Process for the preparation of prostaglandins

Details Process for the preparation of prostaglandins Process for the preparation of prostaglandins

1999-05-14

2001-11-06

Gerstl, Robert (Department: 1613)

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

Organic compounds

Carboxylic acid esters

C562S503000

Reexamination Certificate

active

06313341

ABSTRACT:

TECHNICAL FIELD
The invention relates to a process for preparing prostaglandins having a broad physiological activity and intermediates thereof, easily, efficiently and industrially favorably.
BACKGROUND ART
Natural prostaglandins have a unique structure and are known as compounds showing a broad physiological activity in a small amount, attracting interest of many organic synthetic chemists, and it is desired to purely synthesize natural prostaglandins in which there is a difficulty for naturally obtaining them in a large amount in order to further study a minute biological activity, and furthermore a lot of synthetic work has been done from such reasons that a lot of structural analogues from natural prostaglandins can be synthesized and these prostaglandin analogues are interesting from the aspect of a drug development.
As one of the representative preparation processes of prostaglandins there is the process in which the omega side chain is introduced by affecting an organometallic reagent to an &agr;, &bgr;-unsaturated cyclopentenone. Especially is well known such a process that a vinylstannane compound having an aimed omega side chain structure or its corresponding vinyliodide compound are converted to the vinylcopper complex to carry out the conjugate addition to the &agr;, &bgr;-unsaturated cyclopentenone [U.S. Pat. No. 4,777,275 (JP, A, S63-316786), U.S. Pat. No. 4,543,421 (JP, B, S63-44743)]. Typically, a vinylstannane compound is prepared by affecting tin hydride under a radical condition after the addition of an acid unstable protective group such as a trialkylsilyl group to a free hydroxyl group which a terminal alkyne of a starting material has [U.S. Pat. No. 4,087,447 (JP, A, S53-108929)]. The conversion to the vinyliodide is done by treating the vinylstannane compound with iodine. An alkylmetal reagent is reacted with the obtained vinylstannane compound or its corresponding vinyliodide compound to give a vinylmetal compound, and subsequently a cuprous (I) salt is added to give a vinylcopper complex. Thereto is added an &agr;, &bgr;-unsaturated cyclopentenone to give the 1,4-conjugate addition product. Since one more step is necessary to obtain a vinyliodide compound from a vinylstannane compound and there is no difference between the vinylstannane compound and the vinyliodide compound, there is no special advantage to derivatize it into the vinyliodide compound. Therefore, a vinylmetal compound via a vinylstannane compound is advantageous, though there is an unfavorable problem that a geometrical isomer accompanies in case of preparing the vinylstannane compound by the above process.
DISCLOSURE OF THE INVENTION
There are characteristics that natural type prostaglandins and many prostaglandin analogues have a double bond at 13, 14 positions and its geometrical configuration is (E)-configuration, though (E)-vinylstannane compound having an aimed omega side chain structure is necessary to construct this characteristic geometry. In the conventional preparation process of a vinylstannane compound, that is, the process of reacting a tin hydride compound with hydroxy-1-alkynes after protecting the hydroxy group thereof, (Z)-vinylstannane compound which is the geometrical isomer, is accompanied in ca. 20% (U.S. Pat. No. 4,543,421 (JP, B, S63-44743), and furthermore, the separation of the obtained (E)-and (Z)-vinylstannane compounds is extremely difficult even by the separation procedures by silica gel chromatography or rectification. Therefore, in the conventional process, it is used by the isolation even in an extremely low yield or the mixture of the geometrical isomers is used “in situ”. In the latter case an undesirable geometrical isomer is inevitably coexisting in conjugate addition products after the reaction, and furthermore, the separation of the obtained (13E)-product and its geometrical isomer, (13Z)-product, by silica gel chromatography is extremely difficult, resulting in a low yield.
Further, the introduction of a protecting group to hydroxy-1-alkynes influences the yield of the deprotecting step to give prostaglandins finally. For the deprotecting reagent, an aqueous acid solution is used, though due to the instability of prostaglandins to acid, the reaction condition to use less amount of acid is favorable.
As a process to solve the geometrical problem, a selective process for the (E)-substance synthesis, which uses a zirconium compound, has been developed (B. H. Lipshutz et al., J. Am. Chem. Soc., 112, 7440, 1990). Namely, the (E)-alkenylziruconium intermediate was produced by the terminal alkyne compound constituting the omega side chain and the zirconocene reagent, and reacted with alkyllithium and the copper reagent to give the cuprate intermediate with which the &agr;, &bgr;-unsaturated cyclopentenone was reacted to synthesize the prostaglandin intermediate. However, the zirconocene reagent is expensive, and also difficult to obtain in a large amount. Further, the production step of the terminal alkyne compound also includes a protection step for the hydroxyl group, which is also unfavorable for industrially producing prostaglandins.
As a process to solve the problem of the geometrical isomer without protection of the hydroxyl group in an omega side chain compound, there is a process developed by J. R. Behling et al., starting from (E)-bis(tributylstannyl)ethylene (Tetrahedron Letters, 30, 27, 1989, U.S. Pat. No. 5,075,478). This preparation process carries out the synthesis of the prostaglandin intermediate, wherein lithium 2-thienylcyanocuprate separately prepared is reacted with (E)-bis(tributylstannyl)ethylene to give vinylstannanylcuprate, reacted with epoxides, aldehydes or ketones to give “in situ” alkoxyvinylstannanes corresponding to an omega side chain, further added with the alkyllithium reagent to give the vinyllithium complex, here at added with the organocopper reagent separately prepared, followed by the reaction with the &agr;, &bgr;-unsaturated cyclopentenone. By this method one pot synthesis of the prostaglandin intermediate can be attained, though the starting (E)-bis(tributylstannyl)ethylene must be produced via 2 steps described in the following. Namely, the process is that acetylene is converted to lithium acetylide, subsequently reacted with tributyltin chloride to give tributylethynylstannane with which tributyltin hydride is reacted to give (E)-bis(tributylstannyl)ethylene (J. Org. Chem., 46, 5221, 1981). A series of reaction procedures in the preparation process of the prostaglandin intermediate are fairly complex and the stable preparation with reproducibility starting from the above (E)-bis(tributylstannyl)ethylene can not expected even with a considerable technique. Further, the yield is a level of 30-68% and is not satisfactory. Thus it can not be said that this process is a favorably industrial process.
Therefore, the problem to be solved by the invention is to provide a process preparing prostaglandins and intermediates thereof, simply, efficiently and industrially advantageously.
As the result of making an extensive research to overcome these problems, the inventors found the process by which prostaglandins are prepared industrially advantageously by the process shown in the synthetic route (I).
Namely, hydroxy-1-alkyne shown by the formula (II) is reacted with the tin hydride to give (E,Z)-hydroxyvinylstannanes of the formula (IV) which are subsequently separated by silica gel chromatography to give the (E)-hydroxyvinylstannane of the formula (V). Subsequently, the tin part of the (E)-hydroxyvinylstannane and hydrogen of the hydroxyl group are respectively converted to the reactive copper part and lithium to give a vinylcopper complex of the formula (VI), followed by the 1,4-conjugate addition reaction with an &agr;, &bgr;-unsaturated cyclopentenone of the formula (VII) to give a prostaglandin intermediate of the formula (VIII) It is aprocess for preparing a prostaglandin of the formula (I) finally via the deprotection process with acid.
In the preparation process of prostaglandins by the above

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