Process for the synthesis of propargyl alcohols and their use fo

Details Process for the synthesis of propargyl alcohols and their use fo Process for the synthesis of propargyl alcohols and their use fo

1992-09-29

1994-12-20

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549311, 549312, C07D30793

Patent

active

053747453

DESCRIPTION:

BRIEF SUMMARY
In the synthesis of prostaglandin analogs with a triple bond in position 13.14 (prostane numbering system), as they are described, for example, in EP 0284547, DE 3610556, DE 3725031, DE 3428266, DE 3427797, U.S. Pat. No. 4,628,110, the triple bond is introduced only in a relatively late synthesis stage with comparatively moderate yields. It has now surprisingly been found that starting from compounds of general formula II, the triple bond can be generated in very good yields under mild conditions by elimination of hydrobromic acid with anhydrous cesium acetate and 18-crown 6 already in an early synthesis stage.
The new process thus represents a valuable enrichment synthetic methodology.
The invention thus relates to a process for the production of prostaglandin precursors of formula I ##STR5## as well as their enantiomers in which X is A--W or W--A, modified by etherification or esterification, each or a ##STR6## group, n is 1 to 3, and R.sub.4 each meaning a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, modified as in W, which is characterized in that vinyl bromides of formula II ##STR7## in which Z means the group ##STR8## and R.sub.1, W, D, E and R.sub.2 have the above-indicated meanings and hydroxy groups unprotected in R.sub.1 and W or represented by an optionally substituted benzoyl radical, a C.sub.1 -C.sub.6 alkanoyl group, a tetrahydropyranyl radical, a tetrahydrofuranyl radical, a trialkylsilyl group or a diphenylalkylsilyl group each with alkyl meaning a C.sub.1 -C.sub.4 alkyl, are reacted with anhydrous cesium acetate in the presence of 18-crown 6.


Examples



EXAMPLE 1
-3-hydroxy-4-methyl-nona-1,6-diinyl]-2-oxabicyclo[3.3.0]octan-3-one: ##STR9##
500 mg (1.35 mmol) of (1S,5R,6S,7R)-7-hydroxy-6-[(E)-(3S,4S)-2 -bromo-3 -hydroxy-4 -methyl-1-nonen-6-inyl]-2-oxabicyclo[3.3.0]octan-3-one (for preparation see EP0284547) is dissolved in 40 ml of anhydrous toluene, mixed with 840 mg of anhydrous cesium acetate, 1.0 g of 18-crown 6 and the colorless, heterogeneous mixture is refluxed for 9 hours under an atmosphere of dry argon. After the cooling, it is concentrated by evaporation to about 20 ml and the mixture is purified by chromatography on about 100 ml of fine silica gel with ethyl acetate under pressure. 386 mg (1.33 mmol, 98%) of the title compound is isolated as colorless oil.
IR (Film): 3700-3100, 2970, 2920, 2230, 1755, 1450, 1415, 1370, 1320, 1200, 1085, 1025, 980 and 900 cm.sup.-1.


EXAMPLE 2
-oxabicyclo[3.3.0]octan-3-one: ##STR10##
1.56 g (3.30 mmol) of (1S,5R,6S,7R)-7-benzoyloxy-6-[(E)-(3R,4S) -2-bromo-3-hydroxy-4-methyl-1-nonen-6-inyl]-2 -oxabicylo[3.3.0]octan-3-one (for preparation see EP0284547) is reacted analogously to example 1 and after chromatographic purification, 1.15 g (2.73 mmol, 83%) of the title compound is isolated as colorless oil.
IR (Film): 3700-3100, 3060, 2970, 2920, 2870, 2230, 1770, 1715, 1600, 1450, 1365, 1315, 1270, 1180, 1110, 1070, 1030, 980, 900, 735 and 710 cm.sup.-1. (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-Bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7 -hydroxy-2-oxa-bicyclo[3.3.0]octan-3-one
3.12 g of (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7 -benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-one was dissolved in 18 ml of reagent-grade methanol, mixed with 290 mg of finely powdered potassium carbonate and allowed to stir for 3 hours at 25.degree. C. By adding a 50% hydrochloric acid, it was adjusted to pH 7 and concentrated by evaporation at 30.degree. C. in a water jet vacuum. The residue was taken up in methylene chloride, filtered on magnesium sulfate and Celite, again concentrated by evaporation in a water jet vacuum and chromatographed under pressure on about 200 ml of fine silica gel by using a gradient of hexane/ethyl acetate. 2.00 g (82%) of the title compound was isolated as colorless oil.
IR (film): 3400, 2950, 2910, 1755, 1640, 1440, 1415, 1340, 1300, 1180, 1075, 1030, 968, 905 cm .sup.-1. benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-one
16.7 g of (1S,5R,6R,7R)-6-[(E)-(4S)-2-brom-3-oxo-4-methyl-non-1-en-6-inyl]-7-benzoyl oxy-2-oxa-bicyclo[

REFERENCES:
T. Torisawa et al., "Efficient Inversion of Secondary Alcohols Using Cesium Acetate and 18-Crown-6", Chemistry Letters, pp. 1555-1556, 1984.
E. Dehmlow et al. "Darstellung von Alkinen aus Alkylhalogeniden mit festem Kalium-tert-butylat und Kronenether" Liebigs Annalen der Chemie, vol. 1-174, No. 1, Jan. 1980, pp. 1-13.

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