JPS5888355A - Manufacture of prostaglandin e - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing l-type 42.3g p-staglandin and 1-smoke 3,4-glostaglandin. More specifically, the present invention is based on the general formulas 11 (11) and (11) shown in the diagram.
ll1m11m prostaglandin GI11, PGM
, and PGM5).

Figure formula Mu0HPG! For specific compounds, see, for example, "Zorostablandin Synthesis" by J.B. Ben1ra and R. Ben1ra.
ynth@sis) J Akajisek Zores (19
77).

In particular, this new process can be used to prepare useful compounds of the type described in US patent application Ser. No. 06/247.455, which is incorporated herein by reference in its entirety. This method reduces the number of steps and provides useful l
It is effective in increasing the yield over previous methods of producing d2,5 and 5,4 norostaglandins. E-series fr staglandin compounds are known to have a variety of therapeutic uses. For example, ``Chemistry, Biochemistry and 7 Armacological Activities'' by E. W. Horton (Oh@
mi@try, Bioahemistry ana
Pharmaeologl--1Muti Mighty o
f Prostanoias) J, Pergamon°
See Dulles (1979).

In particular, the present invention provides a method for producing type 1 12.3 prostaglandin, in which a) a higher trialkylsilyl enol ether of O-9 ketone is produced, and b) this higher trialkylsilyl enol ether is treated with a lithium dialkylamide. and then treated with selenium reagent sr or sulfur, yellow reagent to oxidize the product of a) b) and then +1) o)
Δ2,3 obtained by hydrolyzing the product of i with a weak acid.
Provided is a method for producing type IIl Δ2.5f* staglandin, which is characterized in that it produces f-rostaglandin.

In particular, the present invention provides a method for producing round-type Δ3.4f rostagtendin, t) producing a higher serialkylsilyl enol ether of G-9, b) converting the higher trialkylsilyl enol ether into a lithium dialkyl enol ether. c) treating the product of b) with amide and then treating with a selenium reagent or a sulfur reagent; d) treating the product of a) with lithium dialkylatr; and then... forming (1). IC type Δ5.4f rostaglandin, characterized by treating the product with a proton source and then hydrolyzing the product of f)·) with a weak acid to produce the desired Δ5,4ft2 staglandin. A manufacturing method is also provided.

Higher trialkylsilienol ethers vary depending on the compound being produced. Generally, the process is a competitive reaction with the possibility of proton abstraction from multiple sites, so that there is a wide range of possible end products. The trialkylsilyl enol ether used is
e: It must be something that will protect you from the damage. Generally, there is no formula to determine the relative size based on any fixed factors, however, for example (±)methyl 11 G, 16CRB")-dihydroxy-16-methyl-9-oxofa star 5111
Z, 5 Z.

15m-) In the production of Rienoe F, dimethyl t@
rt-Butylsilyl enol ether works well in the preparation of this metal compound. However, relatively smaller or less branched trialkylsilyl enol ethers do not work. An example of an invalid compound for this example is trimethylcy,! t@rt-butyl) or the linear isomer dimethylbutyl. Therefore, some degree of side chain branching is necessary to achieve the desired result, and the exact degree can be determined from compound to compound.

The general mechanism of the invention as applied to the compounds of U.S. Patent Application No. 067247.455 is shown in Scheme 1 and Scheme 0.
is outlined in.

Figure 2 B 81 (alkyl).

Enter f:,.

The Sl(゛hyl)3 ether compound (formula XI) (wherein R4 is 10-tetrahydrotranyl or 10-silyltrialkyl, Rsb and R3 are hydrogen or alkyl) is a suitable II (II) i! ! salt and then with higher trialkylcurlsilanes in the presence of HMPT. The obtained compound (formula XiI') is
It is then treated with a lithium dialkylamide, such as lithium diisozologylamide or lithium isofa t-cyclohexylamide, followed by treatment with diphenyldiselenide', phenylselenium chloritomer or diphenyldisulfide, preferably diphenyldiselenide. quenched with a selenium or sulfur reagent such as
A compound of formula XIII is obtained.

The compound of formula XIII is then oxidized with, for example, hydrogen peroxide or sodium periodate to give formula XIV
or giving a compound of formula XXI. Compounds of formula XXI can be hydrolyzed with a weak solvent such as acetic acid to form formula X of the present invention.
The compound XII can be provided.

Alternatively, a compound of formula XXII can be treated with a lithium dialkyl aryte and then quenched with a proton source such as a weak acid or alcohol, preferably acetic acid, to provide the compounds of the present invention. Compounds in the plate are hydrolyzed with a weak acid such as acetic acid and heated to 2℃■
can give compounds of The invention will be more fully understood from the following examples. These examples are presented for illustrative purposes only and are not to be construed as limiting the invention in spirit or scope, as many modifications, both in material and method, will be apparent to those skilled in the art from this disclosure. Shouldn't.

Example 1 Me+Lure (3(,X1g)-?)U1:PW-
Ran-2-yloxy-5-oxo-cyclobent-1
-ene) hepto-5z-enoate i+ to 7- (3(
Rs) -human aoxy-5-oxocyclobent-1
-en)hept-52-enoe) 2.88 & p-)luenesulfonic acid 50 in a solution of 55 m of ether
Add Wg and 1.1 g of Jihi PW biran. The reaction mixture was allowed to stand at room temperature for about 24 hours, then diluted with ether, washed successively with a 5% aqueous potassium solution and water, dried over anhydrous sulfuric acid, and then stripped of the solvent under reduced pressure. The IJ cutting O residue is chromatographed on silica sol using 25% ethyl acetate in hexane as diluent to produce the title compound.

Example 2 1l-1-()-n-butylstannyl)-4
-Methyl-4-trimethylsilyloxy-1-octyne 4(R8) -)rifthylsiloxy-4-methyl-1-
Octin 2.121! and 6.0 I of tri-n-butyltin hydride are mixed and then irradiated under alyne with a sun lamp for 2 hours at 0 DEG C. and 2 hours at 55 DEG C. The title compound obtained is used immediately in Example 3.

Example 6 Racemic methyl 7-C3(X-tetrapyranyloxy-2β(4(R8)-4-)dimethylsilyloxy-4-methyl-1E-octenyl)-5-
tart-butyldimethylsilyloxy-cyclobent-1(5)-ene]-1tx-hebut-5z-enoate 11.5N of the title compound of the formula
and then cooled to -60°C under alin.
- Add butyl lithium (1.55 m$ liquid 14.-).

Stir this solution for about 45 minutes.In another flask,
@1-Pentinyl y s, ott and hexamethyl phosphoric acid triamy y 7.4 y were dissolved in ether 30 with stirring.
- dissolves in This solution is then added to the reaction mixture. The resulting mixture was stirred at -60° C. for 10 minutes and then the product from Example 1 (5,7
Add the solution of 1').

The reaction mixture is stirred at -60 DEG C. for about 1 hour and then treated sequentially with hexamethylphosphoric triamide 408j and t@rt-butyldimethylchlorosilane 5II dissolved in ether 10d. The temperature of the reaction mixture is raised to -20°C and then kept at this temperature for about 1 hour. Pour the reaction mixture onto a mixture of 1M HOII and ether. The ether layer is separated, then washed twice with water, filtered, dried over sodium sulfate and stripped. This residue is chromatographed in a 2% ethyl acetate and hexane solvent system to give the pure title product.

Example 4 Racemic °methyl 7-[3α-tetrahyrroviranyloxy-2β-(4(R8)-4-)dimethylsilyloxy-4-methyl-1m-octenyl)-5
-t@rt-Butyldimethylsilyloxycyclobent-1(5)-ene]-1α-to7')-2-phenylselenyl-5z-enoe F of cyclohexyl isozolof amine 550111F in 15 m of dry THF. The solution was heated to about -30℃ under alin.
Cool to 1.55 M n-butyllithium solution 2.
31 d. After stirring at -60°C to -20°C for about 1.5 hours, the solution was cooled to -60°C and then ? i! ? 2. A solution of 2.1 g of the enol ether product from Example 3 in Q-2 is added dropwise.

After the addition is complete, a solution of diphenyldiselenyl r11I in 7HylQm is added dropwise. The reaction mixture is diluted with ether, washed twice with water, dried and strung. The residue is chromatographed in a 2% ethyl acetate and hexane solvent system to yield the desired product.

Example 5 Racemic methyl 7-C3eA-tetrahydrogyranyloxy-2β-(4(us)-4-)dimethylsilyloxy-4-methyl-1m-octenyl)-5
-t@rt-butyldimethylsilyloxy-cyclobent-1(5)-ene]-jg-hezotoh2111 t
A solution of the product 11i from Example 4 in methylene chloride 5011j containing 5z-genoate gin 5ooW9 is treated with a solution of 50% hydrogen peroxide 5I in water 5d, and the two-phase system is then allowed to cool at room temperature. Stir vigorously for about 4 hours. The solution is poured into ether, washed once with 1M salt solution and twice with water, dried over sodium sulfate, and the solvent is stripped. 2 residues
Climadography with % ethyl acetate and hexane solvent system affords the title product.

Example 6 Racemic methyl 7-(5''--tetrahuman-giranyloxy-2β-(4(Rs)-4-trimethylsilyloxy-4-methyl-1m-octeny/I/)
-5-t@rt-dityldimethylsilyloxy-cyclobent-1(5)-entoo 1α-hegtor 3KZ
, 5 Z-genoate cyclohexyl isofoviramine 165 ~ and dry TH? The solution of 4 txt is cooled to -50° C. under alyne and then treated with 75 m of 1.55 M n-butyllithium solution Q.

The solution is stirred for 1 hour at about -30°C to -20°C and then cooled to -60°C. THIP j l1
A solution of 250 μl of hexamethylphosphoric acid trioxide in 1J is added.

Product 6301 from Example 5 in Dry Bone H] F61117
1 g of solution is added dropwise over the course of 1 hour. After the addition is complete, 901ag of acetic acid'! 'Add HF solution (117). The reaction mixture is poured into ether and water. The organic layer is washed with water, dried over sodium sulfate and strung. This residue is used immediately in Example 7.

Example 7 (±)Methyl 11α, 16CRB)-·-dihydroxy-16-methyA/-9-oxo7'w star 3KZ, 5Z, 13]! X-)Lienoate The product from Example 6 (630) was treated with acetic acid, water and TH
Dissolve in a 3:1:1U compound of F by stirring. Continue stirring until the mixture is homogeneous. The solution is then left at room temperature for 24 to 48 hours. The solution is diluted with ether, washed four times with water, dried over sodium sulfate and then slitted to remove the solvent.

Dissolve this residue in 70% vinegar ethyl and 50% hexane. The title compound is obtained by performing a togelaf treatment.

Example 8 In Example 6, a higher molecular weight F-alkylsilyl chloride can be substituted and the product is passed through Examples 4 through 7 to give the title product of Example 7.

Example 9 The method of Example 2 but 1 Example 7 is used to provide the title compound of Example 7, except that triethylsilyl groups in positions 0-11 are used in place of the tetrahydrogyrael group.

Oxy-16-methyl-9-oxogloster 2'
m -5Z t 15 ''-trieno'ate The title product of Example 5 is substituted in the method of Example 7 to provide the title compound.

Agent Asamura Hao 4 other people

Claims (1)

[Claims] (lla) producing a higher trialkylsilyl enol ether of O-9 ketone; b) treating the higher trialkylsilyl enol ether with a lithium dialkylamide and then with a selenium reagent or a sulfur reagent; , c) forming the product of b) and then a) hydrolyzing the product of a) with a weak acid to give the desired Δ2,5
Il, characterized in that it produces f*staglandin.
Method for producing lΔ2.5f Sodium Stadalandin. (21a) Preparing a high M) trialkylsilyl enol ether and b) treating the high M) realkylsilyl enol ether with a lithium dialkylamide followed by a selenium reagent and a sulfur reagent. a) melting the product of b), a) treating the product of O) with a lithium dialkylamide, e) treating the product of a) with a proton source, and then f) the product of A method for producing type I Δ3,4f rostaglandin, which comprises hydrolyzing it with a weak acid to produce a desired Δ5.4f rostaglandin. (3) (±) Methyl 11a, 16(Re)-dihydroxy-16-methyl-9-oxozoroster 5N
Z. 5z, 13m-trienony).