DE2436332A1 - SUBSTITUTED TETRAHYDROFURANS AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

CHEMICAL FACTORY
Patent & License Department. Ludwigshafen / Rh. , July 23, 1974

Substituted tetrahydrofurans and processes for their preparation

The invention relates to new, substituted tetrahydrofurans which are suitable for the production of "oxaprostaglandxnen" are.

Prostaglandins are compounds that are relatively difficult to access. Since they have a fairly broad spectrum of activity, a targeted therapeutic application is very difficult. It is therefore of interest to use prostaglandin-like substances that can be used better. Prostaglandin derivatives, which instead of the cyclopentane ring a Have butyrolactone ring are already known, but not those which are derived from a tetrahydrofuran structure.

An intermediate product has now been found from which 11-oxaprostaglandins can easily be prepared.

The invention relates to compounds of the general formula I

509887/1013

ORIGINAL INSPECTED

CHEMICAL FACTORY

4 3 6 3 3

where A is the group

C = O

OH

or

OH

with R meaning an alkyl radical with 1-4 carbon atoms is and

B denotes a branched or unbranched alkyl radical having 1-10 carbon atoms.

The invention also relates to a method of production of compounds of the general formula I, which consists in the fact that one is a compound of the general formula II

CH ₃ -CO-O

CH ₃ CO-

•• ■■ \

00C ₂ H _r

CHORUS-CH ₂ OR

wherein R represents an acetyl or benzoyl radical, with chlorine or Lets hydrogen bromide react, constricts, in the residue with triphenyltin hydride the halogen against hydrogen exchanges the 2ß- (l ', 2'-diacyloxyethyl) -3acarbäthoxymethyl-4a-acetoxy-tetrahydrofuran thus obtained treated with acid, subjected to glycol cleavage and then according to Wittig.

ORIGINAL INSPECTED

509887/1013

CHEMICAL FACTORY

The reaction according to the invention takes place in the following stages:

CH ₃ COO

CH ₃ COO

COOC ₀ H

Halogen-hydrogen

CHORUS-CH ₂ OR CH ₃ CO-O

Hal

COOC ₂ II CHORUS-CH ₂ OR

(C ₆ H ₅ J ₃ SnH

CH ₃ CO-O

COOC ₀ H

CHORUS-CH ₂ OR

JO. 4th

HOH-CH ₂ OH

Wittig

AWAY

Π 9 B B 7 Π η 1 ORIGINAL INSPECTED

2 4 3 B 3 3

CHEMICAL FACTORY

The conversion of the starting material with hydrogen chloride or hydrogen bromide is preferably carried out so that the substance in a solvent such as methylene chloride, chloroform or Ether dissolves and the hydrogen halide to saturation initiates. This reaction step can also be carried out with hydrogen bromide in glacial acetic acid in the presence of acetic anhydride will. The halogen atom is exchanged for a hydrogen atom by reaction with triphenyltin hydride preferably at room temperature.

The yields in the lactonization of 2ß- (l ', 2'-diacyloxyethyl) -3a-carbäthoxymethyl-4a-acetoxy-tetrahydrofuran to 2ß- (1', 2'-dihydroxyethyl) -3a-carboxymethyl-4a-hydroxy-tetrahydrofuran 4-lactone with the usual acids and solvents are usually not very good. However, if this reaction step is carried out with p-toluenesulfonic acid in methanol, yields of over 70 % are obtained.

The glycol cleavage can be carried out in a known manner will. In the present case, sodium periodate has proven to be particularly suitable. Also sales with the Wittig reagent takes place in the usual way.

The present method has the advantage that, as a starting material, a substance is used which is easily is obtainable from glucose, and that a sterically uniform

-S-

7/1013

CHEMICAL FACTORY

Liches, optically active product is obtained. The compounds prepared by the process according to the invention correspond in their steric arrangement to the natural prostaglandins. So far you had to make it of highly substituted tetrahydrofurans start from furan or tetrahydrofuran compounds. These However, syntheses are extremely difficult and expensive because the furan compounds are very sensitive Lich are against acid and alkali and mixtures of stereoisomers are produced.

5 0 9 B % 1 i 1 Π 1 3

3 6 3 3

CHE

Production of the starting material.

a) 250 ml of 0.8% are added to a solution of 27 g of S-deoxy-S-carbäthoxymethyl-1,2-5,6-di-O-isopropylidene-oc-D-allofuranose (l) in 250 ml of methanol ± ge aqueous sulfuric acid. After 16 hours of standing at room temperature, it is neutralized with BaCO 2, heated briefly to boiling for the purpose of better filterability of the precipitate, filtered off and the methanol is removed in vacuo. The remaining aqueous solution is made up to 250 ml, the organic impurities are removed by shaking with η-hexane and concentrated. Yield: 18.9 g or 83 % of S-deoxy-S-carbethoxymethyl-1,2-0-isopropylidene-5i 6-dihydroxy-oc-D-allofuranose.

b) 5 g of S-deoxy-S-carbäthoxymethyl-l ^ -O-isopropylidene-5,6-dihydroxy-aD-allofuranose are dissolved in 10 ml of pyridine and 4 ml of acetic anhydride are added. After standing for three hours at room temperature, it is taken up in 100 ml of chloroform or methylene chloride, washed with 5% ± gev hydrochloric acid, 5% ± ger sodium hydroxide solution and then with water and, after drying, with Na ₃ SO. constricted. Yield: 5.4 g of S-deoxy-S-carbethoxymethyl-l ^ -isopropylidene- 5 $ 6-diacetoxy-aD-allofuranose.

509887/1013

CHEMICAL PLANTS

243633?

c) 5 g of S-deoxy-G-carbäthoxymethyl-1,2-0-isopropylidene-5, o-diacetoxy-oc-D-allofuranose are dissolved in 40 ml of glacial acetic acid and mixed with 4 ml of acetic anhydride and 0.6 ml of concentrated water S0, offset. After standing for two days, the mixture is poured onto 500 ml of ice / water and extracted exhaustively with chloroform, the combined organic phases are dried and concentrated. Yield: 4.8 g (86 %) of S-deoxy-S-carbethoxymethyl-l, 2-5,6-tetraacetyl-aD-allofuranose,

509887/1013

CHEMICAL FACTORY

example 1

A) 6 g of S-deoxy-S-carbethoxymethyl-1,25,6-tetraacetyla-D-allofuranose are dissolved in 30 ml of dry methylene chloride. The solution is passed for 30 minutes a dry HBr stream at room temperature and then evaporated in a water jet vacuum with interposition of a P_0 drying tube initially at room temperature. To remove the still adhering Hydrobromic acid is raised to the temperature for 30 minutes after removal of the solvent 60 ° C.

B) The evaporation residue is dissolved in 30 ml of dry methylene chloride with exclusion of moisture and 20 ml of an ethereal triphenyltin hydride solution, which is made up of 11 g of trxphenyltin chloride and 0.55 g of LiAlH, is added. was prepared. After 30 minutes, it is evaporated and the residue is chromatographed on deactivated silica gel, water content 30 %. The impurity is first separated off by elution with η-hexane, after which it is eluted with chloroform / methanol 10; 1. The yield of 2ß- (1 », 2'-diacetoxyethyl ).3a-carbethoxymethyl-4a-acetoxy-tetrahydrofuran is 4.9 g or 94 %.

~ 9 5Q9887 / in 1 3

2 A 3 R 3 3

CHEMICAL FACTORY

C) 3.5 g 2ß- (l ', 2'-Diacetoxyäthyl) -3oc-carbäthoxymethyl-4oC-acetoxy-tetrahydrofuran contained p-toluenesulfonic acid in 5 ^m l of methanol, which 0.25 g, and treated for 16 hours under reflux kept simmering. It is then concentrated and chromatographed on deactivated silica gel which contains 30 % water with chloroform / methanol 10: 1. The yield of 2β ~ (l ', 2'-dihydroxyethyl) -3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lactone is 1.3 g or 72 %.

D) 5.4 g of 2β- (l ', 2'-dihydroxyethyl) -3a-carboxymethyl-4ahydroxy-tetrahydrofuran-4-lactone are dissolved in 25 ml of water and mixed in portions with 5 g of NaJO. added, while maintaining ρ 7 by adding 5 # aqueous NaOII. Thereafter, isopropanol exhaustively extracted with chloroform /, the combined organic phases with Na ₀ SO- dried and concentrated. The yield of 2β-formyl-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lactone is 4.3 g or 96 %.

E) 12.6 g of 2β-formyl-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-1actone are dissolved in 500 ml of tetrahydrofuran and 60 g of hexanoylmethylene triphenylphosphorane kept at the boil for one hour under reflux. It is evaporated and the residue is dissolved in ethyl acetate, where the main amount of triphenylphosphine

- 10 -

509887/1013

243R332

CHEMICAL FACTORY

oxide crystallized out. One sucks off the contamination from, concentrates the mother liquor and dissolves the evaporation residue in a little ether. When moving the essential solution 2ß- (Oct-1-en-3-onyl) ~ 3oc-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lactone precipitates with η-hexane crystalline

Mp 66 ° C, yield 13.1 g or $ 64.

Example 2

5 g of S-deoxy-S-carbäthoxymethyl-l ^ -Sjo-tetraacetyl-aD-allofuranose are dissolved in a mixture of 20 ml of glacial acetic acid and 4 ml of acetic anhydride. After adding 15 ml of HBr / glacial acetic acid 40 %, the mixture is left to stand at room temperature for 90 minutes and then concentrated in a high vacuum, the temperature gradually increasing to 70.degree. The evaporation residue is treated further as described in Example IB-E. The yield corresponds to that of Example 1.

Example 3

In a solution of 6 g of S-deoxy-S-carbäthoxymethyl-1,25,6-tetraacetyl-a-D-allofuranose in 30 ml of methylene chloride

- Il -

509837/1013

2 k 3 R 3 3 ?

CHEMICAL FACTORY

a stream of dry water is used at OC for about two hours HCl gas and then leave to stand for about a week at room temperature. Then you treat the mixture as described in Example IB-E, the yield on the end product is slightly lower than that of Example 1.

Dr.WK / bu / 2

- 12 -

9 8 * Π Π fH 3

Claims (2)

CHEMICAL FACTORY Patent and License Department P 159 Ludwigshafen am Rhein, July 23, 1974 Claims 1.) Substituted tetrahydrofurans of the general formula I \ a - AWAY where A is the group C = O II or OH OH with R meaning an alkyl radical with 1-4 carbon atoms is and B denotes a branched or unbranched alkyl radical having 1-10 carbon atoms. 2.) Process for the production of substituted tetrahydrofurans according to claim 1, characterized in that a compound of the general formula II -13 - CHEMICAL FACTORY CH ₃ CO ^s COOC ₀ H-CHORUS-CH ₂ OR II where R represents an acetyl or benzoyl radical, reacts with hydrogen chloride or hydrogen bromide, constricts, in the residue with triphenyltin hydride the halogen exchanges for hydrogen, the 2ß- (1 », 2'-diacyloxyethyl) -3a-carbäthoxymethyl-4a-acetoxytetrahydrofuran thus obtained treated with acid, subjected to glycol cleavage and then reacted according to Wittig . 509887/1013