CA1069933A - PREPARATION OF .alpha.-KETO CARBOXYAMIDES - Google Patents
PREPARATION OF .alpha.-KETO CARBOXYAMIDESInfo
- Publication number
- CA1069933A CA1069933A CA285,196A CA285196A CA1069933A CA 1069933 A CA1069933 A CA 1069933A CA 285196 A CA285196 A CA 285196A CA 1069933 A CA1069933 A CA 1069933A
- Authority
- CA
- Canada
- Prior art keywords
- water
- keto
- mole
- methyl
- carboxamides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
? -keto carboxamides of the general formula :
where R represents an aliphatic aromatic, aralkyl, alicyclic or heterocyclic radical,which may or may not be substituted, and is a residue derived from secondary or tertiary aliphatic or aromatic alcohols forming carbocations and selected from the group comprising :
tertiary pentyl alcohol cyclohexanol and benzyl alcohol
? -keto carboxamides of the general formula :
where R represents an aliphatic aromatic, aralkyl, alicyclic or heterocyclic radical,which may or may not be substituted, and is a residue derived from secondary or tertiary aliphatic or aromatic alcohols forming carbocations and selected from the group comprising :
tertiary pentyl alcohol cyclohexanol and benzyl alcohol
Description
~C~6~3~
A process for the manufacture of carboxylic acids from C~-keto carboxamides corresponding to the general formula: ~ ~
______ A -R-CO-CONH-C \ A~
(in which R represents an aliphatic, aromatic, aralkyl, ali-cyclic or heterocyclic radical, which may be ~ubstituted or un-substituted, w~ere A represents a hydrogen atom or an aliphatic or aralkyl radical, A' and A" each represent an aliphatic or aralkyl radical or form together, with the carbon atom to which ~;
they are connected, a cycloalkane residue), i3 described in applicant's Canadian patent No. 977,773.
These carboxamides which are indicated in the above mentionea patent a~ being novel products are derived from an extension of the so called Ritter reaction, namely the condensa-tion in an acid medium of secondary or tertiary alcohols with cyanhydrins to obtain d-hydroxycarboxamides easily convertable, by oxidation, into d-ketocarboxamides. Being provided thus with these startlng compounds, easily, economically and indus-trially available, due to this extension of the Ritter reaction, which compounds are moreover chemically stable, it is possible .
to obtain, by simple hydrolysis, as described in the above-mentioned patent, ~ -keto acids and this, exceptionally econo- :
mically in comparison with prior art technique~ also mentioned ~
in this patent. .: .
~ow, it is an object of the present invention to ;~
provide, more particularly within a class of ~-ketocarboxamides ~
of the general formula: `
R~CO-CO~H-C ~ A' ~ A"
and ~-hydroxycarboxamides of the general formula:
R-CHOH-CONH-C A' ~ A"
~, ~069933 ~where R, A, A', and A" have the above indicated significance), ., ~ .
the compounds corresponding to the formula in which ~
R has the above significance or represents more specially . ' , ,' , a secondary butyl radical ': :
,CH3 - CH
CH- , , . CH3 ' ' -~:
. an isobutyl radical . ,.,,'-~
CH-CH2- ~,.
: ' CH3 or an undecyl radical ' ' - , ,~
CH3-(CH2) ~o_ . ....
. / A
'15 -C _A' are resid,ues derived from the following primary, secondary and tert.iary alcoho].s (easily forming a carbocation) ~
, , methyl-2 butanol-2 or tertiary penty,l alcohol
A process for the manufacture of carboxylic acids from C~-keto carboxamides corresponding to the general formula: ~ ~
______ A -R-CO-CONH-C \ A~
(in which R represents an aliphatic, aromatic, aralkyl, ali-cyclic or heterocyclic radical, which may be ~ubstituted or un-substituted, w~ere A represents a hydrogen atom or an aliphatic or aralkyl radical, A' and A" each represent an aliphatic or aralkyl radical or form together, with the carbon atom to which ~;
they are connected, a cycloalkane residue), i3 described in applicant's Canadian patent No. 977,773.
These carboxamides which are indicated in the above mentionea patent a~ being novel products are derived from an extension of the so called Ritter reaction, namely the condensa-tion in an acid medium of secondary or tertiary alcohols with cyanhydrins to obtain d-hydroxycarboxamides easily convertable, by oxidation, into d-ketocarboxamides. Being provided thus with these startlng compounds, easily, economically and indus-trially available, due to this extension of the Ritter reaction, which compounds are moreover chemically stable, it is possible .
to obtain, by simple hydrolysis, as described in the above-mentioned patent, ~ -keto acids and this, exceptionally econo- :
mically in comparison with prior art technique~ also mentioned ~
in this patent. .: .
~ow, it is an object of the present invention to ;~
provide, more particularly within a class of ~-ketocarboxamides ~
of the general formula: `
R~CO-CO~H-C ~ A' ~ A"
and ~-hydroxycarboxamides of the general formula:
R-CHOH-CONH-C A' ~ A"
~, ~069933 ~where R, A, A', and A" have the above indicated significance), ., ~ .
the compounds corresponding to the formula in which ~
R has the above significance or represents more specially . ' , ,' , a secondary butyl radical ': :
,CH3 - CH
CH- , , . CH3 ' ' -~:
. an isobutyl radical . ,.,,'-~
CH-CH2- ~,.
: ' CH3 or an undecyl radical ' ' - , ,~
CH3-(CH2) ~o_ . ....
. / A
'15 -C _A' are resid,ues derived from the following primary, secondary and tert.iary alcoho].s (easily forming a carbocation) ~
, , methyl-2 butanol-2 or tertiary penty,l alcohol
2-CH3 H0-C _ ~H3, :,' :
'20 ~ CH3 cyclohexanol.
H2 ,H2 , C--C / , ' 25 H2 H2 or benzyl.~lcohol ~, , HOH2C- <~3 , . .
It is also an object of the present invention to ,' ''~
provide a process for the production of~ -keto. acids -'~
corresponding to the process described in the.previous. ~ .
patent,,utilizing the above-mentioned novel compounds.
.3. , .
.
, :-.~ ' .~ :.
~.
~6~33 ,, In order that the invention may be more clearly understood, the following examples are given by way o~
illustration but without belng considered as in any way limiting.
S EXAMPLE 1 : N-tert-buty ~ydroxy-2 methyl-4 pentan mide CH
CH3-CH-CH2-CHOH-CONH-C _ CH3 To 113 g (1 mole) of-hydroxy-2 methyl-4 penta-nonitrile and 111 g of methyl-2 propanol-2, 54 ml of 66 Bé (1 mole) ~ sulfuric acid is added in 1 hour.
The temperature rises ; it is cooled on an ice bath so as not to exceed 70C. It is then kept thus ~or 2 hours at 75C, then poured into 600 mi of ~later. A precipitate is formed which is filtered and washed wlth water until neutrality. After drying in the dessicator, 162.5 g, yield 87 %, ls obtained o~ a crude product melting at 70C
whlch can be recrystallised in three volumes o~ hexane :
MP = 77C
~nalysis ~or CloH21N02 M~= 187.285 C % H % N %
Calculated : 64.13 11.30- 7.48 -Found : 64.22 11.22 7.54 Infrared spectrum (KBr tablet) : bands at 3350 cm 1 (NH), 3260 cm 1 (OH), 1~35 cm 1 (CO), 1530 cm 1 (CONH). ;~
EXAMPLE 2 : N-tert-butyl-methyl-4 xo-2 pentanamide CH-CH2-CO-CONH-C ~ - CH
TO a solution o~ 187 g (1 mole) of N-tert-butyl hydroxy-2 methyl-4 pentanamlde in 375 ml of acetic acid, ; ls added, drop by drop, a solution of 83.35 g (1.25 equiva-.4.
~ ;9~33 -- lentS)of chromicanhydride dissolved in its weight of water.
At the start the tempera-ture rises fairly rapidly to 50C.
It is kept thus until the end of the addition at 50-60C
by means of an ice ba-th.
At the end of the addition, it is again kept for -an hour at 50C9 then allowed to cool, poured on t~ 500 ml of water, extracted with isopropyl ether and washed with water. After evaporation of the solvent the residue was .~.` distilled :~P 15 = 98-109C. 134.35 g, yield 72.5%, is~
obtained.
Analysis for CloHlgN02 ~J= 185.269 C% H% N% - ;~
Calculated : 64.83 10.34 7.56 Found : 64.68` 10.40 7.50 Infrared spectrum tfilm3 : bands at 3390 cm 1 tNH), 1715`cm (CONH), 1525 cm 1 (CONH).
2,4-dinitrophenyl hydrazone : MP = 125-7C (EtOH-H20).
AnalySis for cl6H23N5o5 M~r= 365.395 ` 20 ~ . C% H% N%
Calculated : 52.59 6.34 19.16 - Found : 52.65 6.44 19.12 XAMPLE 3 : ~ ethyl-4 oxo-2 pentanoic acid ~;;
CH3 \ ~ ;
CH-CH2-CO-COOH (ketoleucine) CH
185 g (1 mole) of N-tert-butyl methyl-4 oxo-2 pentanamidej 555 ml of 6N hydrochloric acid and 185 ml of .~ . , acetic acid are brought to reflux with stirring for 24 hours.
Af-ter cooling, it is extracted several times with ethyl ether, washed with water, dried over anhydrous ~ . ' . ` '' . .
. , , ~,.
~9~33 sodium sul~ate, distilled rapidly, and then rectified.
77 g~ yield 59.23%,BP13 ~ 84-6C, of the product is obtained which crystalizes on ice but melts at ambient temperature. ;
Analysis ~or C6H1003 MW= 130.15 ;
C% H% -Calculated : 55.37 7.74 -Found : 55.36 7.73 Infrared spectrum (film) : bands at 3220 cm 1 (OH), 1720 cm I (CO).
Sodium salt :
To 2 g of the acid dissolved in its own weight of water, are added 4N caustic soda up to neutrality. The-~
water is evaporated to dryness and the residue recrystal- ;
lized in acetone-water. The sodium salt is in the form of beautiful brilliant white plates. MP - about 218C
(Kofler bench). -Analysis for C6H903Na~= 152.13 C% H%
Calculated : 47.37 5.96 `~
Found : 47.35 6.03 2,4-dinitrophenyl hydrazone : MP = 180C ~ ~ ~
(benzene) ' Analysis for C12H1406N4 ~i= 310.272 C% H% N%
Calculated : 46.45 4.55 18.06 - Found : 46.31 4.52 17.99 Semicarbazone : MP = 201C (water) AnalysiS for C7H13N303 MW= 187.202 i ~l 30 C% H%N%
-~ Calculated : 44.91 7.00 22.45 ~ Found : 44.76 7.~2 22.55 - , ' ' , ', ' '`~
, . . . . . .. .
, ' ' . ` .
,,,, ,, ,,, . ... .. . ., ,.. , ., .; , . ~. .. . . , . ~
~69933 EXAMPLE 4 : N-ter-t-pentyl hydroxy-2 methyl-4 ~entanamide -
'20 ~ CH3 cyclohexanol.
H2 ,H2 , C--C / , ' 25 H2 H2 or benzyl.~lcohol ~, , HOH2C- <~3 , . .
It is also an object of the present invention to ,' ''~
provide a process for the production of~ -keto. acids -'~
corresponding to the process described in the.previous. ~ .
patent,,utilizing the above-mentioned novel compounds.
.3. , .
.
, :-.~ ' .~ :.
~.
~6~33 ,, In order that the invention may be more clearly understood, the following examples are given by way o~
illustration but without belng considered as in any way limiting.
S EXAMPLE 1 : N-tert-buty ~ydroxy-2 methyl-4 pentan mide CH
CH3-CH-CH2-CHOH-CONH-C _ CH3 To 113 g (1 mole) of-hydroxy-2 methyl-4 penta-nonitrile and 111 g of methyl-2 propanol-2, 54 ml of 66 Bé (1 mole) ~ sulfuric acid is added in 1 hour.
The temperature rises ; it is cooled on an ice bath so as not to exceed 70C. It is then kept thus ~or 2 hours at 75C, then poured into 600 mi of ~later. A precipitate is formed which is filtered and washed wlth water until neutrality. After drying in the dessicator, 162.5 g, yield 87 %, ls obtained o~ a crude product melting at 70C
whlch can be recrystallised in three volumes o~ hexane :
MP = 77C
~nalysis ~or CloH21N02 M~= 187.285 C % H % N %
Calculated : 64.13 11.30- 7.48 -Found : 64.22 11.22 7.54 Infrared spectrum (KBr tablet) : bands at 3350 cm 1 (NH), 3260 cm 1 (OH), 1~35 cm 1 (CO), 1530 cm 1 (CONH). ;~
EXAMPLE 2 : N-tert-butyl-methyl-4 xo-2 pentanamide CH-CH2-CO-CONH-C ~ - CH
TO a solution o~ 187 g (1 mole) of N-tert-butyl hydroxy-2 methyl-4 pentanamlde in 375 ml of acetic acid, ; ls added, drop by drop, a solution of 83.35 g (1.25 equiva-.4.
~ ;9~33 -- lentS)of chromicanhydride dissolved in its weight of water.
At the start the tempera-ture rises fairly rapidly to 50C.
It is kept thus until the end of the addition at 50-60C
by means of an ice ba-th.
At the end of the addition, it is again kept for -an hour at 50C9 then allowed to cool, poured on t~ 500 ml of water, extracted with isopropyl ether and washed with water. After evaporation of the solvent the residue was .~.` distilled :~P 15 = 98-109C. 134.35 g, yield 72.5%, is~
obtained.
Analysis for CloHlgN02 ~J= 185.269 C% H% N% - ;~
Calculated : 64.83 10.34 7.56 Found : 64.68` 10.40 7.50 Infrared spectrum tfilm3 : bands at 3390 cm 1 tNH), 1715`cm (CONH), 1525 cm 1 (CONH).
2,4-dinitrophenyl hydrazone : MP = 125-7C (EtOH-H20).
AnalySis for cl6H23N5o5 M~r= 365.395 ` 20 ~ . C% H% N%
Calculated : 52.59 6.34 19.16 - Found : 52.65 6.44 19.12 XAMPLE 3 : ~ ethyl-4 oxo-2 pentanoic acid ~;;
CH3 \ ~ ;
CH-CH2-CO-COOH (ketoleucine) CH
185 g (1 mole) of N-tert-butyl methyl-4 oxo-2 pentanamidej 555 ml of 6N hydrochloric acid and 185 ml of .~ . , acetic acid are brought to reflux with stirring for 24 hours.
Af-ter cooling, it is extracted several times with ethyl ether, washed with water, dried over anhydrous ~ . ' . ` '' . .
. , , ~,.
~9~33 sodium sul~ate, distilled rapidly, and then rectified.
77 g~ yield 59.23%,BP13 ~ 84-6C, of the product is obtained which crystalizes on ice but melts at ambient temperature. ;
Analysis ~or C6H1003 MW= 130.15 ;
C% H% -Calculated : 55.37 7.74 -Found : 55.36 7.73 Infrared spectrum (film) : bands at 3220 cm 1 (OH), 1720 cm I (CO).
Sodium salt :
To 2 g of the acid dissolved in its own weight of water, are added 4N caustic soda up to neutrality. The-~
water is evaporated to dryness and the residue recrystal- ;
lized in acetone-water. The sodium salt is in the form of beautiful brilliant white plates. MP - about 218C
(Kofler bench). -Analysis for C6H903Na~= 152.13 C% H%
Calculated : 47.37 5.96 `~
Found : 47.35 6.03 2,4-dinitrophenyl hydrazone : MP = 180C ~ ~ ~
(benzene) ' Analysis for C12H1406N4 ~i= 310.272 C% H% N%
Calculated : 46.45 4.55 18.06 - Found : 46.31 4.52 17.99 Semicarbazone : MP = 201C (water) AnalysiS for C7H13N303 MW= 187.202 i ~l 30 C% H%N%
-~ Calculated : 44.91 7.00 22.45 ~ Found : 44.76 7.~2 22.55 - , ' ' , ', ' '`~
, . . . . . .. .
, ' ' . ` .
,,,, ,, ,,, . ... .. . ., ,.. , ., .; , . ~. .. . . , . ~
~69933 EXAMPLE 4 : N-ter-t-pentyl hydroxy-2 methyl-4 ~entanamide -
3 \ ~ / CH2-CH3 CH-CH2-CHOH-CONH-C _ CH3 To 33.95 G (0.3 mole) of hydroxy-2 methyl-4 ;
pentanonitrile and 39.66 g (0.45 mole) of methyl-2 butanol-2 subjected to stirring, are added, drop by drop, in 15 to 20 minutes, 30 g (0.3 mole) of 66Bé sulfuric acid so as ;~
to keep the temperature at close to 50C. It is then heated for one hour at 50-60C, then poured into 225 ml of water. An oil is formed at the surface which is extracted with isopropyl ether (3 times 50 ml), then washed with water (4 times 25 ml), and distilled under vacuum after ; removal of the solvent.
BP15 = 166-7C. 49.89 g, yielcl 82.6%, of an oil is ob-tained which crystallizes on cooling. MP = 39-40C (in a capillary).
Analysis for CllH23N02 ~= 201.3 C% H% N%
i Calculated : 65.63 11.51 6.96 20~ Found : 65.75 11.36 6.86 -~
. Infrared spectrum (film) : bands at 3250-3360 ~ -cm 1 (OH and NH); 1640-1650 cm 1 (CONH). `;~
EXAMPLE 5 :-N-tert-pentyl methyl-4 oxo-2 pentanamide CH3 - / GH2 CH3 ~-To a solution of 49.89 g (0.2478 mole) of N-tert-pentyl hydroxy-2 methyl-4 pentanamide in 180 ml of acetic acid kept at about 50C by means of a cold bath, is added, ~ 30 in 25 minutes, a solution o~ 20.65 g (1.25 equivalent) of ; chromic anhydride in 20.65 ml of water.
, ~ , _ .. . . :
~ '~-" - '' ' ' '' : ' ,' .7.
- . .
:
~6g933 I-t is then kept for 4 hours at 60C and then allowed to cool ; 250 ml of water are added and the organic phase is extracted with isopropyl ether (3 -times 50 ml);
it is washed with water (4 times 50 ml) and dried on ; 5 sodium sul~ate. ;~
After elimination of the solvent, it is distilled:
~P14 = 110-~10.5C.
29.37 g, yielding 59.48%, is obtained.
Analysis ~or CllH21N02 ~= 199.297 `~
C% H% N%
Calculated : 66.29 10.62 7.03 ~-Found : 66.45 10.72 7.14 In~rared spectrum tfilm) : bands at 3400 cm ~NH), 1725 cm 1 (CO~,~1695 cm 1 (CONH), 1530 cm 1 (CoNHj. ;
2,4-dinitrophenyl hydrazone : MP = 122C (meth-anol-water).
Analysis for C17H25N505 ~= 381.433 C% H%N% -~
Calculated : 53.53 7.13 18.36 Found : 53.60 6.98 18.33 EXAMPLE 6 : Methyl-4-oxo-2 pentanoic acid > CH-CH2-CO-COOH (ketoleucine) 13.95 g (0.07 mole) of N-tert-pentyl methyl-4 oxo-2 pentanamide, 55.8 ml of a 6N hydrochloric acid solu-tion and 14 ml of acetic acid are brought to reflux for 48 hours. A~ter cooling, it is extracted with isoProPYl . . . . .
ether and then distilled after driving off the solvent.
B~5 = 85-92C. 3~97 g, yield 44%, is obtalned.
. In~rared spectrum superposable on that o~
the acid obtained in Example 3.
' ~ -~ . '' ' ' :
8. ~
. ~ ' ' ~ '.
6~933 Semicarbazone : MP = about 205C (water); its melting point is not lowered by mixing with that of -the ~
acid obtained in Example 3. ~ -EXAMPLE 7 : N-tert-butyl bydroxy-2 methyl-3 pentanamide To 113 g (1 mole) of hydroxy-2 methyl-3 penta-nonitrile and 111 g (1.5 mole) of methyi-2 propanol-2 is added, in one hour, 54 ml (1 mole) of 66Bé sul~uric acid with cooling on an ice bath in order not to exceed 70C, and it is then poured into 500 ml of cold water. A pre-clpitate is formed which i3 filtered, washed with-water until neutrality and dried to constant weight. There are obtained : 165.5 g, yield 88.5%, of crude product (MP =
about 50C) which can be purified by distillation o ;-12 = 147-150C, MP = 53C (Kofler bench). ~-AnalySis for C1OH21N~2 ~l= 187.287 , .
C% H% N% -Calculated : 64.13 11.30 7.48 Found : 64.11 11.30 7.41 Infrared spectrum (Nujol) : bands at 3260-3370 cm 1 (OH and NH), 1645 cm 1 (CO). :
-EXAMPLE 8 : N-tert-butyl methyl-3 oxo-2 pentanamide CH3-CH2 ~ CH2~CH3 -/ CH-CO-CONH-C CH
To a solution of 37.4 g (0.2 mole) of N-tert-butyl hydroxy-2 methyl-3 pentanamide in 75 ml of acetic , . .,:
acid, cooled by a cold water bath, is added in 30 minutes, - a solution of 16.6 g (1.25 equivalent) of chromic anhydride in 16;6 ml of water. The temperature rises to 55C,.
.9.
~6~933 It is then kept at this temperature for 4 hours and then -~
200 ml of water are added, the organic phase is extracted ` with isopropyl ether, it is washed successivel~ with water, with a 2N caustic soda solution, then again with water until neutrality. After evaporation of the solvent, It is distilled ~P17 = 100-104C.
There is obtained : 27.75 g of product ; yield = 76.5%.
Analysis for C1oH1gN02 M~= 185.269 C% H% N%
; :
- Calculated : 52.59% 6.34 19.16 Found : 52.55 6.35 19.26 Infrared spectrum (film) : bands at 3380 cm 1 (NH), 1730 cm 1 (CO), 1685 cm 1 (CONH), 1525 cm 1 (CONH).
.
2,4-dinitrophenyl hydrazone : MP = 107-8C
(alcohol-water) Analysis for C16H23N505 MW= 365.695 C% H% N%
Calculated : 52.596.34 19.16 - Found : 52.55 6.35 19.26 EXAMPLE 9 : Methyl-3 oxo-2 pentanoie acid CH-CO-COOH (keto Isoleucine) .:
. :.
18.5 g (0.1 mole) of N-tert-butyl methyl-3 oxo-2 ~ -~, .
pentanamide, 74 ml of a 6N hydrochloric acid solution and ` 18.5 ml of acetic acid are brought to reflux with stirring . ~.
for 24 hours.
It is then treated hot with a little carbon -black, filtered and extracted several times with ethyl ,~
ether. It is washed once with a little water9 then dried over anhydrous sodium sulfate. After having driven off the solvent, it is distilled and 9.1g of product is obtained,~
. .; ", . 10 .
.
' . ':
.
~06~g33 `
yield 70%,BP12 - 78-81C, which product cristallises;
MP = 35 40C.
Analysis for C6H1003 M~ =130.15 (Analysis -difficult to do, the product seems to become hydrated).
~: :
C% H~ .
Calculated :55.37 7.74 - -~
Found : 54.66 8.02 ~ -~
Infra-red spec-trum (Nujol) : bands at 3280cm 1 (OH), 1750 cm 1 (CO), 1725 cm 1 (COOH).
Sodium salt :
,: . .
To 2g of acid dissolved in its own volume of ~;-water, is added a 4N caustic soda solution until neutrality. ;~`
, The water is evaporated to dryness and the residue is recristallised from an acetone - water mixture or from . .
alcohol. 2g of beauti~ul white cristals of the sodiu~
salt are obtained.
Analysis for C6H903Na MW= 152.128 C% H% -! Calculated : 47.37% 5.96%
~ Found : 47.42% 5.96%
; - 2,4-dinitrophenyl hydrazone : MP = 171-2C (benzene~
Analysis for C12~14N206 MW= 310.27 ~;
C% H% N%
Calculated : 46.45% 4.55 18.06 Found o 46.05 4.57 17.79 Semicarbazone : MP = 138C (water) Analysis ~or C7H13N303 M~l= 187.202 C% H% N%
Calculated : 44.91 7.00 22.45 Found : 44~83 6.91 22.48 .. . .
.'11. ' ' ~' ` i :
~69~33 ~ E~AMPLE 10 : N-cyclohexyl hydroxy-2 methyl-3 ~ent_namide _ _ _ `` / CH2 - CH2 CH3 CH2 2 ~ I
; 5 To 11.3g (0;1 mole) o~ hydroxy-2 methyl-3 pentanonitrile and 15 g (0.15 mole) of cyclohexanol is added drop by drop for 15 minutes, 20 ml (0.16 mole) of boron trifluoride etherate, and it is then heatad to 75-80C
for 2 hoursO
It is then poured into 200ml of cold water. An , oil separates which is extracted with isopropyl ether, which has the effect o~ precipitating a solid which is drained, washecl wlth a little lsopropyl ether and dried.
6.2g of crystals are obtained : MP = 120C.
By evaporation of the isopropyl ether, an oil is obtained which, digested with petroleum ether, provides a second fraction of 2.3g; MP = 115-120C.
Total yield : 40%
This product can be recrystallised in 4 volumes ~ 20 of an ethanol-water mixture :1-1. MP = 120Cr i~ Analysis for C12H23N02 MW= 213.323 C% N% H% ~ ~ I
Calculated : 67 . 56 6.56 10. 87 - - -Found : 67.55 6.66 10. 85 ~ ~:
Infra-red spectrum (KBr pastille3 : bands at ~ ~;
3300 cm 1 (OH and NH)~ 1635 cm 1 (CONH) . ~`.
EXAMPLE-11 :-N-cyclohexyl methyl-3 oxo-2 pentanamlde `~ CH2 CH2 . . .` ~
CH3 CH2 \
CH-CO-CONH-HC \ CH2 ` `'`:' ;120 . ,; , ' ' ' ' ' ' ,.' ' ' , '. ' ~C~6~93,3 To a mixture of 32g (0.15 mole) of N-cyclohexyl hydrox~-2 methyl-3 pentan~mide and 60 ml of ace-tic acid, is added in 10 minutes a solution of 12.6 g (1.25 equiva- -lent) of chro~ic anhydride in 12 ml of water. The temperature rises~from t5 to 45C. It is then heated for
pentanonitrile and 39.66 g (0.45 mole) of methyl-2 butanol-2 subjected to stirring, are added, drop by drop, in 15 to 20 minutes, 30 g (0.3 mole) of 66Bé sulfuric acid so as ;~
to keep the temperature at close to 50C. It is then heated for one hour at 50-60C, then poured into 225 ml of water. An oil is formed at the surface which is extracted with isopropyl ether (3 times 50 ml), then washed with water (4 times 25 ml), and distilled under vacuum after ; removal of the solvent.
BP15 = 166-7C. 49.89 g, yielcl 82.6%, of an oil is ob-tained which crystallizes on cooling. MP = 39-40C (in a capillary).
Analysis for CllH23N02 ~= 201.3 C% H% N%
i Calculated : 65.63 11.51 6.96 20~ Found : 65.75 11.36 6.86 -~
. Infrared spectrum (film) : bands at 3250-3360 ~ -cm 1 (OH and NH); 1640-1650 cm 1 (CONH). `;~
EXAMPLE 5 :-N-tert-pentyl methyl-4 oxo-2 pentanamide CH3 - / GH2 CH3 ~-To a solution of 49.89 g (0.2478 mole) of N-tert-pentyl hydroxy-2 methyl-4 pentanamide in 180 ml of acetic acid kept at about 50C by means of a cold bath, is added, ~ 30 in 25 minutes, a solution o~ 20.65 g (1.25 equivalent) of ; chromic anhydride in 20.65 ml of water.
, ~ , _ .. . . :
~ '~-" - '' ' ' '' : ' ,' .7.
- . .
:
~6g933 I-t is then kept for 4 hours at 60C and then allowed to cool ; 250 ml of water are added and the organic phase is extracted with isopropyl ether (3 -times 50 ml);
it is washed with water (4 times 50 ml) and dried on ; 5 sodium sul~ate. ;~
After elimination of the solvent, it is distilled:
~P14 = 110-~10.5C.
29.37 g, yielding 59.48%, is obtained.
Analysis ~or CllH21N02 ~= 199.297 `~
C% H% N%
Calculated : 66.29 10.62 7.03 ~-Found : 66.45 10.72 7.14 In~rared spectrum tfilm) : bands at 3400 cm ~NH), 1725 cm 1 (CO~,~1695 cm 1 (CONH), 1530 cm 1 (CoNHj. ;
2,4-dinitrophenyl hydrazone : MP = 122C (meth-anol-water).
Analysis for C17H25N505 ~= 381.433 C% H%N% -~
Calculated : 53.53 7.13 18.36 Found : 53.60 6.98 18.33 EXAMPLE 6 : Methyl-4-oxo-2 pentanoic acid > CH-CH2-CO-COOH (ketoleucine) 13.95 g (0.07 mole) of N-tert-pentyl methyl-4 oxo-2 pentanamide, 55.8 ml of a 6N hydrochloric acid solu-tion and 14 ml of acetic acid are brought to reflux for 48 hours. A~ter cooling, it is extracted with isoProPYl . . . . .
ether and then distilled after driving off the solvent.
B~5 = 85-92C. 3~97 g, yield 44%, is obtalned.
. In~rared spectrum superposable on that o~
the acid obtained in Example 3.
' ~ -~ . '' ' ' :
8. ~
. ~ ' ' ~ '.
6~933 Semicarbazone : MP = about 205C (water); its melting point is not lowered by mixing with that of -the ~
acid obtained in Example 3. ~ -EXAMPLE 7 : N-tert-butyl bydroxy-2 methyl-3 pentanamide To 113 g (1 mole) of hydroxy-2 methyl-3 penta-nonitrile and 111 g (1.5 mole) of methyi-2 propanol-2 is added, in one hour, 54 ml (1 mole) of 66Bé sul~uric acid with cooling on an ice bath in order not to exceed 70C, and it is then poured into 500 ml of cold water. A pre-clpitate is formed which i3 filtered, washed with-water until neutrality and dried to constant weight. There are obtained : 165.5 g, yield 88.5%, of crude product (MP =
about 50C) which can be purified by distillation o ;-12 = 147-150C, MP = 53C (Kofler bench). ~-AnalySis for C1OH21N~2 ~l= 187.287 , .
C% H% N% -Calculated : 64.13 11.30 7.48 Found : 64.11 11.30 7.41 Infrared spectrum (Nujol) : bands at 3260-3370 cm 1 (OH and NH), 1645 cm 1 (CO). :
-EXAMPLE 8 : N-tert-butyl methyl-3 oxo-2 pentanamide CH3-CH2 ~ CH2~CH3 -/ CH-CO-CONH-C CH
To a solution of 37.4 g (0.2 mole) of N-tert-butyl hydroxy-2 methyl-3 pentanamide in 75 ml of acetic , . .,:
acid, cooled by a cold water bath, is added in 30 minutes, - a solution of 16.6 g (1.25 equivalent) of chromic anhydride in 16;6 ml of water. The temperature rises to 55C,.
.9.
~6~933 It is then kept at this temperature for 4 hours and then -~
200 ml of water are added, the organic phase is extracted ` with isopropyl ether, it is washed successivel~ with water, with a 2N caustic soda solution, then again with water until neutrality. After evaporation of the solvent, It is distilled ~P17 = 100-104C.
There is obtained : 27.75 g of product ; yield = 76.5%.
Analysis for C1oH1gN02 M~= 185.269 C% H% N%
; :
- Calculated : 52.59% 6.34 19.16 Found : 52.55 6.35 19.26 Infrared spectrum (film) : bands at 3380 cm 1 (NH), 1730 cm 1 (CO), 1685 cm 1 (CONH), 1525 cm 1 (CONH).
.
2,4-dinitrophenyl hydrazone : MP = 107-8C
(alcohol-water) Analysis for C16H23N505 MW= 365.695 C% H% N%
Calculated : 52.596.34 19.16 - Found : 52.55 6.35 19.26 EXAMPLE 9 : Methyl-3 oxo-2 pentanoie acid CH-CO-COOH (keto Isoleucine) .:
. :.
18.5 g (0.1 mole) of N-tert-butyl methyl-3 oxo-2 ~ -~, .
pentanamide, 74 ml of a 6N hydrochloric acid solution and ` 18.5 ml of acetic acid are brought to reflux with stirring . ~.
for 24 hours.
It is then treated hot with a little carbon -black, filtered and extracted several times with ethyl ,~
ether. It is washed once with a little water9 then dried over anhydrous sodium sulfate. After having driven off the solvent, it is distilled and 9.1g of product is obtained,~
. .; ", . 10 .
.
' . ':
.
~06~g33 `
yield 70%,BP12 - 78-81C, which product cristallises;
MP = 35 40C.
Analysis for C6H1003 M~ =130.15 (Analysis -difficult to do, the product seems to become hydrated).
~: :
C% H~ .
Calculated :55.37 7.74 - -~
Found : 54.66 8.02 ~ -~
Infra-red spec-trum (Nujol) : bands at 3280cm 1 (OH), 1750 cm 1 (CO), 1725 cm 1 (COOH).
Sodium salt :
,: . .
To 2g of acid dissolved in its own volume of ~;-water, is added a 4N caustic soda solution until neutrality. ;~`
, The water is evaporated to dryness and the residue is recristallised from an acetone - water mixture or from . .
alcohol. 2g of beauti~ul white cristals of the sodiu~
salt are obtained.
Analysis for C6H903Na MW= 152.128 C% H% -! Calculated : 47.37% 5.96%
~ Found : 47.42% 5.96%
; - 2,4-dinitrophenyl hydrazone : MP = 171-2C (benzene~
Analysis for C12~14N206 MW= 310.27 ~;
C% H% N%
Calculated : 46.45% 4.55 18.06 Found o 46.05 4.57 17.79 Semicarbazone : MP = 138C (water) Analysis ~or C7H13N303 M~l= 187.202 C% H% N%
Calculated : 44.91 7.00 22.45 Found : 44~83 6.91 22.48 .. . .
.'11. ' ' ~' ` i :
~69~33 ~ E~AMPLE 10 : N-cyclohexyl hydroxy-2 methyl-3 ~ent_namide _ _ _ `` / CH2 - CH2 CH3 CH2 2 ~ I
; 5 To 11.3g (0;1 mole) o~ hydroxy-2 methyl-3 pentanonitrile and 15 g (0.15 mole) of cyclohexanol is added drop by drop for 15 minutes, 20 ml (0.16 mole) of boron trifluoride etherate, and it is then heatad to 75-80C
for 2 hoursO
It is then poured into 200ml of cold water. An , oil separates which is extracted with isopropyl ether, which has the effect o~ precipitating a solid which is drained, washecl wlth a little lsopropyl ether and dried.
6.2g of crystals are obtained : MP = 120C.
By evaporation of the isopropyl ether, an oil is obtained which, digested with petroleum ether, provides a second fraction of 2.3g; MP = 115-120C.
Total yield : 40%
This product can be recrystallised in 4 volumes ~ 20 of an ethanol-water mixture :1-1. MP = 120Cr i~ Analysis for C12H23N02 MW= 213.323 C% N% H% ~ ~ I
Calculated : 67 . 56 6.56 10. 87 - - -Found : 67.55 6.66 10. 85 ~ ~:
Infra-red spectrum (KBr pastille3 : bands at ~ ~;
3300 cm 1 (OH and NH)~ 1635 cm 1 (CONH) . ~`.
EXAMPLE-11 :-N-cyclohexyl methyl-3 oxo-2 pentanamlde `~ CH2 CH2 . . .` ~
CH3 CH2 \
CH-CO-CONH-HC \ CH2 ` `'`:' ;120 . ,; , ' ' ' ' ' ' ,.' ' ' , '. ' ~C~6~93,3 To a mixture of 32g (0.15 mole) of N-cyclohexyl hydrox~-2 methyl-3 pentan~mide and 60 ml of ace-tic acid, is added in 10 minutes a solution of 12.6 g (1.25 equiva- -lent) of chro~ic anhydride in 12 ml of water. The temperature rises~from t5 to 45C. It is then heated for
4 hours at 60C and poured into 300 ml of cold water. A
precipitate is formed which, after draining, washing with water and drying, weighs : 31.3g, namely a crude yield of g9%. MP = 76-7C.
This product is recrystallisable in three volumes of a methanol-water mixture : 80-20, with a recrystallisation yield of 38%l MP = 79-80C. -~
Analysis for C12H21N02 MW- 211.295 ~ C~ H% N%
Calculated : 68.2110.02 6.63 Found : 68.17 9.90 6.70 Infra-red spectrum ~KBr pastille) : bands at 3300 cm 1 (NH), 1720 cm 1 (CO), 1660-1680 cm 1 (CONH), 1540 cm 1 (GONH).
` 20 EXAMPLE 12-: Methyl-3 oxo-2 pentanoic acid CH -CH
CH-CO-COOH (keto Isoleucine) CH
10.55 g (0.05 mole) of N-cyclohexyl methyl-3 oxo-2 pentanamide, 40 ml of a 6N hydrochloric acid solution and lOml of acetic acid are brought to reflux ~or 24 hours.
The mixture which is hetero~eneous at the start becomes homogeneous.
It is extracted several times with methylene chloride, the solvent is evaporated and it is distilled under the vacuum of a water pump.Bpl6 = 82-6C.
There is obtained : 3g, yield 46.10%, of an oil .13.
', . .
:
g33 which crystallises. MP - 38-40C. -~
- Infra-red spectrum (film) : bands at 1730 cm ~(COOH).
2,4-dinitrophenyl hydrazone : MP = ~72~C (acetic acid), its melting point is not lowered by mixing with that of the acid obtained in Example 9.
EX~MPLE 13 : N-ben~y~ hy~roxy-2 methyl-4 pentanamide / ~H~CH2~cH
To 17g (0.15 mole) of hydroxy-2 methyl-4 penta-nonitrile and 24 ml (0.225 mole) of benzyl alcohol, heated ~ ;
on an oil ba-th to 80C is added, in 45 minutes, 30ml (0.24 mole) of boron tri-fl~oride etherate. The temperature of the mixture rises to 100C. -It is then heated to 100C for 2 hours, then it is cooled and poured into lOOml of water. An oil is formed whi.ch is extracted with isopropyl ether. The isopropyl ether solution is washed successively with 2N soda, wi~th~
water, and a saturated sodium chloride solution, and then . ;
dried over sodium sulfate. After evaporation of the solvent, 30.9g of an oily product is obtained which crystallises in part in the presence of hexane. After ~iltration the crystals are recrystaliised in 3 to 4 volumes of isopropyl 25 ~ether. 4.8 g, yield 14.5% is obtained. MP= 95C.
Analysis for C13H1gN02 MW= 221.297 C% H% N%
Calculated : 70.55 8.65 6.33 Found : ?0.17 8.67 5.95 -Infra-re~ spectrum (KLr pas-tille) : bands at 3300-3350 cm 1 (OH and NH), 1645 cm 1 (CO), 1540 cm 1 ~CONH).
EXAMPLE 14-: N~benzyl methyl~4 oxo-2 ~_ntanamide . I ' ' . . ..
' ~";.
~6~933 ~ CH-CH2-CO-CONH-CH2 C~ ' '~
To a solution of 6.63 g (0.03 molej of N-benzyl hydroxy-2 methyl-4 pentanamide is added slowly a solution ~-~
of 2.5 g (1.25 equivalen-t) of chromic anhydride dissolved in its own weight of water. The temperature rises to 60C
and is kept there for the period of the addition. It is then heated for 4 hours on a water bath to G0C. After ' 1 10 cooling, 60 ml of water is added; a precipitate is formed which is drained, washed with water and dried in a dessicator.
, ~ *.
' 5.2 g of a fatty product is obtained. ~ ~
;~, This product is taken up again in 50 ml of !r isopropyl ether (which enables about 0.5g of insoluble product to be separated) and decolorised with animal black.
After evaporation to dryness there remained 3.0g of an `
: :. . . .
I oil which crystallised; MP = about 50-60C; crude yield :
!~ ~ 45.6%.
This product was purlfied by sublimation at ;~
1 100C under 13mm of mercury and finally recrystallised in petroleum ether. MP = 68-9C. This melting point is lowered to 61C by mixing with the product obtained in Example 13.
Thin layer chromatography on silica gel (eluant ~, CHCl3:90-MeOH:10) : the product has a single spot Rf = 0~8. ~ -Under the same conditions, for the product of Example 13, Rf = 0.375.
Analysis for C13H17N02 Ml~= 219.237 % -Calculated : 6.39 Found : 6.32 .15.
- , , ' ~61 69~33 Infra-red spectrum (KBr pastille) : bands at 3260 cm 1 (NH), 1720 cm 1 (CO)1 1670 cm-1 (CONH), 1535 cm 1 (CONH).
_AMPLE 15 : Hydrox~-2 tridecanonitrile CH3-(CH2)10-CHOH-CN
To a rnixture o~ 13.88g (0.102 mo]e) of mono-.
potassium acid phosphate in 30ml o~ water is added 18.43g (0.1 mole) of lauric aldehyde. By cooling on a ;
cold water bath so as not to exceed 20C,there is added, in 5 minutes, a solution o~ 7.16g (0.11 mole) o~ potassium cyanide in 30ml of water~ It is then stirred for 3 hours at room temperature, then extracted with ether .(50 times 2x25ml), the ether extracts are washed wlth 25ml of a ' 0.5N sulfuric acid solution, then with water until neutrality ~4x25ml) and dried over sodium sulfate.
After concentration to dryness, 21g is obtained '~ (theoretical yield) of an oil which crystallises slowly.
I MP - 39C (in a capillary).
' ,: .. .
~j ~ Analysis for C13H24NO MW= 211.35 ~; 20 C% N% H%
Calculated : 73.87 6.63 11.92 I ~ Found : 73.78 6.49 11.78 Literature : This cyanhydrin has been mentioned but not described : C.A. 63 17892c. It was obtained by :
~l 25 the action of cyanhydric acid on a mixture of aldehydes resulting from the reductive ozonization o~ petroselenic acid.
EXAM~LE 1~ : N-tert-butyl hydroxy-2 tridecanamide i . .
.:
CH3 ~ ~ -CH3~-(CH2)10-CHOH-CONH-C - CH3 -\ CH3 ~ ~;
To 15.28g (0.0723 mole) o~ hydroxy-2 tridecano~
' ' ' ~ .' .16.
`.:
, ~6~933 nitrile and lØ85g (0.108 mole) of methyl-2 propanol-2, is addcd in 5 minutes, with cooling on an ice bath, 4.05ml (0.0723 mole) of 66Be sulfuri.c acid. Stirring is then continued at room temperature for 1 hour and it is left until the following day, then heated for 1 hour on a water bath at 70C. -~
After cooling, it is extrac-ted with ether (4~50ml), the ether solution is washed with Q.5N soda (40ml), then with water until neutrali-ty (4x30ml), and dried over sodium sulfate. ~;
A~ter evaporation of the ether and distillation ,:
under nitrogen, 17g (yield 83%) of a thich liquid which crystallises, is obtained. , = 164-8C MP = 38-40C (in a capillary) Chromatography on a thin layer of silica gel (eluant hexane : 3-AcOH:1) : Rf = 0.3.
Analysis for C17H35N02 ~r~.~ 285.48 C% H% N%
. Calculated : 71.53 12.36 4.91 ` 20 Found : 71.60 -12.31 5.01 EXAMPLE 17 : N-tert-butyl oxo-2_trideca~amide , CH3 (cH2)lo~co-coN~-c _ CH3 To a solution of 5.71g (0.02 mole) of N-tert-butyl hydroxy-2 trid~anamide in 20ml of ether, 8 ml of water and then 4.90 ml of 66Be sulfuric acid is added.
To this heterogeneous mixture is added in 1 hour, keeping the temperature below 25C by means of an ice bath, a - 30 solution of 4.0g (0.0133 mole) of sodium dichromate dihydrate with vigorous stirring. The stirring is then ; continued at room temperature for 3 hours, then the,ether ' ' ~; ~
~6~33 phase ls decanted, the aqueous phase is extracted with ether (2x20ml), the combined ether solutions are washed wi-th 5ml of 2N soda solution, then with water until neutrality (4x5ml), then dried over sodium sulfate. After evaporation ~ ~-of the ether, it is distilled under nitrogen and 3.46g of product is obtained (yield 61%) an ~ PO 05 = 105 110C.
Chromatography on a thin layer of silica gel (eluant hexane:3-AcOH:l) : R-f = 0.35.
AnalySis for C17H33N2 i~W= 283.46 - 10 C% H% N% ~ ;
Calculated : 72.04 11.73 4.94 . Found : 72.14 11.68 5.02 `
2,4-dinitrophenyl hydrazone : MP= 77C (methanol) A l i for C H N O M~l-- 463.59 C/O H% N%
I Calculated : 59.59 8.05 15.11 -i Found : 59.49 8.08 15.20 EXAMPLE 18 : 0xo-2 ~ridecanoic acid ;
CH3 (CH2)10 1.417g (0.005 mole) of N-tert-butyl oxo-2 tri-decanamide, 14ml o~ acetic acid and 7ml of concentrated hydrochloric acid (d = 1.19) are heated to reflux for `
25 hours. A~ter cooling, the mixture is poured into 150ml of water with stirring : a precipitate is formed. After ;
filtration, washing with a little water and drying in a dessicator over potash, O.94g is obtained (crude yield 82.5%) of crystals melting at about 48C and which, after ~-2 recrystallisations in petroleum ether (~p= 35-60C), melt at 55-7C (in a capillary). There is obtained : 0.44g, yield 38.5%.
. .
Chromatography on a thin layer of silica gel ~ -(eluant hexane~3-AcOH:l), Rf = 0.25.
...
~8 969~33 Analysis for C13H2403 MW- 228.23 C% H%
Calculated : 68.38 10.59 Found : 68.45 10.54 Literature : this acid was ob-tained ~rom e-thyl laurate and from ethyl oxalate by :
- F. Adickes and G. Andersen, Ann. 555; 41-56 ! ".' tl943) (C.A. 38, 17338); and ~ Michizo Asano, Yoshio Arato and Skoici Ban, ;~
Ji Pharm. Soc. Japan 61, 220-8 (1941) ~C.A. ~ 1518i).
It goes wi~thout saying that the above examples .: -have only been given purely by way of il~tration and ;
are in no way limiting, and that any useful modification could be introduced without departing from the scope of the invention as detined by the appended claims.
.: :. . . .
~ :: ' . .,-;' ~ , :' '' ~ ' , ' ,,', .
, - ~ . :
, ~' , ' ,'~ "
-.~'.~' '.
' ~
.:
': , ,' ':
.. " ., ~.
, .19. ' ',' . '
precipitate is formed which, after draining, washing with water and drying, weighs : 31.3g, namely a crude yield of g9%. MP = 76-7C.
This product is recrystallisable in three volumes of a methanol-water mixture : 80-20, with a recrystallisation yield of 38%l MP = 79-80C. -~
Analysis for C12H21N02 MW- 211.295 ~ C~ H% N%
Calculated : 68.2110.02 6.63 Found : 68.17 9.90 6.70 Infra-red spectrum ~KBr pastille) : bands at 3300 cm 1 (NH), 1720 cm 1 (CO), 1660-1680 cm 1 (CONH), 1540 cm 1 (GONH).
` 20 EXAMPLE 12-: Methyl-3 oxo-2 pentanoic acid CH -CH
CH-CO-COOH (keto Isoleucine) CH
10.55 g (0.05 mole) of N-cyclohexyl methyl-3 oxo-2 pentanamide, 40 ml of a 6N hydrochloric acid solution and lOml of acetic acid are brought to reflux ~or 24 hours.
The mixture which is hetero~eneous at the start becomes homogeneous.
It is extracted several times with methylene chloride, the solvent is evaporated and it is distilled under the vacuum of a water pump.Bpl6 = 82-6C.
There is obtained : 3g, yield 46.10%, of an oil .13.
', . .
:
g33 which crystallises. MP - 38-40C. -~
- Infra-red spectrum (film) : bands at 1730 cm ~(COOH).
2,4-dinitrophenyl hydrazone : MP = ~72~C (acetic acid), its melting point is not lowered by mixing with that of the acid obtained in Example 9.
EX~MPLE 13 : N-ben~y~ hy~roxy-2 methyl-4 pentanamide / ~H~CH2~cH
To 17g (0.15 mole) of hydroxy-2 methyl-4 penta-nonitrile and 24 ml (0.225 mole) of benzyl alcohol, heated ~ ;
on an oil ba-th to 80C is added, in 45 minutes, 30ml (0.24 mole) of boron tri-fl~oride etherate. The temperature of the mixture rises to 100C. -It is then heated to 100C for 2 hours, then it is cooled and poured into lOOml of water. An oil is formed whi.ch is extracted with isopropyl ether. The isopropyl ether solution is washed successively with 2N soda, wi~th~
water, and a saturated sodium chloride solution, and then . ;
dried over sodium sulfate. After evaporation of the solvent, 30.9g of an oily product is obtained which crystallises in part in the presence of hexane. After ~iltration the crystals are recrystaliised in 3 to 4 volumes of isopropyl 25 ~ether. 4.8 g, yield 14.5% is obtained. MP= 95C.
Analysis for C13H1gN02 MW= 221.297 C% H% N%
Calculated : 70.55 8.65 6.33 Found : ?0.17 8.67 5.95 -Infra-re~ spectrum (KLr pas-tille) : bands at 3300-3350 cm 1 (OH and NH), 1645 cm 1 (CO), 1540 cm 1 ~CONH).
EXAMPLE 14-: N~benzyl methyl~4 oxo-2 ~_ntanamide . I ' ' . . ..
' ~";.
~6~933 ~ CH-CH2-CO-CONH-CH2 C~ ' '~
To a solution of 6.63 g (0.03 molej of N-benzyl hydroxy-2 methyl-4 pentanamide is added slowly a solution ~-~
of 2.5 g (1.25 equivalen-t) of chromic anhydride dissolved in its own weight of water. The temperature rises to 60C
and is kept there for the period of the addition. It is then heated for 4 hours on a water bath to G0C. After ' 1 10 cooling, 60 ml of water is added; a precipitate is formed which is drained, washed with water and dried in a dessicator.
, ~ *.
' 5.2 g of a fatty product is obtained. ~ ~
;~, This product is taken up again in 50 ml of !r isopropyl ether (which enables about 0.5g of insoluble product to be separated) and decolorised with animal black.
After evaporation to dryness there remained 3.0g of an `
: :. . . .
I oil which crystallised; MP = about 50-60C; crude yield :
!~ ~ 45.6%.
This product was purlfied by sublimation at ;~
1 100C under 13mm of mercury and finally recrystallised in petroleum ether. MP = 68-9C. This melting point is lowered to 61C by mixing with the product obtained in Example 13.
Thin layer chromatography on silica gel (eluant ~, CHCl3:90-MeOH:10) : the product has a single spot Rf = 0~8. ~ -Under the same conditions, for the product of Example 13, Rf = 0.375.
Analysis for C13H17N02 Ml~= 219.237 % -Calculated : 6.39 Found : 6.32 .15.
- , , ' ~61 69~33 Infra-red spectrum (KBr pastille) : bands at 3260 cm 1 (NH), 1720 cm 1 (CO)1 1670 cm-1 (CONH), 1535 cm 1 (CONH).
_AMPLE 15 : Hydrox~-2 tridecanonitrile CH3-(CH2)10-CHOH-CN
To a rnixture o~ 13.88g (0.102 mo]e) of mono-.
potassium acid phosphate in 30ml o~ water is added 18.43g (0.1 mole) of lauric aldehyde. By cooling on a ;
cold water bath so as not to exceed 20C,there is added, in 5 minutes, a solution o~ 7.16g (0.11 mole) o~ potassium cyanide in 30ml of water~ It is then stirred for 3 hours at room temperature, then extracted with ether .(50 times 2x25ml), the ether extracts are washed wlth 25ml of a ' 0.5N sulfuric acid solution, then with water until neutrality ~4x25ml) and dried over sodium sulfate.
After concentration to dryness, 21g is obtained '~ (theoretical yield) of an oil which crystallises slowly.
I MP - 39C (in a capillary).
' ,: .. .
~j ~ Analysis for C13H24NO MW= 211.35 ~; 20 C% N% H%
Calculated : 73.87 6.63 11.92 I ~ Found : 73.78 6.49 11.78 Literature : This cyanhydrin has been mentioned but not described : C.A. 63 17892c. It was obtained by :
~l 25 the action of cyanhydric acid on a mixture of aldehydes resulting from the reductive ozonization o~ petroselenic acid.
EXAM~LE 1~ : N-tert-butyl hydroxy-2 tridecanamide i . .
.:
CH3 ~ ~ -CH3~-(CH2)10-CHOH-CONH-C - CH3 -\ CH3 ~ ~;
To 15.28g (0.0723 mole) o~ hydroxy-2 tridecano~
' ' ' ~ .' .16.
`.:
, ~6~933 nitrile and lØ85g (0.108 mole) of methyl-2 propanol-2, is addcd in 5 minutes, with cooling on an ice bath, 4.05ml (0.0723 mole) of 66Be sulfuri.c acid. Stirring is then continued at room temperature for 1 hour and it is left until the following day, then heated for 1 hour on a water bath at 70C. -~
After cooling, it is extrac-ted with ether (4~50ml), the ether solution is washed with Q.5N soda (40ml), then with water until neutrali-ty (4x30ml), and dried over sodium sulfate. ~;
A~ter evaporation of the ether and distillation ,:
under nitrogen, 17g (yield 83%) of a thich liquid which crystallises, is obtained. , = 164-8C MP = 38-40C (in a capillary) Chromatography on a thin layer of silica gel (eluant hexane : 3-AcOH:1) : Rf = 0.3.
Analysis for C17H35N02 ~r~.~ 285.48 C% H% N%
. Calculated : 71.53 12.36 4.91 ` 20 Found : 71.60 -12.31 5.01 EXAMPLE 17 : N-tert-butyl oxo-2_trideca~amide , CH3 (cH2)lo~co-coN~-c _ CH3 To a solution of 5.71g (0.02 mole) of N-tert-butyl hydroxy-2 trid~anamide in 20ml of ether, 8 ml of water and then 4.90 ml of 66Be sulfuric acid is added.
To this heterogeneous mixture is added in 1 hour, keeping the temperature below 25C by means of an ice bath, a - 30 solution of 4.0g (0.0133 mole) of sodium dichromate dihydrate with vigorous stirring. The stirring is then ; continued at room temperature for 3 hours, then the,ether ' ' ~; ~
~6~33 phase ls decanted, the aqueous phase is extracted with ether (2x20ml), the combined ether solutions are washed wi-th 5ml of 2N soda solution, then with water until neutrality (4x5ml), then dried over sodium sulfate. After evaporation ~ ~-of the ether, it is distilled under nitrogen and 3.46g of product is obtained (yield 61%) an ~ PO 05 = 105 110C.
Chromatography on a thin layer of silica gel (eluant hexane:3-AcOH:l) : R-f = 0.35.
AnalySis for C17H33N2 i~W= 283.46 - 10 C% H% N% ~ ;
Calculated : 72.04 11.73 4.94 . Found : 72.14 11.68 5.02 `
2,4-dinitrophenyl hydrazone : MP= 77C (methanol) A l i for C H N O M~l-- 463.59 C/O H% N%
I Calculated : 59.59 8.05 15.11 -i Found : 59.49 8.08 15.20 EXAMPLE 18 : 0xo-2 ~ridecanoic acid ;
CH3 (CH2)10 1.417g (0.005 mole) of N-tert-butyl oxo-2 tri-decanamide, 14ml o~ acetic acid and 7ml of concentrated hydrochloric acid (d = 1.19) are heated to reflux for `
25 hours. A~ter cooling, the mixture is poured into 150ml of water with stirring : a precipitate is formed. After ;
filtration, washing with a little water and drying in a dessicator over potash, O.94g is obtained (crude yield 82.5%) of crystals melting at about 48C and which, after ~-2 recrystallisations in petroleum ether (~p= 35-60C), melt at 55-7C (in a capillary). There is obtained : 0.44g, yield 38.5%.
. .
Chromatography on a thin layer of silica gel ~ -(eluant hexane~3-AcOH:l), Rf = 0.25.
...
~8 969~33 Analysis for C13H2403 MW- 228.23 C% H%
Calculated : 68.38 10.59 Found : 68.45 10.54 Literature : this acid was ob-tained ~rom e-thyl laurate and from ethyl oxalate by :
- F. Adickes and G. Andersen, Ann. 555; 41-56 ! ".' tl943) (C.A. 38, 17338); and ~ Michizo Asano, Yoshio Arato and Skoici Ban, ;~
Ji Pharm. Soc. Japan 61, 220-8 (1941) ~C.A. ~ 1518i).
It goes wi~thout saying that the above examples .: -have only been given purely by way of il~tration and ;
are in no way limiting, and that any useful modification could be introduced without departing from the scope of the invention as detined by the appended claims.
.: :. . . .
~ :: ' . .,-;' ~ , :' '' ~ ' , ' ,,', .
, - ~ . :
, ~' , ' ,'~ "
-.~'.~' '.
' ~
.:
': , ,' ':
.. " ., ~.
, .19. ' ',' . '
Claims (2)
1. .alpha. -keto carboxamides of the general formula:
where R is selected from the group comprising the secondary butyl radical the isobutyl radical and the undecyl radical CH3 - (CH2)10-and is a residue derived from secondary or tertiary aliphatic or aromatic alcohols forming carbocations and selected from the group comprising:
tertiary pentyl alcohol cyclohexanol and benzyl alcohol useful in the manufacture of ? -keto-carboxylic acids of the formula R-CO-COOH, where R has the above significance, by hydrolysis of said carboxamides.
where R is selected from the group comprising the secondary butyl radical the isobutyl radical and the undecyl radical CH3 - (CH2)10-and is a residue derived from secondary or tertiary aliphatic or aromatic alcohols forming carbocations and selected from the group comprising:
tertiary pentyl alcohol cyclohexanol and benzyl alcohol useful in the manufacture of ? -keto-carboxylic acids of the formula R-CO-COOH, where R has the above significance, by hydrolysis of said carboxamides.
2. Process for the preparation of ? -keto carboxamides according to claim 1, comprising condensing the corresponding secondary or tertiary alcohols with cyanhydrins to obtain the ? -hydroxy-carboxamides and oxidising the latter to the ? -keto carboxamides.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7625516A FR2362824A2 (en) | 1976-08-23 | 1976-08-23 | NEW PROCESS FOR THE PREPARATION OF A-KETONIC CARBOXYLIC ACIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1069933A true CA1069933A (en) | 1980-01-15 |
Family
ID=9177076
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA285,196A Expired CA1069933A (en) | 1976-08-23 | 1977-08-22 | PREPARATION OF .alpha.-KETO CARBOXYAMIDES |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5340715A (en) |
| BE (1) | BE857819R (en) |
| CA (1) | CA1069933A (en) |
| CH (1) | CH613182A5 (en) |
| DE (1) | DE2738016C3 (en) |
| ES (1) | ES461846A2 (en) |
| FR (1) | FR2362824A2 (en) |
| GB (1) | GB1557101A (en) |
| IT (1) | IT1116782B (en) |
| NL (1) | NL179276C (en) |
| SE (1) | SE7709105L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2733181B2 (en) * | 1977-07-22 | 1979-08-30 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt | Process for the preparation of N-substituted α-ketocarboxamides |
-
1976
- 1976-08-23 FR FR7625516A patent/FR2362824A2/en active Granted
-
1977
- 1977-08-11 SE SE7709105A patent/SE7709105L/en not_active Application Discontinuation
- 1977-08-16 BE BE180199A patent/BE857819R/en not_active IP Right Cessation
- 1977-08-18 CH CH1014877A patent/CH613182A5/en not_active IP Right Cessation
- 1977-08-18 NL NL7709120A patent/NL179276C/en active Search and Examination
- 1977-08-22 CA CA285,196A patent/CA1069933A/en not_active Expired
- 1977-08-22 JP JP10038177A patent/JPS5340715A/en active Pending
- 1977-08-23 ES ES461846A patent/ES461846A2/en not_active Expired
- 1977-08-23 GB GB3520677A patent/GB1557101A/en not_active Expired
- 1977-08-23 DE DE19772738016 patent/DE2738016C3/en not_active Expired
- 1977-08-23 IT IT6890077A patent/IT1116782B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FR2362824B2 (en) | 1979-03-02 |
| DE2738016B2 (en) | 1980-09-25 |
| NL179276C (en) | 1986-08-18 |
| NL179276B (en) | 1986-03-17 |
| CH613182A5 (en) | 1979-09-14 |
| JPS5340715A (en) | 1978-04-13 |
| DE2738016A1 (en) | 1978-03-02 |
| DE2738016C3 (en) | 1981-06-04 |
| BE857819R (en) | 1978-02-16 |
| GB1557101A (en) | 1979-12-05 |
| IT1116782B (en) | 1986-02-10 |
| FR2362824A2 (en) | 1978-03-24 |
| SE7709105L (en) | 1978-02-24 |
| NL7709120A (en) | 1978-02-27 |
| ES461846A2 (en) | 1978-12-16 |
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