IL46657A - Preparation of 2-aminomethyl pyrrolidine - Google Patents
Preparation of 2-aminomethyl pyrrolidineInfo
- Publication number
- IL46657A IL46657A IL46657A IL4665775A IL46657A IL 46657 A IL46657 A IL 46657A IL 46657 A IL46657 A IL 46657A IL 4665775 A IL4665775 A IL 4665775A IL 46657 A IL46657 A IL 46657A
- Authority
- IL
- Israel
- Prior art keywords
- pyrrolidine
- benzyl
- aminomethyl
- acid
- pyrrolidone
- Prior art date
Links
Classifications
-
- 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
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- 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
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- C07D207/20—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1481251 2 - Aminomethylpyrrolidine SOC D'ETUDES SCIENTIFIQUES ET INDUSTTRIELLES DE L'ILE-DE-FRANCE 24 Feb 1975 [4 March 1974] 7645/75 Heading C2C 2 - Aminomethylpyrrolidine and its acid addition salts are prepared by reacting 2-pyrrolidone in a basic medium in a solvent with a reactive benzyl compound of formula wherein X is a reactive atom or group (e.g. a halogen atom or a tosyl group), to produce N- benzyl-2-pyrrolidone, treating the latter with a di(C 1-3 alkyl)sulphate and an alkali metal alcoholate, followed by nitromethane, to produce N-benzyl-2-nitromethylene-pyrrolidine and then (a) reducing the latter to 2-aminomethylpyrrolidine by hydrogen in the presence of a catalyst either directly or via the intermediate N-benzyl-2-aminomethyl-pyrrolidine or (b) reducing to N-benzyl-2-aminomethyl-pyrrolidine by a metal/acid system and then to 2-aminomethyl-pyrrolidine by hydrogen in the presence of a catalyst, the 2-aminomethyl-pyrrolidine being optionally converted to an acid-addition salt by treatment with an acid.
[GB1481251A]
Description
The preparation of 2-amino- methyl pyrrolidine SOCIETE D'ETUDES SCIENTIPIQUES ET INDUSTRIELLES DE L'lLB -DE-FRANCE The present invention concerns a novel process for the preparation of 2-aminoi ethyl pyrrolidine (v) and the synthesis intermediates.
It is known from Israel Patent Specification No. 32830 and from German Patent Application No. 2 , 216 , 738 (corresponding to Israel Patent No . 39668 ) to prepare 1-alkyl- and 1-alkenyl-2-aminomethyl pyrrolidines , respectively , from the corresponding 1- alkyl- and 1-alkenyl 2-pyrrolidones via the corresponding 2- nitromethylene intermediates .
The present invention provides a process for the preparation of the 1-unsubstituted 2-aminomethyl pyrrolidine , which process comprises reacting 2-pyrrolidone (I ) with a reactive benzylated compound, then reacting the resulting N~benzyl 2-pyrrolidine (il) with a lover alkyl sulphate, an alkaline alcohclate, and nitromethane , to form N-benzyl 2-nitromethylene pyrrolidine (ill) , vhich by reduction results in N-benzyl 2-aminomethyl pyrrolidine (iV) , then 2-aminomethyl pyrrolidine (v)^ - The process of the invention can be illustrated by the following diagram: hich X is a reactive group or atom such as a halogen aton or a tosyl group, R1 is a lover alkyl group containing from 1 to 3 carbon atoms, is an alkyl group, J^ M is an alkali metal.
The following can be mentioned as examples of the reactive benzylateu compound used in the first stage of the process: benzyl halides such as chloride, bromide or iodide, or benzyl p-toluene .sulphonate. The action of these compounds on pyrrolidwtone occurs in a solvent such as benzene, toluene or xylene, in a basic medium such as an alkaline alcoholate.
In accordance vith the process of the invention, a lover allcyl sulphate, an alkaline alcoholate and nitromethane are reactedJeS'i-benzyl 2-pyrrolidone (il) to produce compound (ill). The following can be mentioned as examples of a lover alkyl sulphate: dimetheyl, diethyl, dipropyl or diisopropyl sulphates. The alkali metal alcoholate is produced by the action of a alcohol such as methanol, ethanol, propanol, isopropanol, butanol, etc., an alkali metal such as sodium or potassium.
The product produced, having the formula: R^ and Rg being as defined above, can be isolated and purified. It can also be used for the following reaction, without being isolated.
Reduction of N-benzyl 2-nitromethylene pyrrolidine (ill) results in 2-aiainomethyl pyrrolidine (v) through the intermediary of N-benzyl 2-a-ainomethyl pyrrolidine (IV) which can be isolated and purified.
In this latter case, reduction of the compound (ill) to the compound (iv) can be effected by chemical reduction by means of metals such as iron or zinc,* in the presence of acids such as hydrochloric or acetic acid, or by reduction by means of hydrogen in the presence of catalysts such as Haney nickel, palladium-bearing carbon, platinum black, etc. The hydrogenation pressure used varies from atmospheric pressure to 150 atmospheres.
It is also possible to effect the reduction of N-benzyl 2-nitro methylene pyrrolidine (ill) to 2-aminomethyl pyrrolidine (v) without isolating N-benzyl 2-arainomethyl pyrrolidine (IV).
Seduction is effected in an acid medium by hydrogen in the presence of catalysts, as described above.
The 2-aminomethyl pyrrolidine produced can be converted into salts by the addition of a mineral acid such as hydrochloric, hydrobromic or sulphuric acid, or an organic acid such as oxalic acid, tar ic acid, maleic acid, etc.
The process of the present invention has the advantage of producing 2-aminomethyl pyrrolidine from 2-pyrrolidone, a widely available product at moderate cost, in a reduced number of stages (three stages, or four stages if the intermediate (IV) is isolated), in a very good yield and in a very high state of purity.
As 2-aminomethyl pyrrolidine is used as an intermediate in the synthesis of substances having attractive pharmacodynamic properties, the purity criterion is here essential.
The following examples illustrate the present invention but without limiting it.
EXAMPLE 1 2-aiainoaethyl pyrrolidine a) N-bcnsyl 2-pyrrol done 138 g of sodium are introduced into a 6 litre balloon flssk containing 2 100 ml of ethanol. At the end of the reaction, the laixture is cooled ' to from 15 to 20 C and 510 g of 2-pyrrolidone is introduced. After evaporation of the alcohol under reduced pressure, 2400 ml of xylene is added* A part of the solvent is distilled in order completely to remove the alcohol.
With the mixture at reflux temperature, 759 g of benzyl chloride is introduced. After the reaction tctaperature has been maintained for 8 hours at the reflux temperature, the mixture is cooled and filtered. The solvent is distilled under vacuum and after purification by distillation, 862 g of N-henzyl 2-pyrrolidone is produced (yield: 82 j boiling point/ 23 mm Hg: 148 to 150°C). b) N-benzyl 2-nitroroethylene pyrrolidine 875 g of N-benzyl 2-pyrrolidone and 630 g of dimethyl sulphate are introduced into a 6 litre balloon flask. After this mixture has been heated for 1¾ hours at 65*C, followed by cooling to about 15*C, the solution of 115 g of sodium in 3500 ml of methanol is introduced. The reaction mixture is left -with agitation for 30 minutes at ambient temperature and then 460 g of nitromethane is added. Agitation is maintained for 1 hour, then the solution is left at rest for about 12 hours. The solvent is then evaporated under vacuum.
After the addition of 800 ml of water to the residue, crystallisation, filtration of the crystals formed, washing -with vater and drying in a drying oven at 50 C, 764 g of N-benzyl 2-nitromethylene pyrrolidine is produced (yield; 71^5 Belting point: 99*C) c) 2-aminomethyl pyrrolidine Introduced into a 1 litre autoclave are 6l g of N-benzyl 2-nitro- methylene pyrrolidine, 300 ml of ethanol, hydrochloric ethanol in an amount sufficient for the number of hydrochloi'ic acid mols introduced to ^ be double the number of nitromethylene pyrrolidine, approximately 150 g Eaney nickel, and hydrogen, until a pressure of 50 k is produced. The autoclave is left under agitation for 1 hour, then further hydrogen is introduced until the pressure reaches 145 kg. After the mixture has been heated for 5 hours at 100"c, followed by cooling and filtration of the nickel, the solvent is evaporated to dryness at reduced pressure.
The residue is dissolved in 200 ml of methylene chloride, then 40$ sodium hydroxide and potassium hydroxide in pellet form are added.
After .decantation, the organic phase is dried and filtered, and the solvant is evaporated.
Distillation is effected to produce 17g of 2-aminomethyl pyrrolidine (boiling point/52 mm Hg: 86 to § *0 yield: 6θ.7 ) EXAMPLE 2 2-aminomethyl -pyrrolidine a) identical to Example 1 b) identical to Example 1 c) 'N-benzyl 2-aiainomethyl pyrrolidine Introduced into a 5 litre autoclave are 218 g of N-benzyl 2-nitro- methylcne pyrrolidine, 900 ml of methanol, 120 g of Eaney nickel, and hydrogen, until the pressure reaches 40 kg. The autoclave is left under agitation for 1¾· hours. The mixture is then cooled. After filtration, and >/ashing of the nickel with methanol, evaporation of the solvent and distillation of the residue, 179 g of N-benzyl 2-atainoacthyl pyrrolidine is produced (yield: 94#ϊ boiling point/7 nna Hg: 137 to 140*C). d) 2-a¾rinoiaetby? pyrrolidine Introduced into a 1 litre autoclave is 190 g of N-benzyl 2-ominouieth l pyrrolidine, a solution of l60 ml of hydrochloric acid (d =- 1.1S) in 14(i¾ki of vater and approximately 75 g of Raney nickel, and hydrogen until a pressure of 130 kg is reached. The autoclave is agitated and then heated to lOO'Co Further hydrogen is introduced until the pressure reaches 100 kg, and the autoclave is left under agitation for i hour.
After cooling of the mixture, the nickel is filtered and vashed vith water. The filtrate is evaporated to dryness under reduced pressure, then the residue is dissolved in 500 ml of ethanol and the solution is neutralised by means of a solution of 128 g of potassium hydroxide in pellet form, in 6OO ml of ethyl alcohol.
After filtration of the potassium chloride formed and distillation of the solvent under vacuum, the residue is dissolved in benzene. The benzene solution is dried and filtered and the solvent is distilled under reduced pressure. Distillation of the residue provides 78 g of 2-amino- methyl pyrrolidine (yield: 78 ; Boiling point: 167 to 170°C; purity by uiw wwi ilulwa chromatography: 7.6 ).
Claims (2)
1. C L A I M Λ noyel process for the preparation of 2-aminomethyl pyrrolidine bavins: the formula: its salts of addition with mineral or organic acids, characterised in that 2-pyrrolidone is reacted^a. a reactive benzylated compound having the formula in vhich X represents a reactive group or atom such es a halogen atom or a tosyl group, and that the N-benzyl 2-pyrrolidone formed isj treated with a lover alkyl sulphate, an alkaline alcoholate and nitromethane, and hat the N-benzyl 2-nitromethylene pyrrolidine produced is reduced to 2-aminomethyl pyrrolidine, either directly by catalytic reduction or through the intermediary of N-benzyl 2-aminomethyl pyrrolidine by chemical or catalytic reduction, vhich stay or may not be isolated and vhich is then reduced to form
2. -aminomethyl pyrrolidine.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7407342A FR2263239B1 (en) | 1974-03-04 | 1974-03-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
IL46657A true IL46657A (en) | 1977-12-30 |
Family
ID=9135811
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL46657A IL46657A (en) | 1974-03-04 | 1975-02-18 | Preparation of 2-aminomethyl pyrrolidine |
Country Status (33)
Country | Link |
---|---|
JP (1) | JPS5948825B2 (en) |
AR (1) | AR207350A1 (en) |
AT (1) | AT358569B (en) |
BE (1) | BE825728A (en) |
BG (1) | BG25077A3 (en) |
CA (1) | CA1047041A (en) |
CH (1) | CH602636A5 (en) |
CS (1) | CS179935B2 (en) |
DD (1) | DD117450A5 (en) |
DE (1) | DE2506515A1 (en) |
DK (1) | DK83875A (en) |
EG (1) | EG11753A (en) |
ES (1) | ES435139A1 (en) |
FI (1) | FI750558A (en) |
FR (1) | FR2263239B1 (en) |
GB (1) | GB1481251A (en) |
HK (1) | HK27878A (en) |
HU (1) | HU169274B (en) |
IE (1) | IE40685B1 (en) |
IL (1) | IL46657A (en) |
LU (1) | LU71947A1 (en) |
MW (1) | MW875A1 (en) |
NL (1) | NL7502425A (en) |
NO (1) | NO145439C (en) |
OA (1) | OA04856A (en) |
PH (1) | PH11269A (en) |
PL (1) | PL94801B1 (en) |
RO (1) | RO64007A (en) |
SE (1) | SE401367B (en) |
SU (1) | SU591139A3 (en) |
YU (1) | YU36500B (en) |
ZA (1) | ZA751072B (en) |
ZM (1) | ZM2775A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4772459A (en) * | 1986-09-09 | 1988-09-20 | Erbamont, Inc. | Method for controlling emesis caused by chemotherapeutic agents and antiemetic agents useful therein |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1785124A1 (en) * | 1968-08-13 | 1971-11-11 | Prym Werke William | Zipper |
JPS5146901B2 (en) * | 1971-08-24 | 1976-12-11 | ||
CH556836A (en) * | 1971-09-30 | 1974-12-13 | Fratmann Ag | PROCESS FOR THE PREPARATION OF 1-ALKENYL-2-AMINOMETHYLPYRROLIDINES. |
NL7304089A (en) * | 1972-03-30 | 1973-10-02 | ||
CH573404A5 (en) * | 1972-07-28 | 1976-03-15 | Inventa Ag |
-
1974
- 1974-03-04 RO RO7400081539A patent/RO64007A/en unknown
- 1974-03-04 FR FR7407342A patent/FR2263239B1/fr not_active Expired
- 1974-03-04 CH CH272675A patent/CH602636A5/xx not_active IP Right Cessation
-
1975
- 1975-01-01 AR AR257827A patent/AR207350A1/en active
- 1975-02-15 DE DE19752506515 patent/DE2506515A1/en active Pending
- 1975-02-18 IL IL46657A patent/IL46657A/en unknown
- 1975-02-20 ZA ZA00751072A patent/ZA751072B/en unknown
- 1975-02-20 BE BE1006472A patent/BE825728A/en not_active IP Right Cessation
- 1975-02-24 IE IE377/75A patent/IE40685B1/en unknown
- 1975-02-24 GB GB7645/75A patent/GB1481251A/en not_active Expired
- 1975-02-25 EG EG93/75A patent/EG11753A/en active
- 1975-02-26 CA CA220,855A patent/CA1047041A/en not_active Expired
- 1975-02-26 FI FI750558A patent/FI750558A/fi not_active Application Discontinuation
- 1975-02-27 ES ES435139A patent/ES435139A1/en not_active Expired
- 1975-02-28 MW MW8/75A patent/MW875A1/en unknown
- 1975-02-28 NL NL7502425A patent/NL7502425A/en not_active Application Discontinuation
- 1975-03-03 PL PL1975178472A patent/PL94801B1/en unknown
- 1975-03-03 BG BG029132A patent/BG25077A3/en unknown
- 1975-03-03 AT AT160575A patent/AT358569B/en not_active IP Right Cessation
- 1975-03-03 SU SU752111076A patent/SU591139A3/en active
- 1975-03-03 SE SE7502340A patent/SE401367B/en not_active IP Right Cessation
- 1975-03-03 PH PH16855A patent/PH11269A/en unknown
- 1975-03-03 DD DD184512A patent/DD117450A5/xx unknown
- 1975-03-03 HU HUSO1136A patent/HU169274B/hu not_active IP Right Cessation
- 1975-03-03 LU LU71947A patent/LU71947A1/xx unknown
- 1975-03-03 DK DK83875*#A patent/DK83875A/da not_active Application Discontinuation
- 1975-03-03 NO NO750699A patent/NO145439C/en unknown
- 1975-03-04 JP JP50026947A patent/JPS5948825B2/en not_active Expired
- 1975-03-04 ZM ZM27/75A patent/ZM2775A1/en unknown
- 1975-03-04 CS CS7500001451A patent/CS179935B2/en unknown
- 1975-03-04 OA OA55432A patent/OA04856A/en unknown
- 1975-03-19 YU YU00676/75A patent/YU36500B/en unknown
-
1978
- 1978-06-01 HK HK278/78A patent/HK27878A/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR19990013522A (en) | Process for preparing substituted perhydroisoindole | |
US3748341A (en) | Process of preparing 1-substituted-2-aminomethylpyrrolidines and intermediates therefor | |
CN112028806B (en) | Synthetic method of vildagliptin intermediate | |
SU607551A3 (en) | Method of obtaining 2-aminomethyl-n-(omega-oxyalkyl) pyrrolidines | |
CA1074322A (en) | 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-t-butylaminoethyl) pyridine via hydrogenolysis of its benzylidene acetal | |
CA1280426C (en) | 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide, its production and use | |
EP0431521A1 (en) | Aminobutanol derivative and process for the preparation of 3-pyrrolidinol from the same | |
IL46657A (en) | Preparation of 2-aminomethyl pyrrolidine | |
US6630595B2 (en) | Method for producing maleimides | |
US3551498A (en) | Dehydrogenation of 10,11-dihydro-5h-dibenzo(a,d)cycloheptene-5-one | |
US2980693A (en) | Methods for producing same | |
JPH0678304B2 (en) | Method for producing N-alkyl substituted lactam | |
US4721793A (en) | Azetidine-3-carboxylic acid derivatives | |
US4663464A (en) | Process for the preparation of dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione | |
US4469876A (en) | Process for the production of L-proline | |
KR970004595B1 (en) | Process for preparing 3-amino-1-benzylpyrrolidines | |
US4010160A (en) | Process for the manufacture of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine | |
US4011231A (en) | 2-Phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-4H-pyrido[3,2-d]-1,3-dioxin maleate and its use as an intermediate | |
KR820001121B1 (en) | Process for preparing 2-amino-methyl pyrolidine | |
US3668232A (en) | N-substituted 2-aminomethyl-2{40 -biphenylcarboxylic acid and derivatives | |
EP1015428B1 (en) | Sulfo-n-hydroxy succinimide and method of preparation | |
Sheehan et al. | α-Lactams. III. The Reaction of 1-t-Butyl-3, 3-dimethylaziridinone with Lithium Aluminum Hydride | |
KR0156621B1 (en) | Process for preparation of 4-(n-t-butloxycarbonyl)aminomethyl-1-(n-t-butyloxycarbonyl)pyrrolidin-3-ol | |
CS217998B2 (en) | Method of making the 1-alkyl-2-aminomethylpyrrolidine | |
NO801549L (en) | PROCEDURE FOR THE PREPARATION OF PYRROLINE DERIVATIVES |