USRE31260E - Process for the preparation of an acetonitrile derivative - Google Patents

Process for the preparation of an acetonitrile derivative Download PDF

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Publication number
USRE31260E
USRE31260E US06/163,702 US16370280A USRE31260E US RE31260 E USRE31260 E US RE31260E US 16370280 A US16370280 A US 16370280A US RE31260 E USRE31260 E US RE31260E
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US
United States
Prior art keywords
propyl
temperature
sodium
process according
acetonitrile
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Expired - Lifetime
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US06/163,702
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English (en)
Inventor
Michel Chignac
Claude Grain
Charles Pigerol
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Sanofi Aventis France
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Labaz SA
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Assigned to SANOFI reassignment SANOFI CERTIFIED COPY OF MERGER BY NOTARY,PARIS, FRANCE SHOWING MERGER OF ASSIGNORS AND CHANGE OF NAME OF THE SURVIVING CORPORATION FILED ON DECEMBER 29, 1979 AND OCTOBER 21, 1980. (IN FRENCH WITH ENGLISH TRANSLATION ATTACHED. Assignors: LABAZ COMPANY (INTO), OMNIUM FINANCIER AQUITAINE POUR L'HYGIENE ET LA SANTE (CHANGED TO)
Anticipated expiration legal-status Critical
Assigned to SANOFI-SYNTHELABO reassignment SANOFI-SYNTHELABO ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SANOFI
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles

Definitions

  • the present invention relates generally to a novel process for the preparation of an acetonitrile derivative and also to the derivative obtained by this process.
  • the invention is particularly concerned with a novel process for the preparation of di-n-propyl acetonitrile of formula: ##STR3##
  • Di-n-propyl acetonitrile is a known product which is of particular interest for the preparation of compounds having pharmacological properties.
  • di-n-propyl acetonitrile can be used for the preparation of di-n-propyl acetamide, which has extremely valuable neuropsychotropic properties, as described in B.S.M. (French Special Medicament Patent) No. 2442 M.
  • Di-n-propyl acetamide can be easily prepared with excellent yields, of the order of 83%, when starting from the di-n-propyl acetonitrile, by hydrolysing this latter compound, for example, by means of an aqueous solution of 75to 80% sulphuric acid and at a temperature between 80° and 130° C.
  • MARSHALL prepares diisopropyl acetonitrile from a cyanacetic ester, by treating with sodium an alcoholic solution of this ester and by causing this mixture to react for several hours with an excess of isopropyl iodide.
  • the monoalkylated product is eliminated by means of a 10% sodium hydroxide solution and the crude dialkyl ester obtained by this procedure is then treated with a 35% potassium hydroxide solution for 16 hours.
  • the diisopropyl cyanacetic acid obtained is decarboxylated by distillation in the presence of twice its weight of molten potassium hydroxide.
  • BROWN and collaborators obtain diisopropyl acetonitrile first of all by treating, with isopropyl iodide, a solution of cyanacetic ester in n-propanol containing sodium n-propylate, this being effected by refluxing for 2 hours, and then by again adding sodium n-propylate in n-propanol and isopropyl iodide.
  • the reaction medium is once again heated under reflux for 3 hours, the monoalkylated product is eliminated by a 10% sodium hydroxide solution and the diisopropyl cyanacetic ester is then distilled several times in the presence of twice its weight of potassium hydroxide.
  • NEWMAN and collaborators prepare diisopropyl acetonitrile by first of all carrying out a reaction, under reflux for 3 hours, of ethyl cyanacetate with isopropyl iodide in the presence of sodium ethylate in ethanolic medium, further adding sodium ethylate and then isopropyl iodide and once again heating the reaction medium under reflux for 3 hours.
  • di-n-propyl acetonitrile can be obtained in accordance with such a process which can be used industrially, starting from a cyanacetic ester.
  • di-n-propyl acetonitrile is prepared by reacting, in one single stage and in a n-propanol medium, an ester of cyanacetic acid of the general formula: ##STR4## in which R represents an alkyl radical having from 1 to 4 carbon atoms, preferably a methyl or ethyl radical, with n-propyl bromide or n-propyl iodide in the presence of sodium n-propylate, then by saponifying the crude ester thus obtained with a 10 to 20% by weight solution of potassium hydroxide or sodium hydroxide and by acidifying the salt thus formed with a strong acid, such as for example hydrochloric acid, to obtain the crude di-n-propyl cyanacetic acid, which is decarboxylated by heating to a temperature between 140° C. and 190° C., this yielding the di-n-propyl acetonitrile.
  • R represents an alkyl radical having from 1 to 4 carbon atom
  • the starting-products of formula II are either known products which have been mentioned in the foregoing publications, or products which can be obtained by known methods.
  • the reactants are utilised by adding, at a temperature between 45° C. and 55° C., the sodium n-propylate in n-propanol medium to a reaction medium which comprises the cyanacetic ester and the n-propyl halide.
  • the alkylation reaction is then carried out under reflux for about 3 hours.
  • Saponification of the crude di-n-propyl cyanacetic ester is preferably carried out at a temperature between 60° and 70° C. over a period of 3 hours in the proportion of 1.25 to 2 mols of hydroxide/mol of ester, and the subsequent acidification is effected, for example, with a 36% hydrochloric acid solution, at a temperature slightly lower than 40° C.
  • the saponification phase can be carried out in presence of a quaternary ammonium salt such as, for example, trimethyl cetylammonium bromide, benzyl trimethyl ammonium chloride or lauryl trimethyl ammonium bromide.
  • a quaternary ammonium salt such as, for example, trimethyl cetylammonium bromide, benzyl trimethyl ammonium chloride or lauryl trimethyl ammonium bromide.
  • concentration of quaternary ammonium salt may vary from 0.005 mol to 0.1 mol/mol of di-n-propyl cyanacetic ester.
  • Temperature as regards saponification and the time necessary for this operation will vary as a function of the quantity of quaternary ammonium salt used.
  • this latter will be carried out on the crude di-n-propyl cyanacetic acid at a temperature between 140° and 190° C. and preferably between 175° and 190° C.
  • the decarboxylation of the di-n-propyl cyanacetic acid can be carried out in one continuous phase. After the acid concerned is brought to a temperature of 185°-190° C. and the decarboxylation reaction initiated, di-n-propyl cyanacetic acid is continuously introduced, with simultaneous elimination of the liberated carbon dioxide gas and of the di-n-propyl acetonitrile which forms.
  • the process of the invention provides indisputable advantages as compared with the processes disclosed in the previously mentioned prior art.
  • the process of the invention offers the possibility of obtaining considerable yields of pure di-n-propyl acetonitrile, the yields being at least 80% as compared with the initial cyanacetic ester, whereas with the processes suggested by the prior art, it has not been possible to obtain yields higher than 50% with respect to the same starting ester.
  • the process of the invention is definitely more simple than those of MARSHALL, BROWN and collaborators, or NEWMAN and collaborators, referred to above.
  • the process of the invention permits the alkylation phase to be carried out in one single operation, comprising a single use of the n-propyl halide and alkali metal n-propylate.
  • the time which is necessary for this operation will be advantageously reduced in the presence of a quaternary ammonium salt, for example, the trimethyl cetylammonium bromide.
  • a quaternary ammonium salt for example, the trimethyl cetylammonium bromide.
  • This quaternary ammonium salt offers in addition the advantage of reducing the danger of hydrolysis of the nitrile function of the di-n-propyl cyanacetic ester.
  • the decarboxylation phase of the known processes involves the necessity, apart from a raising of the temperature, of adding a supplementary product, either potassium hydroxide or copper powder.
  • the decarboxylation phase occurs simply by heating the di-n-propyl cyanacetic acid.
  • the processes suggested by the prior art envisage the elimination of the monoalkylated product after the alkylation phase, this being effected by means of 10% potassium hydroxide.
  • the alkylation phase as envisaged within the scope of the process according to the invention renders unnecessary the intermediate purification of the di-n-propyl cyanacetic ester, which may be used in its crude form.
  • the use of the alkylation reactants in accordance with the invention permits the content of valeronitrile in the final di-n-propyl acetonitrile to be very substantially reduced, this content passing from approximately 3.6% to only 0.3% according to the invention.
  • the process according to the invention avoids this disadvantage and, at the same time, an intermediate purification of the crude di-n-propyl cyanacetic acid.
  • the dialkylation phase of the process according to the invention combined with the decarboxylation stage of the di-n-propyl cyanacetic acid by being melted with twice its weight of 85% potassium hydroxide, at a temperature between 190° and 360° C., in accordance with the procedure proposed by MARSHALL, only supplied 11% of di-n-propyl acetonitrile with respect to the cyanacetic ester used.
  • MARSHALL MARSHALL
  • a sodium n-propylate solution was prepared from 7.42 g (0.322 mol) of sodium and 180 ml of anhydrous n-propanol, by heating with gentle reflux until complete dissolution of the sodium.
  • the crude ester obtained in this way was then treated with a solution of 7.5 g of flaked sodium hyroxide in 67.5 ml of water.
  • the mixture was introduced into a 250 ml spherical flask, equipped with a condenser, and then the reaction medium was slowly brought to 60°-70° C. This temperature was maintained for 3 hours, whereafter the mixture was cooled to about 50° C. and the ethanol which had formed and the residue of n-propanol were eliminated under a pressure of 70 mm.Hg.
  • the solution thus obtained was cooled to 20° C. and acidified, while stirring, by addition of 26.25 g of 36% hydrochloric acid. During this operation, the temperature of the reaction medium was kept below 40° C.
  • Decarboxylation commenced at a temperature in the region of 140° C.
  • the mixture was then brought to reflux temperature, that is to say, to about 160° C. and then to 190° C. in 2 hours. This temperature was maintained until the release of gas was completed, this taking 2 hours.
  • the di-n-propyl acetonitrile thus formed was then slowly distilled and the fraction passing over between 165° C. and 175° C. was collected. A second distillation was then carried out.
  • n-propylate was prepared from 50 g (2 at.g +10%) of sodium and 804 g (1000 ml) of anhydrous n-propanol, by heating to 50°-55° C. for 60 to 90 minutes.
  • the mixture was brought to reflux for 1 hour, was then cooled to about 50° C., and thereafter the residual alcohols were eliminated under reduced pressure (50 to 100 mm.Hg).
  • the solution obtained was cooled and then acidified, without exceeding 40° C., by means of 175 g of 36% hydrochloric acid.
  • the mixture was maintained in this state for 30 minutes and then the di-n-propyl cyanacetic acid was decanted.
  • the lower aqueous layer was extracted with 250 g of toluene.
  • the two organic phases were combined, washed once with 100 g of purified water and the solvent eliminated by distillation under reduced pressure, to obtain 154.5 g of crude di-n-propyl cyanacetic acid.
  • the speed of introduction was regulated as a function of the speed of distillation of the nitrile, while the temperature of the mass was maintained at 185°-190° C.
  • the operation of introduction lasted for about 41/2 hours, during which 40.9 kg of crude di-n-propyl acetonitrile were recovered. Distillation was continued by gradually raising the temperature of the mass to 206° C. and until the operation was completed. This operation lasted 6 hours, during which there were recovered 16.350 kg and then a further 8.980 kg of crude di-n-propyl acetonitrile.
  • the apparatus was brought under reduced pressure (about 100 mm.Hg) and a new fraction of 1.640 kg of di-n-propyl acetonitrile was collected.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US06/163,702 1977-03-15 1980-06-27 Process for the preparation of an acetonitrile derivative Expired - Lifetime USRE31260E (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7707587A FR2383920A1 (fr) 1977-03-15 1977-03-15 Procede de preparation d'un derive d'acetonitrile et derive obtenu par ce procede
FR7707587 1977-03-15

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US80034677A Continuation 1977-05-25 1977-05-25
US05/904,461 Reissue US4155929A (en) 1977-05-25 1978-05-10 Process for the preparation of an acetonitrile derivative

Publications (1)

Publication Number Publication Date
USRE31260E true USRE31260E (en) 1983-05-31

Family

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US06/163,702 Expired - Lifetime USRE31260E (en) 1977-03-15 1980-06-27 Process for the preparation of an acetonitrile derivative

Country Status (34)

Country Link
US (1) USRE31260E (en, 2012)
JP (1) JPS53112813A (en, 2012)
AR (1) AR212999A1 (en, 2012)
AT (1) AT351012B (en, 2012)
AU (1) AU504487B2 (en, 2012)
BE (1) BE854486A (en, 2012)
CA (1) CA1068302A (en, 2012)
CH (1) CH603563A5 (en, 2012)
CS (1) CS196365B2 (en, 2012)
DD (1) DD129904A5 (en, 2012)
DE (1) DE2721265C2 (en, 2012)
DK (1) DK158038C (en, 2012)
ES (1) ES467125A1 (en, 2012)
FI (1) FI65232C (en, 2012)
FR (1) FR2383920A1 (en, 2012)
GB (1) GB1522450A (en, 2012)
GR (1) GR60808B (en, 2012)
HU (1) HU175110B (en, 2012)
IE (1) IE45345B1 (en, 2012)
IL (1) IL52021A (en, 2012)
IN (1) IN145220B (en, 2012)
IT (1) IT1080764B (en, 2012)
LU (1) LU77305A1 (en, 2012)
MX (1) MX4779E (en, 2012)
NL (1) NL173747C (en, 2012)
NO (1) NO144067C (en, 2012)
NZ (1) NZ184326A (en, 2012)
OA (1) OA05696A (en, 2012)
PL (1) PL108183B1 (en, 2012)
PT (1) PT66542B (en, 2012)
SE (1) SE441596B (en, 2012)
SU (1) SU715017A3 (en, 2012)
YU (1) YU40674B (en, 2012)
ZA (1) ZA773779B (en, 2012)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2470758A1 (fr) 1979-12-07 1981-06-12 Sanofi Sa Procede pour la fixation de groupes alkyles sur une chaine carbonee portant un groupe fonctionnel
JP5036111B2 (ja) * 2001-08-20 2012-09-26 旭化成イーマテリアルズ株式会社 置換シクロペンタジエンの製造方法
DE102008036495A1 (de) 2008-08-04 2010-02-11 Langhals, Heinz, Prof. Dr. Persistente Pery-Imid-Radikalanionen als NIR-Farbstoffe
US9050302B2 (en) 2013-03-01 2015-06-09 Jazz Pharmaceuticals Ireland Limited Method of administration of gamma hydroxybutyrate with monocarboxylate transporters

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE186739C (en, 2012) *

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Brown et al., J.A.C.S., (1955), 77, pp. 1083-1089. *
Hessler et al., J.A.C.S., (1921), 43, pp. 205-208. *
Marshal, J. Chem. Soc., (1930), pp. 2754-2761. *
Newman et al., J.A.C.S., (1958), 80, pp. 6350-6355. *
Newman et al., J.A.C.S., (1960), 82, pp. 873-875. *

Also Published As

Publication number Publication date
IE45345B1 (en) 1982-08-11
IT1080764B (it) 1985-05-16
DE2721265C2 (de) 1982-05-19
LU77305A1 (en, 2012) 1977-08-24
PL108183B1 (pl) 1980-03-31
GR60808B (en) 1978-08-30
GB1522450A (en) 1978-08-23
FR2383920B1 (en, 2012) 1980-12-05
YU40674B (en) 1986-04-30
IN145220B (en, 2012) 1978-09-09
CS196365B2 (en) 1980-03-31
FI771781A7 (fi) 1978-09-16
NO144067B (no) 1981-03-09
OA05696A (fr) 1981-05-31
ZA773779B (en) 1978-05-30
NL173747C (nl) 1984-03-01
AU504487B2 (en) 1979-10-18
JPS5735868B2 (en, 2012) 1982-07-31
IE45345L (en) 1978-09-15
IL52021A0 (en) 1977-07-31
AU2626377A (en) 1979-01-04
AT351012B (de) 1979-07-10
NL7705562A (nl) 1978-09-19
MX4779E (es) 1982-09-15
DD129904A5 (de) 1978-02-15
DE2721265A1 (de) 1978-09-21
FR2383920A1 (fr) 1978-10-13
DK158038B (da) 1990-03-19
AR212999A1 (es) 1978-11-30
BE854486A (fr) 1977-11-14
NL173747B (nl) 1983-10-03
DK195877A (da) 1978-09-16
SE7705257L (sv) 1978-09-16
JPS53112813A (en) 1978-10-02
ES467125A1 (es) 1978-11-01
PT66542B (en) 1978-10-18
FI65232B (fi) 1983-12-30
HU175110B (hu) 1980-05-28
PL198559A1 (pl) 1978-10-09
SU715017A3 (ru) 1980-02-05
CH603563A5 (en, 2012) 1978-08-31
NO771576L (no) 1978-09-18
CA1068302A (en) 1979-12-18
ATA423077A (de) 1978-12-15
DK158038C (da) 1990-08-13
NO144067C (no) 1981-06-17
PT66542A (en) 1977-06-01
NZ184326A (en) 1979-03-16
SE441596B (sv) 1985-10-21
YU149077A (en) 1982-10-31
IL52021A (en) 1980-07-31
FI65232C (fi) 1984-04-10

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Free format text: CERTIFIED COPY OF MERGER BY NOTARY,PARIS, FRANCE SHOWING MERGER OF ASSIGNORS AND CHANGE OF NAME OF THE SURVIVING CORPORATION FILED ON DECEMBER 29, 1979 AND OCTOBER 21, 1980. (IN FRENCH WITH ENGLISH TRANSLATION ATTACHED.;ASSIGNORS:LABAZ COMPANY (INTO);OMNIUM FINANCIER AQUITAINE POUR L HYGIENE ET LA SANTE (CHANGED TO);REEL/FRAME:004343/0123

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