DK152752B - METHOD OF PREPARING L-SULPIRIDE - Google Patents
METHOD OF PREPARING L-SULPIRIDE Download PDFInfo
- Publication number
- DK152752B DK152752B DK066579AA DK66579A DK152752B DK 152752 B DK152752 B DK 152752B DK 066579A A DK066579A A DK 066579AA DK 66579 A DK66579 A DK 66579A DK 152752 B DK152752 B DK 152752B
- Authority
- DK
- Denmark
- Prior art keywords
- ethyl
- levo
- methoxy
- reacted
- pyrrolidinomethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 17
- 229960004940 sulpiride Drugs 0.000 title description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- GNMSLDIYJOSUSW-LURJTMIESA-N N-acetyl-L-proline Chemical compound CC(=O)N1CCC[C@H]1C(O)=O GNMSLDIYJOSUSW-LURJTMIESA-N 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- 238000007580 dry-mixing Methods 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- ZQSFLXDMGBSJKV-UHFFFAOYSA-N ethyl 2-methoxy-5-sulfamoylbenzoate Chemical compound CCOC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC ZQSFLXDMGBSJKV-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 description 3
- SQAILWDRVDGLGY-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzoic acid Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(O)=O SQAILWDRVDGLGY-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- MXBLZLWZAHUKLU-UHFFFAOYSA-N 2-sulfamoylbenzamide Chemical compound NC(=O)C1=CC=CC=C1S(N)(=O)=O MXBLZLWZAHUKLU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- GUFUWKKDHIABBW-UHFFFAOYSA-N pyrrolidin-1-ylmethanol Chemical compound OCN1CCCC1 GUFUWKKDHIABBW-UHFFFAOYSA-N 0.000 description 1
- AUKXFNABVHIUAC-UHFFFAOYSA-N pyrrolidin-2-ylmethylamine Chemical compound NCC1CCCN1 AUKXFNABVHIUAC-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 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
- C07D207/04—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
-
- 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
Description
iin
DK 152752 BDK 152752 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af levo-N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulfamoyl-benzamid, med hvilken forbindelse der kan fremstilles terapeutiske præparater.The present invention relates to a particular process for the preparation of levo-N- (1-ethyl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoyl-benzamide with which compound can be prepared therapeutic compositions.
5 N- (1 -Ethyl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoylbenzamid med formlen CH0-CH~ I 2 I 2 CO - NH - CH0 - CH* CH„ fV' uN- (1-Ethyl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoylbenzamide of the formula CHO-CH-I 2 I 2 CO - NH - CHO - CH * CH
h2no2sJ^Jh2no2sJ ^ J
er en kendt forbindelse, som er kommercielt tilgængelig under navnet sulpirid.is a known compound which is commercially available under the name sulpiride.
Denne forbindelse har fundet udbredt anvendelse på det neurologiske 10 og psykiatriske område, administreret enten alene eller sammen med andre kendte tranquilliserende midler.This compound has been widely used in the neurological and psychiatric fields, administered either alone or in conjunction with other known tranquilizers.
Som det fremgår af den angivne formel, indeholder sulpirid ét asymmetrisk carbonatom (mærket med en stjerne), og forbindelsen er derfor en blanding af to optiske antipoder.As can be seen from the indicated formula, sulpiride contains one asymmetric carbon atom (labeled with an asterisk) and therefore the compound is a mixture of two optical antipodes.
15 Ved opspaltning af en racemisk blanding skulle det forventes, at den aktive isomer højst skulle have den dobbelte aktivitet i forhold til den racemiske blanding, og dette forudsætter, at den inaktive isomer overhovedet ingen aktivitet udviser.In decomposing a racemic mixture, the active isomer should be expected to have at most double activity relative to the racemic mixture, and this assumes that the inactive isomer shows no activity at all.
Det har vist sig, at l-sulpirid er 3-6 gange så aktivt som racemisk 20 sulpirid, og ved dosisniveauer, hvor de udviser samme aktivitet, er l-sulpirid kun 1/5 så toxisk som racemisk sulpirid.It has been found that l-sulpiride is 3-6 times as active as racemic sulpiride, and at dose levels where they exhibit the same activity, l-sulpiride is only 1/5 as toxic as racemic sulpiride.
DK 152752BDK 152752B
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Sulpirid adskiller sig på dette punkt på overraskende måde fra andre racemiske forbindelser, da det er normalt, at højere aktivitet ledsages af større toxicitet, hvilket indebærer, at den højere aktivitet i en bestemt isomer ikke kan udnyttes. Den erkendelse, at I-sulpirid i 5 sammenligning med racemisk sulpirid har så overraskende egenskaber, gør, at det er berettiget at tale om to terapeutisk forskellige stoffer.Sulpiride differs surprisingly from other racemic compounds at this point, as it is normal that higher activity is accompanied by greater toxicity, which means that the higher activity in a particular isomer cannot be exploited. The recognition that I-sulpiride has such surprising properties in comparison with racemic sulpiride makes it justifiable to speak of two therapeutically different substances.
Der var derfor et behov for at finde en industrielt udnyttelig fremgangsmåde, som i høje udbytter og på enkel og økonomisk måde ville føre til l-sulpirid, uden at der opstod behov for at opspalte de to 10 isomerer fra en racemisk blanding.Therefore, there was a need to find an industrially exploitable process which, in high yields and in a simple and economical manner, would lead to l-sulpiride without the need to split the two 10 isomers from a racemic mixture.
Alle tidligere forsøg på at opspalte racemisk sulpirid har enten været helt negative eller højst kun ført til isolering af små mængder af den venstredrejende isomer.All previous attempts to decompose racemic sulphiride have either been completely negative or at most only led to the isolation of small amounts of the left-turn isomer.
Det har derfor været helt umuligt at basere en industriel fremgangs-15 måde på sådanne opspaltningsmetoder.Therefore, it has been quite impossible to base an industrial process on such cleavage methods.
I dansk patentansøgning nr. 3503/77 er der beskrevet en fremgangsmåde til fremstilling af optisk aktive N-substituerede pyrrolidiner og deres anvendelse til dannelse af optisk aktive benzamider. Kernen i denne fremgangsmåde ligger i dannelsen af mellemprodukt-pyrrolidi-20 nerne, idet den sidste omsætning med benzoesyre er kendt. I den i dansk patentansøgning nr. 3503/77 beskrevne reaktionssekvens este-rificeres l-prolin først, hvorefter esteren omdannes til et amid, ami-do-prolinet N-acyleres, og til sidst reduceres amido- og N-acylgrup-perne samtidig.Danish Patent Application No. 3503/77 discloses a process for preparing optically active N-substituted pyrrolidines and their use to form optically active benzamides. The essence of this process lies in the formation of the intermediate pyrrolidines, the last reaction of benzoic acid being known. In the reaction sequence described in Danish Patent Application No. 3503/77, 1-proline is first esterified, then the ester is converted to an amide, the ami-do-proline N-acylated, and finally the amido and N-acyl groups simultaneously reduced.
25 Ved fremgangsmåden ifølge den foreliggende opfindelse N-acyleres l-prolin, hvorefter carboxygruppen og N-acetylgruppen reduceres, den vundne alkoholiske gruppe chloreres, og til slut substitueres chloratomet med en aminogruppe.In the process of the present invention, N-acyl is N-acylated, then the carboxy group and N-acetyl group are reduced, the alcoholic group obtained is chlorinated and finally the chlorine atom is substituted with an amino group.
Ved fremgangsmåden ifølge opfindelsen undgås 2 trin i forhold til den 30 kendte fremgangsmåde, hvilket gør fremgangsmåden ifølge opfindelsen enklere end den kendte, og udbyttet bliver større.In the method according to the invention, 2 steps are avoided over the known method, which makes the method according to the invention simpler than the known and the yield increases.
DK 152752BDK 152752B
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Ved at gå frem efter den kendte syntesemådes trin ville udbyttet af l-sulpirid blive for lavt til en industriel produktion.By following the steps of the known method of synthesis, the yield of l-sulfiride would be too low for an industrial production.
Den industrielle fremgangsmåde, som er genstand for den foreliggende opfindelse, går ud fra et kommercielt tilgængeligt, billigt råmateriale 5 og fører til fremstilling af meget rent venstredrejende N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulfamoylbenzamid i store udbytter under anvendelse af en meget enkel og økonomisk fremgangsmåde.The industrial process which is the subject of the present invention is based on a commercially available, inexpensive feedstock 5 and leads to the preparation of very pure left-turn N- (1-ethyl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoylbenzamide in large yields using a very simple and economical approach.
Fremgangsmåden ifølge den foreliggende opfindelse er ejendommelig ved det i kravets kendetegnende del angivne og er skitseret nedenfor 10 i følgende reaktionsskema: acetylerin^ __The process of the present invention is characterized by the characterizing part of the claim and is outlined below 10 in the following reaction scheme: acetylene
υ COOH L>-C00Hυ COOH L> -C00H
I doI do
H (levo) JH (levo) J
CH^ (levo) ,!) reduktion | -> ^J_ch2ch co ck2 cL (levo) 'cL (levo> 3 3 I 1 chlorering^ ^ 1-1 kNkH2«H2 i Jh CH, CH9 I 2 c'h3 (levo> k (leV0)CH ^ (levo),!) Reduction | -> ^ J_ch2ch co ck2 cL (levo) 'cL (levo> 3 3 I 1 chlorination ^^ 1-1 kNkH2 «H2 i Jh CH, CH9 I 2 c'h3 (levo> k (leV0)
_DK 152752B_DK 152752B
4 cooc^ 4) L X-CHo-NH0 + °CH3 2 24 cooc ^ 4) L X-CHo-NHO + ° CH3 2 2
j H2N02S-"C2H5OHj H2NO2S- "C2H5OH
CH„ -^ ch3 (levo)CH 2 - 3 ch 3 (levo)
CO - NH - CH2—ICO - NH - CH2 - I
A-”3 ch2 H2N02S-kv^ " jH (levo)A - 3 ch 2 H 2 NO 2 S-kv
Det har overraskende nok vist sig, at det ved at starte med venstredrejende prolin, som er et naturligt produkt, der er kommercielt tilgængeligt til lav pris, er muligt at underkaste denne forbindelse en serie kemiske omdannelser til fremstilling af venstredrejende N-ethyl-5 2-aminomethylpyrrolidin, uden at der optræder nogen racemisering eller omdannelse af optisk aktivitet i produktet under fremgangsmådetrinene.Surprisingly, it has been found that by starting with left-turn proline, which is a natural product that is commercially available at low cost, it is possible to subject this compound to a series of chemical conversions to produce left-turn N-ethyl-5 2 -aminomethylpyrrolidine without any racemization or conversion of optical activity in the product during the process steps.
Venstredrejende N-ethyl-2-aminomethylpyrrolidin omsættes med ethyl-esteren af 2-methoxy-5-sulfamoyl-benzoesyre til dannelse af N-(1-eth-10 yl-2-pyrrolidinomethyl)-2-methoxy-5-su!famoylbenzamid, og ved at udføre denne omsætning i fravær af opløsningsmiddel ved en temperatur på 80-85-°C i et tørblandingsapparatur fremstilles det endelige venstredrejende produkt i næsten kvantitative udbytter.Left-turn N-ethyl-2-aminomethylpyrrolidine is reacted with the ethyl ester of 2-methoxy-5-sulfamoyl-benzoic acid to give N- (1-eth-10-yl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoylbenzamide and by carrying out this reaction in the absence of solvent at a temperature of 80-85 ° C in a dry mixing apparatus, the final left-turn product is prepared in almost quantitative yields.
Nærmere detaljer om de forskellige trin i fremgangsmåden ifølge den 15 foreliggende opfindelse gives nedenfor.Details of the various steps of the process of the present invention are given below.
1. Venstredrejende prolin acetyleres med eddikesyreanhydrid i vandig opløsning med et stort overskud af eddikesyreanhydrid.1. Left-turn proline is acetylated with acetic anhydride in aqueous solution with a large excess of acetic anhydride.
Reaktionen er exoterm.The reaction is exothermic.
Det venstredrejende acetylprolin kan udfældes ved afkøling og fraskil-20 les ved filtrering.The left-turn acetylproline can be precipitated by cooling and separated by filtration.
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Der fås et meget rent krystallinsk produkt i et udbytte på ca. 90%.A very pure crystalline product is obtained in a yield of approx. 90%.
2. Det venstredrejende acetylprolin underkastes reduktion med et reduktionssystem, som virker simultant, under samme betingelser, på acetyl- og carboxygruppen. Som reduktionssystem anvendes lithium- 5 aluminiumhydrid i tetrahyd rof uran.2. The left-turn acetylproline is subjected to reduction by a reduction system acting simultaneously, under the same conditions, on the acetyl and carboxy groups. As a reduction system, lithium aluminum hydride is used in tetrahydro-uranium.
Ved denne reaktion fås udbytter i størrelsesordenen ca. 60%.In this reaction, yields on the order of approx. 60%.
Reduktionen udføres under tilbagesvaling, og. produktet kan fraskilles ved at udfælde ikke-omsat acetylprolin fra reaktionsblandingen ved hjælp af en base.The reduction is carried out under reflux, and. the product can be separated by precipitating unreacted acetylproline from the reaction mixture by means of a base.
10 Venstredrejende N-ethyl-2-pyrrolidinomethanol kan skilles fra filtratet ved destillation under vakuum.10 N-ethyl-2-pyrrolidinomethanol left-turn can be separated from the filtrate by distillation under vacuum.
3. Venstredrejende N-ethyl-2-pyrrolidinomethanol omdannes til den tilsvarende 2-methylamin ved først at erstatte hydroxylgruppen med et aktivt chloratom og derefter omsætte chloridet med ammoniak.3. Left-turn N-ethyl-2-pyrrolidinomethanol is converted to the corresponding 2-methylamine by first replacing the hydroxyl group with an active chlorine atom and then reacting the chloride with ammonia.
15 Chlorderivatet af alkoholen fremstilles under anvendelse af thionyl-chlorid i et vandfrit chloreret organisk opløsningsmiddel såsom CHCIg, CCI^ eller Ch^C^, ved en temperatur, der ligger mellem stuetemperatur og 60°C.The chlorine derivative of the alcohol is prepared using thionyl chloride in an anhydrous chlorinated organic solvent such as CHCl 3, CCl 2 or Ch 2 C 2 at a temperature ranging from room temperature to 60 ° C.
Thionylchloridet kan anvendes enten i støkiometrisk mængde eller i et 20 lille overskud.The thionyl chloride can be used either in stoichiometric amounts or in a small excess.
Efter endt reaktion fjernes opløsningsmidlet, og remanensen omsættes med alkoholisk ammoniak ved stuetemperatur.Upon completion of the reaction, the solvent is removed and the residue is reacted with alcoholic ammonia at room temperature.
Det dannede venstredrejende N-ethyl-2-aminomethylpyrrolidin fraskilles i et udbytte på ca. 50% ved at fjerne det alkoholiske opløsnings-25 middel, opløse remanensen i en vandig alkalisk opløsning og ekstrahere forbindelsen fra den vandige opløsning med et egnet organisk opløsningsmiddel, fortrinsvis ethylether.The resulting N-ethyl-2-aminomethylpyrrolidine left-turn is separated in a yield of ca. 50% by removing the alcoholic solvent, dissolving the residue in an aqueous alkaline solution and extracting the compound from the aqueous solution with a suitable organic solvent, preferably ethyl ether.
DK 152752BDK 152752B
6 4. Det venstredrejende N-ethyl-2-aminomethylpyrrolidin omsættes med ethylesteren af 2-methoxy-5-sulfamoylbenzoesyre i fraværelse af et opløsningsmiddel ved en temperatur på 80-90°C, idet denne temperatur opretholdes uden tilførsel af ydre varme, da reaktionen er exo-5 term, og under anvendelse af et tørblandingsapparatur såsom en "Z-mixer" til blanding af reaktanterne, hvilket er kritisk ved udførelse af reaktionen (spansk patentskrift nr. 428.341).6 4. The left-turn N-ethyl-2-aminomethylpyrrolidine is reacted with the ethyl ester of 2-methoxy-5-sulfamoylbenzoic acid in the absence of a solvent at a temperature of 80-90 ° C, maintaining this temperature without the application of external heat as the reaction takes place. is exothermic, and using a dry mixing apparatus such as a "Z-mixer" to mix the reactants, which is critical in carrying out the reaction (Spanish Patent No. 428,341).
Meget rent venstredrejende N-(1-ethyI-2-pyrrolidinomethyl)-2-meth-oxy-5-sulfamoylbenzamid fås ved krystallisation af reaktionsmassen 10 under anvendelse af et egnet opløsningsmiddel, fortrinsvis ethanol, som giver udbytter på 90-95%.Very pure left-turn N- (1-ethyl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoylbenzamide is obtained by crystallizing the reaction mass 10 using a suitable solvent, preferably ethanol, which yields 90-95% yield.
Alternativt kan de ovenfor angivne trin 3 og 4 udføres efter hinanden i samme reaktionsbeholder uden isolering af den som mellemprodukt dannede amin. I dette tilfælde blandes remanensen, efter fjernelse af 15 alkoholen og uomsat ammoniak ved afdampning, direkte med esteren af 2-methoxy-5-sulfamoylbenzoesyre i fraværelse af opløsningsmidler og under anvendelse af en "Z-mixer" til blandingen.Alternatively, steps 3 and 4 above may be carried out in succession in the same reaction vessel without isolating the intermediate amine. In this case, after removing the alcohol and unreacted ammonia by evaporation, the residue is directly mixed with the ester of 2-methoxy-5-sulfamoylbenzoic acid in the absence of solvents and using a "Z-mixer" for the mixture.
Det ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede venstredrejende N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-20 sulfamoylbenzamid har følgende karakteristika:The left-turn N- (1-ethyl-2-pyrrolidinomethyl) -2-methoxy-5-20 sulfamoylbenzamide produced by the process of the present invention has the following characteristics:
Smeltepunkt 186-188°C (n.c.); = -68,5° (c = 1% i dimethylform- amid); renhed 99,5%.Mp 186-188 ° C (n.c.); = -68.5 ° (c = 1% in dimethylformamide); purity 99.5%.
* IR-Spektret fremgår af fig. 1, som viser de overlejrede spektrer for det produkt, der er fremstillet ved fremgangsmåden i henholdsvis fire 25 trin og tre trin.* The IR spectrum is shown in FIG. 1, which shows the superimposed spectra of the product produced by the method in four steps and three steps respectively.
Tyndtlagschromatografi på silicagel, 60 F 254. Eluent: isopropanoi: methanol:koncentreret ammoniakopløsning i forholdet 8:1:1. Detektor: UV 254 eller Dragendorff.Thin layer chromatography on silica gel, 60 F 254. Eluent: isopropanoi: methanol: concentrated ammonia solution in the ratio of 8: 1: 1. Detector: UV 254 or Dragendorff.
DK 152752BDK 152752B
7 R^-Værdi ca. 0,40.7 R 2 -Value approx. 0.40.
Det ved fremgangsmåden ifølge opfindelsen fremstillede produkt kan administreres oralt i blanding med sædvanlige farmaceutiske fortyndingsmidler såsom lactose eller magnesiumstearat til dannelse af kaps-5 ler eller tabletter.The product of the process according to the invention may be administered orally in admixture with conventional pharmaceutical diluents such as lactose or magnesium stearate to form capsules or tablets.
Forbindelsen kan også administreres parenteralt i en vandig opløsning i form af et salt, fx et sulfat.The compound may also be administered parenterally in an aqueous solution in the form of a salt, e.g., a sulfate.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående eksempel:The process according to the invention is further illustrated by the following example:
10 EKSEMPELEXAMPLE
I. Fremstilling af ievo-N-acetylprolin II, 5 kg levo-prolin opløses i 30 liter vand, og til opløsningen sættes under omrøring 21,5 kg eddikesyreanhydrid.I. Preparation of ievo-N-acetylproline II, 5 kg of levo-proline is dissolved in 30 liters of water and to the solution is added 21.5 kg of acetic anhydride with stirring.
Temperaturen stiger spontant, og blandingen lades henstå under 15 omrøring i yderligere 20-30 minutter.The temperature rises spontaneously and the mixture is left under stirring for an additional 20-30 minutes.
Reaktionsbeholderen afkøles til en temperatur på 0-4°C og lades henstå, indtil den krystallinske masse er helt udskilt (ca. 12 timer).The reaction vessel is cooled to a temperature of 0-4 ° C and left to stand until the crystalline mass is completely separated (about 12 hours).
Massen filtreres, og det udfældede stof vaskes med isvand og tørres.The mass is filtered and the precipitate is washed with ice water and dried.
Der fås yderligere 10 kg produkt fra moderluden efter tilsætning af 20 en lille mængde isopropanol.An additional 10 kg of product is obtained from the mother liquor after the addition of a small amount of isopropanol.
Der fås i alt 15 kg levo-N-acetylprolin med et smeltepunkt på 89°C og i et udbytte på 95% af det teoretiske.A total of 15 kg of levo-N-acetylproline is obtained with a melting point of 89 ° C and in a yield of 95% of theory.
Analyse:Analysis:
Beregnet for: C 53,49 H 7,06 N 8,90 25 Fundet: C 53,35 H 7,00 N 8,95Calculated for: C 53.49 H 7.06 N 8.90 Found: C 53.35 H 7.00 N 8.95
DK 152752BDK 152752B
8 2. Fremstilling af levo-N-ethyl-2-pyrrolidinomethanol 15 kg N-acetylprolin sættes til en opløsning indeholdende 14,25 kg li-thiumaluminiumhydrid i 500 liter tetrahydrofuran. Opløsningen opvarmes under tilbagesvaling i 24 timer.8 2. Preparation of levo-N-ethyl-2-pyrrolidinomethanol 15 kg of N-acetylproline is added to a solution containing 14.25 kg of lithium aluminum hydride in 500 liters of tetrahydrofuran. The solution is heated at reflux for 24 hours.
5 Derefter afkøles reaktionsblandingen til 0°C, hvorefter der tilsættes 100 liter tetrahydrofuran indeholdende ca. 4% vand og 12 liter 20%'s NaOH.Thereafter, the reaction mixture is cooled to 0 ° C and 100 liters of tetrahydrofuran are added containing approx. 4% water and 12 liters 20% NaOH.
Det udfældede stof frafiltreres, tetrahydrofuran et afdampes, og remanensen destilleres under vakuum.The precipitated substance is filtered off, the tetrahydrofuran is evaporated and the residue is distilled off under vacuum.
10 Der fås 9 kg N-ethyl-2-pyrrolidinomethanol med et kogepunkt på 80°C/16 mm Hg og i et udbytte på 75% af det teoretiske.10 kg of N-ethyl-2-pyrrolidinomethanol is obtained with a boiling point of 80 ° C / 16 mm Hg and in a yield of 75% of theory.
Analyse:Analysis:
Beregnet for: C 65,07 H 11,70 N 10,84Calcd for: C 65.07 H 11.70 N 10.84
Fundet: C 64,95 H 11,72 N 10,80 15 3. Fremstilling af levo-N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5- sulfamoylbenzamid 9 kg levo-N-ethyl-2-pyrrolidinomethanol opløses i 200 liter C^C^, og til denne opløsning dryppes 6 liter thionylchlorid under afkøling. Opløsningen omrøres i 6 timer ved stuetemperatur og derefter i 2 20 timer under kogning, og der inddampes til tørhed. Den olieagtige remanens optages i ethanol, der er mættet med ammoniak, og blandingen holdes under omrøring ved stuetemperatur natten over.Found: C 64.95 H 11.72 N 10.80 3. Preparation of levo-N- (1-ethyl-2-pyrrolidinomethyl) -2-methoxy-5-sulfamoylbenzamide 9 kg levo-N-ethyl-2 pyrrolidinomethanol is dissolved in 200 liters of C ^C ^ and to this solution is added 6 liters of thionyl chloride while cooling. The solution is stirred for 6 hours at room temperature and then for 2 20 hours while boiling and evaporated to dryness. The oily residue is taken up in ethanol saturated with ammonia and the mixture is kept under stirring at room temperature overnight.
Alkoholen og ammoniakken afdampes under vakuum.The alcohol and ammonia are evaporated under vacuum.
Remanensen optages i en ringe mængde vand, der tildryppes natrium-25 hydroxid, og blandingen ekstraheres med ethylether. Etherfasen tørres og inddampes.The residue is taken up in a small amount of water which is dripped with sodium hydroxide and the mixture is extracted with ethyl ether. The ether phase is dried and evaporated.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20295/78A IT1095415B (en) | 1978-02-16 | 1978-02-16 | PROCESS FOR THE PRODUCTION OF AN OPTICALLY ACTIVE BENZAMIDE, OPTICALLY ACTIVE BENZAMIDE SO OBTAINED AND COMPOSITIONS |
| IT2029578 | 1978-02-16 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK66579A DK66579A (en) | 1979-08-17 |
| DK152752B true DK152752B (en) | 1988-05-09 |
| DK152752C DK152752C (en) | 1988-09-26 |
Family
ID=11165504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK066579A DK152752C (en) | 1978-02-16 | 1979-02-15 | METHOD OF PREPARING L-SULPIRIDE |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS54130562A (en) |
| AT (1) | AT373870B (en) |
| CA (1) | CA1097662A (en) |
| CH (1) | CH639951A5 (en) |
| DE (1) | DE2903891A1 (en) |
| DK (1) | DK152752C (en) |
| EG (1) | EG14440A (en) |
| FR (1) | FR2417498A1 (en) |
| GB (1) | GB2014990B (en) |
| GR (1) | GR78220B (en) |
| IT (1) | IT1095415B (en) |
| MX (1) | MX5632E (en) |
| NL (1) | NL190845C (en) |
| SE (1) | SE430888B (en) |
| YU (1) | YU41145B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1141095B (en) * | 1980-11-27 | 1986-10-01 | Ravizza Spa | RESOLUTION PROCESS OF THE SULPYRID RACEMA |
| EP0088849A1 (en) * | 1982-03-11 | 1983-09-21 | Choay S.A. | Levorotatory compounds of N-substituted benzenesulphone amides, process for their preparation and pharmaceutical compositions containing them |
| SE8602339D0 (en) * | 1986-05-22 | 1986-05-22 | Astra Laekemedel Ab | AND EFFECTIVE STEREOCONSERVATIVE SYNTHESIS OF 1-SUBSTITUTED (S) - AND (R) -2-AMINOMETHYLPYRROLIDINES |
| DE4103451C2 (en) * | 1991-02-02 | 1994-08-25 | Hormosan Kwizda Gmbh | Uses of the active substance sulpiride in its R or S form |
| WO2003055857A1 (en) * | 2001-12-28 | 2003-07-10 | Farmaceutsko-Hemijska Industrija 'zdravlje' | A process for synthesis of heterocyclic aminoalkyl benzamides |
| ITMI20051943A1 (en) * | 2005-10-14 | 2007-04-15 | Procos Spa | ANANTIOMERIC RESOLUTION PROCESS OF 2-AMINOMETHYL-PYRROLIDINES 1-SUBSTITUTED FOR DAMAGE IN THE PRESENCE OF LIPASE |
| CL2012000874S1 (en) | 2012-01-31 | 2013-03-22 | Saverglass | Bottle with a tapered rectangular parallelepipedic body oriented vertically, with its narrowest part located at the lower end, it has all its curved edges, at its upper end it forms a rectangular surface with convex sides, which is joined to the bottle neck by means of slight slopes. |
| CN103772256B (en) * | 2012-10-24 | 2017-10-10 | 江苏天士力帝益药业有限公司 | A kind of preparation method of high-purity Sulpiride or its optical isomer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK350377A (en) * | 1976-08-05 | 1978-02-06 | Synthelabo | PROCEDURE FOR STEREOSPECIFIC PREPARATION OF OPTICALLY ACTIVE N-SUBSTITUTED PYRROLIDINES |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3891671A (en) * | 1968-08-01 | 1975-06-24 | Ile De France | N-(2-pyrrolidyl or piperidyl alkyl)-4-hydroxy benzamides |
| CH605793A5 (en) * | 1974-03-05 | 1978-10-13 | Ile De France | |
| FR2394529A2 (en) * | 1977-06-13 | 1979-01-12 | Synthelabo | 2-METHOXY BENZAMIDES AND THEIR THERAPEUTIC APPLICATION |
| FR2393794A2 (en) * | 1977-06-06 | 1979-01-05 | Synthelabo | Therapeutic 2-methoxy benzamido methyl heterocycle(s) prepn. - from 2-methoxy benzoic ester(s) and amino methyl heterocycle(s) |
| JPS5365875A (en) * | 1976-11-24 | 1978-06-12 | Teijin Ltd | Preparation of benzenesulfone amide derivs. |
-
1978
- 1978-02-16 IT IT20295/78A patent/IT1095415B/en active
-
1979
- 1979-02-01 DE DE19792903891 patent/DE2903891A1/en active Granted
- 1979-02-05 GB GB7903902A patent/GB2014990B/en not_active Expired
- 1979-02-08 FR FR7903216A patent/FR2417498A1/en active Granted
- 1979-02-12 YU YU308/79A patent/YU41145B/en unknown
- 1979-02-13 JP JP1441979A patent/JPS54130562A/en active Pending
- 1979-02-13 MX MX797713U patent/MX5632E/en unknown
- 1979-02-13 AT AT0110179A patent/AT373870B/en not_active IP Right Cessation
- 1979-02-14 CH CH142779A patent/CH639951A5/en not_active IP Right Cessation
- 1979-02-14 EG EG97/79A patent/EG14440A/en active
- 1979-02-15 GR GR58375A patent/GR78220B/el unknown
- 1979-02-15 SE SE7901337A patent/SE430888B/en not_active IP Right Cessation
- 1979-02-15 DK DK066579A patent/DK152752C/en not_active IP Right Cessation
- 1979-02-16 CA CA321,673A patent/CA1097662A/en not_active Expired
- 1979-02-16 NL NL7901251A patent/NL190845C/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK350377A (en) * | 1976-08-05 | 1978-02-06 | Synthelabo | PROCEDURE FOR STEREOSPECIFIC PREPARATION OF OPTICALLY ACTIVE N-SUBSTITUTED PYRROLIDINES |
Also Published As
| Publication number | Publication date |
|---|---|
| DK152752C (en) | 1988-09-26 |
| YU41145B (en) | 1986-12-31 |
| JPS54130562A (en) | 1979-10-09 |
| IT1095415B (en) | 1985-08-10 |
| DE2903891A1 (en) | 1979-08-23 |
| CA1097662A (en) | 1981-03-17 |
| EG14440A (en) | 1984-03-31 |
| SE7901337L (en) | 1979-08-17 |
| GR78220B (en) | 1984-09-26 |
| FR2417498A1 (en) | 1979-09-14 |
| MX5632E (en) | 1983-11-15 |
| DK66579A (en) | 1979-08-17 |
| FR2417498B1 (en) | 1983-01-21 |
| GB2014990A (en) | 1979-09-05 |
| SE430888B (en) | 1983-12-19 |
| ATA110179A (en) | 1983-07-15 |
| DE2903891C2 (en) | 1992-02-06 |
| NL190845B (en) | 1994-04-18 |
| IT7820295A0 (en) | 1978-02-16 |
| GB2014990B (en) | 1982-06-09 |
| NL190845C (en) | 1994-09-16 |
| AT373870B (en) | 1984-02-27 |
| CH639951A5 (en) | 1983-12-15 |
| NL7901251A (en) | 1979-08-20 |
| YU30879A (en) | 1983-02-28 |
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