CH626341A5 - Process for the stereospecific synthesis of N-substituted pyrrolidines and their use - Google Patents
Process for the stereospecific synthesis of N-substituted pyrrolidines and their use Download PDFInfo
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- CH626341A5 CH626341A5 CH4181A CH4181A CH626341A5 CH 626341 A5 CH626341 A5 CH 626341A5 CH 4181 A CH4181 A CH 4181A CH 4181 A CH4181 A CH 4181A CH 626341 A5 CH626341 A5 CH 626341A5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
Description
La présente invention a pour objet un procédé de synthèse stéréospécifique de Pyrrolidines N-substituées optiquement actives et l'utilisation de ces Pyrrolidines pour l'obtention de benzamides optiquement actifs portant un substituant pyrrolidinylméthyle. The subject of the present invention is a process for the stereospecific synthesis of optically active N-substituted pyrrolidines and the use of these pyrrolidines for obtaining optically active benzamides carrying a pyrrolidinylmethyl substituent.
On connaissait déjà des dérivés de la Pyrrolidine de formule proche de celle des composés qui peuvent être obtenus selon la présente invention (demande de brevet allemand publiée sans examen No 1966215) et l'on savait aussi procéder à la séparation d'une Pyrrolidine racémique (demande de brevet allemand publiée sans examen No 1795712). Pyrrolidine derivatives with a formula similar to that of the compounds which can be obtained according to the present invention were already known (German patent application published without examination No. 1966215) and it was also known to separate a racemic pyrrolidine ( German patent application published without examination No 1795712).
Les Pyrrolidines N-substituées obtenues selon la procédé de l'invention répondent aux formules symétriques suivantes I (R) et I (S): The N-substituted pyrrolidines obtained according to the process of the invention correspond to the following symmetrical formulas I (R) and I (S):
Les benzamides II sont des composés doués d'activité thérapeutique et ont déjà été décrits. Benzamides II are compounds with therapeutic activity and have already been described.
Les Pyrrolidines I (R) et I (S) dans lesquelles R est un alkyle peuvent conduire aux benzamides II' suivants: Pyrrolidines I (R) and I (S) in which R is an alkyl can lead to the following benzamides II ':
co-nh-ch ir co-nh-ch ir
CV CV
h h
N NOT
ch„nh, ch „nh,
ch2nh2 ch2nh2
dans lesquelles R représente, in which R represents,
soit un radical alkyle CH2Ri de 1 à 5 atomes de carbone, Ri ayant de 1 à 4 atomes de carbone ou étant un atome d'hydrogène, soit un radical de formule a - either an CH2Ri alkyl radical of 1 to 5 carbon atoms, Ri having from 1 to 4 carbon atoms or being a hydrogen atom, or a radical of formula a -
dans lequel A est une chaîne alkylène linéaire ou ramifiée de 1 à 4 atomes de carbone, et in which A is a linear or branched alkylene chain of 1 to 4 carbon atoms, and
R2, R3 et R4 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène, un atome d'halogène, notamment de chlore ou de fluor, un radical trifluorométhyle, trifluorométhoxy, trifluorométhylthio, alkyle de 1 à 4 atomes de carbone ou alcoxy de 1 à 4 atomes de carbone, R2, R3 and R4 each represent, independently of one another, a hydrogen atom, a halogen atom, in particular of chlorine or fluorine, a trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl atom of 1 to 4 atoms carbon or alkoxy of 1 to 4 carbon atoms,
soit un radical de formule either a radical of formula
(CH^^CH-A- (CH ^^ CH-A-
dans lequel A est une chaîne alkylène linéaire ou ramifiée de 1 à 4 atomes de carbone et m est 2, 3,4 ou 5. in which A is a linear or branched alkylene chain of 1 to 4 carbon atoms and m is 2, 3,4 or 5.
Les composés de formule I sont des intermédiaires de synthèse, utilisables notamment dans la préparation des benzamides substitués optiquement actifs de formule II: The compounds of formula I are synthesis intermediates, usable in particular in the preparation of the optically active substituted benzamides of formula II:
- nh - - nh -
och. och.
k k
15 dans laquelle R est un alkyle de 1 à 5 atomes de carbone, B est un atome d'hydrogène ou un alkyle de 1 à 5 atomes de carbone et C, D et E représentent un atome d'hydrogène, un atome d'halogène, un radical alcoxy de 1 à 5 atomes de carbone, un radical nitro, un radical amino, alkylamino, dialkylamino ou alcanoylamino, un 2o radical acyle de 1 à 5 atomes de carbone, le radical cyano, un radical sulfamoyle, alkylsulfamoyle ou dialkylsulfamoyle, un radical alkyl-sulfonyle, un radical trihalogénométhyle, un radical alkylthio, un radical polyfluoroalkyle ou un radical polyfluoroalkylsulfonyle. In which R is an alkyl of 1 to 5 carbon atoms, B is a hydrogen atom or an alkyl of 1 to 5 carbon atoms and C, D and E represent a hydrogen atom, a halogen atom , an alkoxy radical of 1 to 5 carbon atoms, a nitro radical, an amino, alkylamino, dialkylamino or alkanoylamino radical, a 2o acyl radical of 1 to 5 carbon atoms, the cyano radical, a sulfamoyl, alkylsulfamoyl or dialkylsulfamoyl radical, an alkyl-sulfonyl radical, a trihalomethyl radical, an alkylthio radical, a polyfluoroalkyl radical or a polyfluoroalkylsulfonyl radical.
La configuration absolue des énantiomères de formule I (R) et I 25 (S) a été établie par filiation continue entre le L-prolinol dont la configuration absolue est connue et l'énantiomère lévogyre I (S) (—). The absolute configuration of the enantiomers of formula I (R) and I 25 (S) was established by continuous filiation between L-prolinol whose absolute configuration is known and the levorotatory enantiomer I (S) (-).
Le L-prolinol possède une configuration absolue (S) (Sinister) d'après la règle de Cahn, Ingold et Prélog, puisque dérivant de la L-proline dont la configuration (S) a été déterminée par une étude aux 30 rayons X (Buckingham et al., «Comm.», 1969, 583). L-prolinol has an absolute configuration (S) (Sinister) according to the rule of Cahn, Ingold and Prélog, since deriving from L-proline whose configuration (S) was determined by an X-ray study ( Buckingham et al., "Comm.", 1969, 583).
La suite des réactions chimiques, n'intervenant pas sur la configuration absolue du carbone asymétrique et son appellation (R) ou (S) dans le cadre des règles Cahn, Ingold et Prélog, ne peut donc conduire qu'à l'énantiomère I (S) qui mènera lui-même au dérivé II 35 (S). The sequence of chemical reactions, not intervening in the absolute configuration of asymmetric carbon and its designation (R) or (S) within the framework of the Cahn, Ingold and Prélog rules, can therefore only lead to the enantiomer I ( S) which will itself lead to derivative II 35 (S).
La titulaire a mis au point un procédé de synthèse stéréo-spécifique qui permet d'obtenir les énantiomères (R) ou (S) de formules (I) et (II). The licensee has developed a stereo-specific synthesis process which makes it possible to obtain the (R) or (S) enantiomers of formulas (I) and (II).
Le procédé de l'invention est défini dans la revendication 1 et il 40 est représenté ci-après par un schéma réactionnel. The process of the invention is defined in claim 1 and is shown below by a reaction scheme.
( Voir page suivante) ( See next page)
45 45
50 50
Dans le schéma réactionnel, les significations sont les suivantes: R'=soit Rj (H ou alkyle de 1 à 4 atomes de carbone) In the reaction scheme, the meanings are as follows: R '= either Rj (H or alkyl of 1 to 4 carbon atoms)
soit is
II II
■A'— ■ A'—
CH-A'- CH-A'-
dans laquelle in which
R a la signification donnée ci-dessus et X représente un atome de chlore, un radical S02R5 ou S02NR6R7, R5 représentant un radical alkyle de 1 à 4 atomes de carbone et R6 et R„ qui sont identiques ou différents, représentant un atome d'hydrogène ou un radical alkyle de 1 à 4 atomes de carbone. R has the meaning given above and X represents a chlorine atom, a radical SO2R5 or SO2NR6R7, R5 representing an alkyl radical of 1 to 4 carbon atoms and R6 and R „which are identical or different, representing an atom of hydrogen or an alkyl radical of 1 to 4 carbon atoms.
Les composés de formule II sont obtenus par condensation de l'amine I avec un acide 2-méthoxy 5-X benzoïque ou un de ses dérivés. The compounds of formula II are obtained by condensation of amine I with a 2-methoxy 5-X benzoic acid or one of its derivatives.
soit is
A'=liaison ou alkylène de 1 à 3 atomes de carbone. Les autres significations sont celles données précédemment. Dans le schéma réactionnel, on part de l'acide glutamique (R) pour obtenir l'amine I (R) directement. L'acide glutamique (S) pourrait conduire de la 65 même manière à l'amine I (S). A '= bond or alkylene of 1 to 3 carbon atoms. The other meanings are those given above. In the reaction scheme, we start from glutamic acid (R) to obtain the amine I (R) directly. Glutamic acid (S) could similarly lead to amine I (S).
Le schéma réactionnel est illustré ci-après dans les exemples. Les réductions finales sont effectuées de pféférence à l'aide d'hydrure double de lithium et d'aluminium. The reaction scheme is illustrated below in the examples. The final reductions are carried out preferably using double hydride of lithium and aluminum.
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Schèma réactionnel Reaction diagram
4 4
R' - CHO R '- CHO
hooc hooc
A' AT'
NEU u cooh NEW u cooh
-> ->
'2 » '2'
acide glutamique (R) glutamic acid (R)
hooc hooc
(R) (R)
cooh cooh
A AT
h -« h - "
1ère étape v 1st step v
H2 H2
Pd/C Pd / C
(R) (R)
..cooh h ..cooh h
cyclisation cyclization
<- <-
hooc nh hooc nh
A AT
x:ooh x: ooh
H H
ch ch
2èrne v/ 2nd v /
R" R "
(R) (R)
étape estérification esterification step
COOCH- COOCH-
amidification amidification
3ème étape 3rd stage
,CONh\ , CONh \
(?-) (? -)
Exemple 1: Example 1:
Cyclohexylméthyl-1 aminométhyl-2 Pyrrolidine (R) (+) Cyclohexylmethyl-1 aminomethyl-2 Pyrrolidine (R) (+)
Etape 1 Cyclohexylméthyl-1 carboxy-2 oxo-5 Pyrrolidine (R)(—) Step 1 Cyclohexylmethyl-1 carboxy-2 oxo-5 Pyrrolidine (R) (-)
Dans un erlenmeyer, on introduit, sous courant d'azote et tout en refroidissant, 58,8 g (0,4 mol) d'acide glutamique R et 400 ml de NaOH 2N. On ajoute goutte à goutte 44,8 g (0,4 mol) de cyclo-hexanecarbaldéhyde dans le méthanol. On agite 1 h, on hydrogène le milieu réactionnel en présence de Pd/C à la température ambiante et à la pression atmosphérique. Lorsque le volume d'hydrogène théorique a été absorbé, on filtre le catalyseur et évapore le méthanol. On recueille la phase aqueuse que l'on extrait à l'éther. On ajuste le pH de la phase aqueuse à 2,5 avec de l'acide chlorhydrique IN. On chauffe à 100° C durant 2 h. 58.8 g (0.4 mol) of glutamic acid R and 400 ml of 2N NaOH are introduced into a Erlenmeyer flask, under a stream of nitrogen and while cooling. 44.8 g (0.4 mol) of cyclohexanecarbaldehyde in methanol are added dropwise. The mixture is stirred for 1 h, the reaction medium is hydrogenated in the presence of Pd / C at room temperature and at atmospheric pressure. When the theoretical volume of hydrogen has been absorbed, the catalyst is filtered and the methanol is evaporated. The aqueous phase is collected and extracted with ether. The pH of the aqueous phase is adjusted to 2.5 with IN hydrochloric acid. It is heated to 100 ° C for 2 h.
On refroidit et filtre le solide blanc. On le dissout dans du chloroforme, le sèche sur sulfate de magnésium et évapore. On recueille un solide que l'on triture dans le cyclohexane. The white solid is cooled and filtered. It is dissolved in chloroform, dried over magnesium sulfate and evaporated. A solid is collected which is triturated in cyclohexane.
F=141,5 —142°C. Mp 141.5 -142 ° C.
H "s = —20,5° (c= 1, DMF) H "s = —20.5 ° (c = 1, DMF)
50 50
réduction 4ème étape rCH2NH2 4th step reduction rCH2NH2
/S / S
h h
60 60
(R) (R)
Etape 2 Cyclohexylméthyl-I mëthoxycarbonyl-2 oxo-5 Pyrrolidine Step 2 Cyclohexylmethyl-I methyloxycarbonyl-2 oxo-5 Pyrrolidine
(R)(~) (R) (~)
< Dans un erlenmeyer de 11, on introduit 300 ml de méthanol et 50 g (0,221 mol) du composé obtenu dans l'étape 1. On chauffe à 40° C, et on introduit goutte à goutte 31,7 g (0,266 mol) de chlorure de thionyle. On chauffe à reflux durant 4 h. On évapore à sec et i <300 ml of methanol and 50 g (0.221 mol) of the compound obtained in stage 1 are introduced into an 11 ml Erlenmeyer flask. The mixture is heated to 40 ° C. and 31.7 g (0.266 mol) are added dropwise. thionyl chloride. The mixture is heated at reflux for 4 h. We evaporate to dryness and i
5 5
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recueille une huile que l'on distille et qui cristallise au refroidissement. collects an oil which is distilled and which crystallizes on cooling.
F=87,5-88°C. Mp 87.5-88 ° C.
M 3« = —6° (c= 1, DMF) M 3 "= —6 ° (c = 1, DMF)
Etape 3 Cyclohexylméthyl-1 carbamoyl-2 oxo-5 Pyrrolidine (R)(—) Dans un erlenmeyer, on introduit 400 ml de méthanol et tout en refroidissant, on sature la solution avec de l'ammoniac. On ajoute 41,2 g (0,172 mol) de l'ester obtenu dans l'étape 2, agite 2 h et laisse reposer une nuit. On évapore à sec, recueille un solide que l'on recristallise dans de l'acétate d'éthyle. Step 3 Cyclohexylmethyl-1 carbamoyl-2 oxo-5 Pyrrolidine (R) (-) 400 ml of methanol are introduced into an Erlenmeyer flask and while cooling, the solution is saturated with ammonia. 41.2 g (0.172 mol) of the ester obtained in step 2 are added, the mixture is stirred for 2 h and left to stand overnight. Evaporated to dryness, a solid is collected which is recrystallized from ethyl acetate.
nh2so nh2so
-mh-ch och- -mh-ch och-
(S)(-) (S) (-)
F= 164,5-165°C. Mp 164.5-165 ° C.
W lis = — 116° (c= 1, DMF) W lis = - 116 ° (c = 1, DMF)
Etape 4 Cyclohexylméthyl-1 aminométhyl-2 Pyrrolidine (R) (+) Step 4 Cyclohexylmethyl-1 aminomethyl-2 Pyrrolidine (R) (+)
Dans un erlenmeyer, on introduit 13,6 g (0,356 mol) d'hydrure double de lithium et d'aluminium et de l'éther anhydre. Sous courant d'azote, on ajoute par petites quantités 20 g (0,089 mol) de l'amide obtenu dans l'étape 3. On chauffe à reflux durant 16 h. On hydrolyse avec une solution à 10% de tartrate de sodium et potassium. On filtre le solide et évapore la phase organique. On recueille une huile que l'on distille. 13.6 g (0.356 mol) of lithium aluminum hydride and anhydrous ether are introduced into an Erlenmeyer flask. Under a stream of nitrogen, 20 g (0.089 mol) of the amide obtained in step 3 are added in small amounts. It is hydrolyzed with a 10% solution of sodium and potassium tartrate. The solid is filtered and the organic phase is evaporated. An oil is collected which is distilled.
Eb2S = 140°C. Eb2S = 140 ° C.
Dans un erlenmeyer on introduit 8,8 g (0,057 mol) de la cyclopropylméthyl-1 aminométhyl-2 Pyrrolidine (S)(—), 14,7 g (0,054 mol) de l'ester éthylique de l'acide méthoxy-2 sulfamoyl-5 benzoïque et 18 ml d'eau. On chauffe à 120°C durant 10 h. Par refroidissement, un solide apparaît. On ajoute de l'éther et de l'eau et on agite. On filtre le solide, le dissout dans du chloroforme, le sèche sur sulfate de magnésium, puis on évapore. On recueille un solide que l'on recristallise dans de l'acétate d'éthyle. 8.8 g (0.057 mol) of 1-cyclopropylmethyl-2-aminomethyl-Pyrrolidine (S) (-), 14.7 g (0.054 mol) of 2-methoxy-sulfamoyl ethyl ester are introduced into an Erlenmeyer flask -5 benzoic and 18 ml of water. It is heated to 120 ° C for 10 h. Upon cooling, a solid appears. Add ether and water and stir. The solid is filtered, dissolved in chloroform, dried over magnesium sulfate, then evaporated. A solid is collected which is recrystallized from ethyl acetate.
F= 134-134,5°C. Mp 134-134.5 ° C.
M î)= — 77° (c = 1, DMF) M î) = - 77 ° (c = 1, DMF)
Exemple 4: Example 4:
Utilisation de l'amine I (R):préparation du N-[(p-fluorobenzyl-1 pyrrolidinyl-2) -méthyl]méthoxy-2 sulfamoyl-5 benzamide (R)(+) Use of amine I (R): preparation of N - [(p-fluorobenzyl-1 pyrrolidinyl-2) -methyl] 2-methoxy-5-sulfamoyl benzamide (R) (+)
Dans un erlenmeyer, on introduit 12 g (0,061 mol) de la Pyrrolidine obtenue précédemment, 8,44 g (0,061 mol) de carbonate de potassium et de l'acétone. 12 g (0.061 mol) of the pyrrolidine obtained previously, 8.44 g (0.061 mol) of potassium carbonate and acetone are introduced into an Erlenmeyer flask.
A une température < 10°C et sous courant d'azote, on ajoute goutte à goutte 15,2 g (0,061 mol) de chlorure de l'acide méthoxy-2 sulfamoyl-5 benzoïque dans de l'acétone. At a temperature <10 ° C. and under a stream of nitrogen, 15.2 g (0.061 mol) of 2-methoxy-5-sulfamoyl-benzoic acid chloride in acetone are added dropwise.
On agite durant 2 h. On évapore à sec et triture le résidu dans un mélange eau+éther, On filtre le solide, le dissout dans du chloroforme, le sèche sur sulfate de magnésium et évapore. On recueille un solide que l'on recristallise dans un mélange éther/isoacétate d'éthyle. The mixture is stirred for 2 h. The residue is evaporated to dryness and the residue is triturated in a water + ether mixture. The solid is filtered, dissolved in chloroform, dried over magnesium sulphate and evaporated. A solid is collected which is recrystallized from an ether / ethyl isoacetate mixture.
F= 141,5-142°C. M = 141.5-142 ° C.
[a] 20 = +96 (c= 1, DMF) [a] 20 = +96 (c = 1, DMF)
le méthanesulfonate de ce benzamide a une configuration (R)(-fond à 164-165°C. the methanesulfonate of this benzamide has a configuration (R) (- melts at 164-165 ° C.
[a] 2o=—4,2 (c = 1, DMF) [a] 2o = —4.2 (c = 1, DMF)
•)• H •) • H
Exemple 3: Example 3:
Utilisation de la Pyrrolidine I (S): synthèse du N-[(cyclopropyl-méthyl-1 pyrrolidinyl-2)-méthyl]méthoxy-2 sulfamoyl-5 benzamide (SX-) Use of Pyrrolidine I (S): synthesis of N - [(cyclopropyl-methyl-1 pyrrolidinyl-2) -methyl] 2-methoxy-5-sulfamoyl-benzamide (SX-)
Dans un erlenmeyer, on introduit 4 g (0,019 mol) d'aminométhyl-2 p-fluorobenzyl-1 Pyrrolidine (R)(+), 2,7 g (0,0196 mol) de carbonate de potassium en suspension dans l'acétone. A froid ( < 10°C), on ajoute goutte à goutte une solution de 4,8 g (0,019 mol) de chlorure de l'acide méthoxy-2 sulfamoyl-5 benzoïque dans l'acétone. On agite à tempérautre ambiante durant 2 h. 4 g (0.019 mol) of 2-aminomethyl-1-fluorobenzyl-1 Pyrrolidine (R) (+), 2.7 g (0.0196 mol) of potassium carbonate suspended in acetone are introduced into an Erlenmeyer flask . When cold (<10 ° C.), a solution of 4.8 g (0.019 mol) of 2-methoxy-5-sulfamoyl-5-benzoic acid chloride in acetone is added dropwise. The mixture is stirred at room temperature for 2 h.
On évapore à siccité le milieu réactionnel, sous pression réduite, à température inférieure à 30° C. On lave le résidu avec un mélange chloroforme/eau. On sépare la phase organique et la sèche sur sulfate de magnésium, on évapore et recueille un solide. The reaction medium is evaporated to dryness, under reduced pressure, at a temperature below 30 ° C. The residue is washed with a chloroform / water mixture. The organic phase is separated and dried over magnesium sulfate, evaporated and a solid is collected.
On recristallise le solide dans un mélange éther isopropylique/ alcool éthylique. C'est un solide blanc: The solid is recrystallized from an isopropyl ether / ethyl alcohol mixture. It's a solid white:
Fx= 148-148,5°C M i)= +92° (c=0,6 DMF) Fx = 148-148.5 ° C M i) = + 92 ° (c = 0.6 DMF)
Exemple 5: Example 5:
Application de la Pyrrolidine I (S) (—) Application of Pyrrolidine I (S) (-)
L'éthyl-1 aminométhyl-2 Pyrrolidine I (S) (—), par condensation avec le chlorure de l'acide méthoxy-2 sulfamoyl-5 benzoïque, de préférence en milieu acétonique alcalinisé par un carbonate basique, conduit au méthoxy-2 sulfamoyl-5 benzamide (II) de structure (S) (-)• 2-ethyl-2-aminomethyl Pyrrolidine I (S) (-), by condensation with 2-methoxy-5-sulfamoyl-5 benzoic acid chloride, preferably in acetonic medium basified with a basic carbonate, leads to 2-methoxy 5-sulfamoyl benzamide (II) of structure (S) (-) •
Le N-[éthyl-l pyrroIidinyl-2]-méthylméthoxy-2 sulfamoyl-5 benzamide (S) (—) obtenu fond à 185-186°C. The N- [ethyl-1 pyrroIidinyl-2] -methylmethoxy-2 sulfamoyl-5 benzamide (S) (-) obtained melts at 185-186 ° C.
H 2d5= -66,8° (c=0,5, DMF) H 2d5 = -66.8 ° (c = 0.5, DMF)
Dans le tableau I sont indiqués les composés I obtenus selon l'invention. In Table I are indicated the compounds I obtained according to the invention.
626341 626341
6 6
Les analyses et spectres IR et RMN ont confirmé, dans chaque Les points de fusion ont été déterminés à l'aide d'un appareil cas, la structure des composés obtenus. Tottoli. The analyzes and IR and NMR spectra confirmed, in each The melting points were determined using a case apparatus, the structure of the compounds obtained. Tottoli.
Tableau I Table I
Composé No Compound No
R R
Schéma réact. React diagram.
Caractéristiques / Structure Features / Structure
Benzamide obtenu Benzamide obtained
I I
£>—CH2 ; £> —CH2;
1 1
(S) (—) Eb2o=88°C (S) (-) Eb2o = 88 ° C
[a] *°= -68,5° (c= 1, DMF) [a] * ° = -68.5 ° (c = 1, DMF)
(S) (-)F= 134-134,5°C [a] jj= —77°tc= 1, DMF) (S) (-) F = 134-134.5 ° C [a] dd = —77 ° tc = 1, DMF)
2 2
O-* O- *
1 1
(S) (—) Eb15 = 106°C [a] 2°= -76° (c=0,5 DMF) (S) (-) Eb15 = 106 ° C [a] 2 ° = -76 ° (c = 0.5 DMF)
(S) (-)F= 153-153,5°C [a] 2d°= -92° (c=0,5 DMF) (S) (-) F = 153-153.5 ° C [a] 2d ° = -92 ° (c = 0.5 DMF)
3 3
O* O *
(S) (—) Eb20 = 124°C [a] 2£= —73° (c= 1, DMF) (S) (-) Eb20 = 124 ° C [a] 2 £ = —73 ° (c = 1, DMF)
(S) (-)F=123-123,5°C [a] 2d°= -99,5° (c=0,5 DMF) (S) (-) F = 123-123.5 ° C [a] 2d ° = -99.5 ° (c = 0.5 DMF)
4(ex. 1) 4 (ex. 1)
<OCHI <OCHI
2 2
(R)(+)Eb25 = 140°C W 365 = +263° (c= 1, DMF) (R) (+) Eb25 = 140 ° C W 365 = + 263 ° (c = 1, DMF)
(R) (+) F= 141,5-142°C ta]2D0=+96°(c=1,DMF) (R) (+) F = 141.5-142 ° C ta] 2D0 = + 96 ° (c = 1, DMF)
5 5
ch2 ch2
3 3
(R) (+) Eba,o5=92° C [a] «= +81,8° (c=0,5 DMF) (R) (+) Eba, o5 = 92 ° C [a] «= + 81.8 ° (c = 0.5 DMF)
(R)(+) F=148,5°C [a] 2d5= +92° (c=0,6 DMF) (R) (+) F = 148.5 ° C [a] 2d5 = + 92 ° (c = 0.6 DMF)
6 6
<^^_CH2 <^^ _ CH2
3 3
(S) (—) Ebo,o5=90°C (S) (-) Ebo, o5 = 90 ° C
[a] 22= -78,2° (c=0,6 DMF) [a] 22 = -78.2 ° (c = 0.6 DMF)
(S) (-)F= 146-146,5°C [a] 2ds= -91,9° (c=0,6 DMF) (S) (-) F = 146-146.5 ° C [a] 2ds = -91.9 ° (c = 0.6 DMF)
7 7
c2h5 c2h5
4 4
(S) (—) Eb25 =78-80°C [a] 2d5= -86,1° (c = 0,6 DMF) (S) (-) Eb25 = 78-80 ° C [a] 2d5 = -86.1 ° (c = 0.6 DMF)
(S) (—) F = 185-186°C [a] 2d5= -66,8° (c=0,5 DMF) (S) (-) F = 185-186 ° C [a] 2d5 = -66.8 ° (c = 0.5 DMF)
R R
Claims (3)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7623910A FR2360572A1 (en) | 1976-08-05 | 1976-08-05 | Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals |
| FR7635476A FR2372157A1 (en) | 1976-11-25 | 1976-11-25 | Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals |
| FR7719391A FR2395261A2 (en) | 1977-06-24 | 1977-06-24 | Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH626341A5 true CH626341A5 (en) | 1981-11-13 |
Family
ID=27250658
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH959477A CH624933A5 (en) | 1976-08-05 | 1977-08-04 | |
| CH4181A CH626341A5 (en) | 1976-08-05 | 1981-01-06 | Process for the stereospecific synthesis of N-substituted pyrrolidines and their use |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH959477A CH624933A5 (en) | 1976-08-05 | 1977-08-04 |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5325563A (en) |
| AT (1) | AT364818B (en) |
| AU (1) | AU510454B2 (en) |
| CA (1) | CA1083586A (en) |
| CH (2) | CH624933A5 (en) |
| DE (1) | DE2735036C2 (en) |
| DK (1) | DK350377A (en) |
| ES (1) | ES461342A1 (en) |
| FI (1) | FI772363A (en) |
| GB (1) | GB1555890A (en) |
| GR (1) | GR63594B (en) |
| IE (1) | IE45544B1 (en) |
| IL (1) | IL52645A (en) |
| IT (1) | IT1085696B (en) |
| LU (1) | LU77917A1 (en) |
| NL (1) | NL7708571A (en) |
| NO (2) | NO772745L (en) |
| NZ (1) | NZ184832A (en) |
| PT (1) | PT66894B (en) |
| SE (2) | SE7708902L (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1095415B (en) * | 1978-02-16 | 1985-08-10 | Ravizza Spa | PROCESS FOR THE PRODUCTION OF AN OPTICALLY ACTIVE BENZAMIDE, OPTICALLY ACTIVE BENZAMIDE SO OBTAINED AND COMPOSITIONS |
| IT1141095B (en) * | 1980-11-27 | 1986-10-01 | Ravizza Spa | RESOLUTION PROCESS OF THE SULPYRID RACEMA |
| SE8602339D0 (en) * | 1986-05-22 | 1986-05-22 | Astra Laekemedel Ab | AND EFFECTIVE STEREOCONSERVATIVE SYNTHESIS OF 1-SUBSTITUTED (S) - AND (R) -2-AMINOMETHYLPYRROLIDINES |
| DE4425070A1 (en) * | 1994-07-15 | 1996-01-18 | Degussa | Process for the preparation of optically active l-substituted 2- (aminomethyl) pyrrolidines |
| CA2497062A1 (en) * | 2004-02-18 | 2005-08-18 | Dr. Reddy's Laboratories Limited | Preparation of amino acid amides |
| CN104086475B (en) * | 2014-07-15 | 2016-10-05 | 苏州天马精细化学品股份有限公司 | A kind of preparation method of N-benzyloxycarbonyl group-L-prolineamide |
| CN106045869A (en) * | 2016-06-30 | 2016-10-26 | 宜兴市前成生物有限公司 | Method for preparing DL-glutamic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1528014A (en) * | 1967-04-24 | 1968-06-07 | Ile De France | Process for the preparation of optical isomers of ethyl-1, aminomethyl-2-pyrrolidine |
| CH507938A (en) * | 1968-08-01 | 1971-05-31 | Ile De France | Process for the preparation of heterocyclic benzamides |
-
1977
- 1977-08-02 IL IL52645A patent/IL52645A/en unknown
- 1977-08-03 DE DE2735036A patent/DE2735036C2/en not_active Expired
- 1977-08-03 NZ NZ184832A patent/NZ184832A/en unknown
- 1977-08-03 NL NL7708571A patent/NL7708571A/en not_active Application Discontinuation
- 1977-08-03 GR GR54101A patent/GR63594B/en unknown
- 1977-08-04 NO NO772745A patent/NO772745L/en unknown
- 1977-08-04 CH CH959477A patent/CH624933A5/fr not_active IP Right Cessation
- 1977-08-04 SE SE7708902A patent/SE7708902L/en not_active Application Discontinuation
- 1977-08-04 GB GB32790/77A patent/GB1555890A/en not_active Expired
- 1977-08-04 LU LU77917A patent/LU77917A1/xx unknown
- 1977-08-04 CA CA284,104A patent/CA1083586A/en not_active Expired
- 1977-08-04 IT IT26497/77A patent/IT1085696B/en active
- 1977-08-04 ES ES461342A patent/ES461342A1/en not_active Expired
- 1977-08-04 DK DK350377A patent/DK350377A/en not_active Application Discontinuation
- 1977-08-04 IE IE1633/77A patent/IE45544B1/en unknown
- 1977-08-04 FI FI772363A patent/FI772363A/fi not_active Application Discontinuation
- 1977-08-04 AU AU27641/77A patent/AU510454B2/en not_active Expired
- 1977-08-04 PT PT66894A patent/PT66894B/en unknown
- 1977-08-04 JP JP9404477A patent/JPS5325563A/en active Pending
- 1977-08-05 AT AT0577377A patent/AT364818B/en not_active IP Right Cessation
-
1980
- 1980-12-22 SE SE8009074A patent/SE8009074L/en not_active Application Discontinuation
-
1981
- 1981-01-06 CH CH4181A patent/CH626341A5/en not_active IP Right Cessation
- 1981-08-25 NO NO812871A patent/NO812871L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATA577377A (en) | 1981-04-15 |
| FI772363A (en) | 1978-02-06 |
| PT66894A (en) | 1977-09-01 |
| GR63594B (en) | 1979-11-26 |
| IL52645A0 (en) | 1977-10-31 |
| ES461342A1 (en) | 1978-06-01 |
| JPS5325563A (en) | 1978-03-09 |
| IT1085696B (en) | 1985-05-28 |
| NL7708571A (en) | 1978-02-07 |
| DE2735036C2 (en) | 1983-10-13 |
| IE45544B1 (en) | 1982-09-22 |
| NZ184832A (en) | 1979-11-01 |
| CA1083586A (en) | 1980-08-12 |
| IL52645A (en) | 1980-02-29 |
| NO772745L (en) | 1978-02-07 |
| AU2764177A (en) | 1979-02-08 |
| GB1555890A (en) | 1979-11-14 |
| DE2735036A1 (en) | 1978-02-16 |
| PT66894B (en) | 1979-01-26 |
| AT364818B (en) | 1981-11-25 |
| SE8009074L (en) | 1980-12-22 |
| LU77917A1 (en) | 1977-11-14 |
| SE7708902L (en) | 1978-02-06 |
| AU510454B2 (en) | 1980-06-26 |
| CH624933A5 (en) | 1981-08-31 |
| IE45544L (en) | 1978-02-05 |
| NO812871L (en) | 1978-02-07 |
| DK350377A (en) | 1978-02-06 |
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| Date | Code | Title | Description |
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| PL | Patent ceased |