RS49867B - PROCEDURE FOR THE SYNTHESIS OF 4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE - Google Patents
PROCEDURE FOR THE SYNTHESIS OF 4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDEInfo
- Publication number
- RS49867B RS49867B YUP-634/99A YU63499A RS49867B RS 49867 B RS49867 B RS 49867B YU 63499 A YU63499 A YU 63499A RS 49867 B RS49867 B RS 49867B
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- methyl
- hydroxy
- pyridyl
- dioxide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Postupak dobijanja jedinjenja 4-hidroksi-2-metil-2H-1,2-benzotiazin-3-karboksamid-1,1-dioksida, opšte formule I, gde R ima jedno od sledećih značenja: alkil grupa (C1-C6), cikloalkil, benzil, fenil, piridil, metil-piridil, pirimidil, tiazol ili izotiazol, prvenstveno piroksikama (4 - hidroksi - 2 - metil - (2 - piridinil) - 2H - 1,2 – benzotiazin-3-karboksamid-1,1-dioksid) kada R ima značenje 2-piridinil, što reaguje hlorsirćetna kiselina formule III sa apsolutnim alkoholom kao što je metanol ili etanol, u prisustvu odgovarajućeg katalizatora: suvog hlorovodonika, sulfonskih kiselina, kiselih jonskih izmenjivača, prvenstveno konc. sumporne kiseline, na temperaturi refluksa, čime se dobija etilestar hlorsirćetne kiseline, formule IV, IV koji dalje reaguje sa natrijum saharinatom, formule V V u dimetilformamidu, na temperaturi refluksa, da bi se dobio 3-oksi-1,2- benzotiazol-2-acetat etil estar, formule VI, VI naznačen time, što putem Gabrijel-Kolmanovog premeštanja katalizovanog bazom daje mesto intermedijernom jedinjenju etil-4-hidroksi-2H-1,2benzotiazin-3 -karboksilat-1, 1-dioksid, formule VII, VII zatim se vrši N-metilovanje intermedijera formule VII pomoću dimetil sulfata u prisustvu alkalije u acetonskoj sredini, na temperaturi 20-65°C, u vremenu od 30 minuta do 3 sata i dobija se etil-4-hidroksi-2-metil-2H-1,2-benzotiazin3-karboksilat-1,1-dioksid, formule VIII, VII koji dalje u reakciji kondenzacije sa aminom opšte formule NH2-R, gde je R: 2-piridil, alkil supstituisani 2-piridil, 2-tiazoil, 2-tiazoil supstituisan sa jednom ili dve alkil grupe pri čemu svaki alkil ima od 1 do 4 ugljenikova atoma ili 5-metil-3-izoksazolil, prvenstveno 2-aminopiridina formule IX, IX pri čemu se faza kondenzacije odvija u inertnoj atmosferi i u inertnom rastvaraču: benzen, toluen, ksilen, etilbenzen, tetrahidrofuran, dimetilformamid, dimretilsulfoksid i acetonitril uz korišćenje specifičnih katalizatora, prema dva postupka, tako što se po jednom postupku reakcija odvija uz azeotropnu destilaciju, ili prema drugom postupku uz korišćenje specifičnih apsorpcionih sredstava za sprečavanje obrazovanja azeotropa tokom sinteze čime obezbeđuje potrebnu visoku i konstantnu temperaturu reakcije, na temperaturi refluksa, daje jedinjenje opšte formule (I)A process for the preparation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide compound of general formula I, wherein R has one of the following meanings: alkyl group (C1-C6), cycloalkyl , benzyl, phenyl, pyridyl, methyl-pyridyl, pyrimidyl, thiazole or isothiazole, preferably pyroxamic (4-hydroxy-2-methyl- (2-pyridinyl) -2H-1,2-benzothiazine-3-carboxamide-1,1- dioxide) when R has the meaning of 2-pyridinyl, which is reacted with hydrochloric acid of formula III with an absolute alcohol such as methanol or ethanol in the presence of a suitable catalyst: dry hydrochloric acid, sulfonic acids, acidic ion exchangers, preferably conc. sulfuric acid at reflux temperature to give ethyl chloroacetic acid ethyl ester of formula IV, IV which is further reacted with sodium saccharinate of formula VV in dimethylformamide at reflux to give 3-oxy-1,2-benzothiazole-2- acetate ethyl ester of formulas VI, VI which, by Gabriel-Coleman displacement, catalyzes the base to give an intermediate of ethyl 4-hydroxy-2H-1,2benzothiazine-3-carboxylate-1,1-dioxide, formulas VII, VII then N-methylation of the intermediate of Formula VII is carried out using dimethyl sulfate in the presence of alkali in acetone, at a temperature of 20-65 ° C, for a period of 30 minutes to 3 hours to give ethyl-4-hydroxy-2-methyl-2H-1 , 2-benzothiazine 3-carboxylate-1,1-dioxide, of formulas VIII, VII which is further in the condensation reaction with an amine of general formula NH2-R, wherein R: 2-pyridyl, alkyl substituted 2-pyridyl, 2-thiazoyl, 2- thiazolyl substituted with one or two alkyl groups wherein each alkyl has from 1 to 4 carbon atoms or 5-methyl-3-isoxazolyl, preferably 2-aminopyridine of formula IX, IX wherein the condensation phase takes place in an inert atmosphere and in an inert solvent: benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and acetonitrile using specific according to two methods, by one method the reaction being carried out by azeotropic distillation, or by another method using specific absorption agents to prevent the formation of azeotropes during synthesis, thus providing the required high and constant reaction temperature, at reflux temperature, to give the compound of the general formula (I )
Description
Predloženi pronalazak odnosi se na područije organske hemijske tehnologije, specifično na postupak dobijanja jedinjenja4- hidroksi- 2- metil- 2H-l, 2- benzotiazin- 3- karboksamid- l, l- dioksida,opšte formule (I), The proposed invention relates to the field of organic chemical technology, specifically to the procedure for obtaining the compound 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, general formula (I),
gde R ima značenje jednog od sledećih radikala:alkil grupa(C)-C6),cikloalkil, benzil, fenil, piridil, metil- piridil, pirimidil, tiazoliliizotiazol.Poseban interes kada se radi o kliničkoj praksi kao nesteroidni antireumatici sa antiinflamatornim i analgetskim svojstvima imaju: piroksikam{ 4- hidroksi- 2- metil- N-( 2- piridinil)-2H- l, 2- benzotiazin- 3- karboksamid- l, l- dioksid),izoksikam{ 4- hidroksi- 2- metil-N-( 5- metil- 3- izoksazolil) - 2H - 1, 2 — benzotiazin — 3—karboksamid - 1, 1 —where R has the meaning of one of the following radicals: alkyl group (C)-C6), cycloalkyl, benzyl, phenyl, pyridyl, methyl-pyridyl, pyrimidyl, thiazolylisothiazole. Of special interest when it comes to clinical practice as non-steroidal anti-rheumatic drugs with anti-inflammatory and analgesic properties are: piroxicam { 4- hydroxy- 2- methyl- N-( 2- pyridinyl)-2H- 1, 2- benzothiazine- 3-carboxamide-1,1-dioxide), isoxycam{ 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl) - 2H - 1, 2 — benzothiazine — 3—carboxamide - 1, 1 —
dioksid )i sudoksikam( 4- hidroksi- 2- metil- N- 2- tiazolil- 2H~ l, 2- benzotiazin- 3-dioxide (and sudoxicam) 4- hydroxy- 2- methyl- N- 2- thiazolyl- 2H~ l, 2- benzothiazine- 3-
karboksamid- l, 1 - dioksid.carboxamide-1,1-dioxide.
Tehnički problemTechnical problem
Postojala je potreba da se dođe do tehnološki savršenijeg postupka za dobijanje jedinjenja opšte formule4- hidroksi- 2- metil- 2H- l, 2- benzotiazin- 3-karboksamid- 1, 1- dioksida,prvenstveno piroksikama, izoksikama i sudoksikama, sa visokim prinosom i visokim stepenom čistoće, koji omogućuje njihovu primenu u farmaceutskoj industriji, gde se koriste kod lečenja reumatskog artritisa, ankilozantnog spondilitisa, osteoartroze i drugih inflamantornih procesa reumatoloških, kao i nereumatoloških, uključujući i napade i traumatološke lezije. There was a need to find a technologically more perfect procedure for obtaining compounds of the general formula 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, primarily piroxicams, isoxicams and sudoxicams, with a high yield and a high degree of purity, which enables their use in the pharmaceutical industry, where they are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and others inflammatory processes rheumatological, as well as non-rheumatological, including attacks and traumatological lesions.
Stanje tehnikeState of the art
Abei saradnici (J,Pharm.Soc. Japan,1956,76,1058-63) bili su prvi koji su primeniliGabrijel- Kolmanovopremeštanje na derivate saharina da bi dobili različite 4-hidroksi-2H-l,2-benzotiazin-l,l-diokside. Abei co-workers (J, Pharm. Soc. Japan, 1956, 76, 1058-63) were the first to apply the Gabriel-Kolman displacement to saccharin derivatives to obtain various 4-hydroxy-2H-1,2-benzothiazine-1,1-dioxides.
Slično,Zinnes(J.Org. Chem; 1965,30,2241) je proširio ove studije da bi dobio nove derivate. Similarly, Zinnes (J.Org. Chem; 1965,30,2241) extended these studies to obtain new derivatives.
Poznato je dobijanje određenih 4-hidroksi-2H~l,2-benzotiazin-3-karboksiamida putem pregrupacije specifičnih derivata saharina. TakoLombardinou J. Med. Chem. 14, 1171-1175 (1971) opisuje upotrebumetilacetatnog estra saharinaza dobijanje3, 4- dihidro- 4 - oksi- l, 2- benzotiazin- 3-karboksilat~ l, l- dioksidmetilestra,koristećidimetilsulfoksidinatrijummetoksidi ukazujući dadimetilformamiddaje loše prinose. Kasnije se dobijeni produkt metiluje sametil- jodidomi4 - hidroksi - 2 - metil - 2H - 1, 2-benzotiazin - 3-karboksilat metilestar- 1, 1- dioksid,Lombardino u J. Med. Chem. 16, 493-496 It is known to obtain certain 4-hydroxy-2H~1,2-benzothiazine-3-carboxyamides through the rearrangement of specific saccharin derivatives. Thus Lombardinou J. Med. Chem. 14, 1171-1175 (1971) describes the use of methylacetate ester of saccharinase to obtain 3,4-dihydro-4-oxy-1,2-benzothiazine-3-carboxylate~1,1-dioxidemethylester using dimethylsulfoxide ditriium methoxides indicating that dimethylformamide gives poor yields. Later, the obtained product is methylated with methyl-iododom4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxylate methylester-1, 1-dioxide, Lombardino in J. Med. Chem. 16, 493-496
(1973) ukazuje dajedobio 4- hidroksi- 2- metil- N-( 2- piridil)- 2H- l, 2- benzotiazin - 3- karboksilat- 1, 1- dioksidpolazeći od4- hidroksi- 2- metil- 2H- l, 2- benzotiazin- 3-karboksilat metilestar, 1, 1- dioksid,ali bez objašnjenja metode ukazujući na prinos od 45%. (1973) indicates that he obtained 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide starting from 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate methylester, 1,1-dioxide, but without explaining the method indicating a yield of 45%.
U američkom patentu U.S. 3591584 dat je analogni postupak za dobijanje sličnih jedinjenja, koji ukazuje na potrebu prisustva katalizatora u poslednjoj fazi sinteze zbog niskog prinosa. In US Pat. 3591584, an analogous procedure for obtaining similar compounds is given, which indicates the need for the presence of a catalyst in the last stage of the synthesis due to the low yield.
Predmet izuma španskog patenta ES 495 727 ima za pojedinačne karakteristike upotrebuetilestraidimetilformamida sanatrijumetoksidomza otvaranje ciklusa pri vrlo niskim temperaturama. Zatim se vrši metilovanje i finalno kondenzovanje u mraku, koristeći atmosferu azota u fazi kondenzacije. The subject of the invention of the Spanish patent ES 495 727 has as its individual characteristics the use of ethyl ester and dimethylformamide with sanatriium methoxy for opening the cycle at very low temperatures. Methylation and final condensation are then carried out in the dark, using a nitrogen atmosphere in the condensation phase.
U JP 57-70888, koriste se razni derivati aminopiridina za dobijanje piroksikama i objašnjeni su uslovi kondenzacije. Odnos amina je 1,1-1,3 prema količini estra, temperatura reakcije u intervalu 100-145°C, vreme reakcije 5-30 sati. In JP 57-70888, various aminopyridine derivatives are used to obtain piroxicam and the condensation conditions are explained. The amine ratio is 1.1-1.3 according to the amount of ester, the reaction temperature is in the interval 100-145°C, the reaction time is 5-30 hours.
Lombardinoje u U.S 4,289,879 naglasio teškoće pri dobijanju piroksikama sa prihvatljivom bojom zbog formiranja sporednih proizvoda jako obojenih koji se teško uklanjaju kristalizacijom. Ova sinteza ima ozbiljan industrijski nedostatak da značajno podiže cenu proizvoda zbog korišćenja zaštićenih intermedijera, a manje koristi lako dostupne intermedijere. Lombardino in U.S. 4,289,879 emphasized the difficulties in obtaining piroxicams with acceptable color due to the formation of highly colored side products that are difficult to remove by crystallization. This synthesis has a serious industrial disadvantage that it significantly raises the price of the product due to the use of protected intermediates, and less use of readily available intermediates.
U.S. 4,100347 opisuje dobijanjekiselinskog hlorida 4- hidroksi- 2- metil- 2H-1, 2- benzotiazin- 3- karboksilne kiselinei njegovu kondenzaciju sa2-aminopiridinom.U.S. 4,100347 describes the preparation of the acid chloride of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid and its condensation with 2-aminopyridine.
O pis rešenia tehničkog problema sa<p>rimerima izvođenjaAbout writing a solution to a technical problem with performance parameters
Predloženi pronalazak odnosi se na postupak dobijanja jedinjenja4-hidroM- 2- metil- 2H- l, 2- benzotiazin- 3- karboh<miidAopšte formule I, The proposed invention relates to the procedure for obtaining the compound 4-hydro-M-2-methyl-2H-1,2-benzothiazine-3-carboxamide of the general formula I,
gde je R:alkil grupa(CrC6),cikloalkil, benzil, fenil, piridil, metil- piridil, pirimidil, tiazoliliizotiazolPronalazak se prvenstveno odnosi na sintezu4-hidroksi- 2- metil- N-( 2- piridinil)- 2H- l, 2- bemotiazin- 3- karb^tj.piroksikama(za R =piridil),formule II, koja se odvija preko sledećeg niza reakcija. Šema tehnološkog postupka sinteze piroksikama data je u prilogu 1. Sinteza počinje katalitičkom esterifikacijomhlorsirćetne kiseline(formule III), pomoćuetilalkoholada bi se dobioetilestar hlorsirćetne kiseline('formule IV), koji dalje reaguje sanatrijum saharinatom(formule V) udimetilformamiduda bi se dobio3- oksi- l, 2- benzotiazol- 2- acetat etil estar(formule VI), koji putemGabrijel- Kolmanovogpremeštanja sanatrijum etoksidomudimetilformamidu,pri niskim i kontrolisanim temperaturama vodi do intermedijernog jedinjenjaetil- 4- hidroksi- 2H- l, 2- benzotiazin- 3- karboksilat- l, 1-dioksid(formule VII), a zatim se vrši reakcija N-metilovanja pomoćudimetil sulfatailimetil jodidau vodeno-acetonskoj baznoj sredini i dobija seetil- 4- hidroksi- 2- metil- 2H- l, 2-benzotiazin- 3- karboksilat- l, l- dioksid(formule VIII), where R: alkyl group (CrC6), cycloalkyl, benzyl, phenyl, pyridyl, methyl-pyridyl, pyrimidyl, thiazolylisothiazole. The invention primarily relates to the synthesis of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1, 2- bemothiazine-3-carb^i.e. piroxicams (for R = pyridyl), formula II, which takes place through the following series of reactions. The scheme of the technological procedure for the synthesis of piroxicam is given in attachment 1. The synthesis begins with the catalytic esterification of chloroacetic acid (formula III), using ethyl alcoholate chloroacetic acid ethyl ester (formula IV) would be obtained, which further reacts with sodium saccharinate (formula V) in dimethylformamide to obtain 3-oxyl, 2-benzothiazole-2-acetate ethyl ester (formula VI), which through Gabriel- The Coleman displacement of sodium ethoxide to dimethylformamide, at low and controlled temperatures, leads to the intermediate compound ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (formula VII), and then the N-methylation reaction is carried out using dimethyl sulfate or methyl iodide in an aqueous-acetone basic environment and obtains ethyl-4-hydroxy-2-methyl-2H- l, 2-benzothiazine-3- carboxylate-l,l-dioxide (formula VIII),
koji dalje u reakciji kondenzacije sa aminom, prvenstveno2- aminopiridinomwhich further in a condensation reaction with an amine, primarily 2-aminopyridine
(formule IX) (formula IX)
u inertnoj atmosferi daje4- hidroksi- 2- metil- N-( 2- piridinil)- 2H- l, 2~ benzotiazin- 3-karboksamid- lfl- dioksid,tj. piroksikam (formule II). in an inert atmosphere it gives 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide-lfl-dioxide, i.e. piroxicam (formula II).
Za sintezu jedinjenja formule IV potreban je sledeći optimalan odnos reaktanata u reakciji esterifikacije: 1 molkarbonske kiseline,5 molova odgovarajućegapsolutnog alkohola,0,2 mola koncentrovanesumporne kiseline,a reakcija se izvodi u vremenu 2-9 sati na temperaturi refluksa. For the synthesis of compounds of formula IV, the following optimal ratio of reactants in the esterification reaction is required: 1 mole of carboxylic acid, 5 moles of the corresponding absolute alcohol, 0.2 moles of concentrated sulfuric acid, and the reaction is carried out in 2-9 hours at reflux temperature.
Sinteza jedinjenja formule VI se izvodi udimetilformamiduna temperaturi od 90°C do 150°C u vremenu od 2 do 7 sati. The synthesis of compounds of formula VI is carried out in dimethylformamide at a temperature of 90°C to 150°C in a time of 2 to 7 hours.
Reakcija premeštanja jedinjenja formule VI za dobijanje jedinjenja formule VII izvodi se pri niskim i kontrolisanim temperturama u opsegu 30-100°C uz optimalno vreme odigravanja reakcije od 10 minuta do 4 sata. The reaction of moving the compound of formula VI to obtain the compound of formula VII is carried out at low and controlled temperatures in the range of 30-100°C with an optimal reaction time of 10 minutes to 4 hours.
Prednost predmetnog pronalaska je što se N-metilovanje jedinjenja formule VII izvodi pomoćudimetilsulfatau acetonskoj sredini u prisustvu alkalije, za razliku od postupka datog u pronalasku EP 0 284 514, gde se reakcija odvija u alkoholnoj sredini korišćenjemizopropanola.Reakcija se odvija u vremenu od 30 minuta do 3 sata na temperaturi između 20-65°C, pri čemu se dobija jedinjenje bele boje u visokom prinosu, formule VIII. The advantage of the present invention is that the N-methylation of the compound of formula VII is carried out using dimethylsulfate in an acetone environment in the presence of alkali, unlike the procedure given in the invention of EP 0 284 514, where the reaction takes place in an alcoholic environment using misopropanol. The reaction takes place in a time of 30 minutes to 3 hours at a temperature between 20-65°C, whereby a white colored compound is obtained in high yield, formula VIII.
Faza kondenzacije jedinjenja formule VIII saaminomizvodi se na temperaturi refluksa u inertnom reakcionom medijumu u vremenu od 10 do 55 sati pri Čemu se dobija finalni proizvod formule I . U reakciji se odaminakoristearomatičniiliheterociklični amini,opšte formule NH2-R, gde je R:2- piridil,alkil supstituisani2- piridil, 2- tiazoil, 2- tiazoilsupstituisan sa jednom ili dve alkil grupe pri čemu svaki alkil ima od 1 do 4 ugljenikova atoma ili5- metil- 3- izoksazolil,Prvenstveno korišćenjem2- aminopiridinadobija se jedinjenje formule II. Kao inertni reakcioni medijum mogu se koristiti sledeći rastvarači:benzen, toluen,ksilen, etilbenzen, tetrahidrofuran, dimetilformamid, dimretilsulfoksid iThe phase of condensation of the compound of formula VIII with amines is carried out at reflux temperature in an inert reaction medium for a period of 10 to 55 hours, whereby the final product of formula I is obtained. In the reaction, aromatic or heterocyclic amines of the general formula NH2-R are used as amines, where R: 2- pyridyl, alkyl substituted 2- pyridyl, 2- thiazolyl, 2- thiazolyl substituted with one or two alkyl groups, where each alkyl has from 1 to 4 carbon atoms or 5- methyl-3- isoxazolyl, Primarily using 2- aminopyridine, the compound of formula II is obtained. The following solvents can be used as an inert reaction medium: benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and
acetonitril.acetonitrile.
Karakteristika ovog pronalaska je da faza kondenzacije ide uz katalizator koji obezbeđuje dobijanje veoma čistog finalnog proizvoda bez problema sa obojenošću, uz ostvarenje visokog prinosa; kao i uz korišćenje adsorbensa, koji omogućava izvođenje reakcije sinteze na temperaturi ključanja rastvarača (uz totalni refluks). The characteristic of this invention is that the condensation phase is accompanied by a catalyst that ensures obtaining a very pure final product without problems with coloration, while achieving a high yield; as well as with the use of an adsorbent, which enables the synthesis reaction to be carried out at the boiling temperature of the solvent (with total reflux).
Za sintezu piroksikama obezbeđeni su apsolutno suvi uslovi odvijanja reakcije kondenzacije, što se postiže inertnom atmosferom (reakcija se izvodi u strujiazotd)i korišćenjem suvih reaktanata. Na primer, pri korišćenju2-aminopiridina,formule IX, koja je jako higroskopna supstanca može doći do neželjene hidrolize u toku reakcije i smanjenja prinosa. Takođe, ako se koristio-ksilen,neophodno je da on bude suv, jer se zbog prisustvavodeilialkoholaznatno smanjuje temperatura ključanjao- ksilena,a neophodno je da se reakcija kondenzacije odvija na temperaturi od 140 do 144°C. For the synthesis of piroxicam, absolutely dry conditions for the condensation reaction are provided, which is achieved with an inert atmosphere (the reaction is carried out in nitrogen stream) and the use of dry reactants. For example, when using 2-aminopyridine, formula IX, which is a very hygroscopic substance, unwanted hydrolysis may occur during the reaction and yield reduction. Also, if xylene was used, it is necessary that it be dry, because due to the presence of water or alcohol, the boiling temperature of xylene decreases significantly, and it is necessary that the condensation reaction takes place at a temperature of 140 to 144°C.
Da bi dobili priozvod visoke farmakopejske čistoće sa visokim prinosom i da bi izbegli obrazovanje sporednih proizvoda (smolastih materija) tokom reakcije sinteze piroksikama, korišćeni sukatalizatori: BF3( C2H^ 20, BF3, NH4Cl.In order to obtain a product of high pharmacopoeial purity with a high yield and to avoid the formation of side products (resinous substances) during the synthesis reaction with piroxicam, cocatalysts were used: BF3(C2H^20, BF3, NH4Cl.
Pronalaskom je pojednostavljen i drugi postupak dobijanja piroksikama time što je korišćen katalizator i takav optimalan odnos reaktanata kojim je izbegnuta azeotropna destilacija, a sama sinteza se odvija na temperaturi ključanja rastvaračao- ksilena(140-144°C). Izvođenje sinteze na temperaturi refluksa, omogućava korišćenje i do četiri puta manje količine rastvarača{ o- ksilena)što je prednost ovog pronalaska u laboratorijskim i u industrijskim uslovima u odnosu na poznate patentirane postupke, kod kojih se koristi isključivo azeotropna destilacija. Prednost predmetnog pronalaska je što se koristi i apsorpciono sredstvo( silika- gel, kalcijum hlorid, kalijum karbonat)koje onemogućava obrazovanje azeotropa( o- ksilen- etanol)tokom sinteze čime obezbeđuje potrebnu visoku i konstantnu temperaturu reakcije (140-144°C) u cilju dobijanja visokog prinosa finalnog proizvoda odgovarajućeg farmakopejskog kvaliteta. The invention simplified the second procedure for obtaining piroxicam by using a catalyst and such an optimal ratio of reactants that avoided azeotropic distillation, and the synthesis itself takes place at the boiling temperature of the solvent - xylene (140-144°C). Carrying out the synthesis at reflux temperature allows the use of up to four times less solvent (oxylene), which is an advantage of this invention in laboratory and industrial conditions compared to known patented procedures, where only azeotropic distillation is used. The advantage of the present invention is that an absorption agent (silica gel, calcium chloride, potassium carbonate) is also used, which prevents the formation of azeotropes (oxylene-ethanol) during the synthesis, which ensures the necessary high and constant reaction temperature (140-144°C) in order to obtain a high yield of the final product of appropriate pharmacopoeial quality.
Prednosti predloženog postupka u reakciji N-metilovanja u odnosu na dosada poznate postupke su: The advantages of the proposed procedure in the N-methylation reaction compared to previously known procedures are:
- reakcija se odvija u acetonskoj sredini, - the reaction takes place in an acetone environment,
- znatno smanjeno vreme trajanja reakcije sinteze, - significantly reduced duration of the synthesis reaction,
- dobija se proizvod u visokom prinosu. - the product is obtained in high yield.
Prednosti predloženog postupka u fazi kondenzacije u odnosu na dosada poznate postupke su: The advantages of the proposed procedure in the condensation phase compared to previously known procedures are:
- apsolutno suvi uslovi za odvijanje reakcije, - absolutely dry conditions for the reaction to take place,
- reakcija se izvodi u inertnoj atmosferi, - the reaction is carried out in an inert atmosphere,
- reakcija kondenzacije ide uz katalizator, - the condensation reaction goes with the catalyst,
- onemogućeno stvaranje sporednih proizvoda, - disabled creation of secondary products,
- dobijanje proizvoda visoke farmakopejske čistoće, - obtaining products of high pharmacopoeial purity,
- visok prinos proizvoda. - high product yield.
Prednosti predloženog postupka sinteze u laboratorijskim i u industrijskim uslovima u fazi kondenzacije, u odnosu na dosada poznate postupke su: The advantages of the proposed synthesis procedure in laboratory and industrial conditions in the condensation phase, compared to previously known procedures, are:
- reakcija kondenzacije ide uz katalizator i uz adsorbens, - the condensation reaction goes with the catalyst and with the adsorbent,
- izvođenje reakcije na temperaturi refluksa, - carrying out the reaction at reflux temperature,
- izbegnuta azeotropna destilacija, - avoided azeotropic distillation,
- tehnička jednostavnost izvođenja postupka i aparature, - technical simplicity of performing the procedure and apparatus,
- maksimalno smanjenje količine rastvarača, - maximum reduction of the amount of solvent,
- veća ekonomičnost postupka, - greater economy of the procedure,
- visok prinos proizvoda. - high product yield.
Da bi se olakšalo razumevanje postupka koji je predmet ovog pronalaska, dati su primeri različitih faza procesa, ali ih ne treba smatrati za ograničavajuće. In order to facilitate the understanding of the process that is the subject of the present invention, examples of the various stages of the process are provided, but should not be considered limiting.
Primer 1.Example 1.
Dobijanjeetilestra hlorsirćetne kiseline(IV) Production of ethyl ester of chloroacetic acid(IV)
U 282 cm<3>apsolutnog etanola dodati 17,9 cm<3>konc.sumporne kiselinei 384,6 ghlorsirćetne kiseline(III). Reakciona smeša refluktuje 5 h a zatim se izlije u 800 cm<3>ledene vode.Organska faza se odvoji a vodena se ispirahloroformom.Spojene organske faze se isperu rastvoromnatrijum bikarbonata,suše prekonatrijum sulfatai rastvarač se upari. Dobija se 458,8getilestra hlorsirćetne kiselined4<20=>l,1498, nD<20=>l,4227, tačkaključanja 144-146°C (prinos 92%). Add 17.9 cm<3> conc. sulfuric acid and 384.6 chloroacetic acid(III) to 282 cm<3> of absolute ethanol. The reaction mixture is refluxed for 5 h and then poured into 800 cm<3> of ice water. The organic phase is separated and the aqueous phase is washed with chloroform. The combined organic phases are washed with sodium bicarbonate solution, dried over sodium sulfate and the solvent is evaporated. 458.8 gethyl ester of chloroacetic acid is obtained d4<20=>1.1498, nD<20=>1.4227, boiling point 144-146°C (yield 92%).
Primer 2. Example 2.
Dobijanje3- oksi- l, 2- benzotiazol- 2- acetat etilestra(VI) Obtaining 3-oxy-1,2-benzothiazole-2-acetate ethyl ester (VI)
lOOgetilestra hlorsirćetne kiseline(IV) doda se rastvoru 166,5gnatrijum saharinata(V) u 372cm<3>dimetilformamida.Reakciona smeša refluktuje 4 sata a zatim se izlije u 470cm<3>ledene vode.Nakon 2 sata talog se filtrira, ispire vodom i suši. Dobija se 175,6g3- oksi- l, 2- benzotiazol- 2- acetat etilestra -kristalne, bele, čvrste supstance, tačke topljenja 104-106°C (prinos 80%). Chloroacetic acid 100 ethyl ester (IV) is added to a solution of 166.5 gnatrium saccharinate (V) in 372 cm<3>dimethylformamide. The reaction mixture is refluxed for 4 hours and then poured into 470 cm<3> ice water. After 2 hours the precipitate is filtered, washed with water and dried. 175.6g of 3-oxy-1,2-benzothiazole-2-acetate ethyl ester is obtained - crystalline, white, solid substance, melting point 104-106°C (80% yield).
Primer 3. Example 3.
Dobijanjeetil- 4- hidroksi- 2H- l , 2- benzotiazin- 3- karboksilat- l, 1- dioksida(VII) Production of ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (VII)
Pripremljen rastvor od 58g3- oksi- l, 2- benzotiazol- 2- acetat etilestar(VI) u 336 cm<3>dimetilformamidakoji je zagrejan na 50°C dodaje se u 215cm<3>21%natrijum etilata.Smeša se zagreva oko 30 minuta na 55°C kada se formira postepeno narandžasti talog. Smeša se izliva u 960cm<3>3Mhlorovodonične kiselineuz mešanje i na temperaturi manjoj od 5°C. Nakon pola sata mešanja, talog se odvoji filtriranjem a zatim se ispere hladnom vodom i suši. Dobija se 43,5getil- 4- hidroksi- 2H- l, 2- benzotiazin- 3- karboksilat- 1, 1- dioksida -bele, čvrste supstance, tačke topljenja 136-139°C (prinos 75%). A prepared solution of 58 g of 3-oxy-l, 2-benzothiazole-2-acetate ethyl ester (VI) in 336 cm<3>dimethylformamide heated to 50°C is added to 215 cm<3>21% sodium ethylate. The mixture is heated for about 30 minutes at 55°C when an orange precipitate is gradually formed. The mixture is poured into 960 cm<3>3M hydrochloric acid with stirring and at a temperature of less than 5°C. After half an hour of mixing, the precipitate is separated by filtration and then washed with cold water and dried. 43,5-gethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide is obtained as a white, solid substance, melting point 136-139°C (75% yield).
Primer 4. Example 4.
Sintezaetil- 4- hidroksi- 2- metil- 2H- l, 2- benzotiazin- 3- karboksilat- l, 1-dioksida(VIII) Synthezaethyl- 4- hydroxy- 2- methyl- 2H- 1, 2- benzothiazine- 3- carboxylate- 1, 1-dioxide (VIII)
15getil- 4- hidroksi- 2H- l, 2- bemotiazin- 3- karboksilat- 1, 1- dioksid(VII) se rastvori u 122,8cm<3>acetona,a zatim se doda 2,24gnatrijum hidroksidarastvorenog u 115cm<3>vode a zatim i 16cm<3>dimetilsulfata.Reakciona smeša se održava uz mešanje tokom 2 sata na 50°C. Nakon hlađenja do 0-5°C, obrazovani kristali se filtriraju i ispiraju hladnom vodom. Dobija se 14,04getil- 4- hidroksi- 2-metil- 2H- l, 2- benzotiazin- 3- karboksilat- 1, 1- dioksida -bele, čvrste supstance tačke topljenja 140-142°C (prinos 89%). 15-ethyl-4-hydroxy-2H-1,2-bemothiazine-3-carboxylate-1,1-dioxide (VII) is dissolved in 122.8 cm<3> of acetone, and then 2.24 gnatrium hydroxide dissolved in 115 cm<3> of water and then 16 cm<3> of dimethylsulfate are added. The reaction mixture is maintained with stirring for 2 hours at 50°C. After cooling to 0-5°C, the formed crystals are filtered and washed with cold water. 14,04-ethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide is obtained as a white, solid substance with a melting point of 140-142°C (89% yield).
Primer 5. Example 5.
Sinteza piroksikama (II), tj.4- hidroksi- 2- metil- N-( 2- piridinil)- 2H- ll2-benzotiazin- 3- karboksamid- l, l- dioksidaSynthesis of piroxicams (II), i.e. 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-112-benzothiazine-3-carboxamide-1,1-dioxide
U reakcioni sud u kome se nalazi 226cm suvogo- ksilenadoda se 9,3getil-4- hidroksi- 2- metil- 2H- l, 2- benzotiazin- 3- karboksilat- 1, 1- dioksida(VIII), 1,8g NH4C1 i uključiti dovodazotai grejanje. Zatim se doda 3,8g2- aminopiridina(IX) i prekine dovodazota.Smeša se zagreva 10 sati uz azeotropnu destilaciju. Tokom destilacije dodaje se svežo- ksilenu količini od oko 170cm<3>. Nakon završene sinteze nastavi se destilovanje do zapremine reakcione smeše oko 165cm<3>, a potom se izlije i hladi do 0-5°C. Nagrađeni kristali se filtriraju i ispirajuheksanomi suše. Dobija se 6,7g4- hidroksi- 2- metil- N-( 2- piridinil)- 2H- l, 2- benzotiazin- 3-karboksamid- 1, 1- dioksida(II) - kristalnog, belog, proizvoda tačke topljenja 197-201°C (prinos 61%). Add 9,3-ethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide(VIII), 1.8 g of NH4C1 to the reaction vessel containing 226 cm of dry carbon-xylene and turn on the nitrogen supply and heating. Then 3.8g of 2-aminopyridine (IX) was added and the nitrogen supply was stopped. The mixture was heated for 10 hours with azeotropic distillation. During distillation, fresh xylene is added to an amount of about 170cm<3>. After the completed synthesis, distillation continues until the volume of the reaction mixture is about 165cm<3>, and then it is poured and cooled to 0-5°C. The resulting crystals are filtered and washed with hexanes to dryness. 6.7g of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide(II) is obtained - crystalline, white, melting point product 197-201°C (yield 61%).
Primer 6. Example 6.
Sinteza piroksikama (II), tj.4- hidroksi- 2- metil- N-( 2- piridinil)- 2H- l, 2-benzotiazin- 3- karboksamid- l1- dioksidaSynthesis of piroxicams (II), i.e. 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide-11-dioxide
U reakcioni sud u kome se nalazi 210cmo- ksilena(suvog) dodati lOgetil-4- hidroksi- 2- metil- 2H- l, 2- benzotiazin- 3- karboksilat- l, 1- dioksida(VIII), 3,55g NH4CI i zagrevati do rastvaranja u strujiazotai uz prisustvo 0,8g CaCl2na ulazu u kondenzator. Zatim se doda 4,94 g2- aminopiridina(IX) i prekine dovod azota. Nakon 12 sati refluksa, reakciona masa se izlije i hladi do 0-5°C. Dobijeni kristali se filtriraju i ispiraju hladnimmetanolom.Dobija se 7,02g4- hidroksi- 2- metil- N-( 2- piridinil)- 2H- l, 2- benzotiazin- 3- karboksamid- l, 1- dioksida- kristalnog, belog, proizvoda, tačke topljenja 197-201°C (prinos 60%). Add 10-ethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide(VIII), 3.55g of NH4Cl to the reaction vessel containing 210cm-xylene (dry) and heat until it dissolves in a stream of nitrogen with the presence of 0.8g of CaCl2 at the inlet to the condenser. Then 4.94 g of 2-aminopyridine(IX) is added and the nitrogen supply is stopped. After 12 hours of reflux, the reaction mass is poured and cooled to 0-5°C. The obtained crystals are filtered and washed with cold methanol. 7.02g of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is obtained as a crystalline, white product, melting point 197-201°C (60% yield).
Claims (7)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YUP-634/99A RS49867B (en) | 1999-12-06 | 1999-12-06 | PROCEDURE FOR THE SYNTHESIS OF 4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE |
| PCT/YU2000/000009 WO2001040208A2 (en) | 1999-12-06 | 2000-04-06 | Process for synthesis of 4-hydroxy-2h-1,2-benzothiazine-3-carboxamides |
| AU36333/00A AU3633300A (en) | 1999-12-06 | 2000-04-06 | Process for synthesis 4-hydroxy-2h-1,2-benzothiazine-3-carboxamides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YUP-634/99A RS49867B (en) | 1999-12-06 | 1999-12-06 | PROCEDURE FOR THE SYNTHESIS OF 4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE |
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| YU63499A YU63499A (en) | 2002-06-19 |
| RS49867B true RS49867B (en) | 2008-08-07 |
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Country Status (3)
| Country | Link |
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| AU (1) | AU3633300A (en) |
| RS (1) | RS49867B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3957772A (en) * | 1975-05-21 | 1976-05-18 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide |
| DE3212485A1 (en) * | 1982-04-03 | 1983-10-13 | Gödecke AG, 1000 Berlin | METHOD FOR PRODUCING 4-HYDROXY-3- (HETEROCYCLOCARBAMOYL) -2H-1,2-BENZOTHIAZINE-1,1-DIOXIDES |
| IT1194522B (en) * | 1983-12-16 | 1988-09-22 | Prodotti Antibiotici Spa | SYNTHESIS METHOD OF BENZOTHIAZINIC DERIVATIVES |
| ES2002646A6 (en) * | 1987-03-27 | 1988-09-01 | Induspol Sa | Process for obtaining 4-hydroxy-2-methyl-N-(2-piridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. |
-
1999
- 1999-12-06 RS YUP-634/99A patent/RS49867B/en unknown
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2000
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| WO2001040208A2 (en) | 2001-06-08 |
| WO2001040208A3 (en) | 2001-11-29 |
| AU3633300A (en) | 2001-06-12 |
| YU63499A (en) | 2002-06-19 |
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