IL33642A - Method for the preparation of 4-alkylprolines and 4-alkyl-2,2-dicarboalkoxy-pyrrolidines - Google Patents

Description

METHOD FOR THE PREPARATION OF 4-AlKYLPROlINES AND 4- ALKYL 2, 2-DICARBAALKOXY-PYRROLIDINES 2,2-'7"»p'7N-4-i o^^na-^^p^ miro -p nn ABSTRACT OF THE DISCLOSURE 4-Alkylprolines are prepared in relatively high yields by reacting a 2-alkylacrolein with a dialkyl N-alkanoylamido-malonate, dehydrating the obtained 4-alkylpyrrolidine , and thereafter hydrolyzing, decarboxylating , and catalytically hydrogenating the produced 4 -alkyl-4-pyrroline . The 4-alkyl-prolines are useful as intermediates for the preparation of 4-alkylhygric acids which, in turn, are a source of component acids that are reacted with amino sugars to form antibiotics of the lincomycin type.

BACKGROUND OF THE INVENTION 4-Alkylhygric acids are starting materials for the preparation of antibiotics of the lincomycin type as set forth in U. S. Patent 3,297,716 issued on 10 January 1967. It is very desirable to produce said acids and their 4 -alkylproline precursors in high yields and at a commercially attractive cost The present invention provides a method whereby the foregoing is readily achieved.

SUMMARY OF THE INVENTION The method of the herein claimed invention contemplates the reaction of 2-alkylacrolein with dialkyl N-alkanoylamido-malonate so as to produce a 4^alkylpyrrolidine , dehydrating the latter to the corresponding ,,4-alkyl-4-pyrroline and thereafter hydrolyzing, decarboxylating, and catalytically hydrogenating said 4-pyrroline. Also contemplated and within the purview of the present invention are the particular 4-alkyl-4-pyrrolines, -4""cilkyl 5 " y rrolincs — nn - n l'lry l pyrm l i d i n m produced at intermediate stages in the aforesaid method.

DETAILED DESCRIPTION OF THE INVENTION The overall reaction sequence contemplated by the present In the above formulas, R can be alkyl containing from 1 to 8 carbon atoms, inclusive, i.e., methyl, ethyl, the propyls, the butyls, the pentyls , the hexyls, the heptyls , and the octyls . z R can be alkanoyl containing from 1 to 4 carbon atoms, inclusive, 3 i.e., formyl , acetyl, propionyl, and butyryl . R and R can be alike or different and can be alkyl containing from 1 to 6 carbon atoms, inclusive, i.e., methyl, ethyl, the propyls, the butyls, the pentyls, and the hexyls. The term HX is used to designate an acid' addition salt which can be of a monovalent or polyvalent acid.

As set forth in the foregoing reaction sequence, the starting materials contemplated for the method of the present invention are a dialkyl N-alkanoylaminomalonate (I) and a 2-alkylacro!ein (II) . Both groups of materials are known in the art and some are commercially available. 2-Alkylacroleins can be prepared in accordance with the teachings of Green et al . , J. Chem. Soc . 1957, p. 3262.

The reaction, between the dialkyl N-alkanoylamidomalonate (I) and 2-alkylacrolein (II) (STEP 1) is brought about by admixing these compounds in the presence of a base such as an alkali metal alkoxide, e.g. sodium methoxide,, sodium ethoxide, potassium methoxide, or the like, and in an inert organic solvent such as benzene, ethahol, methanol, or the like. While the reaction normally is carried but at ambient temperatures, the reaction temperature can be as low as about 0° C, or lower, or as high as about 60° C, or higher, depending on the boiling point of the solvent used.

The reaction product thus obtained is the corresponding 4-alkylpyrrolidine (III) which is then dehydrated (STEP 2) by means of an acid dehydrating agent such as hydrochloric acid, sulfuric acid, P2O5, or the like, in an inert, non-aqueous The dehydration is preferably carried out at ambient temperature; however, the temperature can be as low as about 10° C, or lower, or as high as about 100° C. or higher, depending on the desired reaction rate and the decomposition temperatures of the reactants and reaction products.

The aforesaid dehydration produces a 4 -alky1 -4-pyrroline (IV) which is then subjected to hydrolysis and decarboxylation (STEP 3) followed by catalytic hydrogenation (STEP 4) , or in the alternative, subjected to catalytic hydrogenation (STEP 5) followed by hydrolysis and decarboxylation (STEP 6). Hydrolysis and decarboxylation of a 4-alkyl-4-pyrroline (STEP 3) yields the corresponding 4-alkyl-5-pyrroline (V) which is then catalyti- . cally hydrogenated to the desired end product 4-alkylproline (VI) (STEP 4). On the other hand, catalytic hydrogenation of a 4-alkyl-4-pyrroline (STEP 5) yields the corresponding 4-alkylpyrrolidine (VII which is then hydrqlyzed and decarboxy-lated to the desired end product 4-alkylproline (VI) (STEP 6) .

Hydrolysis and decarboxylation (STEP 3 or STEP 6) is achieved by treating the 4-alkyl-4-pyrroline (IV) with a strong, non-oxidizing acid such as hydrochloric acid, trichloroacetic acid, trifluoroacetic acid, or the like. This reaction is preferably carried out at the reflux temperature of the reaction mixture; however, the reaction temperature can be as high as about 150° C, or higher. Before hydrolysis and decarboxylation is commenced, the inert, non-aqueous solvent present in the reaction mixture resulting after STEP 2 can be removed therefrom, if desired, by evaporation or similar means. This is not essential, however.

Catalytic hydrogenation (STEP 4 or STEP 5) is carried out using hydrogen gas in the presence of a hydrogenation catalyst such as aney Nickel, the noble metal catalysts, i.e., A' pall ad i urn- on- carbon, platinum, rhodium, or the like. The catalytic hydrogenation proceeds sat isfactor i 1 y at ambient -temperatures; however, temperatures up to about 200 ° C, or higher, can be utilized. Reaction pressure can range from atmospher i c up to about 1000 atmospheres, or higher. An absolute pressure of about 1 to about 2 atmospheres is preferred The desired end product, the corresponding 4-al kylprol i ne ( V I ) , is recovered from the reaction mixture in the conventional manner by evaporation followed by trituration and optional recrysta 1 1 i zat ion depending on the desired degree of purity, usually as an acid addition salt. The free base compound is readily obtained from the salt by treatment with a suitable base using techniques commonly employed in the art.

The present invention is further illustrated by the following examples.

EXAMPLE I : Preparation of l-Acetyl- 2, 2-Dicarbethoxy-5-Hydroxy- -Pentylpyrrol idine Diethyl acetami domalonate (about 86. 8 grams, 0 . 4 mole) is dissolved in benzene (about 800 milliliters). To the resulting solution is added, wi th st i rr i ng, al pha-penty 1 acrol ei n (about 55. 6 grams, 0 .44 mole), followed by sodium methoxide in methanol (about 2 milliliters of a 25 percent w/v solution).

The thus produced admixture is permitted to stand at ambient temperature for about 18 hours, and thereafter the solvent is removed therefrom by d i st i 1 1 at ion under reduced pressure. Thin layer chromatograph (TLC) of the obtained residue (on silica gel, 2 : 1 mixture of cyclohexane and acetone) shows the absence of diethylacetamidomalonate and the appearance of a new, slower moving spot (Rf ^so. 5 ) which does not absorb in the ultraviolet range. Nuclear magnetic resonance (NMR) is - - - - ~ In a similar manner, but starting with diethyl propion-amidomalonate and 2-pentylacrolein the l-propionyl-2 ,2-dicarb-ethpxy-5-hydroxy-4-pentylpyrrolidine is prepared.

Starting with dipropyl butyramidomalonate and 2-ethylacro-lein the 1-butyryl- 2 , 2-dicarbpropoxy-5-hydroxy-4-ethylpyrroli-dine is prepared.

Starting with dibutyl formamidomalonate and 2-propyl-acrolein the l^f0rmyl-2,2-dicarbbutoxy-5-hydroxy-4-propyl-pyrrolidine is prepared.

Starting with diethyl acetamidomalonate and 2-octylacrolein the l-;actyl-2,2-dicarbethoxy-5-hydroxy-4-octylpyrrolidine is prepared.

EXAMPLE II: Preparation of 1 -Acetyl -2 , 2-Dicarbethoxy-4-Pentyl- 4-Pyrroline ♦ ■ .. - - . , ' The crude residue obtained in Example I is dissolved in ' absolute ethanbl (about 450 milliliters) and HC1 gas is bubbled through the resulting solution for about 5 minutes.

The solution is then permitted to stand at ambient temperature for about 1.5 hours, and then filtered and evaporated to dryness .

The obtained residue is purified by chromatography over silica gel using a 2:1 mixture of cyclohexane and acetone for elution. The major fraction obtained therefrom is identified as l-acetyl-2 , 2-d,icarbethoxy-4 -pentyl -4-pyrroline .

Analysis for Ci7H27N0s: Calc'd: C, 62.74; H, 8.37; N, 4.31 Found: C, 62.14; H, 8.62; N, 4.40 λ max. 236, ε 9300 (diethyl ether) Similarly, starting with l-propionyl-2,2-dicarbethoxy-5-hydroxy-4-pentylpyrrolidine the l-propionyl-2 , 2-dicarbethoxy-4-pentyl-4-pyrroline is prepared.

Starting with l-butyryl-2 , 2-dicarbpr0poxy-5-hydroxy-4-ethylpyrrolidine the.' l-butyryl-2, 2-dicarbpropoxy-4-ethyl-4-pyrroline is prepared.

Starting with l-formyl-2 , 2-dicarbbutoxy- 5-hydroxy-4-propyl-pyrrolidine the l-formyl-2 , 2-dicarbbutoxy-4-propyl-4-pyrroline is prepared.

Starting with l-acetyl-2,2-dicarbethoxy-5-hydroxy-4-octyl-pyrrolidine the l-acetyl-2,2-dicarbethoxy:-4-octyl-4-pyrroline is prepared.

EXAMPLE III: Preparation of l-Acetyl-2,2-Dicarbethoxy-4-Pentyl- 4-Pyrroline ' ■ l-Acetyl-2 , 2-dicarbethoxy-5-hydroxy-4-pentylpyrrolidine (about 20 grams, 0.0.62 mole) is dissolved in benzene (about 200 milliliters) , and phosphorus pentoxide (about 10 grams, 0.070 mole) is added to the resulting solution. The resulting admixture is warmed to about 50° C. and is permitted to stand for about 0.5 hour at ambient temperature. Thereafter additional phosphorus pentoxide (about 2 grams , 0.014 mole) is added to the admixture followed by the warming thereof to about 45° to 50° C.

Thin layer chromatography of the reaction product shows almost complete dehydration with no change following the second addition of phosphorus pentoxide - the dehydrating agent.

EXAMPLE IV: Preparation of 2-Carboxy-4-Pentyl-5-Pyrroline Hydrochloride .

The entife crude product of l-acetyl-2 , 2-dicarbethoxy-4-pentyl-4-pyrroline obtained in Example II is admixed with 6N hydrochloric acid (about 460 milliliters) and the resulting mixture heated at reflux for about 2.5 hours. Thereafter the as to remove a small amount of deeply colored oil observed to be present.

The extract is evaporated under reduced pressure and a reddish oil, identified as 2-carboxy-4-pentyl- 5-pyrrol ine hydrochloride, is obtained as the residue.

In a like manner, but starting with l-propionyl- 2, 2-dicarb-ethoxy-4-pentyl-4- pyrro1 ine the 2-carboxy-4-pentyl- 5-pyrrol ine hydrochloride is prepared.

Starting with 1-butyryl - 2, 2-d i carbpropoxy-4-ethy 1 -4-pyr ro-line the 2-carboxy-4-ethyl- 5-pyrrol ine hydrochloride is prepared Starting with l-formyl- 2, 2-dicarbbutoxy-4-propyl- 4-pyrroline the 2-carboxy-4-propyl- 5-pyrrol ine hydrochloride is prepared.

Starting with 1-acety 1 - 2, 2-di carbethoxy-4-octy 1 -4-pyrrol ine the 2-carboxy-4-octyl- 5-pyrrol ine hydrochloride is prepared. EXAMPLE V: Preparation of 4- Penty 1 prol ? ne Hydrochloride 2-Carboxy-4-pentyl- 5~pyi*rol ine hydrochloride obtained in Example IV (about 15 grams, 0.082 mole) and 10 percent w/w palladium-on-carbon catalyst (about 7.5 grams) in methanol (about i80 milliliters) is admixed and shaken under hydrogen at ambient temperature for about 18 hours. Thereafter the catalyst is removed by filtration and the filtrate evaporated to dryness.

About 14. 1 grams of a residue is obtained. The residue is triturated with acetone (about 5 milliliters) and filtered. The f i 1 tered resi due (about 8.74 grams) . is. i dent i fi id as 4-pentylprol ine hydrochloride, melting at 194° C. to 199° C. (sinter at 187° C), obtained in about 68 percent yield based on diethyl acetami domalonate, the starting material.

EXAMPLE VI: Preparation of 4-Pentyl prol i ne Hydrochloride by Prior Art Method of l-acetyl-2, 2-di carbethoxy-5- hydroxy-4-penty 1 pyrrol idi ne (about I3.7 grams, 0.042 mole) and 6N hydrochloric acid (about 274 mi 1 1 i 1 i ters) . The resulting admixture is stirred at about reflux temperature for about 1 hour and then decanted. Evapora-"tion at reduced pressure gives a solid residue (about 16.7 grams) which is then dissolved in hot water (about 450 milliliters). Zinc salts are precipitated from the resulting solution by the addition of hydrogen sulfide and removed therefrom by filtration. The precipitation and filtration are repeated several times.

Evaporation of the solution yields a solid residue (about 3.0 grams) which is then tri turated wi th acetoni tr i le. The obtained crude crystals are then collected and recrystal 1 i zed from aqueous aceton i tr i 1 e. About 1.4 grams of 4-penty 1 prol i ne hydrochloride melting at 197° to 200° C. (sinter at l83° C.) is obtained. This represents a l6 percent yield based on diethyl acetami domal onate .

EXAMPLE VII: Preparation of l-Acetyl- 2, 2-Dicarbethoxy-4- Pentyl pyrrol ? d? ne ■ l-Acetyl-2, 2-di carbethoxy-4- penty 1 -4-pyrrol i ne (about grams, 0.033 mole) is admixed with 10 percent w/w palladium-on-carbon catal yst (about 2.4 grams) in. methanol (about l6o mi 1 1 i 1 i ters) and the mixture shaken under hydrogen at atmospheric pressure for about 3 hours. Thereafter the catalyst is removed from the reaction mixture by filtration. Thin layer chromatography does not provide a sample having ultraviolet absorption. The reaction product is identified as l-acetyl-2,2-d i carbethoxy-4- pentyl pyrrol idi ne.

'·', In a manner similar to the above but starting with 1-propi0nyl-2,2-dicarbethoxy-4-pentyl-4-pyrrol ine the 1-propionyl- 2,2-d?carbethoxy-4-pentylpyrrol idine is prepared.

Starting with 1-butyry 1 -2, 2-di carbpropoxy-4-ethy 1 -4-pyrroline the 1-butyry 1 -2, 2-d i carbpropoxy-4-ethy 1 pyrrol i d i ne is prepared.

Starting with l-formy1-2,2-dicarbbutoxy-4-propyl-4-pyrrol ine the l-formyl-2,2-dicarbbutoxy-4-propylpyf"rol idine is prepared.

Starting with l-acetyl-2,2-dicarbethoxy-4-octyl-4-pyrrol ine the l-acetyl-2,2-dicarbethoxy-4÷octylpyrrol idine is prepared. EXAMPLE VIM: Preparation of 4-Pentyl prol i ne Hydrochloride Crude l-acetyl-2,2-dicarbethoxy-4-pentylpyrrol idine (about 2 grams, O.065 mole), prepared in Example VII, is mixed with 6N hydrochloric acid (about 8 mi 11 i 1 i ters) and the resulting mixture heated at reflux for about 2.5 hours. Thereafter the obtained reaction mixture is cooled and evaporated to dryness. The obtained residue is recrystal 1 i zed from acetone and about 110 milligrams of 4-pentylprol ine hydrochloride melting at I9I0 C. to 19 ° C. (sinter at 176° C.) is recovered.

EXAMPLE IX: Preparation of 2-Carboxy-4-Pentyl-5-Pyrrol ine Crude 2-carboxy-4-pentyl-5-pyrrol ine hydrochloride (about 45.8 grams), prepared in a manner similar to Example I is dissolved in water (about 300 milliliters), and the resulting solution is passed through a cation-exchange resin column in a hydrogen cycle. A basic solution is eluted therefrom and evaporated to dryness. The obtained residue is identified as 2-carboxy-4-pentyl -5- pyrrol i ne.

Analysis for CipHiyNOg: Calc'd: C, 65.54; H, 9-35 Found:- C, 64.48; H, 9.1 As set forth above, the method of the present invention is useful for the production of 4-al ky 1 prol i nes which, in turn, serve as intermediates for the production of 4-al ky 1 hygr i c acids that are known starting materials for the preparation of antibiotics of the lincomycin type. The conversion of 4-alkyl-prolines to 4-al kyl hygric acids is brought about by alkylation of 4-al kylprol ines with formalin and hydrogen in the presence of palladium-on-carbon catalyst.

In the production of antibiotics the 4-al kyl hygr i c acids are reacted with amino sugars as disclosed in U. S. Patent 3,096,912, for example.

Moreover, the 4-al kyl hygr i c acids can be converted to the corresponding amides which, in turn, can be converted to alkyl halide quaternary ammonium salts. The latter are electrocon-ductive wetting agents and can be used to prepare electrocardiographic jellies.

The 4-al kyl-4-pyrrol ines, 4-al kyl-5-pyrrol i nes, and 4-a 1 ky 1 pyrrol i d i nes di scl osed herein are useful for the production of the corresponding 4-al kylprol ines as set forth in detai l above.

Claims (8)

WHAT IS CLAIMED IS:

1. » A method for the preparation of a 4-alkylproline and acid addition salts thereof which comprises reacting a 2-alkylacroleln with a dialkyl N-alkanoylamidomalonata in the presence of a base* dehydrating the resulting 1-alkanoyl-4-alkyl-2 ,2-di(carboalkoxy)-5-hydroxy-pyrroiidine with a acidic agent in an inert* non-aqueous solvent so as< to produce the corresponding l-alkanoyl-4-alkyl-2 ,2-di(carboalkoxy)-4-pyrroline and then either subjecting . the latter compound to hydrolysis* monodecarboxylation and then cayalytic hydrogenation of of the resulting 4-alkyl-4-pyrroline derivative or to catalytic hydrogenation and then hydrolfrsis and demonodecarboxylati'on of the resulting 4-alkylpyrrolidine to produce -the desired 4-alkylprollne or its acid addition salt*

2. · The method in accordance with claim 1' wherein the dehydration is carried out at room temperature*

3. The method in accordance with claim wherein the hydrolysis and decarboxylation, are carried out with a strong * non-oxidizing acid at the reflux temperature of the resulting reaction mixture*

4. * The method in accordance with claim 1 wherein the catalytic hydrogenation is carried out with hydrogen in the presence of an effective amount of a hydrogenation catalyst at room temperature and at a pressure in the range from 1 to 2 atmospheres*

5. The method in accordance with claim 1 wherein after dehydration the solvent present in the reaction mixture is removed before proceeding with hydrolysis* decarboxylation* , and catalytic hydrogenation*

6. The method in accordance with claim.1 wherein the l-alkanoyl-4-alk l-2*2-dl(carboalkoxy)-4-pyrroline is first hydrolyzed and decarboxylated and thereafter catalytically > 336^2/2

7. The method in accordance with Claim 1 wheroin the l-alkanoyl-^-alkyl-2,2-di (carbSaikoxy)-fc-pyrrollne is first catalytically .hydrogenated and thereafter hydrolyzed and decarboxylated..

8. Ά-method for. the preparation, o . ¾-alkylproline and... acid, addition salts thereof, substantially as hereinbefore described and with reference to any of the ·■ Examples.. 9· A-!^ralkyl-^-pyrroline represented by the general' formula wherein R is alkyl containing from 1 to 8 carbon atoms,, inclusive, R 2 is alkanoyl containing from 1 to ,carbon atoms,, inclusive, and R^ and ^ are alkyl containing from 1 to 6 carbon atoms,, inclusive* A -alkyl-4-py.rroline in accordance with Claim 9 wwhheerreeii]n R1 is n -pentyl,, R2 is acyl and R-* and ^ are ethyl «¾d. Paten* Af,Q