DET0010029MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration day: September 27, 1954 Announcement night on July 26, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION

CLASS 120 GROUP 25 INTERNAT. CLASS C07d

T 10029 IVb / 12 ο

Yasuo Abe, Osaka, Tadatsugu Harukawa, Kyoto,

Hisashi Ishikawa, Kobe, Takuichi Miki, Hyogo, Masoa Sumi, Osaka,

and Tadashi Toga, Hyogo (Japan)

have been named as inventors

Takeda Pharmaceutical Industries, Ltd., Osaka (Japan)

Representative: Dr.-Ing. A. von Kreisler and Dr.-Ing. K. Schönwald, patent attorneys, Cologne 1

Process for the preparation of dihydrosantonine derivatives

The priority of filings in Japan on October 2 and October 27, 1953 is used

The invention relates to a process for the production of dihydrosantonine derivatives.

The invention is based on the observation that in the oxidation of (2-acyloxy-i, io-dimethyl-3, 4, 5, 6, 7, ιo-hexahydro-7-naphthyl) malonic acid or their derivatives of the general formula

CH

CH,

in the U an acyloxy group, R hydrogen or methyl, Y and Z a carboxyl, ester, carboxamide or nitrile group and Z can also mean an acyl group, lactones of (2-keto-8-trans-oxyi, io-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro-7-naphthyl) malonic acid or their descendants, d. H. Dihydrosantonine seedlings are obtained. The starting materials may or may not be optically active. It is known 3, 4-dihydro-6-methoxynaphthalm, i.e. a bicyclic compound, one of which is ring is completely aromatic and in which the double bond of the non-aromatic ring is conjugated is to be oxidized to the aromatic ring with benzoperic acid or phthaloperic acid. This is a

609 576/525

T 10029 IVb / 12 ο

Epoxy compound or as its rearrangement product get a ketone.

In the process according to the invention, an epoxy compound can under certain circumstances also be formed, but only as an intermediate product that only contains an OH group on carbon atom 8 after hydrolysis results, which forms a lactone ring with the acid residue in the side chain located on carbon atom 7. The implementation according to the invention is with

ίο oxidizing agents such as hydrogen peroxide and organic percarboxylic acids, for example performic acid, peracetic acid, perphthalic acid, perbenzoic acid, accomplished.

The percarboxylic acid can also only be formed during the reaction .; For example, the oxidation is carried out with Peressigsäm ^- e, which is formed from acetic acid, its anhydride or a mixture of these two substances and hydrogen peroxide. This method is particularly suitable for technical purposes.

Catalysts can be used in the reaction, for example ferrous sulfate is often used in the form of Fenton's reagent (hydroperoxide in the presence of ferroion, cf. GiIman, Organic Chemistry an advanced treatise, Vol. IV, 1953, p. 1157, ■ 1158) is used.

The reaction takes place in a solvent and generally at room temperature. Examples of suitable solvents are:

Carboxylic acids, alcohol, acetone, dioxane. Although the reaction is generally carried out at room temperature, can optionally also at lower or higher temperatures, for example at 90 ^0, to work; in the latter case, this shortens the response time.

The end products are apparently formed via intermediates, which are likely 8, 9- or 2, 8-oxides of the end products. These intermediates, which can sometimes be separated from the reaction mixture are converted into the end products regulated hydrolysis transferred.

To separate the end products, the reaction mixtures are mixed with solvents such as ether, Ethyl acetate, acetone, benzene, chloroform, extracted and the solvents then driven off. In the Evaporation of the extracts, crystalline products are obtained by recrystallization or on be purified by chromatography.

According to the invention, the compounds according to the general formula given below, in which Z is not a carboxyl group, but an ester, carboxamide, nitrile or acyl group Convert hydrolysis with alkali into the corresponding carboxylic acids.

The end products according to the invention can be represented by the following general formula:
CH ₃ O CO

o ==

CH,

in which R and Z have the meaning given above and the lactone ring is closed. ~ ■

The end products which can be prepared according to the invention are generally insoluble in water, but soluble in organic solvents such as methanol, ethanol, ether, esters, benzene, chloroform, Acetone, and have an absorption maximum at 240 to 246 m / i (log ε = over 4). :

These end products are ... important intermediate products for making santonin. For example, if the end products are at carbon atom 3 halogenated or an acyloxy group is introduced on the same carbon atom and becomes the halogen or the acyloxy group cleaved together with the hydrogen on carbon atom 4 or with If selenium dioxide is oxidized, santonin or its derivatives are obtained. ....

The implementation according to the invention proceeds according to the following scheme:

CH

CHoO

C-R

O =,

C-R

CH,

CH,

example 1

To a solution of 10 g of (2-acetoxy-i, io-dimethyl-3, 4, 5, 6, 7, 10-hexahydro-7-naphthyl) -methylmalonic acid dimethyl ester in 50 cm ^{3 of} glacial acetic acid, 4 ecm 30 ° / ₀ iges Given hydrogen peroxide, and the solution is left to ^{stand at 30 0} overnight. The reaction mixture is then concentrated in vacuo to two thirds of its original volume, diluted with a little water and extracted with ether. The ethereal solution is washed successively with water, io ° / ₀ sodium bicarbonate solution and water and evaporated. 3.4 g of a yellow oil are obtained, which is taken up in 100 ecm of dioxane and ^{shaken with 30 cm 3 of} 10% strength sulfuric acid for 4 minutes at room temperature. The reaction mixture is then quickly neutralized with sodium bicarbonate and extracted with ether. The ethereal solution is washed with water, dried and evaporated. 3 g of a pale yellow oil are obtained. When the oil is chromatographed with aluminum oxide, 1.5 g of lactone des (2-keto-8-trans-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro-7 - naphthyl) - methylmalonsäuremonomethylesters obtained from methanol in rectangular tips crystallized having a melting point of 136 ^0th

Example 2,

3.15 cm ³ 3O ° / _{Given 0} iges hydrogen peroxide and the mixture left to stand at 20 ^{0 for} 3 hours. The reaction mixture .wird extracted with ether and the ethereal solution with

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T 10029 IVb / 12 ο

Washed water, dried and evaporated. A crystalline product is obtained which, washed with petroleum ether, contains 3.7 g of lactone des (2-keto-8-trans-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro - 7 - naphthyl) - methylmalonsäuremonoäthylesters yields crystallized from methanol in diamonds having a melting point of 124 ^0th Chromatography of the mother liquor

. ■ material atom 11 isomeric compound obtained from Methanol in the form of colorless rectangular platelets with a melting point of. 132 ° is obtained.

Example 3

· ;. To a solution of 10 g (2-acetoxy-i, io-dimethyl-3, 4, 5, 6, 7, io-hexahydro-7-naphthyl) diethyl malonate in 100 cm ³ of formic acid, 3.2 g of 34 ° / ₀ iges hydrogen peroxide given at 20 to 22 ⁰ , and the mixture is left to stand for 4.5 hours at the same temperature and then worked up exactly as in Example 2. The lactone of (2-keto-8-trans-oxy-i, 10-dimethyl-2, 3, 4; 5, 6, 7, 8, 10-octahydro-7-naphthyl) -malonic acid monoethyl ester is obtained. When recrystallizing from

- diluted methanol are obtained two isomers, one of which melts a rhombic in form of platelets with a melting point of 142 ⁰ and the other (containing water of crystallization) at 86 °.

Example 4

. To a solution of 3 g (2-acetoxy-i, io-dimethyl- ■ 3, 4, 5, 6, 7, io-hexahydro-7-naphthyl) -methylmalonsäuremonoäthylester in.30 cm ³ of formic acid are 0.9 cm ³ 34 added ° / ₀ sodium peroxide, and the mixture is allowed to stand for 2 hours at room temperature. By working up the reaction mixture according to Example 2, 1.5 g of crude lactone des (2-keto-S-trans-oxy-i, io-dimethyl-2, 3, 4, 5,6,7,8, io-octahydro- 7-naphthyl) methylmalonic acid

y monoethyl ester obtained. By hydrolysis with io ° / ₀ strength potassium hydroxide solution at room temperature (2-keto-8-trans-oxy-i, io-dimethyl-2,3, 4, 5, 6, 7, 8, io-octahydro-7-naphthyl ) -methylmalonic acid obtained, which melts at 215 ° with decomposition.

Example 5

To a solution of 10 g of (2-acetoxy-i, io-dimethyl-3 ». 4.5» 6, 7, io-hexahydro-7-naphthyl) methylmalonic acid diethyl ester in 50 cm ^{3 of} methanol are added 5.6 cm ^{3 of} 34 ₀ % hydrogen peroxide and 0.5 g of ferrous sulfate are added, and the mixture is left to stand for 4 days at room temperature. The methanol is distilled off from the reaction mixture, the residue is taken up in ether and the ethereal solution, after it has been washed with sodium bicarbonate solution and water and dried; evaporated. There are 0.2 g of lactone of (2-keto-trans-oxy-i, 10-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro-7-naphthyl) methylmalonic acid monoethyl ester with a melting point received from 124 ⁰ .

, Example 6

A solution of 10 g of (2-acetoxy-i, io-dimethyl-3> 4. 5. 6, 7, io-hexahydro-7-naphthyl) -methylmalonic acid diethyl ester in 50 cm ^{3 of} propionic acid is heated in boiling water, and then be 4 cc of 34 ° / ₀ sodium hydrogen peroxide added in one portion to the hot solution. The mixture is stirred at the same temperature for 4 hours and then worked up according to Example 2. There are 3.8 g of lactone of (2-keto-8-trans-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro-7-naphthyl) methylmalonic acid monoethyl ester with a melting point of 124 ⁰ obtained. . _; . _:

Example 7

A solution of 10 g of (2-acetoxy-i, io-dimethyl-3, 4, 5, 6, 7, io-hexahydro-7-naphthyl) -methylmalonic acid diethyl ester in 50 cm ^{8 of} n-butyric acid is heated in boiling water and then 34 cm ³ under stirring 10 ° / ₀ sodium hydrogen peroxide to the hot solution. The mixture is stirred at the same temperature for a further 40 minutes and the reaction mixture is then worked up as in Example 2. There are 2.5 g of lactone of (2-keto-8-transoxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, 10-octahydro 7-naphthyl) - methylmalonic acid monoethyl ester with a melting point of 124 ⁰ received.

Example 8

A solution of 10 g of (2-benzoxy-i, io-dimethyl-3, 4, 5, 6, 7, io-hexahydro-7-naphthyl) -methylmalonic acid diethyl ester in 60 ecm acetic acid is heated to 6o °, and it is then 4.4 ecm 3O ° / ₀ iges hydrogen, substance superoxide added to the hot solution. The temperature is slowly increased and the mixture is heated to a gentle boil for 5 minutes and then worked up according to Example 2. When recrystallizing from alcohol, 2 g of lactone of (2-keto-8-trans-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro-7-naphthyl) -methylmalonic acid monoethyl ester obtained with a melting point of 124 ⁰ . '

Example 9

A solution of 10 g of (2-benzoxy-i, io-dimethyl-3; 4/5/6> 7 »io-hexahydro-7-naphthyl) -methylmalonic acid diethyl ester in a mixture of 45 cm ^{3 of} acetic acid and 15 cm ^{3 of} formic acid is heated to 60 to 65 °, and then 4.4 cm ^{3 of} 30 ° / _O hydrogen peroxide are added to the hot solution. The reaction mixture is kept at the same temperature for 1 hour and worked up according to Example 2 after cooling. 2.3 g of lactone of (2-keto-8-trans-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, 10-octahydro-7-naphthyl) -methylmalonic acid monoethyl ester are added a melting point of 124 ⁰ obtained.

Example 10

A solution of 10 g of (2-benzoxy-i, io-dimethyl-3; 4.5; 6. 7. io-hexahydro-7-naphthyl) -methylmalonic acid diethyl ester in 50 cm ^{8 of} acetic acid is heated to 70 °, and then are to the hot solution 2.2 cm ³ 3O ° / ₀ sodium peroxide given as soon as the temperature door has reached 8o °. The mixture 'is held for 30 minutes at 60 to 70 ° and according to

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T 10029 IVb / 12 ο

Example 2 worked up. There are 2.5 g of lactone of (2-keto-S-trans-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, 10-octahydro-7-naphthyl) -methylmalonic acid monoethyl ester with a melting point of 124 ⁰ obtained.

Example 11

6 g of a- (2-acetoxy-i, 10-dimethyl-3, 4, 5, 6, 7, io-hexahydro-7-naphthyl) propionic acid (R ₁ , R ₂ , R ₃ = CH ₈ ; U = CH ₃ COO; Y = COOH; Z = H) are dissolved in 50 ecm ^{3 of} glacial acetic acid and a solution of 5.4 g of chromic acid in glacial acetic acid is added to the solution at 10 to 12 ° while stirring. After adding the chromic acid solution, stirring is continued for 2 hours at the same temperature. The excess chromic acid is destroyed by the gradual addition of sodium bisulfite solution. It is then acidified with hydrochloric acid and concentrated in vacuo to remove the acetic acid. The separated oil is taken up with ether, the ethereal solution is evaporated after washing with water and sodium bicarbonate solution. There are 1.3 g of residue

. obtained, which are first recrystallized from ether (F. = 120 to 125 ⁰ ), then from methanol, with colorless prisms of the lactone of a- (2-keto-i, io-dimethyl-8-cis-oxy-2, 3 , 4, 5, 6, 7, 8, 10-octahydro-7-naphthyl) propionic acid with a F. = 125 to 12g ⁰ can be obtained.

Example 12

5 g (2-Aetoxy-i, 10-dimethyl-3, 4, 5, 6, 7, ία-hexahydro-7-naphthyl) -methylmalonic acid diethyl ester (R ₁ , R ₂ , R ₃ = CH ₃ ; U = CH ₃ COO; Y, Z = COOC ₂ H ₅ ) are dissolved in 25 cm ^{3 of} glacial acetic acid, and 1.5 g of sodium chlorite (NaClO ₂ ) are gradually added. The solution is then left to stand for 20 hours. A little ether is added to the reaction mixture, washed with water and sodium carbonate solution, dried and the solvent is driven off. A neutral oily substance is left behind, which is combined with potassium hydroxide solution

Saponified at room temperature. It is the lactone of (2-keto-8-cis-oxy-i, io-dimethyl-2, 3, 4, 5, 6, 7, 8, io-octahydro-7-naphthyl) -methylmalonic acid in an amount of 0.5 g and a F. of 216 ⁰ (with decomposition).

Claims (2)

PATENT CLAIMS: i. Process for the preparation of dihydrosantonine derivatives the general formula CHoO CH ₃ in which R is hydrogen or methyl and Z is a carboxyl, ester, carboxylic acid amide or nitrile Acyl group means, characterized in that compounds of the general formula CH C-R in which R and Z have the abovementioned meaning, U is an acyloxy and Y is a carboxyl, Mean ester, carboxamide or nitrile group, treated with an oxidizing agent will. 2. The method according to claim 1, characterized in that that hydrogen peroxide or an organic percarboxylic acid is used as the oxidizing agent will. Considered publications: German Patent Specifications No. 708 114, 714