SI8810889A - Process for preparation of 3-///2-(diaminomethylen)amino/-4- thiazolyl/methyl/thio/-n-sulphamoylpropionamidine - Google Patents

Description

Pri enem od postopkov (britanska patentna prijava 2055800 - Yamanouchi) pripravijo iz spojine s formulo II alkilni ester propanimidne kisline s formulo lilaIn one of the processes (British Patent Application 2055800 - Yamanouchi), the propanylic acid alkyl ester of the formula lyl is prepared from a compound of formula II

kjer je R₁ nižji alkil in R₂ vodik.wherein R _{1 is} lower alkyl and R _{2 is} hydrogen.

Metilni derivat (R^ je metil, R^ je vodik) pripravijo v zmesi kloroforma-metanola pri temperaturi 0 do 4°C. HCl, ki katalizira reakcijo, delno uparijo in nevtralizirajo z vodno raztopino kalijevega karbonata. Proizvod izolirajo kot olje z ekstrakcijo z zmesjo kloroforma metanola. Spojino lila refluktirajo z 2 ekvivalentoma sulfamida (NH₂-S0₂-NH₂) v metanolu in izolirajo famotidin s kolonsko kromatografijo. Celotni izkoristek je 58,7 %.The methyl derivative (R ^ is methyl, R ^ is hydrogen) is prepared in a mixture of chloroform-methanol at a temperature of 0 to 4 ° C. The reaction-catalyzed HCl is partially evaporated and neutralized with an aqueous solution of potassium carbonate. The product is isolated as an oil by extraction with a mixture of chloroform methanol. The lilac compound was refluxed with 2 equivalents of sulfamide (NH ₂ -SO ₂ -NH ₂ ) in methanol and isolated famotidine by column chromatography. The overall yield is 58.7%.

Izboljšana metoda je opisana v evropski patentni prijavi 0 128 736 (Yamanouchi). Iz spojine s formulo II pripravijo metilni ester propanimidne kisline s formulo lila (R^ je metil, R₂ je vodik) v zmesi dimetilformamidametanola pri temperaturi 0 do 5°C v 2 dneh. Za katalizo reakcije uporabijo okoli 12 ekvivalentov HCl. Reakcijsko zmes nevtralizirajo z vodno raztopino kalijevega karbonata. Izločeni proizvod očistijo z maceracijo v vodi. Sulfamid, ki ga dajo v 2,2-kratnem prebitku, reagira s proizvodom lila v metanolu pri sobni temperaturi v 3 dneh. Surov famotidin dobijo iz metanola s celotnim dobitkom 48,9 % ter ga očistijo s prekristalizacijo iz dimetilformamida-vode in obarjanjem z bazo iz ocetnokisle vodne raztopine.An improved method is described in European patent application 0 128 736 (Yamanouchi). From the compound of formula II, a propanylic acid methyl ester of the formula lyl (R ₂ is methyl, R ₂ is hydrogen) is prepared in a mixture of dimethylformamidamethanol at 0 to 5 ° C for 2 days. About 12 equivalents of HCl are used for the catalysis of the reaction. The reaction mixture was neutralized with an aqueous solution of potassium carbonate. The cleaned product is cleaned by maceration in water. The sulphamide given in 2.2 times excess reacts with the lilac product in methanol at room temperature for 3 days. The crude famotidine was obtained from methanol in an overall yield of 48.9% and purified by recrystallization from dimethylformamide-water and precipitation with an acetic acid aqueous solution base.

Opis rešitve tehničnega problema z izvedbenimi primeriDescription of solution to a technical problem with implementation examples

Postopek za pripravo 3-///2-/(diaminometilen)amino/-4-tiazolil/metil/tio/-N-sulfamoilpropionamidina s formulo IProcess for the preparation of 3 - /// 2 - [(diaminomethylene) amino] -4-thiazolyl (methyl) thio] -N-sulfamoylpropionamidine of formula I

H₂N H,H ₂ NH,

CH₂SCH₂CH₂C^°2^NH2 izvedemo tako, da spojino s formulo IIICH ₂ SCH ₂ CH ₂ C ₂ O 2 ^NH 2 is carried out by the compound of formula III

III v kateri je R^ ostanek s formulo IV ^(CH2⁾n’^0R3 ^IV’ kjer je Rg vodik ali nižji alkil in je n 2 do 4, ter R₂ vodik, presnovimo s sulfamidom NH₂~S0₂-NH₂.III in which R ^ is a radical of formula IV ^(CH 2 ⁾ n ' ^{O R} 3 ^IV ' wherein Rg is hydrogen or lower alkyl and n is 2 to 4, and R _{2 is} hydrogen, reacted with sulfamide NH ₂ ~ S0 ₂ -NH ₂ .

Prednostno je n 2 in Rg metil ali etil.Preferably n is 2 and R8 is methyl or ethyl.

• Reakcija s sulfamidom poteče v organskih topilih, prednostno v metanolu. Glede temperature ni posebnih omejitev. Sulfamid uporabimo optimalno v 2- do• The reaction with sulfamide takes place in organic solvents, preferably in methanol. There are no specific restrictions on temperature. Sulfamide is used optimally in 2- to

5-kratnem prebitku in ga lahko regeneriramo.5x excess and can be regenerated.

::

Nove estre s formulo III pripravimo s kislo katalizirano reakcijo spojine II z alkoholom s formulo VNew esters of formula III are prepared by the acid-catalyzed reaction of compound II with an alcohol of formula V

R₃-O-(CH₂)_n-OH, kjer imata Rg in n enak pomen kot zgoraj.R _{3 is} -O- (CH ₂ ) _n -OH, where R g and n have the same meaning as above.

Reakcijo izvajamo v zmesi z organskimi topili, kot so kloroform, dimetilformamid, dioksan, 1,2-dimetoksietan ali prednostno v prebitku reagenta kot topila. HC1 uporabimo v prebitku. Proizvod III izoliramo s filtracijo kot nestabilni dihidroklorid in ga prevedemo v bazo ali nevtraliziramo in istočasno ekstrahiramo z organskim topilom, kot je kloroform, metilenklorid, etilacetat.The reaction is carried out in admixture with organic solvents such as chloroform, dimethylformamide, dioxane, 1,2-dimethoxyethane or preferably in excess of the reagent as solvent. HC1 is used in excess. Product III is isolated by filtration as an unstable dihydrochloride and converted to base or neutralized and simultaneously extracted with an organic solvent such as chloroform, methylene chloride, ethyl acetate.

Spojina s formulo II je tržno dostopna.The compound of formula II is commercially available.

Bistvena novost postopka za pripravo spojine I je, da izhajamo iz novih intermediatov s formulo III.An essential novelty of the process for the preparation of compound I is that we are starting from new intermediates of formula III.

Pri pripravi novih intermediatov s formulo III je za razliko od znanih intermediatov s formulo lila (R^ je metil) reagent hkrati tudi topilo, poraba HCl pa je bistveno nižja. Alkanoli, ki jih uporabimo, se široko uporabljajo v industriji in so ekonomsko ugodnejši kot topilo, prav tako pa imajo višje temperature plamenišča. Nove intermediate III dobimo z visokim izkoristkom.In the preparation of new intermediates of formula III, unlike the known intermediates of formula lyl (R 4 is methyl), the reagent is also a solvent and the HCl consumption is significantly lower. The alkanols we use are widely used in the industry and are more economically advantageous than solvent and also have higher flash point temperatures. New intermediates III are obtained in high yield.

Spojine III reagirajo s sulfamidom z dobrim izkoristkom do surovega famotidina.Compounds III were reacted with sulfamide in good yield to crude famotidine.

Postopek podrobneje pojasnjujejo, vendar ne omejujejo, naslednji izvedbeni primeri.The following examples are explained in more detail, but not limited to, the process.

PRIMER 1EXAMPLE 1

Priprava spojine s formulo IIIPreparation of a Compound of Formula III

V 60 ml 2-etoksietanola uvedemo 12,7 g (0,348 molov) suhega plinskega HC1 in med mešanjem in hlajenjem pod 5°C dodamo 16,99 g (0,070 mola) 3-(2-gvanidinotiazol-4il-metiltio)-propionitrila. Raztopino pustimo stati preko noči pri temperaturi 0 do 5°C. Ko po kromatogramu poteče reakcija do konca, nevtraliziramo proizvod z dokapavanjem v zmes raztopine 48,1 g ^CO^ (0,348 molov) v 290 ml vode in . 290 ml metilenklorida pri 0 do 5°C. Po nevtralizaciji organsko fazo odločimo in vodno fazo ekstrahiramo s 150 ml metilenklorida. Združeni organski fazi 2-krat ekstrahiramo s po 150 ml vode, sušimo z natrijevim sulfatom in uparimo do suhega. Dobimo 20,93 g (89,7 %) 2-etoksietilnega estra 3-///2-/(diaminometilen)amino/-4-tiazolil/metil/tio/propanimidne kisline.Introduce 12.7 g (0.348 mol) of dry gas HCl in 60 ml of 2-ethoxyethanol and add 16.99 g (0.070 mol) of 3- (2-guanidinothiazol-4-methylthio) -propionitrile during stirring and cooling at 5 ° C. The solution was allowed to stand overnight at 0 to 5 ° C. After the reaction was complete, the product was neutralized by adding dropwise to a mixture of a solution of 48.1 g of CO 2 (0.348 mol) in 290 ml of water and. 290 ml of methylene chloride at 0 to 5 ° C. After neutralization, the organic phase is removed and the aqueous phase is extracted with 150 ml of methylene chloride. The combined organic phases are extracted twice with 150 ml of water each, dried with sodium sulfate and evaporated to dryness. 20.93 g (89.7%) of 3 - [(2) - ((diaminomethylene) amino] -4-thiazolyl / methyl / thio) propanamidic acid 2-ethoxyethyl ester are obtained.

NMR(DMS0)6:NMR (DMSO) 6:

1,02 (t, 3H, <Η₂%)1.02 (t, 3H, <Η ₂ %)

2,35 (m , 4H , -CH₂CH₂- )2.35 (m, 4H, -CH ₂ CH ₂ -)

5,80 te,IH,5.80 te, IH,

H) /NH₂ i, 16 (šs, )H) / NH ₂ i, 16 (ws,)

PRIMER 2EXAMPLE 2

Priprava spojine s formulo IIIPreparation of a Compound of Formula III

V 20 ml 2-metoksietanola uvedemo 5,07 g (0,139 molov) suhega plinskega HC1 in med mešanjem in hlajenjem pod 5°C dodamo 5,59 g (0,023 molov) 3-(2-gvanidinotiazol-4 il—~metiltio)-propionitrila. Raztopino pustimo stati preko noči pri temperaturi 0 do 5°C. Proizvod nevtraliziramo z dokapavanjem v zmes raztopine 19,2 g I^C 0^ (0,139 molov) v 120 ml vode, 96 ml kloroforma in 24 ml metanola pri 0 do 5°C. Po nevtralizaciji organsko fazo odločimo in vodno fazo ekstrahiramo s 100 ml kloroforma. Združeni organski fazi 2-krat ekstrahiramo s po 100 ml vode, sušimo z natrijevim sulfatom in uparimo do suhega.Introduce 5.07 g (0.139 mol) of dry gas HCl in 20 ml of 2-methoxyethanol and add 5.59 g (0.023 mol) of 3- (2-guanidinothiazol-4-ylmethylthio) while stirring and cooling at 5 ° C. propionitrile. The solution was allowed to stand overnight at 0 to 5 ° C. The product was neutralized by adding dropwise to a mixture of a solution of 19.2 g of 1 N -C 0 (0.139 mol) in 120 ml of water, 96 ml of chloroform and 24 ml of methanol at 0 to 5 ° C. After neutralization, the organic phase is removed and the aqueous phase is extracted with 100 ml of chloroform. The combined organic phases are extracted twice with 100 ml of water each, dried with sodium sulfate and evaporated to dryness.

Dobimo 6,43 g (87,45 %) 2-metoksietilnega estra 3- ///2-/(diaminometilen)amino/-4-tiazolil/metil/tio/propanimidne kisline.6.43 g (87.45%) of 3-methoxyethyl 3-methoxyethyl ester of 3 H -di (2- diaminomethylene) amino (4-thiazolyl) methyl-thio / propanamidic acid are obtained.

NMR (DMSO)δ:NMR (DMSO) δ:

2,32 (m , 4H, -CH₂CH2)2.32 (m, 4H, -CH ₂ CH ₂ )

2,95 (S , 3H , -OCH₃ )2.95 (S, 3H, -OCH ₃ )

5,80 (s,IH, ^H)5.80 (s, 1H, 1H)

6,16 (šs , 4H ,-N=C<^² )6.16 (bs, 4H, -N = C <^ ² )

M* 2M * 2

PRIMER 3EXAMPLE 3

Priprava spojine s formulo IPreparation of a compound of formula I

14,5 g (0,151 molov) sulfamida z blagim segrevan jem raztopimo v 60 ml metanola. Raztopini sulfamida dodamo 14,5 g (0,044 molov) 2-etoksietilnega estra 3-///2-/(diaminometilen)amino/-4-tiazolil/metil/tio/propa9 nimidne kisline v 3 porcijah. Drugo porcijo dodamo po 8 in tretjo po 24 urah. Mešamo še 2 dni, izločeni famotidin odnučamo in izperemo z malo metanola. Dobimo 9,4 g (63,7 %) famotidina. S kristalizacijo iz metanola dobimo proizvod s tal. 163 do 164°C.Gently dissolve 14.5 g (0.151 mol) of sulfamide in 60 ml of methanol. To the sulfamide solution was added 14.5 g (0.044 moles) of 3-ethoxyethyl ester of 3 - [(2- (diaminomethylene) amino] -4-thiazolyl / methyl / thio / propanoic acid in 3 portions. The second portion is added after 8 hours and the third after 24 hours. Stirred for 2 more days, the eliminated famotidine was filtered off and washed with a little methanol. 9.4 g (63.7%) of famotidine are obtained. Crystallization from methanol gives the product from the ground. 163 to 164 ° C.

Matično lužnico ohladimo na -30°C, pri čemer se izloči 4,32 g sulfamida s tal. 87 do 90°C.Cool the mother liquor to -30 ° C, removing 4.32 g of sulfamide from the soil. 87 to 90 ° C.

PRIMER 4EXAMPLE 4

Priprava spojine s formulo IPreparation of a compound of formula I

Delamo na enak način kot v primeru 3, vendar izhajamo iz 2,9 g 2-metoksietilnega estra namesto 2-etoksietilnega estra. Dobimo 1,8 g (58,4 %) famotidina.We proceed in the same manner as in Example 3, but proceed from 2.9 g of 2-methoxyethyl ester instead of 2-ethoxyethyl ester. 1.8 g (58.4%) of famotidine are obtained.

Claims (2)

PATENTNI ZAHTEVEKPATENT APPLICATION Postopek za pripravo 3-///2-/(diaminometilen)amino/-4-tiazolil/metil/tio/-N-sulfamoilpropionamidina s formulo IProcess for the preparation of 3 - /// 2 - [(diaminomethylene) amino] -4-thiazolyl (methyl) thio] -N-sulfamoylpropionamidine of formula I CH₂SCH₂CH₂C^°2^NH2 označen s tem, da spojino s formulo IIICH ₂ SCH ₂ CH ₂ C ^ 2 ^NH 2 characterized in that the compound of formula III -(CH₂)_n-O-R₃ IV, kjer je R^ vodik ali nižji alkil in je n 2 do 4, ter R₂ vodik, presnovimo s sulfamidom NH₂-S0₂-NH₂·- (CH ₂ ) _n -OR ₃ IV where R ₂ is hydrogen or lower alkyl and n 2 to 4 and R _{2 is} hydrogen is reacted with the sulfamide NH ₂ -SO ₂ -NH ₂ · ZaFor KRKA,tovarna zdravil,n.sol.oKRKA, drug factory, n.sol.o 2O385-VII-89/KA2O385-VII-89 / KA POVZETEKSUMMARY Opisan je postopek za pripravo 3-///2-/(diaminometilen) amino/-4-tiazolil/metil/tio/-N-sulfamoilpropionamidina s formulo IA process for the preparation of 3 - [(2- (diaminomethylene) amino] -4-thiazolyl / methyl / thio) -N-sulfamoylpropionamidine of formula I is described I pri katerem spojino s formulo IIII wherein the compound of formula III -^(CH2>n-°-^R3- ^(CH 2> n- ° - ^R 3 IV, kjer je vodik ali nižji alkil in je n 2 do 4, ter R₂ vodik, presnovimo s sulfamidom NH₂~SO₂NH₂,IV, where hydrogen or lower alkyl and n is 2 to 4 and R _{2 is} hydrogen, is reacted with sulfamide NH ₂ ~ SO ₂ NH ₂ ,