Sodium hydride → 6-(5-Chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl 4-methylpiperazine-1-carboxylate

HRID 1604965Notes

Reaction equation

HRID 1604965 reaction equation
[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:16]([OH:17])[C:15]3[S:18][CH2:19][CH2:20][S:21][C:14]=3[C:13]1=[O:22])=[N:7]2.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27]>CN(C)C=O.CS(O)(=O)=O.C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:13]([O:22][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])[C:14]3[S:21][CH2:20][CH2:19][S:18][C:15]=3[C:16]1=[O:17])=[N:7]2

Participants

8

Reactant 3

HCID 24758Sodium hydrideHCID 30169354-Methyl-1-piperazinecarbonyl chlorideHCID 21527040HCID 21527040, compound

Product 1

HCID 1038386-(5-Chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl 4-methylpiperazine-1-carboxylateYield 49.5%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 6395Methanesulfonic AcidSolvent

Conditions

Temperature
5 °C

Procedure

6-(5-Chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (11.9 g.) is added, at 0° C., to a suspension of sodium hydride (1.2 g.) in anhydrous dimethylformamide (120 cc.). The reaction mixture is stirred for 1 hour at 5° C., and 1-chlorocarbonyl-4-methylpiperazine (16.6 g.) dissolved in anhydrous dimethylformamide (80 cc.) is then added. After stirring for 21/2 hours at 5° C., the crystals which have appeared are filtered off and washed twice with diethyl ether (60 cc.). The product thus isolated is dissolved in an ice-cold 2N aqueous solution of methanesulphonic acid (200 cc.). The aqueous acid solution is washed with diethyl ether (80 cc.), and rendered alkaline by adding an excess of 10N sodium hydroxide solution. The oil which separates out is extracted twice with methylene chloride (total 400 cc.). The organic solution is washed three times with distilled water (total 240 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. The crystals obtained (10.1 g.), m.p. 238° C., are dissolved in a boiling mixture of acetonitrile (200 cc.) and methylene chloride (180 cc.). After distilling off the methylene chloride and then cooling the residue for 1 hour at 2° C., the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 40 cc.) and dried under reduced pressure (20 mm. Hg). 6-(5-Chloro-1,8-naphthyridin-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.0 g.), melting at 240° C., is thus obtained.

Workup

  1. additionis then added
  2. stirringAfter stirring for 21/2 hours at 5° C.
  3. filtrationthe crystals which have appeared are filtered off
  4. washwashed twice with diethyl ether (60 cc.)
  5. customThe product thus isolated
  6. washThe aqueous acid solution is washed with diethyl ether (80 cc.)
  7. additionby adding an excess of 10N sodium hydroxide solution
  8. extractionThe oil which separates out is extracted twice with methylene chloride (total 400 cc.)
  9. washThe organic solution is washed three times with distilled water (total 240 cc.)
  10. dry with materialdried over anhydrous sodium sulphate
  11. additiontreated with decolourising charcoal (0.2 g.)
  12. customevaporated
  13. customThe crystals obtained (10.1 g.), m.p. 238° C.
  14. distillationAfter distilling off the methylene chloride
  15. temperaturecooling the residue for 1 hour at 2° C.
  16. filtrationthe crystals which have appeared are filtered off
  17. washwashed twice with ice-cold acetonitrile (total 40 cc.)
  18. customdried under reduced pressure (20 mm. Hg)

Sources & evidence

ORD record
ord-3d3f1f0db5d3498789c17b03eafd4e6a
Source dataset
uspto-grants-1976_04
Patent number
US03948917

Reaction notes

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