Hydrochloric Acid → Alvespimycin hydrochloride

HRID 2180912Notes

Reaction equation

HRID 2180912 reaction equation
[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>C(Cl)Cl.O1CCOCC1>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[ClH:47]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 66053N,N-DimethylethylenediamineHCID 5288382Geldanamycin

Product 1

HCID 9852573Alvespimycin hydrochlorideYield 82%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

A mixture of geldanamycin (15 g, 26.75 mmol) (SAIC-Frederick, Lot No. 3155-28-1) and N,N-dimethyl-ethylenediamine (15 mL, 37.83 mmol) (Aldrich, Lot No. HN04216AL) in dry methylene chloride (300 mL) (Mallinckrodt, Lot No. 4881KVJP) was stirred at room temperature for 1 hour and subsequently poured into ice water (500 mL). After the organic layer and aqueous layer became visually separated, the aqueous layer was extracted with methylene chloride (2×100 mL). The combined methylene chloride solution was washed with water (2×100 mL), dried with MgSO4 (Spectrum, Lot No. HJ302), and evaporated in a diaphragm pump. The remaining residue (16.5 g, 26.75 mmol) was dissolved in methylene chloride (130 mL). Dissolved hydrogen chloride (1.1 eq, 29.43 mmol) (Matheson, Lot No. T410242) in dioxane (Aldrich, Lot No. 16619CQ) was added to the solution resulting in immediate precipitation. After stirring for 30 minutes, the solids were collected, rinsed with methylene chloride (50 mL), and air-dried for 18 hours to give the crude hydrochloride salt (17.2 g). A solution of the crude product (17.2 g) in aqueous alcohol (50% v/v, 200 mL) (Aaper Alcohol, Lot. No. 97A28UARAT) was heated to reflux, filtered, and allowed to cool for 30 minutes. After cooling on ice for an additional 30 minutes, the solids were collected, washed with cold anhydrous alcohol (50 mL), and air-dried for 1 hour. The product was dried further at 70° C./0.1 mmHg for 17 hours to give pure target compound. Approximately 13.4 g of 17-Demethoxy-17-[[2(dimethylamino)ethyl]amino]geldanamycin hydrochloride (82%) was isolated as a violet crystalline solid and used in Examples 1 and 2.

Workup

  1. customAfter the organic layer and aqueous layer became visually separated
  2. extractionthe aqueous layer was extracted with methylene chloride (2×100 mL)
  3. washThe combined methylene chloride solution was washed with water (2×100 mL)
  4. dry with materialdried with MgSO4 (Spectrum, Lot No. HJ302)
  5. customevaporated in a diaphragm pump
  6. customresulting in immediate precipitation
  7. stirringAfter stirring for 30 minutes
  8. customthe solids were collected
  9. washrinsed with methylene chloride (50 mL)
  10. customair-dried for 18 hours
  11. customto give the crude hydrochloride salt (17.2 g)
  12. temperature97A28UARAT) was heated
  13. temperatureto reflux
  14. filtrationfiltered
  15. temperatureto cool for 30 minutes
  16. temperatureAfter cooling on ice for an additional 30 minutes
  17. customthe solids were collected
  18. washwashed with cold anhydrous alcohol (50 mL)
  19. customair-dried for 1 hour
  20. customThe product was dried further at 70° C./0.1 mmHg for 17 hours
  21. customto give pure target compound

Sources & evidence

ORD record
ord-5175b38d39ad4b96ae85d1496b9abd59
Source dataset
uspto-grants-2005_05
Patent number
US06890917B2

Reaction notes

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