EP0000679B1 - Nouveau procédé de préparation de la glafénine - Google Patents
Nouveau procédé de préparation de la glafénine Download PDFInfo
- Publication number
- EP0000679B1 EP0000679B1 EP78400060A EP78400060A EP0000679B1 EP 0000679 B1 EP0000679 B1 EP 0000679B1 EP 78400060 A EP78400060 A EP 78400060A EP 78400060 A EP78400060 A EP 78400060A EP 0000679 B1 EP0000679 B1 EP 0000679B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- glafenine
- glycerol
- quinoline
- anthranilate
- glyceryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title claims description 6
- GWOFUCIGLDBNKM-UHFFFAOYSA-N glafenine Chemical compound OCC(O)COC(=O)C1=CC=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 GWOFUCIGLDBNKM-UHFFFAOYSA-N 0.000 title description 19
- 229960001650 glafenine Drugs 0.000 title description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 claims description 12
- VHWSRELATOUTAG-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-aminobenzoate Chemical compound NC1=CC=CC=C1C(=O)OCC(O)CO VHWSRELATOUTAG-UHFFFAOYSA-N 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 230000001376 precipitating effect Effects 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- WVTMZTPCIVQJGS-UHFFFAOYSA-N 2-[(7-chloroquinolin-2-yl)amino]benzoic acid Chemical compound C(=O)(O)C1=C(C=CC=C1)NC1=NC2=CC(=CC=C2C=C1)Cl WVTMZTPCIVQJGS-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 0 *c1cc2nccc(Cl)c2cc1 Chemical compound *c1cc2nccc(Cl)c2cc1 0.000 description 1
- VRJKNLYNNGCTPS-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-chlorobenzoate Chemical compound OCC(O)COC(=O)C1=CC=CC=C1Cl VRJKNLYNNGCTPS-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- NDRZSRWMMUGOBP-UHFFFAOYSA-N 4-Amino-7-chloroquinoline Chemical compound ClC1=CC=C2C(N)=CC=NC2=C1 NDRZSRWMMUGOBP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WCDGNZGMCOMSIK-UHFFFAOYSA-N C(C(O)CO)CC([CH2-])=O Chemical compound C(C(O)CO)CC([CH2-])=O WCDGNZGMCOMSIK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- COYZKKICEBRUSU-UHFFFAOYSA-N [O-][NH+]1O[NH+]([O-])Sc2ccccc12 Chemical compound [O-][NH+]1O[NH+]([O-])Sc2ccccc12 COYZKKICEBRUSU-UHFFFAOYSA-N 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
Definitions
- the present invention carried out at the Pierre FABRE Research Center relates to a new process for the preparation of the ⁇ -monoglyceride of 4 (2 '- carboxyphenylamino) - 7 - chloro-quinoline of formula:
- This chemical compound is known for its analgesic properties; it is used as an active ingredient in many pharmaceutical specialties. This molecule will be mentioned below by its international common name: glafenine.
- Glafenine (I) is prepared by condensation in hydrochloric medium of dichloro - 4,7 - quinoline (II) with methyl anthranilate (III), this intermediate methyl ester is then transesterified by glycerol acetonide (V) and finally the acid hydrolysis of the compound (VI) leads to glafenine (I) according to the reaction scheme:
- the present invention relates to a very simple process which makes it possible to prepare glafenine under very economical conditions.
- glafenine is prepared by condensation of the glyceryl anthranilate of formula: on 4.7 - dichloro-quinoline:
- This condensation is preferably carried out in a hydrochloric medium.
- the glafenine obtained is separated from the reaction medium by known methods, it can in particular be precipitated by neutralization of the reaction medium.
- the crude glafenine obtained can be purified for example by recrystallization from a solvent or mixture of organic solvent such as the chloroform-ethanol mixture.
- the glyceryl anthranilate is itself prepared according to the invention by condensation of glycerol on isatoic anhydride in basic medium as a condensing agent.
- This process is preferably carried out using an excess of glycerol as solvent, so the glyceryl anthranilate is obtained in solution in glycerol and this solution can be used in the process according to the present invention without having to isolate the anthranilate. which further improves the overall yield of the process.
- This process for the preparation of glafenine has the advantage of using only products widely available commercially and inexpensively.
- isatoic anhydride which is experiencing an industrial development as a synthesis intermediary in the dye industry can, thanks to new synthesis processes, be obtained at prices much lower than the prices of anthranilic acid which constitutes the basic product in known syntheses of glafenine.
- this synthetic method makes it possible to significantly increase the yields of glafenine compared to known methods, in particular by limiting the number of reaction steps.
- reaction medium is then cooled to 20 ° C. and transferred to a 200 I tank in which it is treated slowly with 60 l of an aqueous sodium hydroxide solution N, then neutralization is completed by adding sodium bicarbonate.
- the purification is carried out by return to a solution of glafenine hydrochloride and reprecipitation of the base gléfenine by operating as follows: to the aqueous suspension is added 2830 cm 3 of HCl with density 1.18, the hydrochloride formed dissolves, one filters on a single disc filter, one adds sodium hydroxide N, then one ends the neutralization with a solution of baking soda.
- the precipitate is separated as previously by wringing; the crude glafenine thus obtained has, after drying, a melting point of 163 ° C.
- glafenine is obtained with a yield varying according to the case from 65 to 75% compared to 4,7-dichloro-quinoline with an instant melting point in the Kofler block of 169-170 ° C. .
- the present invention also relates, as a medicament, to glafenin obtained by implementing the method according to the present invention.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7722900 | 1977-07-26 | ||
FR7722900A FR2398733A1 (fr) | 1977-07-26 | 1977-07-26 | Nouveau procede de preparation de la glafenine |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000679A1 EP0000679A1 (fr) | 1979-02-07 |
EP0000679B1 true EP0000679B1 (fr) | 1981-06-24 |
Family
ID=9193813
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78400060A Expired EP0000679B1 (fr) | 1977-07-26 | 1978-07-18 | Nouveau procédé de préparation de la glafénine |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0000679B1 (it) |
JP (1) | JPS5424881A (it) |
CA (1) | CA1107737A (it) |
DE (1) | DE2860803D1 (it) |
ES (1) | ES472072A1 (it) |
FR (1) | FR2398733A1 (it) |
IT (1) | IT1156878B (it) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2549830B1 (fr) * | 1983-07-25 | 1987-04-30 | Corbiere Jerome | Nouveau procede d'obtention de quinoleines substituees |
-
1977
- 1977-07-26 FR FR7722900A patent/FR2398733A1/fr active Granted
-
1978
- 1978-07-18 EP EP78400060A patent/EP0000679B1/fr not_active Expired
- 1978-07-18 DE DE7878400060T patent/DE2860803D1/de not_active Expired
- 1978-07-20 CA CA307,785A patent/CA1107737A/fr not_active Expired
- 1978-07-24 IT IT50438/78A patent/IT1156878B/it active
- 1978-07-24 JP JP9031478A patent/JPS5424881A/ja active Pending
- 1978-07-26 ES ES472072A patent/ES472072A1/es not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPS5424881A (en) | 1979-02-24 |
FR2398733A1 (fr) | 1979-02-23 |
FR2398733B1 (it) | 1980-02-29 |
CA1107737A (fr) | 1981-08-25 |
IT7850438A0 (it) | 1978-07-24 |
IT1156878B (it) | 1987-02-04 |
ES472072A1 (es) | 1979-03-16 |
EP0000679A1 (fr) | 1979-02-07 |
DE2860803D1 (en) | 1981-10-01 |
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