Tetrahydrofuran → HCID 178481968, compound

HRID 2082781Notes

Reaction equation

HRID 2082781 reaction equation
C(C1[C:4](F)=[CH:5][C:6]2[N:12]=[C:11]([N:13]([CH3:15])[NH2:14])[CH:10](C(C)C)[N:9]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25]CCC)[C:7]=2[CH:29]=1)C.C(N(CC)CC)C.O1CCCC1.[C:43](Cl)(Cl)=[S:44].[CH2:47]([Cl:49])Cl.CO>>[OH-:25].[Cl:49][C:47]1[CH:4]=[CH:5][C:6]2[N:12]3[C:43]([SH:44])=[NH+:14][N:13]([CH3:15])[CH:11]3[CH2:10][N:9]=[C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:7]=2[CH:29]=1

Participants

6

Reactant 5

HCID 8028Tetrahydrofuran2×HCID 8471TriethylamineHCID 10040ThiophosgeneHCID 21226129Dichloromethane methanolHCID 54224656HCID 54224656, compound

Product 1

HCID 178481968HCID 178481968, compound

Procedure

A stirred mixture of 4.48 g. (0.015 mole) of 7-chloro-2-(1-methylhydrazino)-5-phenyl-3H-1,4-benzodiazepine (III), (prepared as in Example 1), 4.68 ml. (0.033 mole) of triethylamine and 60 ml. of tetrahydrofuran is cooled, under nitrogen, in a salt bath, and treated dropwise during about 1 hour and 20 minutes with a solution of 1.26 ml. of thiophosgene in 30 ml. of tetrahydrofuran. The mixture is allowed to warm slowly to room temperature, stand for about 16 hours and heated under reflux for about 70 minutes. The mixture, after cooling, is poured into ice water, the solid collected by filtration, dissolved in chloroform, washed with brine and dried with sodium sulfate. The aqueous filtrate is concentrated under vacuum to remove tetrahydrofuran and then extracted with chloroform. The extract is washed with brine and dried with sodium sulfate. The chloroform solutions are combined and concentrated and the residue chromatographed on 300 g. of silica gel with 2% methanol-98% chloroform. The product thus obtained is recrystallized from a mixture of methylene chloride and methanol to give a first crop weighing 1.33 g. with a melting point of 261.5° to 267° C. (with decomposition) and a second weighing 1.94 g. with a melting point of 258° to about 267° C. (with decomposition) with softening at 245° C. These two samples are apparently different polymorphic crystalline forms since they have different solubility in methylene chloride-methanol, different infrared (ir) (Nujol) absorption spectra but identical ultraviolet (uv) (EtOH) absorption spectra and nuclear magnetic resonance (nmr) (DMSO) spectra. They also show the same empirical formulae by elemental and mass spectral analysis. The second crop is recrystallized twice from methylene chloride-methanol for analysis. The analytical sample of this crop of the product, 8-chloro-1-mercapto-3-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinium hydroxide inner salt (IV), has a melting point of 258° to 262° C. (with decomposition) with softening at 245° C.; uv (EtOH) λmax. 219.5 mμ (ε=46,100), 245 (shoulder 19,150), 260 (sh 11,250), 278 (sh 8250), 310 (sh 4200). The ir, nmr and mass spectra of the compound support its proposed structure.

Workup

  1. additionA stirred mixture of 4.48 g
  2. additiontreated dropwise during about 1 hour and 20 minutes with a solution of 1.26 ml
  3. temperatureheated
  4. temperatureunder reflux for about 70 minutes
  5. temperatureThe mixture, after cooling
  6. filtrationthe solid collected by filtration
  7. dissolutiondissolved in chloroform
  8. washwashed with brine
  9. dry with materialdried with sodium sulfate
  10. concentrationThe aqueous filtrate is concentrated under vacuum
  11. customto remove tetrahydrofuran
  12. extractionextracted with chloroform
  13. washThe extract is washed with brine
  14. dry with materialdried with sodium sulfate
  15. concentrationconcentrated
  16. customthe residue chromatographed on 300 g
  17. customThe product thus obtained
  18. customis recrystallized from a mixture of methylene chloride and methanol
  19. customto give a first crop
  20. customwith softening at 245° C
  21. custom(ir) (Nujol) absorption spectra but identical ultraviolet (uv) (EtOH) absorption spectra and nuclear magnetic resonance (nmr) (DMSO) spectra
  22. customThe second crop is recrystallized twice from methylene chloride-methanol for analysis
  23. customwith softening at 245° C.

Sources & evidence

ORD record
ord-7cbeb095d5cd418b8ceeb109a9b225bd
Source dataset
uspto-grants-1978_04
Patent number
US04082761

Reaction notes

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