Tetrahydrofuran → 21-Desacetoxy-21-Chloro Anecortave

HRID 1111059Notes

Reaction equation

HRID 1111059 reaction equation
[C:1]([C@@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:19](=[CH:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#N.[Cl:24][CH2:25][Si](C)(C)Cl.[Li+].CC([N-]C(C)C)C.C1C[O:41]CC1>CN(C)C1C=CN=CC=1>[Cl:24][CH2:25][C:1](=[O:41])[C@:3]1([OH:23])[C@:4]2([CH3:5])[C@H:6]([C@H:9]3[C:19](=[CH:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:8]1

Participants

6

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 74393Silane, chloro(chloromethyl)dimethyl-HCID 2724682Lithium diisopropylamideHCID 10859900(17alpha)-17-Hydroxy-3-oxoandrosta-4,9(11)-diene-17-carbonitrile

Product 1

HCID 1303765421-Desacetoxy-21-Chloro Anecortave

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

17β-Cyano-17α-hydroxyandrosta-4,9(11)-dien-3-one (I, 3,316 gm) and 4-dimethlaminopyridine (63 mg) are slurried in dry THF (5 ml), treated with TEA (1.9 ml) and immediately cooled in an ice-acetone bath. With rapid stirring chloromethyldimethylchlorosilane (1.54 ml) is added dropwise. After 1 hr, the mixture is allowed to warm to 20°-25° over the course of 2 hrs, giving a mixture containing 17β-cyano-17α-hydroxyandrosta-4,9(11)-dien-3-one 17-(chloromethyl)dimethylsilyl ether (II). This mixture is transferred dropwise (10 min) to a solution of LDA (which is prepared from diisopropyl amine [7.0 ml] and 7-butyllithium-hexanes [1.6 molar, 26.6 ml, 42.6 mmol]) in dry THF (75 ml), stirring rapidly in a dry ice-acetone bath. After stirring 1 hr, the mixture is quenched with aqueous hydrochloric acid (6M, 25 ml), allowing the exotherm to carry the temperature to about 0°. Water (.50 ml) and methanol (~50 ml) are added, and the mixture is allowed to stir vigorously for 20 hrs at 20°-25°. The product is recovered by filtration and washed successively with water and methanol to give the title compound. A second crop is obtained on concentrating the mother liquors.

Workup

  1. temperatureimmediately cooled in an ice-acetone bath
  2. additionis added dropwise
  3. temperatureto warm to 20°-25° over the course of 2 hrs
  4. customgiving a mixture
  5. custom(10 min)
  6. stirringAfter stirring 1 hr
  7. customthe mixture is quenched with aqueous hydrochloric acid (6M, 25 ml)
  8. customto about 0°
  9. additionWater (.50 ml) and methanol (~50 ml) are added
  10. stirringto stir vigorously for 20 hrs at 20°-25°
  11. filtrationThe product is recovered by filtration
  12. washwashed successively with water and methanol

Sources & evidence

ORD record
ord-17d61c5f79934bf0b241813a251cde9f
Source dataset
uspto-grants-1990_12
Patent number
US04977255

Reaction notes

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