JPS5946946B2 - Method for producing cyclopentanone derivative compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing 11-hydroxy and 11-deoxy-9-keto (or hydroxy) prostanoic acid derivatives useful as bronchodilators, hypotensive agents or anti-ulcer agents. This invention relates to a method for producing a novel intermediate compound.

This new intermediate compound converts the compound prepared by the following formula into the following formula: (C6H5)3P=CH-(CH2)PCOO-M+(
Here, p is an integer from 2 to 6, and M+ represents a metal cation)
It can be obtained by reacting with a compound expressed in dimethyl sulfoxide to obtain cyclopentanol, and then oxidizing this cyclopentanol to obtain the corresponding cyclopentanone derivative compound.

If the chemical reaction in the method of the present invention is shown in a flow sheet, it is as follows: 9. If the above reaction order is followed, 3, 4
-Epoxylactone {]) [E. J. COery and R
．． NOyOri, TetrahedrOnLetter
s, 3ll (1970)] was processed with Iritte),
Prostaglandin 2 series with α single chain, 3,
4-Epoxycyclopetano L (11?) is produced.

Oxidation of this (e.g. using H2crO4.H2sO4-ether or Johns reagent)
・? When z is produced and further treated with a mild base, 4-hydroxycyclopent-2-ene-1-one and its heteroexciter 3-hydroxycyclobent-4ene-1
-OnM becomes a mixture. This mixture is prepared using a dilute base under mild conditions (preferably PHLO.3-1
0.6 for 24 hours), the 3-hydroxy isomer M isomerized to the desired end product, the 4-hydroxy isomer. The inventors have determined that ethoxyketone (fV)/l
We believe that the isomerization of hydroxycyclopentenone (V) and hydroxycyclopentenone (V) occurs through an intermediate step of 3,4-dione WY. The method of the present invention will be explained by giving reference examples and examples.

Reference Example A Production of allosis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol Allosis-5-hydroxy-2,3-oxidocyclopentyl acetaldehyde γ- Lactol (E.J.
．． Corey and R. Noyori. Tetrahedr
onLetters. 1970.311) 1.429(
13.39 (30 mmol) of 4-carboxybutyltriphenylphosphonium bromide 2.52
9 (60 mmol) of a 57% sodium hydride dispersion,
and 70 ml (7) of Witt prepared from DMSO.
ig reagent [E. J. Coreyeta1. JACS, 9
1,5675 (1959)] with stirring.
Add for 1 minute at ℃.

The solution was stirred at ambient temperature for 20 h, then diluted with methylene chloride, ice.
and hydrochloric acid with stirring, the organic phase is separated and the aqueous phase is extracted with methylene chloride, saturated with common salt and extracted with ether.

Combine the organic extracts and partition with sodium bicarbonate. The aqueous basic extract is acidified with dilute HCI, saturated with sodium chloride and extracted with ethyl acetate. Reference Example B Allcis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone when the extract is washed with brine, dried over magnesium sulfate and concentrated to give the crude title compound as an organic oil. Manufacturing 1
．． 1.6 mol of crude allcis-2-(6-carboxy-2-cis-hexenyl)-3 in 6 ml of ether
, 1.6 ml of 4.0N chromic acid dissolved in 4N sulfuric acid was added to the solution containing 4-oxide cyclopentanol (Reference Example A) for 9 minutes at O0C while stirring.

After stirring for 5 minutes at 0° C., the solution is diluted with brine, ether and ethyl acetate. The organic phase is treated with isopropanol, washed with brine and dried over magnesium sulfate.
Evaporation of the solvent gives the title compound as an oil. Reference Example C Production of 2-(6-carboxy-2-cis-hexenyl)4-hydroxycyclopent-2-en-1-one All-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxide Cyclopentanone (Reference example B
) 1.0 mmol and sodium carbonate3. A solution of O mmol dissolved in 15 ml of water is allowed to stand at room temperature for 3 hours.

The solution is acidified with HCI, saturated with sodium chloride and extracted with ether. The extracts were washed with brine, dried over magnesium sulfate, and concentrated to yield the title compound and isomeric compounds, 2(6-carboxy-2-cis-hexenyl)-3-
to give a mixture with hydroxycyclopent-4-en-1-one. Further treatment of this mixture with 10N caustic soda at room temperature for 30 minutes rearranges the latter isomer to give the title compound, which is isolated from the basic solution as described above. Reference Example D Production of 2-(6-carboxy-2-cis-hexenyl)4-hydroxycyclopent-2-ene-1-one cis-anti-cis-hydroxy-2,3-oxidecyclopentyl acetaldehyde γ- Lactol (E.
J. Coreyl:. R. Noyori. Tetra
hedronLetters. 1970.311) with 4-carboxybutyltriphenylphosphonium bromide as described in Reference Example A, 2β-(6-
carboxy-2-cis-hexenyl)3α,4α-oxidecyclopentan-1β-ol, which when oxidized by the method of Reference Example B gives 2β-(6-carboxy-
2-cis-hexenyl)-3α,4α-oxide cyclopentanone which, when eventually treated with aqueous base in the manner of Reference Example C, gives the title compound.

Reference Example E Preparation of 4-carboxybutyltriphenylphosphonium bromide A mixture of 5-bromovaleric acid 1039 and triphenylphosphine 1529 in 400 ml of acetonitrile was refluxed for 48 hours, cooled, diluted with 1007 nl of benzene and allowed to stand. and crystallize it.

When the crystals are filtered and washed with benzene and ether, M. p. 2
Produces a colorless material at 07-209°C. Reference Examples F-H When the ω-bromoalkanoic acids shown in Table 1 are treated with triphenylphosphine according to the method described in Reference Example E, the phosphonium bromides shown in the table are produced.

Reference Example 1-K All cis-5-hydroxy-2,3-oxide cyclopentyl acetal dehydrol lactol was treated with the Wittig reagent prepared from the phosphonium bromide shown in the table by Method V of Reference Example A (see Table 1). of the product.

4i1 = + Reference Example 0-Q When 3,4-oxidocyclopentanone in Table 4 below is treated with alkali by the method described in Reference Example C, 4- in Table 4-
Produces hydroxycyclopentynone.

Reference Example R Preparation of 4-detrahydropyranyloxy-2-(6tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1-one 5.599 (24.6 mmol) was added to 100 ml of methylene chloride. 4-hydroxy-2
-(6-carboxyhexyl)cyclopent-2-ene 1-one and 20.79 (246 mmol) of dihydropyran are added to a stirred solution of 47 to (0.246 mmol) of p-toluenesulfonic acid monohydrate. Add the mixture at 20°C and reduce the temperature to 2'-25°C by cooling.
and stir at this temperature for 1 hour.

This solution is diluted with 200 ml of ether and poured into a mixture of 40 ml of saturated sodium bicarbonate solution, 40a of saturated sodium chloride solution and 80 ml of water. The phases are separated and the aqueous phase is extracted with fresh ether. The entire extract was subsequently washed with water and saturated sodium chloride solution, dried over potassium carbonate,
The volatiles are removed by concentration under reduced pressure to give an oil. Its properties are as follows. MeOH λ = 223 mμ (9500); νMax. max
．． l73O (ester carbonyl group), 1705 (ketone carbonyl group),} and 1030C7rL-1 (tetrahydropyranyloxy group).

Reference example SV 4-hydroxycyclopent-2 shown in Table 5 below
Treatment of -en-1-one with dihydropyran (as in Reference Example R) yields the corresponding bis-tetrahydropyranyl ether-esters of the table.

Reference Example Cyclopent-2-en-1-one 5f! 5.49 ml of trimethylsilyl chloride was added to the solution in a nitrogen atmosphere.

The resulting solution was cooled in a bath of tap water and 5.5% of triethylamine in 10 ml of N,N-dimethylformamide was added.
059 was added dropwise. The resulting mixture was stirred in an oil bath at 60° C. for 2 hours and then at ambient temperature for 18 hours. The triethylamine hydrochloride was filtered off and the sap was allowed to dry. When the residual oil is distilled, it has a boiling point of 156-157.
A product of 2.69 C (0.07 mm) was obtained. Reference example Y4-(dimethylisopropylsiloxy)-2(6-
Preparation of cyclopent-2-en-1-one (carbodimethylisopropylsiloxyhexyl)dimethylisopropylsilyl chloride [E. J. Corey. R. K. VaIr
na. J. ．． Amer. Ch8n. SOc. ,93,7
32O (1971)] 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-ene in 2 ml of dry N,N-dimethylformamide containing 1.81y.
-one in 2 ml of N,N-dimethylformamide by the method described in Reference Example X.
After two distillations with toluene, the product 1
．． 459 is obtained.

Reference Example Z Production of 4-(dimethyl-t-butylsiloxy)-2-(6-carbodimethyl-t-butylsiloxyhexyl)cyclopent-2-en-1-one 4-hydroxy-2-( 6-carboxyhexyl)cyclopent-2-en-1-one (2-(6-carboxyhexyl)-4-hydroxy-cyclopent-
2-eryrin-1-one) 2.09 (8.55 mol) and imidazole 3.65 g (54 mol) were dissolved in a bath at 0°C.
dimethyl-t in 5 ml of dimethylformamide to a solution of
- Add a slurry consisting of 4.079 (27 moles) of butylchlorosilane.

Add 1 ml of dimethylformamide and pour in the slurry. Remove the ice bath and stir the solution at 37°C for 4 hours. The solution is then poured into 140 d of water and the aqueous solution is extracted twice with 70 ml of isomeric hexane. The organic layers are combined, dried over magnesium sulfate, and concentrated in vacuo to an oil. Toluene (5
0ml) twice and evaporated in vacuum to remove unnecessary impurities that boil at low temperatures. 3. Keep the residue under vacuum overnight.
389 (7.45 mol) of oil which shows no hydroxyl or carboxyl absorption in the infrared.

0max: 1720C71L-1 (unsaturated ketone and silyl ester), 840,815,795,780cT
n-1 (silyl ether and silyl ester).

Reference example A1 -E1 4-hydroxycyclopent-2 shown in Table 6 below
-En-1-one was treated with the trialkylsilyl chloride indicated in the method described in Reference Example Xv to give the bistrilkylsilyl chloride shown in the table. yields ether-ester.

Example 1 2-(6-carboxy-2-cis-hexenyl)3,4
-Production of oxidocyclopentanol 5-hydroxy-2,3-oxidocyclopentylacetaldehyde γ-lactol (isomer mixture: E. J. Core
y and R. Noyori. Tetrahedron Let
ters. 1970.311) 5.09 (35 mm) A solution of 25 ml of DMSO was dissolved in 4-carboxybutyl triphenylphosphonium bromide 23
．． 59 (53 mmol), 57% sodium hydride dispersion 6.19 (140 mmol) and DMSO
Wi prepared from 230 ml (dimethyl sulfoxide)
ttig reagent [E. J. Coreyetal. JACS
, 91, 5675 (1969)] and dimsyl sodium. Add for 5 minutes at 20°C.

The solution was stirred at ambient temperature for 2 hours and then diluted with methylene chloride,
Stir the mixture of water, hexagrams and hydrochloric acid and pour into it.

The reaction mixture is worked up as described in Reference Example A and the crude product is purified by dry column chromatography on silica gel to give the title compound (a mixture of two stereoisomers) as an oil. IR (film) 3540,
1710, and 832儂-1 Example 2 2-(6-carboxy-2-cis-hexenyl)-3,
Production of 4-oxide cyclopentanone Acetone 66m
2-(6-carboxy-2cis-hexenyl)-
3,4-oxide cyclopentanol (Example 1) 2
．． A stirred solution of 989 (13.2 mmol) was added to 3.30 ml of 8N chromic acid in 8NM2S04.
Treat drop by drop at -10 to -5°C for 20 minutes.

Claims (1)

[Claims] One mole of a compound represented by the primary formula ▲ There are mathematical formulas, chemical formulas, tables, etc.
The desired compound is obtained by reacting an excess molar amount of a compound represented by O^-M^+ (where p is an integer of 2 to 6, M^+ indicates a metal cation) in dimethyl sulfoxide at room temperature. After the cyclopentanol is produced, it is oxidized with a solution of chromic acid H_2CrO_4 and sulfuric acid to produce the corresponding cyclopentanone, which is separated from the reaction mixture. There are chemical formulas, tables, etc. ▼ (where p is as above) A method for producing a cyclopentanone derivative compound represented by.