EP0625152A1 - Verfahren zur herstellung eines racemischen 2-aminonaphthyridin derivats - Google Patents
Verfahren zur herstellung eines racemischen 2-aminonaphthyridin derivatsInfo
- Publication number
- EP0625152A1 EP0625152A1 EP93901039A EP93901039A EP0625152A1 EP 0625152 A1 EP0625152 A1 EP 0625152A1 EP 93901039 A EP93901039 A EP 93901039A EP 93901039 A EP93901039 A EP 93901039A EP 0625152 A1 EP0625152 A1 EP 0625152A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- product
- racemic
- salt
- preparation
- 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.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- CRADWWWVIYEAFR-UHFFFAOYSA-N 1,8-naphthyridin-2-amine Chemical class C1=CC=NC2=NC(N)=CC=C21 CRADWWWVIYEAFR-UHFFFAOYSA-N 0.000 title claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 7
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- -1 hypnotic Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 4
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- PRYPJBOCKVNGFP-UHFFFAOYSA-N CCC(CCC(C)C1NC(C2=CC=CC=C12)=O)=O Chemical compound CCC(CCC(C)C1NC(C2=CC=CC=C12)=O)=O PRYPJBOCKVNGFP-UHFFFAOYSA-N 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a process for the preparation of a derivative of the racemic 2-amino-naphthyridine of formula:
- the active entity or eutomer is the dextrorotatory isomer.
- the dextrorotatory isomer of the product of formula (II) can also be obtained by cyclization of the dextrorotatory isomer of the product of formula (I) by means of thionyl chloride, optionally operating in the presence of a condensing agent such as imidazole or pyridine in an organic solvent such as methylene chloride.
- a condensing agent such as imidazole or pyridine
- the dextrorotatory isomer of the product of formula (I) can be obtained by resolution of the corresponding racemic by means of a chiral base. To this end, it is particularly advantageous to carry out the succession of the following operations: 1) formation of a salt with a chiral base or a chiral acid,
- the dextrorotatory isomer of the product of formula (I) After displacement of its salt with cinchonine, the dextrorotatory isomer of the product of formula (I), which is mainly found in the filtration mother liquors of the levorotatory salt, is transformed into an insoluble salt with cinchonidine.
- the dextrorotatory isomer of the product of formula (I) is displaced from its salt by means of a strong acid such as hydrochloric acid.
- the product of racemic formula (I) can be obtained by opening the pyrrolidinone ring of a product of racemic formula (H) in basic medium.
- the pyrrolidinone cycle is opened using a mineral base at a temperature between 0 and 50 ° C and, preferably, between 0 and 30 ° C.
- the levorotatory isomer of the product of formula (II) is transformed into a racemic product of formula (I) by the action of a mineral base such as sodium hydroxide in a basic organic solvent such as pyridine at a temperature comprised between 0 and 50 ° C and preferably close to 20 ° C.
- a mineral base such as sodium hydroxide
- a basic organic solvent such as pyridine
- the levorotatory isomer of the product of formula (Et) can be obtained by cyclization of the levorotatory isomer of the product of formula (I) by means of thionyl chloride in the presence of a condensing agent such as imidazole or pyridine by operating in an organic solvent such as methylene chloride.
- the levorotatory isomer of the product of formula (I) can be obtained, for example, from the mother liquors of crystallization of the salt of the dextrorotatory isomer of the product of formula (I) with the (+) - ephedrine.
- the levorotatory isomer of the product of formula (I) is obtained by displacement of its salt according to the usual methods after concentration of the ethanolic mother liquors of crystallization.
- the chiral base used [(-) -é ⁇ hédrine] can also be recovered.
- the suspension obtained is filtered.
- the precipitate is washed with 5 times 525 cm3 of distilled water and then dried under reduced pressure (15 mm of mercury; 2 kPa) for 16 hours at 60 ° C.
- the levorotatory isomer of [(7-chloro-naphthyridine-1,8 yl) -2] -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 can be obtained in the following way:
- the organic phase is concentrated under atmospheric pressure to a volume of approximately 2200 cm3.
- the product obtained is transformed into the levorotatory isomer of [(7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 using thionyl chloride (96.9 g) in the presence of imidazole (222.8 g).
- the chloromethylenic phase (2614 g) is distilled under atmospheric pressure in the presence of 1000 cm3 of ethanol.
- EXAMPLE 3 120 g of salt of ⁇ [(7-chloro-naphthyridin-1,8 yl-2) amino] -2 methyl-6-oxo-3 heptyl ⁇ -2 benzoic acid are dissolved with (+) - ephedrine in 2350 cm3 of methylene chloride. The organic phase is washed with 400 cm3 of 0.5N hydrochloric acid and then 400 cm3 of water. The combined aqueous phases are treated under the conditions of Example 2 to give an ethanolic solution of (+) - ephedrine which is used as it is in a new salification operation.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9114983 | 1991-12-04 | ||
| FR9114983A FR2684673B1 (fr) | 1991-12-04 | 1991-12-04 | Procede de preparation d'un derive de l'amino-2 naphtyridine racemique. |
| PCT/FR1992/001122 WO1993011125A1 (fr) | 1991-12-04 | 1992-12-02 | Procede de preparation d'un derive de l'amino-2 naphtyridine racemique |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0625152A1 true EP0625152A1 (de) | 1994-11-23 |
Family
ID=9419639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93901039A Ceased EP0625152A1 (de) | 1991-12-04 | 1992-12-02 | Verfahren zur herstellung eines racemischen 2-aminonaphthyridin derivats |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0625152A1 (de) |
| JP (1) | JPH07501535A (de) |
| CA (1) | CA2121690A1 (de) |
| FR (1) | FR2684673B1 (de) |
| WO (1) | WO1993011125A1 (de) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU783516B2 (en) | 2001-04-30 | 2005-11-03 | Warner-Lambert Company | Methods, kits and compositions for using pyrrole derivatives |
| IL164377A0 (en) | 2002-03-29 | 2005-12-18 | Indevus Pharmaceuticals Inc | Methods of preparation of the 2-(7-chloro-1,8-naphthyridine-2yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2607503B1 (fr) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | Nouveaux derives de l'isoindolinone, leur preparation et les compositions pharmaceutiques qui les contiennent |
-
1991
- 1991-12-04 FR FR9114983A patent/FR2684673B1/fr not_active Expired - Fee Related
-
1992
- 1992-12-02 WO PCT/FR1992/001122 patent/WO1993011125A1/fr not_active Ceased
- 1992-12-02 CA CA 2121690 patent/CA2121690A1/fr not_active Abandoned
- 1992-12-02 JP JP5509892A patent/JPH07501535A/ja active Pending
- 1992-12-02 EP EP93901039A patent/EP0625152A1/de not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9311125A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2684673A1 (fr) | 1993-06-11 |
| CA2121690A1 (fr) | 1993-06-10 |
| WO1993011125A1 (fr) | 1993-06-10 |
| JPH07501535A (ja) | 1995-02-16 |
| FR2684673B1 (fr) | 1994-01-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19940527 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE |
|
| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: DAVID-COMTE, MARIE-THERESE |
|
| 17Q | First examination report despatched |
Effective date: 19950817 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
| 18R | Application refused |
Effective date: 19960204 |