NO145439B - PROCEDURE FOR PREPARING 2-AMINOMETHYL-PYRROLIDINE - Google Patents
PROCEDURE FOR PREPARING 2-AMINOMETHYL-PYRROLIDINE Download PDFInfo
- Publication number
- NO145439B NO145439B NO750699A NO750699A NO145439B NO 145439 B NO145439 B NO 145439B NO 750699 A NO750699 A NO 750699A NO 750699 A NO750699 A NO 750699A NO 145439 B NO145439 B NO 145439B
- Authority
- NO
- Norway
- Prior art keywords
- pyrrolidine
- aminomethyl
- benzyl
- nitromethylene
- approx
- Prior art date
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- AUKXFNABVHIUAC-UHFFFAOYSA-N pyrrolidin-2-ylmethylamine Chemical compound NCC1CCCN1 AUKXFNABVHIUAC-UHFFFAOYSA-N 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 15
- QGRRJDFZPVWRGG-UHFFFAOYSA-N 1-benzyl-2-(nitromethylidene)pyrrolidine Chemical compound [O-][N+](=O)C=C1CCCN1CC1=CC=CC=C1 QGRRJDFZPVWRGG-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- -1 nitromethylene group Chemical group 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- LVUQCTGSDJLWCE-UHFFFAOYSA-N 1-benzylpyrrolidin-2-one Chemical compound O=C1CCCN1CC1=CC=CC=C1 LVUQCTGSDJLWCE-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- JGMIHIAAGUSENI-UHFFFAOYSA-N 1,5-dibromopentan-2-yl acetate Chemical compound CC(=O)OC(CBr)CCCBr JGMIHIAAGUSENI-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- OEYAFMGVIFWPQI-UHFFFAOYSA-N (1-benzylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1CC1=CC=CC=C1 OEYAFMGVIFWPQI-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- IBUPNDMHIOTKBL-UHFFFAOYSA-N 1,5-diaminopentan-2-ol Chemical compound NCCCC(O)CN IBUPNDMHIOTKBL-UHFFFAOYSA-N 0.000 description 1
- DSQKLPXLRYKLHE-UHFFFAOYSA-N 1-benzyl-3-methylidene-2-nitropyrrolidine Chemical compound C(C1=CC=CC=C1)N1C(C(CC1)=C)[N+](=O)[O-] DSQKLPXLRYKLHE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- HWBLTYHIEYOAOL-UHFFFAOYSA-N Diisopropyl sulfate Chemical compound CC(C)OS(=O)(=O)OC(C)C HWBLTYHIEYOAOL-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- OVHDZBAFUMEXCX-UHFFFAOYSA-N benzyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1=CC=CC=C1 OVHDZBAFUMEXCX-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
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- 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)
Description
Denne oppfinnelse angår en ny fremgangsmåte ved fremstilling av 2-aminomethyl-pyrrolidin, i ett enkelt trinn ut fra N-benzyl-2-nitromethylen-pyrrolidin. Oppfinnelsen omfatter også fremstillingen av syreaddisjonssaltene av forbindelsen. This invention relates to a new process for the production of 2-aminomethyl-pyrrolidine, in a single step from N-benzyl-2-nitromethylene-pyrrolidine. The invention also encompasses the preparation of the acid addition salts of the compound.
Fra vesttysk offentliggjørelsesskrift nr. 1 941 536 From West German publication document no. 1 941 536
er det kjent en fremgangsmåte ved reduksjon av l-alkyl-2-nitromethylen-pyrrolidiner til de tilsvarende l-alkyl-2-aminomethyl-pyrrolidiner. Ved reduksjonen, som vanligvis utføres ved et trykk mellom atmosfæretrykk og et trykk på noen få atmosfærer, men som angis å kunne utføres innenfor et bredt trykkområde, overføres nitromethylengruppen til en amino-methylgruppe, uten at alkylgruppen i 1-stillingen påvirkes. a method is known for the reduction of 1-alkyl-2-nitromethylene-pyrrolidines to the corresponding 1-alkyl-2-aminomethyl-pyrrolidines. In the reduction, which is usually carried out at a pressure between atmospheric pressure and a pressure of a few atmospheres, but which is stated to be able to be carried out within a wide pressure range, the nitromethylene group is transferred to an amino-methyl group, without the alkyl group in the 1-position being affected.
En tilsvarende fremgangsmåte for fremstilling av 1-alkylen-2-aminomethyl-pyrrolidin er beskrevet i norsk patentsøknad nr. 3495/72. A corresponding method for the production of 1-alkylene-2-aminomethyl-pyrrolidine is described in Norwegian patent application no. 3495/72.
For fremstilling av 2-aminomethyl-pyrrolidin er det For the production of 2-aminomethyl-pyrrolidine it is
fra Coll. Czech. Chem. Commun. 30 (6) - 2074-9 (1965) , (CA. from Coll. Czech. Chem. Commun. 30 (6) - 2074-9 (1965) , (CA.
vol. 63 -6340 g) kjent en fremgangsmåte ved hvilken 1,5-dibrom-2-acetoxy-pentan behandles med kaliumfthalimid i to timer ved 100°C, hvoretter det erholdte 1,5-difthalimido-2-acetoxy-pentan kokes med tilbakeløpskjøling i nærvær av salt-syre_og . eddiksyre ..i-25—timer...-Det-derved-erholdte diklor- . hydrat av 1,5-diamino-2-hydroxy-pentan kromatograferes på-ionebytterharpiks, hvorved diklorhydratet av 2-aminomethyl-pyrrolidin erholdes. Da imidlertid 1,5-dibrom-2-acetoxy-pentanet som anvendes som utgangsmateriale ved sistnevnte fremgangsmåte, ikke er noe handelsprodukt, må det fremstilles, f.eks. etter fremgangsmåten beskrevet i J. Chem. Soc. Japan 57, 768-69 (1964), i henhold til hvilken fremstillingen skjer ved behandling av tetrahydrofurfurylalkohol med eddiksyre mettet med hydrogenbromidgass. Fremstillingen av 2-aminomethyl-pyrrolidin ut fra en forbindelse som fåes i handelen (tetrahydrofurfurylalkohol) , skjer altså i fire trinn, ved en lang og omstende- Vol. 63 -6340 g) known a method in which 1,5-dibromo-2-acetoxy-pentane is treated with potassium phthalimide for two hours at 100°C, after which the 1,5-diphthalimido-2-acetoxy-pentane obtained is boiled with reflux cooling in presence of hydrochloric acid_and . acetic acid ..in-25—hours...-The-thereby-obtained dichlor- . hydrate of 1,5-diamino-2-hydroxy-pentane is chromatographed on ion-exchange resin, whereby the dihydrochloride of 2-aminomethyl-pyrrolidine is obtained. Since, however, the 1,5-dibromo-2-acetoxy-pentane, which is used as starting material in the latter method, is not a commercial product, it must be prepared, e.g. according to the method described in J. Chem. Soc. Japan 57, 768-69 (1964), according to which the preparation takes place by treating tetrahydrofurfuryl alcohol with acetic acid saturated with hydrogen bromide gas. The production of 2-aminomethyl-pyrrolidine from a commercially available compound (tetrahydrofurfuryl alcohol) takes place in four steps, by a long and
lig fremgangsmåte. similar procedure.
Det har nu vist seg mulig å fremstille 2-aminomethyl-pyrrolidin på en langt enklere måte, nemlig i ett trinn ut fra N-benzyl-2-nitromethylen-pyrrolidin, som i sin tur lar seg fremstille i ett trinn ut fra en forbindelse som føres i It has now proved possible to prepare 2-aminomethyl-pyrrolidine in a much simpler way, namely in one step from N-benzyl-2-nitromethylene-pyrrolidine, which in turn can be prepared in one step from a compound that is carried in
handelen, nemlig l-benzyl-2-pyrrolidinon. the trade, namely l-benzyl-2-pyrrolidinone.
I henhold til oppfinnelsen tilveiebringes der så-ledes en ny fremgangsmåte ved fremstilling av 2-aminomethyl-pyrrolidin av formelen: According to the invention, a new method for the production of 2-aminomethyl-pyrrolidine of the formula is thus provided:
og dets addisjonssalter med uorganiske eller organiske syrer, hvilken fremgangsmåte utmerker seg ved at N-benzyl-2-nitro-methylen-pyrrolidin i ett trinn reduseres katalytisk med hydrogen i et surt medium, idet reduksjonen utføres ved trykk ca. 150 kg/cm<2> og temperatur ca. 100°C i løpet av ca. 5 timer, og at det erholdte 2-aminomethyl-pyrrolidin eventuelt over-føres på i og for seg kjent måte til et addisjonssalt med and its addition salts with inorganic or organic acids, which method is characterized by N-benzyl-2-nitro-methylene-pyrrolidine being catalytically reduced in one step with hydrogen in an acidic medium, the reduction being carried out at a pressure of approx. 150 kg/cm<2> and temperature approx. 100°C during approx. 5 hours, and that the 2-aminomethyl-pyrrolidine obtained is optionally transferred in a manner known per se to an addition salt with
en uorganisk eller organisk syre. an inorganic or organic acid.
Fremgangsmåten ifølge oppfinnélsen illustreres ved følgende reaksjonsskjerna: The method according to the invention is illustrated by the following reaction core:
Reduksjonen av N-benzyl-2-nitromethylen-pyrrolidinet (III) fører til 2-aminomethyl-pyrrolidin (V) gjennom mellom-produktet N-benzyl-2-aminomethyl-pyrrolidin (IV). Som kata-lysator kan der f.eks. anvendes Raney-nikkel, palladium på carbon, platinasort/ osv. The reduction of the N-benzyl-2-nitromethylene-pyrrolidine (III) leads to 2-aminomethyl-pyrrolidine (V) through the intermediate product N-benzyl-2-aminomethyl-pyrrolidine (IV). As a catalyst, there can e.g. used Raney nickel, palladium on carbon, platinum black/ etc.
Det fremstilte 2-aminomethyl-pyrrolidin kan omdannes til salter ved tilsetning av en uorganisk syre slik som salt-syre, hydrobromsyre eller svovelsyre, eller en organisk syre slik som oxalsyre, vinsyre, maleinsyre, etc. The produced 2-aminomethyl-pyrrolidine can be converted into salts by adding an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as oxalic acid, tartaric acid, maleic acid, etc.
Fremgangsmåten ifølge oppfinnelsen medfører den fordel at 2-aminomethyl-pyrrolidin fåes i et meget godt utbytte og i en meget høy renhetsgrad. The method according to the invention entails the advantage that 2-aminomethyl-pyrrolidine is obtained in a very good yield and in a very high degree of purity.
Ettersom 2-aminomethyl-pyrrolidin blir benyttet som utgangsmateriale ved fremstilling av forbindelser med fordel-aktige farmakodynamiske egenskaper, er renhetskriteriet her vesentlig. As 2-aminomethyl-pyrrolidine is used as starting material in the production of compounds with advantageous pharmacodynamic properties, the purity criterion is essential here.
Utgangsmaterialet som anvendes ved fremgangsmåten ifølge oppfinnelsen, N-benzyl-2-nitromethylen-pyrrolidin (III), kan fremstilles i henhold til følgende reaksjonsskjerna: hvor X er en reaktiv gruppe, såsom et halogenatom eller en tosylgruppe, R^ er en lavere alkylgruppe inneholdende 1-3 carbonatomer, R2 er en alkylgruppe, og M er et alkalimetall. The starting material used in the process according to the invention, N-benzyl-2-nitromethylene-pyrrolidine (III), can be prepared according to the following reaction core: where X is a reactive group, such as a halogen atom or a tosyl group, R^ is a lower alkyl group containing 1-3 carbon atoms, R2 is an alkyl group, and M is an alkali metal.
2-Pyrrolidon (I) omsettes med en reaktiv benzylforbindelse, hvoretter det resulterende N-benzyl-2-pyrrolidon (II) omsettes med et lavere alkylsulfat, et alkalimetallalko-holat og nitromethan, hvorved N-benzyl-2-nitromethylen-pyrrolidin (III) fåes. Reaksjonen mellom benzylforbindelsen og pyrrolidonet skjer i et oppløsningsmiddel som benzen, toluen eller xylen, i nærvær av et basisk medium, såsom et alkali-metallalkoholat. 2-Pyrrolidone (I) is reacted with a reactive benzyl compound, after which the resulting N-benzyl-2-pyrrolidone (II) is reacted with a lower alkyl sulfate, an alkali metal alcoholate and nitromethane, whereby N-benzyl-2-nitromethylene-pyrrolidine (III ) can be obtained. The reaction between the benzyl compound and the pyrrolidone takes place in a solvent such as benzene, toluene or xylene, in the presence of a basic medium, such as an alkali metal alcoholate.
Eksempler på den reaktive benzylforbindelse som anvendes, er benzylhalogenider, som kloridet, bromidet eller jodidet, eller benzyl-p-toluensulfonat. Eksempler på det lavere alkylsulfat som anvendes, er dimethyl-, diethyl-, di-propyl- og diisopropylsulfat. Alkalimetallalkoholatet kan fremstilles ved omsetning av en alkohol som methanol, Examples of the reactive benzyl compound used are benzyl halides, such as the chloride, bromide or iodide, or benzyl p-toluenesulfonate. Examples of the lower alkyl sulphate used are dimethyl, diethyl, dipropyl and diisopropyl sulphate. The alkali metal alcoholate can be prepared by reacting an alcohol such as methanol,
ethanol, propanol, isopropanol, butanol, etc, med et alkalimetall som natrium eller kalium. ethanol, propanol, isopropanol, butanol, etc, with an alkali metal such as sodium or potassium.
I det følgende illustreres fremstillingen av utgangsmaterialet N-benzyl-2-nitromethylen-pyrrolidin. In the following, the production of the starting material N-benzyl-2-nitromethylene-pyrrolidine is illustrated.
a) Fremsti lling av N- benzyl- 2- pyrrolidon a) Preparation of N-benzyl-2-pyrrolidone
138 g natrium ble innført i en 6 liters rundkolbe inneholdende 2100 ml ethanol. Etter endt reaksjon ble blandingen avkjølt til 15 - 20°C, og 510 g 2-pyrrolidon ble innført. 138 g of sodium were introduced into a 6 liter round bottom flask containing 2100 ml of ethanol. After the end of the reaction, the mixture was cooled to 15-20°C, and 510 g of 2-pyrrolidone was introduced.
Etter fordampning av alkoholen under redusert trykk ble After evaporation of the alcohol under reduced pressure,
2400 ml xylen tilsatt. En del av oppløsningsmidlet ble destillert fra for å fullføre fjerningen av alkoholen. 2400 ml xylene added. A portion of the solvent was distilled off to complete the removal of the alcohol.
Blandingen ble bragt til tilbakeløpstemperatur, hvoretter 759 g benzylklorid ble tilsatt. Etter at reaksjonstem-peraturen hadde vært holdt ved tilbakeløpstemperaturen i 8 timer, ble blandingen avkjølt og filtrert. Oppløsningsmidlet ble destillert under vakuum, og etter rensning ved destillasjon ble det erholdt 862 g N-benzyl-2-pyrrolidon (utbytte: 82%; kokepunkt/2 3 mm Hg: 14 8 - 150°C.) The mixture was brought to reflux temperature, after which 759 g of benzyl chloride were added. After the reaction temperature had been maintained at the reflux temperature for 8 hours, the mixture was cooled and filtered. The solvent was distilled under vacuum, and after purification by distillation, 862 g of N-benzyl-2-pyrrolidone were obtained (yield: 82%; boiling point/2 3 mm Hg: 14 8 - 150°C.)
b) Fremstilling av N- benzyl- 2- nitroraethylen- pyrrolidin b) Preparation of N-benzyl-2-nitroraethylene-pyrrolidine
875 g N-benzyl-2-pyrrolidin og 630 g dimethylsulfat ble 875 g of N-benzyl-2-pyrrolidine and 630 g of dimethyl sulfate were
innført i en 6 liters rundkolbe. Etter at denne blanding var blitt oppvarmet 1 1/2 time ved 65°C og avkjølt til ca. 15°C, introduced into a 6 liter round flask. After this mixture had been heated for 1 1/2 hours at 65°C and cooled to approx. 15°C,
ble en oppløsning av 115 g natrium i 3500 ml methanol tilsatt. Reaksjonsblandingen fikk stå under omrøring 30 minutter ved romtemperatur, hvoretter 460 g nitromethan ble tilsatt. Røringen ble fortsatt 1 time, hvoretter oppløsningen fikk a solution of 115 g of sodium in 3500 ml of methanol was added. The reaction mixture was allowed to stand under stirring for 30 minutes at room temperature, after which 460 g of nitromethane were added. Stirring was continued for 1 hour, after which the solution was obtained
stå 12 timer. Oppløsningsmidlet ble deretter fordampet under vakuum. stand 12 hours. The solvent was then evaporated under vacuum.
Etter tilsetning av 800 ml vann til residuet ble der foretatt krystallisering, filtrering av de dannede krystaller, vasking med vann og tørking i ovn ved 50°C, hvorved det ble erholdt 764 g N-benzyl-2-nitromethylen-pyrrolidin (utbytte: 71%; sm.p. 99°C). After adding 800 ml of water to the residue, crystallization was carried out, filtering the formed crystals, washing with water and drying in an oven at 50°C, whereby 764 g of N-benzyl-2-nitromethylene-pyrrolidine were obtained (yield: 71 %; m.p. 99°C).
I det følgende eksempel illustreres fremstillingen The following example illustrates the preparation
av 2-aminomethyl-pyrrolidin ved fremgangsmåten ifølge oppfinnelsen. of 2-aminomethyl-pyrrolidine by the method according to the invention.
Eksempel Example
Fremstilling av 2- aminomethyl- pyrrolidin Preparation of 2-aminomethyl-pyrrolidine
I en 1 liters autoklav ble det innført 61 g N-benzyl-2-nitromethylen-pyrrolidin, 300 ml methanol, ethanolisk salt-syre i en mengde tilstrekkelig til at antall mol innført salt-syre var dobbelt så stort som antall mol nitromethylen-pyrro-lidih, ca. 150 g Raney-nikkel, og hydrogen, inntil et trykk på 50 kg. Autoklaven ble omrørt 1 time, hvoretter ytterligere hydrogen ble innført inntil trykket nådde 145 kg. Etter at blandingen var oppvarmet 5 timer ved 100°C, etterfulgt av av-kjøling og filtrering av nikkelet, ble oppløsningsmidlet fordampet til tørrhet ved redusert trykk. Residuet ble oppløst i 200 ml methylenklorid, deretter ble 4 0% natriumoxyd og kalsiumhydroxyd tilsatt i form av pellets. In a 1 liter autoclave, 61 g of N-benzyl-2-nitromethylene-pyrrolidine, 300 ml of methanol, ethanolic hydrochloric acid were introduced in a quantity sufficient so that the number of moles of hydrochloric acid introduced was twice as large as the number of moles of nitromethylene-pyrro -lidih, approx. 150 g Raney nickel, and hydrogen, up to a pressure of 50 kg. The autoclave was stirred for 1 hour, after which additional hydrogen was introduced until the pressure reached 145 kg. After the mixture was heated for 5 hours at 100°C, followed by cooling and filtration of the nickel, the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in 200 ml of methylene chloride, then 40% sodium oxide and calcium hydroxide were added in the form of pellets.
Etter dekantering ble den organiske fase tørket og filtrert og oppløsningsmidlet fordampet. After decantation, the organic phase was dried and filtered and the solvent evaporated.
Destillasjon ga 17 g 2-aminomethyl-pyrrolidin (k.p./ Distillation gave 17 g of 2-aminomethyl-pyrrolidine (b.p./
32 mm Hg: 86 - 89°C; utbytte 60,7%). 32 mm Hg: 86 - 89°C; dividend 60.7%).
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7407342A FR2263239B1 (en) | 1974-03-04 | 1974-03-04 |
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|---|---|
| NO750699L NO750699L (en) | 1975-09-05 |
| NO145439B true NO145439B (en) | 1981-12-14 |
| NO145439C NO145439C (en) | 1982-03-24 |
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| 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) |
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| 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 |
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1974
- 1974-03-04 FR FR7407342A patent/FR2263239B1/fr not_active Expired
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1975
- 1975-01-01 AR AR257827A patent/AR207350A1/en active
- 1975-02-15 DE DE19752506515 patent/DE2506515A1/en active Pending
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- 1975-02-20 ZA ZA00751072A patent/ZA751072B/en unknown
- 1975-02-24 GB GB7645/75A patent/GB1481251A/en not_active Expired
- 1975-02-24 IE IE377/75A patent/IE40685B1/en unknown
- 1975-02-25 EG EG93/75A patent/EG11753A/en active
- 1975-02-26 FI FI750558A patent/FI750558A/fi not_active Application Discontinuation
- 1975-02-26 CA CA220,855A patent/CA1047041A/en not_active Expired
- 1975-02-27 ES ES435139A patent/ES435139A1/en not_active Expired
- 1975-02-28 NL NL7502425A patent/NL7502425A/en not_active Application Discontinuation
- 1975-02-28 MW MW8/75A patent/MW875A1/en unknown
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- 1975-03-03 PH PH16855A patent/PH11269A/en unknown
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- 1975-03-03 LU LU71947A patent/LU71947A1/xx unknown
- 1975-03-03 DD DD184512A patent/DD117450A5/xx unknown
- 1975-03-03 SU SU752111076A patent/SU591139A3/en active
- 1975-03-03 NO NO750699A patent/NO145439C/en unknown
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- 1975-03-03 DK DK83875*#A patent/DK83875A/da not_active Application Discontinuation
- 1975-03-04 CS CS7500001451A patent/CS179935B2/en unknown
- 1975-03-04 JP JP50026947A patent/JPS5948825B2/en not_active Expired
- 1975-03-04 ZM ZM27/75A patent/ZM2775A1/en unknown
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1978
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