Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Patent
1987-08-07
1989-02-21
Shaver, Paul F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
568426, C07F 708, C07F 718
Patent
active
048066680
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the production of 9beta-chloroprostaglandins,
9beta-Chloroprostaglandins are described in the following publications:
1. Chem., Biochem., Pharmacol. Act. Prostanoids, Incl. Proc. Symp. 1978 (Pub. 1979) 39-60, see also Chemical Abstracts 91, 107690 f
2. Prostaglandins 16, 47-65 (1978), see also Chemical Abstracts 89, 146467 s
3. J. Am. Chem. Soc. 99, 7738 (1977)
4. Advances in Prostaglandin, Thromboxane and Leukotriene Research 14, 274 (1985)
5. European Patent Specification No. 0 030 377.
Generally 9-chloroprostaglandins are produced from the corresponding 9-hydroxy compounds or the corresponding 9-sulfonic acid esters by reaction with a chlorocompound. In this case, mixtures always occur of the desired 9-chloroprostaglandin derivative and the .DELTA..sup.8,9 or .DELTA..sup.9,10 olefins, which so far in some cases could be separated only with great expense.
These experimental difficulties can be circumvented by starting with a crystal-clear product which already contains chlorine and which starting from easily available initial materials can be produced without difficulties.
9-Chloroprostaglandins are valuable drugs (see loc. cit. 1 and 5). With Nocloprost (1) in the case of test subjects stomach mucous membrane damages, as they are caused by nonsteroid anti-inflammatory agents, can be prevented or at least greatly diminished.
The invention serves for the simplified production of important active substances. The process according to the invention is to be explained more in detail by the production of Nocloprost. For a man of the art it is possible on the basis of this invention to produce an abundance of other 9-chloroprostaglandins. ##STR3##
The invention includes the production of the intermediate product of formula II for the production of 9-chloroprostaglandins.
Thus, the invention relates to a process for the production of (5-chloro-3-hydroxycyclopenyl)acetaldehydes of formula II ##STR4## in which R signifies a benzyl radical, a tertbutyldimethylsilyl radical or a tert-butyldiphenylsilyl radical, characterized in that a compound of formula I ##STR5## in which R has the meanings already mentioned, is reduced in the presence of a reduction agent, preferably diisobutylaluminum hydride.
The reduction is performed in hydrocarbons, preferably toluene, at temperatures between -120.degree. C. and -20.degree. C., preferably at -70.degree. C.
For conversion of the compounds of formula II into 9beta-chloroprostaglandins the hydroxy group in II is protected by reaction with dihydropyran as tetrahydropyranyl ether III. This is followed by a cleavage of protection group R to IV. For the case of R=benzyl, the cleavage is performed under hydrogenolytic conditions with hydrogen in the presence of palladium catalysts. For the case of R=tert-butyldimethylsilyl or tert-butyldiphenylsilyl the cleavage is performed with tetrabutylammonium fluoride, with the operation preferably being performed at -20.degree. C. to avoid the elimination of hydrogen chloride. ##STR6## The compound IV is reacted with the ylene from 4-carboxybutyltriphenylphosphonium bromide to compound V, from which methyl ester VI is obtained with diazomethane. Then oxidation is performed with Collins reagent or according to the Swern method to aldehyde VII, which by reaction with the anion from 3,3-dimethyl-2-oxoheptane phosphonic acid dimethyl ester is converted into unsaturated ketone VIII. But at this point any other substituted or unsubstituted 2-oxo-alkyl or 2-oxo-aralkyl phosphonic acid ester can be used, so that an abundance of 9beta-chloroprostaglandins with modified lower side chain becomes available. ##STR7##
EXAMPLE 1
(.+-.)-(1R,2S,3R,5R)-(benzyloxymethyl-5-chloro-3-hydroxycyclopentyl)acetald
ehyde (II, R.dbd.CH.sub.2 C.sub.6 H.sub.5)
1 g of (.+-.)-8-anti-benzyloxymethyl-6-oxo-chloro-3-oxo-2-oxabicyclo[3.2.1]octane (I, R.dbd.CH.sub.2 C.sub.6 H.sub.5) is dissolved in 20 ml of toluene and mixed drop by drop at -78.degree. C. with 5.9 ml of a 1.2M solution of diisobutylaluminum hydride in toluene. It is
REFERENCES:
patent: 4039563 (1977-08-01), Tanaka et al.
patent: 4703127 (1987-10-01), Rickards et al.
Raduechel Bernd
Skuballa Werner
Vorbrueggen Helmut
Schering Aktiengesellschaft
Shaver Paul F.
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