SE430888B - OPTICALLY ACTIVE LEFT ROTATING N- (1-ETHYL-2-PYRROLIDINYL-METHYL) -2-METOXY-5-SULFAMOYL BENZAMIDE AND PROCEDURE TO PREPARE THIS - Google Patents
OPTICALLY ACTIVE LEFT ROTATING N- (1-ETHYL-2-PYRROLIDINYL-METHYL) -2-METOXY-5-SULFAMOYL BENZAMIDE AND PROCEDURE TO PREPARE THISInfo
- Publication number
- SE430888B SE430888B SE7901337A SE7901337A SE430888B SE 430888 B SE430888 B SE 430888B SE 7901337 A SE7901337 A SE 7901337A SE 7901337 A SE7901337 A SE 7901337A SE 430888 B SE430888 B SE 430888B
- Authority
- SE
- Sweden
- Prior art keywords
- ethyl
- levo
- methoxy
- pyrrolidinylmethyl
- process according
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- -1 1-ETHYL-2-PYRROLIDINYL-METHYL Chemical class 0.000 title description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 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
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- BGRJTUBHPOOWDU-UHFFFAOYSA-N sulpiride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 3
- 229910010082 LiAlH Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical class 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 description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- OPXOXISNSVAALO-UHFFFAOYSA-N 1-ethyl-6-methoxy-6-(pyrrolidin-1-ylmethyl)-3-sulfamoylcyclohexa-2,4-diene-1-carboxamide Chemical compound C(C)C1(C(=O)N)C(C=CC(=C1)S(N)(=O)=O)(OC)CN1CCCC1 OPXOXISNSVAALO-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GHQCZUMSSZNLJP-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanol Chemical compound CCN1CCCC1CO GHQCZUMSSZNLJP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 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
- 238000002156 mixing Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004940 sulpiride Drugs 0.000 description 2
- 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
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 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
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
15 20 25 30 35 7901337~1 2 toxicitet är även mycket lägre mot alla logiska förvänt- ningar. 15 20 25 30 35 7901337 ~ 1 2 toxicity is also much lower against all logical expectations.
Efter att ha bestämt den höga terapeutiska för- mågan hos vänsterroterande N-(l-etyl-2-pyrrolidinylmetyl)- -2-metoxi-5-sulfamoylbensamid framlades problemet med att separera racemisk Sulpiride innehållande denna genom en ekonomisk industriell process.After determining the high therapeutic capacity of left-rotating N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide, the problem of separating racemic Sulpiride containing it was presented by an economical industrial process.
Emellertid har alla försök som gjorts för att upplösa racemisk Sulpiride antingen varit totalt nega- tiva eller har som mest lett endast till isolering av små mängder av den vänsterroterandeisomeren.However, all attempts to dissolve racemic Sulpiride have either been totally negative or have at most led to the isolation of only small amounts of the left-rotating isomer.
Det var därför absolut omöjligt att basera en industriell process på dessa upplösningsmetoder.It was therefore absolutely impossible to base an industrial process on these dissolution methods.
En industriell process'har nu utvecklats och utgör ändamålet med föreliggande uppfinning, vilken utgår från ett kommersiellt tillgängligt råmaterial med låg kostnad och möjliggör erhållandet av mycket ren vänster- roterandeN-(l-etyl-2-pyrrolidinylmetyl)-2~metoxi-5- -sulfamoylbensamid med mycket höga utbyten under an- vändning av ett mycket enkelt och ekonomiskt förfarande.An industrial process has now been developed and is the object of the present invention, which is based on a commercially available raw material at low cost and enables the obtaining of very pure left-rotating N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5- -sulfamoylbenzamide in very high yields using a very simple and economical procedure.
Det nya förfarandet enligt föreliggande uppfinning representeras schematiskt med följande reaktionsschema: i-ïï 1) [ KN Com, KN C001* . I H (levo) fo CH3 (levo) 2) 1 '- d k 1 re u tion _ - kN/-coon , oN/-cazon ! I ?° ÉH2 CH3 (levo) CH3 (levo) 7901337-1 3 ) »m3 i . . ' klorerin ~ CH -Cl -å CH NH Mï/-cazofl ----9a \ 2 \N/' 2 2 b? .The novel process of the present invention is schematically represented by the following reaction scheme: i-ïï1) [KN Com, KN C001 *. I H (levo) fo CH3 (levo) 2) 1 '- d k 1 re u tion _ - kN / -coon, oN / -cazon! I? ° ÉH2 CH3 (levo) CH3 (levo) 7901337-1 3) »m3 i. . 'chlorine ~ CH -Cl -å CH NH Mï / -cazo fl ---- 9a \ 2 \ N /' 2 2 b? .
QR* ÉHZ (1 > çflz (levo) evo (levo) CH3 CH3 CH3 CO-OR 4) ' 1-1 { ~\ ocH3 N/*cnz - Nnz + Hzuozs ,/ ' ROH _ I _ CH2 1 (levo) CH3 CO - NH ” CH2 | ~_~ocn CH // I 3 ènz (levo) 3 I H2No2s flä/ 7961337 '-1 10 15 20 25 30 35 4 Man har i själva verket överraskande funnit att med utgångspunkt från vänsterroterandeprolin, som är en naturlig kommersiellt tillgänglig produkt till låg kostnad,är det möjligt att utsätta denna för en serie kemiska omvandlingar för att erhålla vänsterroterande N-etyl-2-aminometyl-pyrrolidin, utan att det blir någon racemisering eller invertering av produktens optiska aktivitet under processtegen.QR * ÉHZ (1> ç fl z (levo) evo (levo) CH3 CH3 CH3 CO-OR 4) '1-1 {~ \ ocH3 N / * cnz - Nnz + Hzuozs, /' ROH _ I _ CH2 1 (levo) CH3 CO - NH ”CH2 | ~ _ ~ ocn CH // I 3 ènz (levo) 3 I H2No2s fl ä / 7961337 '-1 10 15 20 25 30 35 4 It has in fact surprisingly been found that on the basis of left-rotating proline, which is a naturally commercially available product for low cost, it is possible to subject it to a series of chemical conversions to obtain left-rotating N-ethyl-2-aminomethyl-pyrrolidine, without any racemization or inversion of the optical activity of the product during the process steps.
Den som slutprodukt vid dessa kemiska omvandlingar av prolin erhållna vänsterroterandeN-etyl-2-aminometyl- -pyrrolidinen kan omsättas med en ester av 2-metoxi-5- esulfamoylbensoesyra under lämpliga betingelser för att ge N-(l-etYl-2*PYrrOlidinyl-metyl)-2-metoxi-5-sulfamoyl- bensamid vilket görs under ganska drastiska betingelser vad beträffar temperatur, tid och mekanisk homogeni- sering av massan, för att ge den slutliga vänsterroterande produkten med nästan kvantitativa utbyten. aNedan beskrivs i detalj de individuella stegen i förfarandet enligt föreliggande uppfinning: 1. Vänsterroterandeprolin acetyleras i lösning med ett lämpligt acetylerande ämne, såsom acetylklorid eller ättiksyraanhydrid. Acetyleringen genomföres före- trädesvis i en vattenlösning med ett stort överskott av ättiksyraanhydrid. Reaktionen är exoterm. Den vänsterroterandeacetylprolinen utfälles genom kylning och separeras genom filtrering. En mycket ren kris- tallin produkt erhålles med ett utbyte av ca 90 %. 2. Den vänsterroterandeacetylprolinen undergår reduktion med ett reducerande system, vilket verkar samtidigt under samma betingelser på acetyl- och karboxyl- grupperna. Goda resultat erhålles genom användning fav metallhydrider i ett organiskt lösningsmedel.The left-rotating N-ethyl-2-aminomethyl-pyrrolidine obtained as a final product in these chemical conversions of proline can be reacted with an ester of 2-methoxy-5-esulfamoylbenzoic acid under suitable conditions to give N- (1-ethyl-2 * PYrrOlidinyl). methyl) -2-methoxy-5-sulfamoylbenzamide which is done under rather drastic conditions in terms of temperature, time and mechanical homogenization of the pulp, to give the final left-rotating product with almost quantitative yields. The individual steps of the process of the present invention are described in detail below: 1. Left-rotating proline is acetylated in solution with a suitable acetylating agent, such as acetyl chloride or acetic anhydride. The acetylation is preferably carried out in an aqueous solution with a large excess of acetic anhydride. The reaction is exothermic. The left-rotating acetylproline is precipitated by cooling and separated by filtration. A very pure crystalline product is obtained with a yield of about 90%. The left-rotating acetylproline undergoes reduction with a reducing system, which acts simultaneously under the same conditions on the acetyl and carboxyl groups. Good results are obtained by using fav metal hydrides in an organic solvent.
Särskilt goda utbyten, ca 60 %, erhålles med LiAlH4 i tetrahydrofuran. Reduktionen genomföres under äter- flöde och produkten separeras genom utfällning av den oreagerade acetylprolinen ur reaktionsblandningen medelst en alkalisk bas. Den vänsterroterandeN>etyl- 10 15 20 25 30 35 7901337 -1 5 -2-pyrrolidinylmetanolen separeras från filtratet genom destillation under vakuum.Particularly good yields, about 60%, are obtained with LiAlH 4 in tetrahydrofuran. The reduction is carried out under reflux and the product is separated by precipitating the unreacted acetylproline from the reaction mixture by means of an alkaline base. The left-rotating ethyl acetate-2-pyrrolidinylmethanol is separated from the filtrate by distillation under vacuum.
Den vänsterroteranæaN-etyl-2-pyrrolidinylmetanolen omvandlas till den motsvarande 2-metylaminen genom att först ersätta hydroxylen med en aktiv kloratom och därefter omsätta kloriden med ammoniak. Klor- derivatet av alkoholen kan framställas med användning av vilket lämpligt reaktantsystem som helst.The left-hand rotanane N-ethyl-2-pyrrolidinylmethanol is converted to the corresponding 2-methylamine by first replacing the hydroxyl with an active chlorine atom and then reacting the chloride with ammonia. The chlorine derivative of the alcohol can be prepared using any suitable reactant system.
Företrädesvis genomföras reaktionen med tionylklorid i ett vattenfritt klorerat organiskt lösningsmedel, såsom CHCI3, CCI4, CH2Cl2, mellan omgivningens tem- peratur och 60°C. Tionylkloriden kan användas an- tingen i stökiometriskt förhållande eller i litet överskott. När reaktionen är avslutad elimineras lösningsmedlet och återstoden omsättes med en metanol- eller etanollösning av ammoniak vid omgivande temperatur.Preferably, the reaction is carried out with thionyl chloride in an anhydrous chlorinated organic solvent, such as CHCl 3, CCl 4, CH 2 Cl 2, between ambient temperature and 60 ° C. The thionyl chloride can be used either in a stoichiometric ratio or in a small excess. When the reaction is complete, the solvent is eliminated and the residue is reacted with a methanol or ethanol solution of ammonia at ambient temperature.
Den vänsterroteranmaN-etyl-2-aminometyl-pyrrolidinen, som har bildats, separeras, med utbyten av ca 50 %, genom eliminering av alkohollösningsmedlet, lösning i en alkalisk vattenlösning och extrahering från vattenlösningen genom ett lämpligt organiskt lösningsmedel, företrädesvis etyleter.The left-hand rotanan-N-ethyl-2-aminomethyl-pyrrolidine which has formed is separated, in yields of about 50%, by elimination of the alcohol solvent, solution in an alkaline aqueous solution and extraction from the aqueous solution by a suitable organic solvent, preferably ethyl ether.
Den vänsterroteramkeN-etyl-2-aminometyl-pyrrolidinen omsättes med en ester av 2-metoxi-5-sulfamoylbensoe- syra i frånvaro av lösningsmedel vid en temperatur av 80-90°C, vilken temperatur upprätthålls utan till- försel av yttre värme p g a reaktionens exoterma natur och med användning av blandning av reaktions- deltagarna i en Z-blandare, vilket är kritiskt och nödvändigt för att genomföra reaktionen (spanska patentskriften 428 341).The left rotary frame N-ethyl-2-aminomethyl-pyrrolidine is reacted with an ester of 2-methoxy-5-sulfamoylbenzoic acid in the absence of solvent at a temperature of 80-90 ° C, which temperature is maintained without the addition of external heat due to the reaction. exothermic nature and using mixing of the reactants in a Z-mixer, which is critical and necessary to carry out the reaction (Spanish Patent 428 341).
Mycket ren vänsterroteramàaN-(l-etyl-2-pyrrolidinyl- metyl)-2-metoxi-5-sulfamoylbensamid erhålles genom kristallisation ur reaktionsmassan med användning av ett lämpligt lösningsmedel, företrädesvis etanol, vilket ger utbyten av 90-95 %. 10 15 20 25 30 35 ?901337'1 6 Alternativt kan de ovan beskrivna stegen 3 och 4 c genomföras i följd i samma reaktor utan separation av aminmellanprodukten. I detta fallet blandas, efter eli- minering av alkoholen och oreagerad ammoniak genom in- dunstning, återstoden direkt med estern av 2-metoxi-5- -sulfamoylbensoesyran i frånvaro av lösningsmedel och med användning av en Z-blandare för blandningsändamålen.Very pure left-rotamanol- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide is obtained by crystallization from the reaction mass using a suitable solvent, preferably ethanol, to give yields of 90-95%. Alternatively, steps 3 and 4c described above can be performed sequentially in the same reactor without separation of the amine intermediate. In this case, after elimination of the alcohol and unreacted ammonia by evaporation, the residue is mixed directly with the ester of the 2-methoxy-5-sulfamoylbenzoic acid in the absence of solvent and using a Z-mixer for the mixing purposes.
Den vänstervridande N-(l-etyl-2-pyrrolidinylmety1)- -2-metoxi-5-sulfamoylbensamiden som erhålles genom för- farandet enligt föreliggande uppfinning har följande .egenskaper: smp = 186-l88°C (n.c.); [a_7š°° = -sa,s° 'cc = 1 s 1 nns-n renhet = 99,5 %; ' IR: se fig 1, vilken visar de ovanför varandra belägna spektra för produkten erhâllen genom förfarandet i fyra steg och genom förfarandet i tre steg.The left-handed N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide obtained by the process of the present invention has the following properties: mp = 186-188 ° C (n.c.); [a_7š °° = -sa, s ° 'cc = 1 s 1 nns-n purity = 99.5%; IR: see Fig. 1, which shows the superimposed spectra of the product obtained by the four-step process and by the three-step process.
Tunnskiktskromatografi på silikagel 60 F 254: Elueringsmedel isopropanol:metanolzammoniak, koncentration s=1=1. ' Detektor: UV 254 eller Drägendorff.Thin layer chromatography on silica gel 60 F 254: Eluent isopropanol: methanol ammonia, concentration s = 1 = 1. 'Detector: UV 254 or Drägendorff.
Rf = approximativt 0,40.Rf = approximately 0.40.
Den nya produkten kan administreras oralt blandad med normala farmaceutiska spädmedel, såsom laktos, mag- nesiumstearat etc, för att bilda kapslar eller tabletter.The new product can be administered orally mixed with normal pharmaceutical diluents, such as lactose, magnesium stearate, etc., to form capsules or tablets.
Den kan även administreras parenteralt i vatten- lösning i form av ett salt, t ex ett sulfat.It can also be administered parenterally in aqueous solution in the form of a salt, for example a sulphate.
För att underlätta reproduktionen av förfarandet enligt föreliggande uppfinning beskrivs nedan en praktisk utföringsform medelst ett på inget sätt begränsande I exempel.In order to facilitate the reproduction of the method according to the present invention, a practical embodiment is described below by means of a non-limiting example.
EXEMEL l.Framställning av levo-N-acetyl-prolin. 11,5 kg levo-prolin löses i 30 liter vatten och 21,5 kg ättiksyraanhydrid tillsättes till lösningen under omröring. Temperaturen stiger spontant och bland- ningen får stå under omröring i ytterligare 20-30 min. 10 15 20 25 30 35 7901337-1 7 Reaktorn kyls därefter till en temperatur av 0-4°C och får stå tills den kristallina massan fullständigt sepa- rerar (ca 12 h). Den filtreras, fällningen tvättas med isvatten och torkas. Ytterligare lO kg av produkten utvinnes i moderluten efter tillsats av litet isopro- panol. Totalt erhålles 15 kg levo-N-acetyl-prolin som har en smältpunkt av 89°C med ett utbyte av 95 %.EXAMPLE 1. Preparation of levo-N-acetyl-proline. 11.5 kg of levoproline are dissolved in 30 liters of water and 21.5 kg of acetic anhydride are added to the solution with stirring. The temperature rises spontaneously and the mixture is allowed to stir for an additional 20-30 minutes. 10 15 20 25 30 35 7901337-1 7 The reactor is then cooled to a temperature of 0-4 ° C and allowed to stand until the crystalline mass completely separates (approx. 12 hours). It is filtered, the precipitate is washed with ice water and dried. An additional 10 kg of the product is recovered in the mother liquor after the addition of a little isopropanol. A total of 15 kg of levo-N-acetyl-proline is obtained which has a melting point of 89 ° C with a yield of 95%.
Procentuell analys: beräknat funnet C 53,49 53,35 H 7,06 7,00 N 8,90 8,95 2. Framställning av levo-N-etyl-2-pyrrolidinylmetano1. 15 kg N-acetyl-prolin sättes till en lösning inne- hållande 14,25 kg LiAlH4 i 500 liter tetrahydrofuran.Percent analysis: calculated found C 53.49 53.35 H 7.06 7.00 N 8.90 8.95 2. Preparation of levo-N-ethyl-2-pyrrolidinylmethanol. 15 kg of N-acetyl-proline are added to a solution containing 14.25 kg of LiAlH4 in 500 liters of tetrahydrofuran.
Lösningen uppvärmes under återflöde i 24 h.The solution is heated under reflux for 24 hours.
Efter denna tid kyls den till O°C och därefter tillsättes 100 liter tetrahydrofuran innehållande ca 4 % vatten och 12 liter 20 % Na0H. Den bildade fäll- ningen filtreras, tetrahydrofuranen indunstas och åter- stoden destilleras under vakuum. 9 kg N-etyl-2-pyrrolidinylmetanol erhålles, vilken har en kokpunkt av 80°C/16 mm, med ett utbyte av 75 %.After this time it is cooled to 0 ° C and then 100 liters of tetrahydrofuran containing about 4% water and 12 liters of 20% NaOH are added. The precipitate formed is filtered off, the tetrahydrofuran is evaporated and the residue is distilled under vacuum. 9 kg of N-ethyl-2-pyrrolidinylmethanol are obtained, which has a boiling point of 80 ° C / 16 mm, with a yield of 75%.
Procentuell analys: beräknat funnet C 65,07 64,95 H 11,70 ll,72 N 10,84 10,80 3. Framställning av levo-N-(l-etyl-2-pyrrolidinyl- metyl)-2-metoxi-5-sulfamoylbensamid. 9 kg levo-N-etyl-2-pyrrolidinylmetanol löses i 200 liter CH2Cl2 och 6 kg tionylklorid droppas ner i denna lösning under kalla betingelser. Lösningen omröres i 6 h vid omgivande temperatur och därefter i 2 h under kokning och indunstas till torrhet. Den oljiga återstoden upptas i etanol mättad med ammoniak och blandningen hålls under omröring vid omgivande temperatur i en natt. 10 15 20 25 30 7901 337--1 8 Alkoholen och ammoniaken indunstas därefter under vakuum. Återstoden upptas i litet vatten, NaOH droppas i och blandningen extraheras med etyleter. Eterfasen torkas och indunstas. Återstoden från indunstningen (ca 5 kg) tillsammans med 9 kg etyl-2-metoxi-5-sulfamoylbensoat matas in i en Z-blandare och blandningen uppvärmes till 85°C.Percent analysis: calculated found C 65.07 64.95 H 11.70 11.72 N 10.84 10.80 3. Preparation of levo-N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy- 5-sulfamoylbenzamide. 9 kg of levo-N-ethyl-2-pyrrolidinylmethanol are dissolved in 200 liters of CH 2 Cl 2 and 6 kg of thionyl chloride are dropped into this solution under cold conditions. The solution is stirred for 6 hours at ambient temperature and then for 2 hours under boiling and evaporated to dryness. The oily residue is taken up in ethanol saturated with ammonia and the mixture is kept under stirring at ambient temperature for one night. The alcohol and ammonia are then evaporated in vacuo. The residue is taken up in a little water, NaOH is added dropwise and the mixture is extracted with ethyl ether. The ether phase is dried and evaporated. The residue from the evaporation (about 5 kg) together with 9 kg of ethyl 2-methoxy-5-sulfamoylbenzoate is fed into a Z-mixer and the mixture is heated to 85 ° C.
Efter en viss tid börjar ett kristallint pulver att separera från den flytande massan. Reaktionen är exoterm och temperaturen kvarhâlls spntant vid 80-8S°C utan någon ytterligare tillförsel av värme. Reaktionen är fullständig på 8 h.After a certain time, a crystalline powder begins to separate from the liquid mass. The reaction is exothermic and the temperature is maintained spontaneously at 80-8S ° C without any additional supply of heat. The reaction is complete in 8 hours.
Det erhållna pulvret löses under kalla betingelser i 400 liter vatten innehållande 4 liter koncentrerad klorvätesyra, lösningen filtreras och neutraliseras med natriumvätekarbonat. Det erhållna kristallina pulvret omkristalliseras ur etanol. ll kg levo-N-(l-etyl-2- ~pyrr0liåinylmetyl)-2-metoxi-5-sulfamoylbensamid erhålles med en renhet av 99,5 % och ett utbyte av 92 % beräknat på estern.The resulting powder is dissolved under cold conditions in 400 liters of water containing 4 liters of concentrated hydrochloric acid, the solution is filtered and neutralized with sodium bicarbonate. The resulting crystalline powder is recrystallized from ethanol. 11 kg of levo-N- (1-ethyl-2-pyrrolinylmethyl) -2-methoxy-5-sulfamoylbenzamide are obtained with a purity of 99.5% and a yield of 92% calculated on the ester.
Den erhållna produkten har följande egenskaper: smp = 186-l88°C; [@_7â°° = 6s,s° (c = 1 æ i omr) renhet = 99,5 %; Procentuell analys: beräknat funnet C 52,77 52,65 9 H 6,79 6,72 N 12,30 12,20The product obtained has the following properties: mp = 186-188 ° C; [@ _7â °° = 6s, s ° (c = 1 æ in omr) purity = 99.5%; Percentage analysis: calculated finding C 52.77 52.65 9 H 6.79 6.72 N 12.30 12.20
Claims (7)
Applications Claiming Priority (1)
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE7901337L SE7901337L (en) | 1979-08-17 |
| SE430888B true SE430888B (en) | 1983-12-19 |
Family
ID=11165504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7901337A SE430888B (en) | 1978-02-16 | 1979-02-15 | OPTICALLY ACTIVE LEFT ROTATING N- (1-ETHYL-2-PYRROLIDINYL-METHYL) -2-METOXY-5-SULFAMOYL BENZAMIDE AND PROCEDURE TO PREPARE THIS |
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 |
Family Cites Families (6)
| 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) |
| IL52645A (en) * | 1976-08-05 | 1980-02-29 | Synthelabo | Optically active 1 substituted 2 aminomethyl pyrrolidines stereospecifics synthesis thereof and process for the preparation of optically active 2 methoxy n pyrrolidylmethyl benzamides |
| 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 AT AT0110179A patent/AT373870B/en not_active IP Right Cessation
- 1979-02-13 JP JP1441979A patent/JPS54130562A/en active Pending
- 1979-02-13 MX MX797713U patent/MX5632E/en unknown
- 1979-02-14 EG EG97/79A patent/EG14440A/en active
- 1979-02-14 CH CH142779A patent/CH639951A5/en not_active IP Right Cessation
- 1979-02-15 DK DK066579A patent/DK152752C/en not_active IP Right Cessation
- 1979-02-15 SE SE7901337A patent/SE430888B/en not_active IP Right Cessation
- 1979-02-15 GR GR58375A patent/GR78220B/el unknown
- 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
Also Published As
| Publication number | Publication date |
|---|---|
| DE2903891A1 (en) | 1979-08-23 |
| EG14440A (en) | 1984-03-31 |
| YU30879A (en) | 1983-02-28 |
| YU41145B (en) | 1986-12-31 |
| FR2417498A1 (en) | 1979-09-14 |
| NL7901251A (en) | 1979-08-20 |
| GB2014990A (en) | 1979-09-05 |
| DK152752C (en) | 1988-09-26 |
| MX5632E (en) | 1983-11-15 |
| FR2417498B1 (en) | 1983-01-21 |
| JPS54130562A (en) | 1979-10-09 |
| CA1097662A (en) | 1981-03-17 |
| IT1095415B (en) | 1985-08-10 |
| ATA110179A (en) | 1983-07-15 |
| GR78220B (en) | 1984-09-26 |
| NL190845B (en) | 1994-04-18 |
| DK66579A (en) | 1979-08-17 |
| DK152752B (en) | 1988-05-09 |
| GB2014990B (en) | 1982-06-09 |
| CH639951A5 (en) | 1983-12-15 |
| IT7820295A0 (en) | 1978-02-16 |
| NL190845C (en) | 1994-09-16 |
| SE7901337L (en) | 1979-08-17 |
| AT373870B (en) | 1984-02-27 |
| DE2903891C2 (en) | 1992-02-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3242190A (en) | 3-hydroxy-5-aminomethylisoxazole compounds | |
| SE430888B (en) | OPTICALLY ACTIVE LEFT ROTATING N- (1-ETHYL-2-PYRROLIDINYL-METHYL) -2-METOXY-5-SULFAMOYL BENZAMIDE AND PROCEDURE TO PREPARE THIS | |
| CN116171270A (en) | Preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride and (S) -4-chloro-2-aminobutyric acid ester | |
| CN112679498B (en) | Quaternary ammonium sulfonate compound and preparation method and application thereof | |
| JPH0674243B2 (en) | Optically active atenolol salt with high optical purity and process for producing atenolol | |
| EP3524592B1 (en) | Method for preparing a phenylalanine compound | |
| CA1085420A (en) | 1-aminomethyl-1-cycloalkane-acetic acid | |
| Tipson | N, N-phthaloyl-L-glutamic acid and some derivatives | |
| US3401194A (en) | Process for the resolution of stereoisomers from racemic 1-hydroxy-2-amino butane | |
| EP0382506B1 (en) | Optically active diastereomer salts of tetrahydro-2-furoic acid | |
| EP0053584B1 (en) | Raceme sulpiride resolution process | |
| US2762841A (en) | Process of producing l-glutamine | |
| US6087499A (en) | Process for producing 5-perfluoroalkyluracil derivatives | |
| US4010160A (en) | Process for the manufacture of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine | |
| EP0293244A2 (en) | N epsilon-trifluoroacetyl-L-lysyl-L-proline.D-1O-camphorsulfonic acid salt and process for producing the same | |
| US4048169A (en) | 1,3-Bis-(β-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine-naphthalene-1,5-disulphonate | |
| EP0484742A1 (en) | 2-Chloropropionaldehyde trimer and production process thereof | |
| EP0406567A2 (en) | Process for the production of sulfonium compounds and novel methylthiophenol derivatives | |
| US3178437A (en) | Process for simultaneously producing prolinols and 3-hydroxy-piperidines | |
| KR800001178B1 (en) | Process for the preparation of acetic nytriyl derivatives | |
| JP3169681B2 (en) | Method for producing 2-alkyl-4-hydroxymethylimidazole | |
| US2517496A (en) | Preparation of symmetrical monoaminodihydroxytoluene | |
| CN116606238A (en) | N-Boc-3-nitroindole and preparation method thereof | |
| CN116655601A (en) | Synthesis method of octreotide | |
| CN115710213A (en) | Preparation method of cis-chiral 3-fluoro-4-hydroxypiperidine and derivatives thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| NAL | Patent in force |
Ref document number: 7901337-1 Format of ref document f/p: F |
|
| NUG | Patent has lapsed |
Ref document number: 7901337-1 Format of ref document f/p: F |