Dichloromethane → Tigecycline Hydrochloride

HRID 1893150Notes

Reaction equation

HRID 1893150 reaction equation
[OH-].[Na+].[CH3:3][C:4]([NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([N:42]([CH3:44])[CH3:43])[C:15]2[CH2:27][C@@H:26]3[C:21](=[C:22]([OH:41])[C@:23]4([OH:40])[C:31](=[O:32])[C:30]([C:33]([NH2:35])=[O:34])=[C:29]([OH:36])[C@@H:28]([N:37]([CH3:39])[CH3:38])[C@@H:24]4[CH2:25]3)[C:19](=[O:20])[C:16]=2[C:17]=1[OH:18])=[O:10])([CH3:6])[CH3:5].C(Cl)[Cl:46]>>[CH3:6][C:4]([NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([N:42]([CH3:44])[CH3:43])[C:15]2[CH2:27][C@@H:26]3[C:21](=[C:19]([OH:20])[C:16]=2[C:17]=1[OH:18])[C:22](=[O:41])[C@@:23]1([OH:40])[C@H:24]([C@H:28]([N:37]([CH3:38])[CH3:39])[C:29]([C:30]([C:33]([NH2:35])=[O:34])=[C:31]1[OH:32])=[O:36])[CH2:25]3)=[O:10])([CH3:3])[CH3:5].[ClH:46]

Participants

4

Reactant 3

HCID 6344Dichloromethane3×HCID 14798Sodium HydroxideHCID 178482955HCID 178482955, compound

Product 1

HCID 54749425Tigecycline Hydrochloride

Procedure

The collected main pool was transferred into a 2 L Schmizo double coated reactor before, 488 mL methylene chloride were added. A pH of 8.0±0.1 was adjusted by the addition of 10 mL 20% aqueous sodium hydroxide while vigorously stirring. After stirring for 10 minutes the two phases were separated. The aqueous phase was washed two times with 488 mL methylene chloride, whereas the pH was held at 8.0±0.1 by the addition of either 0.1 M sodium hydroxide or 0.2 M hydrochloric acid. The obtained aqueous phase was thrown away. The collected methylene chloride phases were filtered over a fluted filter before the volume was reduced to 500 ml on the rotavapor (50-55° C., 500 mbar). Then 500 ml acetonitrile were added and the solution was again reduced to a volume of 230 ml. The solution is transferred into a 2 l Schmizo double coated reactor and 845 ml acetonitrile are added to obtain a total volume of 1075 ml. The solution was adjusted to a methylene chloride amount of 5% by the addition of approximately 20 ml methylene chloride. 0.2 g Tigecycline dihydrochloride (e.g. obtained from example 1) were added as seed crystals and Tigecycline crystallized at room temperature before 7.8 ml 5 M hydrochloric acid in 50 ml acetonitrile were added over a period of 15 to 20 minutes. The suspension was stirred for 16 hours at 20 to 25° C. whereas a change in color from yellow to orange was observed. To complete the crystallization the suspension was further stirred for 1 hour at 0 to 5° C. The solid was filtered off, washed with 80 ml of cold acetonitrile and dried under vacuum at room temperature for 16 hours to obtain 14 g of crystalline Tigecycline hydrochloride form C.

Workup

  1. additionwere added
  2. stirringAfter stirring for 10 minutes the two phases
  3. customwere separated
  4. washThe aqueous phase was washed two times with 488 mL methylene chloride
  5. additionwhereas the pH was held at 8.0±0.1 by the addition of either 0.1 M sodium hydroxide or 0.2 M hydrochloric acid
  6. filtrationThe collected methylene chloride phases were filtered over
  7. filtrationa fluted filter before the volume
  8. customwas reduced to 500 ml on the rotavapor (50-55° C., 500 mbar)
  9. additionThen 500 ml acetonitrile were added
  10. additionare added
  11. customto obtain a total volume of 1075 ml
  12. customcrystallized at room temperature before 7.8 ml 5 M hydrochloric acid in 50 ml acetonitrile
  13. additionwere added over a period of 15 to 20 minutes
  14. stirringThe suspension was stirred for 16 hours at 20 to 25° C. whereas a change in color from yellow
  15. customthe crystallization the suspension
  16. stirringwas further stirred for 1 hour at 0 to 5° C
  17. filtrationThe solid was filtered off
  18. washwashed with 80 ml of cold acetonitrile
  19. customdried under vacuum at room temperature for 16 hours

Sources & evidence

ORD record
ord-b3ee99a7ea3d4141b2e7490ceb92e88d
Source dataset
uspto-grants-2013_08
Patent number
US08513224B2

Reaction notes

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