Process for production of prostaglandin intermediates

Details Process for production of prostaglandin intermediates Process for production of prostaglandin intermediates

1990-03-01

1992-01-07

Fan, Jane T.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D307935

Patent

active

050793713

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention is a process for the condensation of a bicyclic lactone containing an aldehyde function at what is known as the C.sub.12 position of a prostaglandin (I), with a .beta.-ketophosphonate (II) to form a known ketolactone (III) which is a useful intermediate in the synthesis of prostaglandins.
2. Description of the Related Art
The aldehyde lactone (I) containing the aldehyde function at what is known as the C.sub.12 position of a prostaglandin is well known to those skilled in the art. It is known as the "Corey Aldehyde".
Reaction of the (protected) Corey aldehyde with a ketophosphonate anion, producing a prostaglandin intermediate, is what is known as the Emmons reaction. This reaction is well known, see U.S. Pat. Nos. 4,210,669, 4,212,811, 4,191,823 and 4,321,275. These patents report yields of 13.4, 14.7, 44, about 60, 64 and 90%.
The Corey Aldehyde is known to be quite unstable, eliminating to the enal, see J. Am. Chem. Soc., 96, 5855 (1974) and Tet. Letters, 3275 (1976) particularly under basic conditions (potassium carbonate/methanol), see Tet. Letters, 1319 (1973). This elimination reaction is what is generally responsible for the poor yields of the Emmons reaction.
It would be highly desireable to be able to react the Corey aldehyde (I) with the appropriate reagent in a Wittig Reaction to produce the desired side chain at C.sub.12 in the .beta. configuration. The problem is that the Corey Aldehyde (I) gives substantial elimination; 10-50%, to the enal under standard conditions.
The use of lithium chloride and an amine in a Horner-Wadsworth-Emmons reaction involving base sensitive readily epimerizable aldehydes is known, see Tet. Letters, 25, 2183 (1984). The addition of the aldehyde to a premixed phosphonate-lithium chloride-amine mixture is disclosed. While the aldehydes were known to be readily epimerizable, they differ from the aldehydes of the present invention in that the aldehyde lactones (I) do not epimerize in base but rather eliminate to the enal. The fact that readily epimerizable aldehydes did not epimerize is no indication that readily eliminatable aldehydes would not eliminate. The fact that epimerizable aldehydes did not epimerize only demonstrates that the bases involved (trialkylamines) are not basic enough to deprotonate (enolize) a carbonyl compound; the pK.sub.a of the conjugate acid was greater than approximately 16 to 18. As explained in "Advanced Organic Chemistry--Part A" second edition, by F. A. Corey and R. J. Sundberg in Chapter 6, there is a "continuum of mechanistic possibilities" for the elimination reaction ranging from an Elcb type with initial deprotonation followed by loss of the leaving group, which would require a strong base, to an E1 type with initial ionization of the leaving group followed by proton loss in which "the base plays no role in the rate determining step". For elimination reactions one must consider both the base and the leaving group; use of a non-epimerizing base for the Wittig reaction does not guarantee elimination will be prevented in a system prone to elimination (a system with a good leaving group). In fact, if the Wittig reaction is greatly slowed by use of too weak a base so that the elimination prone aldehyde is not rapidly converted but exposed to the basic system, elimination may actually be promoted.
The use of triethylamine as the amine in the Horner-Wadsworth-Emmons reactions using simple, stable aldehydes was disclosed in J. Org. Chem., 50, 2624 (1985).
The reaction of a more complex aldehyde and a phosphonate in the presence of lithium chloride and DBU provides the enone product in only 35-60% yield with recovery of 35-50% aldehyde, see J. Am. Chem. Soc., 107, 3731 (1985).
It has been discovered that if the appropriate .beta.-ketophosphonate (II) to produce the desired ketolactone (III) is contacted with a lithium or magnesium salt, a trialkylamine and the aldehyde lactone (I), the ketolactone is produced in excellent yields.


SUMMARY OF INVENTION

Disclosed is

REFERENCES:
patent: 4013695 (1977-03-01), Lin

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