NaHC03, which upon acidificatlon, extraction ~ith ethyl acetate, evaporation of solvent and trituration with ether, yielded 1.11 g of alpha - benzamido - gamma ~ oxovaleric acid (44% yield) which had a mel~ing point of 138C. (from ethyl acetate - hexane). The heutral fraction, after removal of solvent and trituration with petroleum ether yielded methyl -alpha - benzamido - gamma - oxovalerate (1.06 g, 43.5% yield) with melting point 85-86C ~from hexane). Thus the overall yield ~ 20 is 87.5%.
:` :
By adding methanol prior to the reaction, it is possible to obtain the above ester as the only reaction product.
The alpha - benzamido - gamma - oxovaleric acid obtained could be easily transformed into the corresponding lactone. By dissolving the alpha - benzamido - gamma - oxovaleric acid in methanol and - reducing it with NaBH4,N - benzamido - gamma - valerolactone was obtained (as two diasteroisomers) with a yield of 92%. By several re-crystallization operations from ethyl acetate the less polar isomer was obtained in pure form, having a melting point of 139 C. Catalytic hydrogenation afforded the same lactone with a yield of 87%.
:
3 07'79~S
Example 2 Preparation of alpha - benzamido - beta -acetyl levulinic acid _ _ In this Example acetylacetone was reacted with alpha -hydroxhippuric acid under the same experimental conditions as previously described. The amounts of reagents used are :
1.95 9 alpha - hydroxyhippuric acid (0.01 mole)
Example 2 Preparation of alpha - benzamido - beta -acetyl levulinic acid _ _ In this Example acetylacetone was reacted with alpha -hydroxhippuric acid under the same experimental conditions as previously described. The amounts of reagents used are :
1.95 9 alpha - hydroxyhippuric acid (0.01 mole)
4.0 9 acetyl acetylacetone (0.04 mole) 10 mls conc. sulfuric acid.
An amount of 1.6 9 alpha - benzamido - beta - acetyl -levulinic acid (60% yield) was obtained, which had melting i point 145C.
~' Example 3 Preparation of alpha - benzamido - beta -; 15 benzoylPropionic acid In this Example ethyl benzoylacetate was reacted with alpha - hydroxyhippuric acid under the same experimental conditions as in Example 1. The amounts of reagents used were :
1,95 g alpha - hydroxyhippuric acid and 7.8 g ethyl benzoylacetate (0.04 mole).
An amount of 1.95 9 of alpha - benzamido - beta -benzoylpropionic æid (65% yield) was obtained, which had melting point 181C.
Example 4 Preparation of alpha - benzamido - beta -benzoylpropionic acid In this Example benzoyl acetone was reacted with alpha -hydroxyhippuric acid under the same experimental conditions as in Example 1, the amounts of reagents used were :
.~' ?
.
1C177S~S
:.
1.95 g alpha - hydroxyhippuric acid and 6.4 g (0.04 mole) benzoyl acetone.
An amount of 1.72 g alpha - benzamido - beta-benzoylpropionic acid (54% yield) was obtained, which had melting point 181C.
~xample 5 Preparation of alpha - benzyloxycarbonylamino - beta - acetyl levulinic acid An amount of 2.25 g (0.01 mole) of the adduct alpha - hydro - N -` benzyloxycarbonylglycine was dissolved in 10 ml of a mixture sulfuricacid - acetic acid (10% by volume). The mixture was cooled to 0C while acetylacetone (4.0 g, 0.04 mole) was added. The reaction was stirred at ambient temperature for 48 hours, poured into ice and extracted with ethyl acetate. The product obtained melted at 126C, after crystallization from ethyl acetate - petroleum ether. The yield of product obtained was 50% (1.53 g).
~xample 6 ` Preparation of N - benzyloxycarbonyl - beta~- beta - dibenzoylalanine In this experiment 4.48 g (0.02 mole) of dibenzoyl methane were reacted with alpha - hydroxy - N - benzyloxycarbon_ylglycine (2.25 g, 0,01 mole) as described in ~xample S. An amount of 1.95 g (45% yield) of N - benzyloxycarbonyl - beta - beta - dibenzoyl alanine was obtained which had mclting point 165C.
'' .
.
.
" ' . . .
~077g45 Example 7 Preparation of alpha - benzyloxycarbonylamino - beta -benzoyl levulinic acid In this experiment 6.4 9 (0.04 mole) of benzoylacetone were reacted with alpha - hydroxy - N - benzyloxycarbony-glycine (2.25 9, 0.01 mole) as described in Example 5.
An amount of 2.01 9 (55% yield) of alpha - benzyloxy-carbonylamino - beta - benzoyl levulinic acid was obtained.
The melting point of the product was 124C.
Example 8 Preparation of N - benzoyl - 3, 5 - dimethyl pyrazolyglycine C~H3 HN ~ CH - COOH
CH3 NH - COPh :
An amount of 2.77 9 (0.01 mole) of alpha - benzamido - beta -acetyl levulinic acid (prepared as in Example 2) was refluxed with hydrazine hydrate (1. 1 9, 0.022 mole) in methanol (50 ml) for 24 hours. The methanol was removed in vacuum, and the residue dissolved in water (50 ml), acidified with phosphoric acid (10%) and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate, evaporated and the residue crystallized from ethyl acetate - petroleum ether.
The product obtained amounted to 2.2 9 (80% yield) having melting point 238C.
., :
1077~3~S
Example 9 Preparation of N - benzyloxycarbonyl - 3, 5 -dimethyl pyrazolyl ~lycine _ _ _ An amount of 3.07 9 (0.01 mole) of alpha - benzylox-carbonylamino - beta - acetyl levulinic acid (prepared as in Example 5) was reacted with 1.1 9 (0.022 mole) hydrazine as described ;n Example 8. The product obtained amounted to 2.52 9 (84% yield) having melting point 208C.
Example 10 Preparation of alpha - benzamido - beta - gamma -dimethyl alPha~ beta butenolide_ _ An amount of 2.88 g (0.02 mole) of ethyl alpha -methylacetoacetate was treated with 1.95 9 (0.01 mole) of hydroxyhippuric acid as described in Example 1. The neutral fraction gave the unsaturated lactone (yield 44%) which had melting point 144C. The reaction involved is as follows:
CH3 - CO-CH - COOC2H5 + HO - CH - COOH
CH3 HN - COPh ~ ~'~ NHCOPh O
The butenolide can be hydrogenated in the presence of Pd (over carbon) resulting the saturated lactone (melting point 125C).
, .
1~779~5 Example 11 . Preparation of alpha - benzamido - beta -methyl - gamma - ethyl - alPha~ beta - butenolide An amount of 3.16 9 (0.02 mole) of ethyl alpha - methyl -propionylacetate was treated with 1.95 9 (0.01 mole ) of hydroxy-hippuric acid as described in Example 1. The neutral fraction gave the unsaturated lactone (yield 47%) which had melting point . of 141C.
CH3 CH2 COCH - COOC2H5 + HO - CH - COOPh CH3 NHCOPh CH
CH3 - CH2` ~ 3 O ~ HCOPh !l .. o
An amount of 1.6 9 alpha - benzamido - beta - acetyl -levulinic acid (60% yield) was obtained, which had melting i point 145C.
~' Example 3 Preparation of alpha - benzamido - beta -; 15 benzoylPropionic acid In this Example ethyl benzoylacetate was reacted with alpha - hydroxyhippuric acid under the same experimental conditions as in Example 1. The amounts of reagents used were :
1,95 g alpha - hydroxyhippuric acid and 7.8 g ethyl benzoylacetate (0.04 mole).
An amount of 1.95 9 of alpha - benzamido - beta -benzoylpropionic æid (65% yield) was obtained, which had melting point 181C.
Example 4 Preparation of alpha - benzamido - beta -benzoylpropionic acid In this Example benzoyl acetone was reacted with alpha -hydroxyhippuric acid under the same experimental conditions as in Example 1, the amounts of reagents used were :
.~' ?
.
1C177S~S
:.
1.95 g alpha - hydroxyhippuric acid and 6.4 g (0.04 mole) benzoyl acetone.
An amount of 1.72 g alpha - benzamido - beta-benzoylpropionic acid (54% yield) was obtained, which had melting point 181C.
~xample 5 Preparation of alpha - benzyloxycarbonylamino - beta - acetyl levulinic acid An amount of 2.25 g (0.01 mole) of the adduct alpha - hydro - N -` benzyloxycarbonylglycine was dissolved in 10 ml of a mixture sulfuricacid - acetic acid (10% by volume). The mixture was cooled to 0C while acetylacetone (4.0 g, 0.04 mole) was added. The reaction was stirred at ambient temperature for 48 hours, poured into ice and extracted with ethyl acetate. The product obtained melted at 126C, after crystallization from ethyl acetate - petroleum ether. The yield of product obtained was 50% (1.53 g).
~xample 6 ` Preparation of N - benzyloxycarbonyl - beta~- beta - dibenzoylalanine In this experiment 4.48 g (0.02 mole) of dibenzoyl methane were reacted with alpha - hydroxy - N - benzyloxycarbon_ylglycine (2.25 g, 0,01 mole) as described in ~xample S. An amount of 1.95 g (45% yield) of N - benzyloxycarbonyl - beta - beta - dibenzoyl alanine was obtained which had mclting point 165C.
'' .
.
.
" ' . . .
~077g45 Example 7 Preparation of alpha - benzyloxycarbonylamino - beta -benzoyl levulinic acid In this experiment 6.4 9 (0.04 mole) of benzoylacetone were reacted with alpha - hydroxy - N - benzyloxycarbony-glycine (2.25 9, 0.01 mole) as described in Example 5.
An amount of 2.01 9 (55% yield) of alpha - benzyloxy-carbonylamino - beta - benzoyl levulinic acid was obtained.
The melting point of the product was 124C.
Example 8 Preparation of N - benzoyl - 3, 5 - dimethyl pyrazolyglycine C~H3 HN ~ CH - COOH
CH3 NH - COPh :
An amount of 2.77 9 (0.01 mole) of alpha - benzamido - beta -acetyl levulinic acid (prepared as in Example 2) was refluxed with hydrazine hydrate (1. 1 9, 0.022 mole) in methanol (50 ml) for 24 hours. The methanol was removed in vacuum, and the residue dissolved in water (50 ml), acidified with phosphoric acid (10%) and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate, evaporated and the residue crystallized from ethyl acetate - petroleum ether.
The product obtained amounted to 2.2 9 (80% yield) having melting point 238C.
., :
1077~3~S
Example 9 Preparation of N - benzyloxycarbonyl - 3, 5 -dimethyl pyrazolyl ~lycine _ _ _ An amount of 3.07 9 (0.01 mole) of alpha - benzylox-carbonylamino - beta - acetyl levulinic acid (prepared as in Example 5) was reacted with 1.1 9 (0.022 mole) hydrazine as described ;n Example 8. The product obtained amounted to 2.52 9 (84% yield) having melting point 208C.
Example 10 Preparation of alpha - benzamido - beta - gamma -dimethyl alPha~ beta butenolide_ _ An amount of 2.88 g (0.02 mole) of ethyl alpha -methylacetoacetate was treated with 1.95 9 (0.01 mole) of hydroxyhippuric acid as described in Example 1. The neutral fraction gave the unsaturated lactone (yield 44%) which had melting point 144C. The reaction involved is as follows:
CH3 - CO-CH - COOC2H5 + HO - CH - COOH
CH3 HN - COPh ~ ~'~ NHCOPh O
The butenolide can be hydrogenated in the presence of Pd (over carbon) resulting the saturated lactone (melting point 125C).
, .
1~779~5 Example 11 . Preparation of alpha - benzamido - beta -methyl - gamma - ethyl - alPha~ beta - butenolide An amount of 3.16 9 (0.02 mole) of ethyl alpha - methyl -propionylacetate was treated with 1.95 9 (0.01 mole ) of hydroxy-hippuric acid as described in Example 1. The neutral fraction gave the unsaturated lactone (yield 47%) which had melting point . of 141C.
CH3 CH2 COCH - COOC2H5 + HO - CH - COOPh CH3 NHCOPh CH
CH3 - CH2` ~ 3 O ~ HCOPh !l .. o
Claims (22)
1. A method for the direct preparation of N-acyl derivatives of alpha-amino-gamma-keto acids of the formula wherein X is hydrogen or the group R"CO- or R"OCO- and wherein R' and R" may be the same or different and each represents an alkyl or aryl radical, and R is an alkyl, aryl, alkoxy or aryloxy radical; which comprises forming an adduct between a primary amide or primary carbamate of the formula wherein R is an alkyl, aryl, alkoxy or aryloxy radical, and glyoxylic acid or an ester thereof and reacting the said adduct with a 1,3 dicarbonyl compound of the formula wherein Y represents the group R"CO- or R"OCO-, R' and R"
may be the same or different and each represents an alkyl or aryl radical, and Z represents H when Y is R"CO-, or Z
represents H or an alkyl group when Y is R"OCO-.
may be the same or different and each represents an alkyl or aryl radical, and Z represents H when Y is R"CO-, or Z
represents H or an alkyl group when Y is R"OCO-.
2. A method for the direct preparation of N - acyl derivatives of alpha - amino - gamma - keto acids according to Claim 1, wherein the acid catalyst is selected from sulfuric acid, boron trifluoride, phos-phoric acid and mixtures of sulfuric acid and acetic acid.
3. A method for the direct manufacture of N - acyl derivatives of alpha - amino - gamma - keto acids according to Claim 1, wherein the reaction between the adduct and the 1, 3 dicarbonyl compound is performed in the presence of an inert solvent.
4. A method for the direct manufacture of N - acyl derivatives of alpha - amino - gamma - keto acids according to claim 1, 2 or 3, wherein an excess of 1, 3 dicarbonyl compound is used in the reaction with the adduct.
5. A method for the manufacture of lactones having the formula wherein R', R and Z are as defined in claim 1, wherein the alpha - amino - gamma - keto acids obtained according to Claim 1 are cyclized and, if desired, catalytically hydrogenated.
6. A method for the manufacture of nitrogen heterocyclic derivatives having the formula wherein R' and R" are as defined in claim 1 and R may be Ph -or PhCH2O-, wherein the alpha - amino - gamma - keto acids obtained according to claim 1 are reacted with hydrazine.
7. A method according to claim 6 which comprises reacting alpha - benzamido - beta - acetyl levulinic acid with hydrazine hydrate in methanol to give N-benzoyl-3,5-dimethyl pyrazolylglycine.
8. A method according to claim 6 which comprises reacting alpha - benzyloxycarbonylamino - beta - acetyl levulinic acid with hydrazine hydrate in methanol to give n-benzyloxycarbonyl-3,5-dimethyl pyrazolyl glycine.
9. A method according to claim 5 which comprises reacting ethyl alpha - methylacetoacetate with hydroxy hippuric acid in the presence of sulfuric acid to give alpha -benzamido - beta - gamma - dimethyl alpha, beta butenolide.
10. A method according to claim 1 which comprises reacting benzoylacetone with alpha - hydroxy - N -benzyloxycarbonyl - glycine as said adduct in the presence of sulfuric acid to give alpha - benzyloxycarbonyl amino -beta - benzoyl levulinic acid.
11. A method according to claim 1 which comprises reacting alpha - hydroxy hippuric acid as said adduct with methyl acetoacetate in the presence of sulfuric acid to give alpha - benzamido - gamma - oxovaleric acid.
12. A method according to claim 1 which comprises reacting alpha - hydroxy hippuric acid as said adduct in the presence of sulfuric acid to give alpha - benzamido - beta - acetyl levulinic acid.
13. A method according to claim 1 which comprises reacting alpha - hydro - N -benzyloxycarbonylglycine as said adduct with acetylacetone in the presence of a mixture of sulfuric acid and acetic acid to give alpha -benzyloxycarbonylamino - beta - acetyl levulinic acid.
14. A method according to claim 1 which comprises reacting dibenzoylmethane with alpha - hydroxy - N -benzyloxycarbonylglycine as said adduct in the presence of a mixture of sulfuric acid and acetic acid to give N-benzyloxycarbonyl - beta, beta - dibenzoyl-alanine.
15. N - benzoyl - 3,5 dimethyl pyrazoylglycine, whenever prepared by the process of claim 7, or by an obvious chemical equivalent.
16. N - benzyloxycarbonyl - 3, 5 - dimethyl pyrazolyl glycine, whenever prepared by the process of claim 8 or by an obvious chemical equivalent.
17. Alpha - benzamido - beta - gamma - dimethyl alpha, beta butenolide, whenever prepared by the process of claim 9 or by an obvious chemical equivalent.
18. Alpha - benzyloxycarbonylamino - beta - benzoyl levulinic acid, whenever prepared by the process of claim 10 or by an obvious chemical equivalent.
19. Alpha - benzamido - gamma - oxovaleric acid, whenever prepared by the process of claim 11 or by an obvious chemical equivalent.
20. Alpha - benzamido - beta - acetyl levulinic acid, whenever prepared by the process of claim 12 or by an obvious chemical equivalent.
21. Alpha - benzyloxycarbonylamino - beta - acetyl levulinic acid, whenever prepared by the process of claim 13 or by an obvious chemical equivalent.
22. N - benzyloxycarbonyl - beta, beta - dibenzoylalanine, whenever prepared by the process of claim 14 or by an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL48047A IL48047A0 (en) | 1975-09-04 | 1975-09-04 | A method for the direct manufacture of n-acyl derivatives of alpha-amino ypsilon-keto acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077945A true CA1077945A (en) | 1980-05-20 |
Family
ID=11048439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA259,378A Expired CA1077945A (en) | 1975-09-04 | 1976-08-18 | Method for the direct manufacture of n-acyl derivatives of alpha-amino-gamma-keto acids and compounds thereof |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5233619A (en) |
| AU (1) | AU506345B2 (en) |
| BE (1) | BE845878A (en) |
| CA (1) | CA1077945A (en) |
| DE (1) | DE2639805A1 (en) |
| DK (1) | DK399676A (en) |
| ES (1) | ES450879A1 (en) |
| FR (1) | FR2322854A1 (en) |
| GB (1) | GB1547619A (en) |
| IL (1) | IL48047A0 (en) |
| LU (1) | LU75725A1 (en) |
| NL (1) | NL7609791A (en) |
| SE (1) | SE7609687L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH021494A (en) * | 1988-03-31 | 1990-01-05 | Yoshitomi Pharmaceut Ind Ltd | Removal of organic tin compound |
| CN115043753A (en) * | 2022-08-04 | 2022-09-13 | 东莞理工学院 | A kind of method for synthesizing 4-hydroxyvaleric acid amide with γ-valerolactone |
-
1975
- 1975-09-04 IL IL48047A patent/IL48047A0/en unknown
-
1976
- 1976-04-20 ES ES450879A patent/ES450879A1/en not_active Expired
- 1976-08-18 CA CA259,378A patent/CA1077945A/en not_active Expired
- 1976-08-25 AU AU17128/76A patent/AU506345B2/en not_active Expired
- 1976-09-02 NL NL7609791A patent/NL7609791A/en not_active Application Discontinuation
- 1976-09-02 GB GB36484/76A patent/GB1547619A/en not_active Expired
- 1976-09-02 SE SE7609687A patent/SE7609687L/en unknown
- 1976-09-03 FR FR7626678A patent/FR2322854A1/en not_active Withdrawn
- 1976-09-03 DE DE19762639805 patent/DE2639805A1/en not_active Withdrawn
- 1976-09-03 DK DK399676A patent/DK399676A/en unknown
- 1976-09-03 LU LU75725A patent/LU75725A1/xx unknown
- 1976-09-04 JP JP51105446A patent/JPS5233619A/en active Pending
- 1976-09-06 BE BE8000148A patent/BE845878A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU506345B2 (en) | 1979-12-20 |
| IL48047A0 (en) | 1975-11-25 |
| SE7609687L (en) | 1977-03-05 |
| BE845878A (en) | 1976-12-31 |
| AU1712876A (en) | 1978-03-02 |
| DE2639805A1 (en) | 1977-03-10 |
| JPS5233619A (en) | 1977-03-14 |
| ES450879A1 (en) | 1978-01-16 |
| FR2322854A1 (en) | 1977-04-01 |
| LU75725A1 (en) | 1977-06-15 |
| NL7609791A (en) | 1977-03-08 |
| DK399676A (en) | 1977-03-05 |
| GB1547619A (en) | 1979-06-27 |
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