DK154504B - PROCEDURE FOR PREPARING BENZOTIAZINE Dioxide AND INTERMEDIATE PRODUCT FOR USE IN EXERCISING THE PROCEDURE - Google Patents
PROCEDURE FOR PREPARING BENZOTIAZINE Dioxide AND INTERMEDIATE PRODUCT FOR USE IN EXERCISING THE PROCEDURE Download PDFInfo
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- DK154504B DK154504B DK471284A DK471284A DK154504B DK 154504 B DK154504 B DK 154504B DK 471284 A DK471284 A DK 471284A DK 471284 A DK471284 A DK 471284A DK 154504 B DK154504 B DK 154504B
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- dioxide
- procedure
- benzothiazine
- methyl
- preparing
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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
Description
DK 154504 BDK 154504 B
Dé'n foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af farmaceutisk anvendeligt 2-metyl-4-hydroxy-2H-l,2-benzotiazin-l,l-dioxyd-3(N-2-pyridyl)- karboxamid, en forbindelse der har trivial-5 navnet piroxicam og har formlenThe present invention relates to a particular process for the preparation of pharmaceutically useful 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3 (N-2-pyridyl) carboxamide, a compound which has the trivial-5 name piroxicam and has the formula
OHOH
sJt-CH3 °2sJt-CH3 ° 2
Opfindelsen angår desuden et hidtil' ukendt mellemprodukt, 2-metyl-4-mesyloxy-2H-l,2-benzotiazin-l,l-dio-xyd-3-karboxylsyre, til anvendelse ved udøvelse af fremgangsmåden ifølge opfindelsen. Formlen for dette 10 mellemprodukt er ch3-so2-o i^V^v'00011 °2The invention further relates to a novel intermediate, 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid, for use in the practice of the invention. The formula for this intermediate is ch3-so2-o in ^ V ^ v'00011 ° 2
Piroxicam har vist sig at være et meget værdifuldt antiinflammatorisk og analgetisk middel som ikke er behæftet med de skadelige virkninger der sædvanligvis knytter sig til steroider. Fremgangsmåder til frem-15 stilling af piroxicam er angivet i tålrige finske og andre patentskrifter, hvoriblandt kan nævnes de finske patentskrifter nr. 51189, 59592, 62297, 63573 og 72719.Piroxicam has been found to be a very valuable anti-inflammatory and analgesic agent which does not suffer from the harmful effects usually associated with steroids. Methods for preparing piroxicam are disclosed in numerous Finnish and other patents, including Finnish Patent Nos. 51189, 59592, 62297, 63573 and 72719.
Den bedste fremgangsmåde, for så vidt angår udbyttet, 20 er angivet i de finske patentskrifter nr. 51189 og 72719. Ved fremgangsmåden ifølge finsk patentskrift nr’. 51189 bringes 3-karboxylsyreesteren af 3,4- 2The best method for yield is given in Finnish Patent Nos. 51189 and 72719. In the method of Finnish patent no. 51189, the 3-carboxylic acid ester is brought down by 3,4-2
DK 154504 BDK 154504 B
dihydro-4-oxo-2H-l,2-benzotiazin-karboxamid-l,l-dioxyd til at reagere med en mindst ækvimolær mængde af en amin der indeholder den ønskede aromatiske del af molekylet, hvilket i tilfælde af piroxicam er pyridyl.dihydro-4-oxo-2H-1,2-benzothiazine-carboxamide-1,1-dioxide to react with a least equimolar amount of an amine containing the desired aromatic portion of the molecule, which in the case of piroxicam is pyridyl.
5 Det opnåede udbytte ved denne fremgangsmåde er ca.70%.The yield obtained in this process is about 70%.
Et noget bedre udbytte Opnås ved fremgangsmåden ifølge finsk patentskrift nr. 72719, der kun afviger fra fremgangsmåden ifølge finsk patentskrift nr. 51189 med hensyn til estergruppen. Således bruges der ifølge finsk 10 patentskrift nr. 51189 metylesteren som ester af kari.A somewhat better yield is obtained by the method of Finnish Patent No. 72719, which differs only from the method of Finnish Patent No. 51189 with respect to the ester group. Thus, according to Finnish patent specification No. 51189, the methyl ester is used as the ester of kari.
boxylsyren i 3-stillingen, mens der ifølge finsk patent-skrift nr. 72719 i stedet bruges metoxyætylesteren.the acetic acid in the 3-position, while the methoxyethyl ester is used instead according to Finnish patent specification 72719.
De ovennævnte metoder, baseret på en aminolysereaktion af vedkommende ester af 1,2-benzotiazin-3-karboxylsyre og 15 2-^aminopyridin, er ganske vist egnede til produktion i industriel målestok på grund af de udbytter de giver og også på grund af deres andre egenskaber, men ulemper ved disse fremgangsmåder er bl.a. anvendelse af høj temperatur, der indebærer temperaturen af kogende 20 xylen, og en. meget lang reaktionstid, sædvanligvis mere end' 20 timer. Både temperaturen og den lange reaktionstid har tendens til at have nedbrydende virkning på det ønskede produkt, i hvilke tilfælde rensningen af produktet er vanskelig og udbyttet får tilbøjelighed 25 til at gå ned på grund af nedbrydningen. Rensningen er desuden kompliceret, især fordi der ved de beskrevne fremgangsmåder frembringes farvede biprodukter som fordrer talrige udludninger og omkrystallisationer, og også andre behandlingstrin, for at tilvejebringe 30 et acceptabelt slutprodukt.The above methods, based on an aminolysis reaction of the ester concerned of 1,2-benzothiazine-3-carboxylic acid and 2- 2-aminopyridine, are indeed suitable for industrial scale production because of the yields they give and also because of their yields. other properties, but disadvantages of these methods include: use of high temperature, involving the temperature of boiling xylene, and one. very long reaction time, usually more than 20 hours. Both the temperature and the long reaction time tend to have a degradative effect on the desired product, in which case the purification of the product is difficult and the yield tends to decrease due to the degradation. The purification is further complicated, especially because the by-described processes produce colored by-products which require numerous leaches and recrystallizations, and also other processing steps, to provide an acceptable final product.
En anden fremgangsmåde til fremstilling af piroxicam som er værd at nævne er den der repræsenteres i finsk patentskrift nr. 63573. I dette skrift er udgangsma- térialet en forbindelse med formlenAnother method of preparing piroxicam which is worth mentioning is that represented in Finnish Patent No. 63573. In this specification, the starting material is a compound of the formula
ZZ
al .CONHR2 s^n-ch3al.CONHR2 s ^ n-ch3
3 DK 154504 B3 DK 154504 B
2 hvor Z ec en isopropoxygruppe og R en 2-pyridylgruppe, når det ønskede produkt er piroxicam. Forbindelsen bringes i kontakt med emnuorganisk syre hvorved bevirkes, at isopropoxygruppen fraspaltes. Det samlede udbytte 5 der opnåes ved denne fremgangsmåde er meget dårligt, for før fjernelse af isopropoxygruppen indbefatter fremstillingsprocessen også kobling af en:aminopyri-dylgruppe til benzotiazinet, hvilket trin forudgås af omdannelse af 3-acetylforbindelsen til vedkommende 10 3-karboxylsyre. Det totale opnåede udbytte er således kun ca. 2¾. Ulemperne ved denne metode er ikke begrænset til dårligt udbytte, for den indbefatter adskillige trin hvori der anvendes skadelige opløsningsmidler såsom benzen og stærke syrer, såsom 32¾ brombrin-15 tesyre, ved hjælp af hvilke isopropylgruppen brydes af. Metoden er ikke egnet til industriel produktion.2 where Z is an isopropoxy group and R is a 2-pyridyl group when the desired product is piroxicam. The compound is brought into contact with the organic matter which causes the isopropoxy group to be cleaved. The overall yield 5 obtained by this process is very poor because prior to removal of the isopropoxy group, the production process also includes coupling of an: aminopyridyl group to the benzothiazine, which step is preceded by conversion of the 3-acetyl compound to the 3-carboxylic acid. The total yield thus obtained is only approx. 2¾. The disadvantages of this method are not limited to poor yields, for it includes several steps in which harmful solvents such as benzene and strong acids such as 32¾ bromobutyric acid are used by which the isopropyl group is broken off. The method is not suitable for industrial production.
Det er den foreliggende opfindelses formål af tilvejebringe en fremgangsmåde ved hvilken piroxicam kan fremstilles med meget godt udbytte og under anvendelse af 20 reakt ionstrin som både er lette at udføre og som kan fuldføres hurtigt. Et led i formålet er at opnå et så rent slutprodukt som muligt.It is the object of the present invention to provide a process by which piroxicam can be prepared in very good yield and using 20 reactive ion steps which are both easy to perform and which can be completed quickly. One part of the purpose is to obtain as clean a final product as possible.
Fremgangsmåden ifølge opfindelsen til fremstilling af piroxicam, 2-metyl-4-hydroxy-2H-l,2-benzotiazin-l,l-diox-25 yd-3-(N-2-pyridyl)-karboxamid,The process of the invention for the preparation of piroxicam, 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide 25-3- (N-2-pyridyl) carboxamide,
OHOH
rrVC0'”OrrVC0 ' "O
f 3 1 °2 er ejendommelig ved at 2-metyl-4-mesyloxy-2H-l,1-ben-zotiazin-1,l-dioxyd-3-karboxylsyre med formlenf 3 1 ° 2 is characterized in that 2-methyl-4-mesyloxy-2H-1,1-benzothiazine-1,1-dioxide-3-carboxylic acid of the formula
CH -SO -o ICH -SO -o I
J 2 IJ 2 I
cooH-cH3-cotr / UJLs.N-CH3 ^CH3 „ i 4cooH-cH3-cotr / UJLs.N-CH3 ^ CH3 + i4
DK 154504BDK 154504B
eller et solvat deraf med dimetylacetamid omsættes ved en temperatur på omkring 40-80°C med tionylklorid og 2-aminopyridin med formlen i et inert opløsningsmiddel.or a solvate thereof with dimethylacetamide is reacted at a temperature of about 40-80 ° C with thionyl chloride and 2-aminopyridine of the formula in an inert solvent.
5 Udgangsmaterialet II og 2-aminopyridin bruges i til nærmelsesvis ækvimolære mængder, mens tionylklorid kan bruges i overskud, f.eks. omkring den dobbelte støkiometriske mængde. Inerte opløsningsmidler som egner sig til anvendelse ved reaktionen er bl.a. klo-10 rerede kulbrinter såsom diklormetan og 1,2-diklorætan, samt acetonitril. Reaktionen går til fuldførelse i løbet af 2 - 3 timer. Om ønsket er det muligt i reaktionen at bruge en tertiær amin såsom 2,6-dimetylpy-ridin, men dette har dog meget lille virkning på reak-15 tionen.The starting material II and 2-aminopyridine are used in approximately equimolar amounts, while thionyl chloride can be used in excess, e.g. about the double stoichiometric amount. Inert solvents suitable for use in the reaction include chlorinated hydrocarbons such as dichloromethane and 1,2-dichloroethane, as well as acetonitrile. The reaction goes to completion in 2 - 3 hours. If desired, it is possible in the reaction to use a tertiary amine such as 2,6-dimethylpyridine, but this has very little effect on the reaction.
Når fremgangsmåden ifølge opfindelsen bruges til fremstilling af piroxicam, finder hele reaktionen sted under ganske milde betingelser. Således forløber reaktionen med 2-amino-pyridin ved moderat temperatur og 20 hurtigt. Ligeledes kan mesylgruppen fjernes under meget milde betingelser, idet fraspaltningen finder sted umiddelbart efter acyleringsreaktionen ved anvendelse af en tynd NaOH-opløsning.When the process of the invention is used to prepare piroxicam, the entire reaction takes place under very mild conditions. Thus, the reaction proceeds with 2-amino-pyridine at moderate temperature and rapidly. Likewise, the mesyl group can be removed under very mild conditions, the cleavage taking place immediately after the acylation reaction using a thin NaOH solution.
På grund af den lave temperatur, den korte reaktions-25 tid og de milde betingelser er det piroxicam der vindes som et slutprodukt meget rent, hvorved adskillige af de trin der bruges til rensning ved de kendte fremgangsmåder til fremstilling af forbindelsen kan elimineres. På grund af de ovennævnte faktorer er udbyt-50 tet højt, gennemsnitlig 86¾. Fremgangsmåden ifølge opfindelsen indebærer desuden et yderligere overraskende trin, nemlig at der ikke nødvendigvis behøves et syrebindende middel i det hele taget ved udøvelse af fremgangsmåden. Åbenbart katalyserer det anvendte N,N-33 ..........._______ 5Due to the low temperature, the short reaction time and the mild conditions, the piroxicam obtained as an end product is very pure, thereby eliminating several of the steps used for purification by the known methods of preparing the compound. Due to the above factors, the yield is high, on average 86¾. The process of the invention further comprises a further surprising step, namely that an acid binding agent is not necessarily required at all in the practice of the process. Obviously, the used N, N-33 catalyzes ..........._______ 5
DK 154504 BDK 154504 B
alet, i kraft af at det er et aprotisk opløsningsmiddel, effektivt acyleringsreaktionen af 2-aminopyridin, hvorved det bliver unødvendigt at bruge en syreacceptor.alet, because it is an aprotic solvent, effectively acylates the 2-aminopyridine acylation reaction, thereby making it unnecessary to use an acid acceptor.
Som nævnt angår opfindelsen også et mellemprodukt med c „ , ch,-so9-o ' 5 formlen J ά |As mentioned, the invention also relates to an intermediate having the c ", ch, -so9-o 'formula J ά |
UvXs-^-CH3 °2 der er en hidtil ukendt forbindelse. Specielt med hen-syln til fremgangsmåden ifølge opfindelsen er det fordelagtigt at dette mellemprodukt danner et solvat med dimetylacetamid.UvXs - ^ - CH3 ° 2 which is a novel compound. Particularly with respect to the process of the invention, it is advantageous for this intermediate to form a solvate with dimethylacetamide.
10 Fr emst il ling enr af mellemproduktet II (udgangsmateria- levfor fremgangsmåden ifølge opfindelsen) udføres bedst ved at man hydrogenerer benzyl-2-metyl-4-mesyloxy-l,2-benzotiazin-1,l-dioxyd-3-karboxylat med formlen ch3-so2-o r**Y^COOCH2_/-\ U, ^c^N-CH iv 3 °2 i nærværelse af N,N-dimetylacetamid og en hydrogene-15 ringskatalysator i et inert opløsningsmiddel. Udgangs materialet for denne reaktion, benzyl-2-metyl-4-mesy-loxy-1,2-benzotiazin-l,l-dioxyd-3-karboxylat, kan for sit vedkommende fremstilles i næsten det teoretisk mulige udbytte ved mesylering ved konventionel frem-20 gangsmåde ud fra vedkommende 4-hydroxyforbindelse.Preparation of the intermediate II (starting material for the process of the invention) is best performed by hydrogenating benzyl-2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate of the formula ch3-so2-o r ** Y ^ COOCH2 _ / - \ U, ^ c ^ N-CH iv 3 ° 2 in the presence of N, N-dimethylacetamide and a hydrogenation catalyst in an inert solvent. The starting material for this reaction, benzyl-2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate, can, for its part, be prepared in almost theoretically possible yield by mesylation by conventional process. -20 procedure based on the 4-hydroxy compound.
Benzyl-2-metyl-4-hydroxy-l,2-benzotiazin-l,1-dioxyd- 3-karbo>i:ylat er en kendt forbindelse der er angivet i f.eks. europæisk patentansøgning nr. 82303978.9, publikation nr. 77 603.Benzyl-2-methyl-4-hydroxy-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid is a known compound disclosed in e.g. European Patent Application No. 82303978.9, Publication No. 77 603.
25 De følgende eksempler tjener til nærmere belysning afThe following examples serve to illustrate
c DK 154504 Bc DK 154504 B
' 6 fremgangsmåden og mellemproduktet ifølge opfindelsen. Eksempel 1.The method and intermediate of the invention. Example 1.
2-Metyl-3-karboxyl-4-mesyloxy-2H-l,2-benzotiazin-l,l- dioxyd-N,N-dimetylacetamid-s.olvat____ 5 En opløsning indeholdende 42,3 g (o,l mol) benzyl-2- metyl-4-mesyloxy-2H-l,2-benzotiazin-l,l-dioxyd-3-kar-boxylat (smp. 110-112°C), 8,7 g (0,1 mol) N,N-dime-tylacetamid og 2 g 10¾s palladium på kul katalysator hydrogeneredes i 3 timer ved normalt tryk og stuetem-10 peratur. Katalysatoren frafiltreredes og opløsningsmidlet afdestilleredes ved nedsat tryk hvorved der vandtes 41,8 (99,5% af det teoretisk mulige) af det ønskede produkt, der havde smp. 102-104°C.2-Methyl-3-carboxyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-N, N-dimethylacetamide-solvate A solution containing 42.3 g (0.1 mol) of benzyl -2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate (mp 110-112 ° C), 8.7 g (0.1 mole) N, N-dimethylacetamide and 2 g of 10¾ palladium on carbon catalyst were hydrogenated for 3 hours at normal pressure and room temperature. The catalyst was filtered off and the solvent was distilled off at reduced pressure to give 41.8 (99.5% of the theoretically possible) of the desired product which had m.p. 102-104 ° C.
Eksempel 2.Example 2.
15 2-Metyl-4-hydroxy-2H-l,2-benzotiazin-l,l-dioxyd-3- (N-2-pyridyl)-karboxamid (piroxicam)._2-Methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide (piroxicam)
Til en opløsning indeholdende 16,8 g (0,040 mol) af det ifølge eksempel 1 fremstillede mellemprodukt og 4,0 g (0,043 mol) 2-aminopyridin i 200 ml kogende 20 1,2-diklorætan (samt eventuelt 4,3 g (0,40 mol) 2,6- dimetylpyridin) sattes der 9,5 g (0,08 mol) tionyi-klorid under omrøring i løbet af 1/2 time. Blandingen tilbagesvaledes i 2 timer hvorefter den afkøledes til ca. 40°C og der gradvis under omrøring tilsattes 25 ca. 500 ml 0,5N NaOH. Omrøringen fortsattes i yderligere 1/2 time ved en temperatur på 40°C. Dereftér fraskiltes det vandige lag og det vaskedes med metylen-klorid, filtrereredes og gjordes mildt surt ved hjslp af eddikesyre, hvorved det ønskede produkt udkrystalli-30 serede. Produktet filtreredes og tørredes og der vandtes herved 11,4 g (86¾ af det teoretisk mulige) af det i overskriften angivne produkt med smp. 198-200°C (renhed >985S).To a solution containing 16.8 g (0.040 mol) of the intermediate of Example 1 and 4.0 g (0.043 mol) of 2-aminopyridine in 200 ml of boiling 20 1,2-dichloroethane (and optionally 4.3 g (0 , 40 moles of 2,6-dimethylpyridine 9.5 g (0.08 mole) of thionyl chloride were added with stirring over 1/2 hour. The mixture was refluxed for 2 hours and then cooled to ca. 40 ° C and gradually stirring about 25 hours. 500 ml of 0.5N NaOH. Stirring was continued for a further 1/2 hour at a temperature of 40 ° C. Then, the aqueous layer was separated and washed with methylene chloride, filtered and mildly acidified using acetic acid to crystallize the desired product. The product was filtered and dried, yielding 11.4 g (86¾ of the theoretically possible) of the title product, m.p. 198-200 ° C (purity> 985S).
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI833628 | 1983-10-06 | ||
| FI833628A FI72317C (en) | 1983-10-06 | 1983-10-06 | PROCEDURE FOR THE FRAMEWORK OF PHARMACEUTICALS 2-METHYL-4-HYDROXY-2H-1,2-BENZOTHIAZINE-1,1-DIOXIDE -3- (N-2-PYRIDYL)-CARBOXAMIDE |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK471284D0 DK471284D0 (en) | 1984-10-02 |
| DK471284A DK471284A (en) | 1985-04-07 |
| DK154504B true DK154504B (en) | 1988-11-21 |
| DK154504C DK154504C (en) | 1989-04-10 |
Family
ID=8517867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK471284A DK154504C (en) | 1983-10-06 | 1984-10-02 | PROCEDURE FOR THE PREPARATION OF BENZOTIAZINE Dioxide AND INTERMEDIATE PRODUCT FOR USE IN EXERCISING THE PROCEDURE |
Country Status (16)
| Country | Link |
|---|---|
| AT (1) | AT387775B (en) |
| BE (1) | BE900758A (en) |
| CA (1) | CA1246066A (en) |
| CS (1) | CS253593B2 (en) |
| DD (1) | DD224594A5 (en) |
| DK (1) | DK154504C (en) |
| ES (1) | ES8505937A1 (en) |
| FI (1) | FI72317C (en) |
| HU (2) | HU195493B (en) |
| IT (1) | IT1218850B (en) |
| NO (1) | NO159275C (en) |
| PL (1) | PL143957B1 (en) |
| PT (1) | PT79326B (en) |
| SE (2) | SE460789B (en) |
| SU (1) | SU1405703A3 (en) |
| YU (2) | YU43381B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4289879A (en) * | 1980-09-29 | 1981-09-15 | Pfizer Inc. | Synthetic method and intermediate for piroxicam |
| JPH08270888A (en) * | 1995-03-30 | 1996-10-15 | Nec Eng Ltd | Heat insulating engagement mechanism |
-
1983
- 1983-10-06 FI FI833628A patent/FI72317C/en not_active IP Right Cessation
-
1984
- 1984-10-01 NO NO843949A patent/NO159275C/en not_active IP Right Cessation
- 1984-10-02 DK DK471284A patent/DK154504C/en not_active IP Right Cessation
- 1984-10-03 CS CS847493A patent/CS253593B2/en unknown
- 1984-10-03 HU HU844649A patent/HU195493B/en unknown
- 1984-10-03 HU HU843746A patent/HU194559B/en unknown
- 1984-10-04 YU YU1708/84A patent/YU43381B/en unknown
- 1984-10-04 PT PT79326A patent/PT79326B/en not_active IP Right Cessation
- 1984-10-04 IT IT22981/84A patent/IT1218850B/en active
- 1984-10-05 ES ES536544A patent/ES8505937A1/en not_active Expired
- 1984-10-05 PL PL1984249918A patent/PL143957B1/en unknown
- 1984-10-05 DD DD84268074A patent/DD224594A5/en not_active IP Right Cessation
- 1984-10-05 CA CA000464861A patent/CA1246066A/en not_active Expired
- 1984-10-05 AT AT0316384A patent/AT387775B/en active
- 1984-10-05 BE BE0/213782A patent/BE900758A/en not_active IP Right Cessation
- 1984-10-05 SE SE8405002A patent/SE460789B/en not_active IP Right Cessation
- 1984-10-05 SU SU843805901A patent/SU1405703A3/en active
-
1986
- 1986-08-27 YU YU1496/86A patent/YU43603B/en unknown
-
1989
- 1989-01-24 SE SE8900248A patent/SE464411B/en not_active IP Right Cessation
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