DER0013691MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: March 1, 1954. Advertised on July 5, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION

CLASS 12q GROUP 16 R 13691 IVb / 12 q

Dipl.-Chem. Dr. rer. nat. Wolfgang Riedl, Munich

has been named as the inventor

Dipl.-Chem. Dr. rer. nat. Wolfgang Riedl, Munich

Process for the preparation of ring-alkylated phloracylophenones

From patent application K 11340 IVc / i2q (now Patent 899 198) it is known that in 2, 4, 6-Trioxyacylophenone [of type (A)] or, as a result, introduced alkyl radicals into their nucleus-alkylated derivatives can be that the monovalent or polyvalent metal compounds of 2, 4, 6-Trioxyacylophenone or of their nucleus alkylated derivatives with

OH OH

HO—

Η - V ρ COR ₁ HO - H Tan (A)

Reacts alkyl or aralkyl halides, the halogen of which is particularly reactive (ζ. Β. Γ, y-dimethyl-allyl bromide). This process is preferably carried out in a slightly dissociating solvent (benzene, ether, ether plus a little methanol) and compounds of type (B), (C) and (D) (or tautomeric forms) are obtained.

OH OH

R ₂ R ₂

(D)

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R 13691 IVb / 12q

It has now been found, surprisingly, that these core alkylation reactions are heavily dependent on the dielectric constant of the solvent used and more advantageous in strongly dissociating Run solvents, with such alkyl halides, the halogen of which is not particularly reactive can be used.

According to the invention, the method for production of ring-alkylated phloracylophenones by reaction of the metal compounds of the phloracylophenones or of their nucleus-alkylated derivatives with alkyl halides in a strongly dissociating manner acting solvents made with inert alkyl halides.

Process products cannot be used, only the mono- [type (B)], di- [type (C)] and tri-ring alkylated Isolate [Type (D)] phloracylophenones, but the tetraalkylated ones are also obtained in a complete series Products [type (E)] as well as the geminal-di-substituted

[yp ()] g

iert of type (F), the production of which is the first time is done.

(E)

(F)

The yields of purely ring-alkylated phloracylophenones of types (B) -bis (E) ■ are about JO ⁰ I ₀ of theory or 85 to 95% of the total isolable material.

Process products of type (A) to (F) have saturated alkyl side chains and are therefore against temperature, atmospheric oxygen and other physical and chemical influences are considerably more stable than theirs in the patent application K 11340 IVc / i2q (now - Patent 899 198) described analogs with unsaturated alkyl side chains.

As alkyl halides according to the process, for. B. methyl] odide, ethyl iodide, n-propyl iodide, n-butyl iodide, . Isoamyl iodide and isoamyl bromide are used.

Strong, 'dissociating' solvents are used which, like the various alcohols, ketones, or water or mixtures thereof, show a good solution solution for both reactants (alkyl halide ^:: '' unCp ^.: "Phloracylophenon - metal compound)? ; :: '- ¹ ',

In the phloracylophenones that are used [Type .: (A)] or in their already nucleus-alkylated derivatives [of type (B) to (D)], the the further Kernalky.lierung are also accessible, the Äcykest can be varied and optionally be substituted .: Λ,,.;, ■

The further reaction conditions such as concentration of the reactants, the type of metal compound and ^the: reaction temperature are selected so that speedy conversion takes place with substantial avoidance of hydrolysis of the starting material ^or: the, Verfährensprodukte (elimination of the acyl ^radical!.!).

The work-up to the process products is carried out by using. Customary methods, such as Shaking out with alkalis, sublimation, chromatography or using a specific solubility.

The products of the process are used for the production of physiologically active agents and have a stronger bacteriostatic effectiveness than those in patent application K 11340 IVc / i2q (now Patent 899198) called ring-alkylated phloracylophenones. So inhibits z. B. the i-acetyl-3, 3, 5-tri- (7, y-dimethylallylj-cyclohexa-i, 5-dien-2,6-diol-4-one the growth of staph. aureus only at a concentration of 1: 1Ό0.0; while that according to the invention produced i-acetyl-3, 3, 5-triisoamyl-cyclohexa-i, 5-dien-2, 6-diol-4-one is already effective at 1: 5 million.

example 1

3-methyl-phloracetophenone
OH

a) For monomethylation: 4 g of anhydrous phloracetophenone (1 mol), dissolved in 30 ecm of absolute methanol, are added to the freshly prepared, ice-cold solution of 0.547 S sodium (1 equivalent) in 10 ecm of methanol and then 20 g of methyl iodide (6 mol ) admitted. It is left to stand for a few hours in the refrigerator, then for another 5 days at room temperature and works up as follows: The practically neutral reaction mixture is weakly acidified, excess methyl iodide and solvent are distilled off and the residue is taken up in ether. The ethereal layer is then shaken out one after the other with saturated aqueous sodium bicarbonate solution, with 10% aqueous soda solution and finally with 2η sodium hydroxide solution.

Acidifying the soda extract, washed beforehand with ether, gives crude 3-methyl-phloracetophenbii in the form of yellowish ^! Needles; Yield 2.77 g (64 ⁰ Z ₀ of theory; mp 160 to 180 °; after two recrystallization from about .50 ecm of water, almost colorless tufts of needles are obtained; mp 207 ⁰ .

Changing the molar ratio of Phloracetophenon: sodium: methyl iodide of 1: 2: 1 or 1: 3: 1, is obtained in accordance with yields of 3-methyl-phloracetophenon of 42% and 44 ° / ₀ of theory.

b) For dimethylation: Phloracetophenone, sodium methylate and methyl iodide are used in a molar ratio 1: 2: 6, but otherwise as under a), you also get 44% of theory of 3-methylphloroacetophenone.

c) For trimethylation: Phloracetophenone, sodium methylate and methyl iodide are used in a molar ratio 1: 3: 6 and works in different

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those solvents, 3-methyl-phloracetophenone is obtained as a by-product in the following yields:

Reaction medium yield

Methanol ² 5% of theory

Ethanol 20% -

tert. Butanol! 9 ⁰ Zo - "

Acetone 32% -

Similar yields are obtained with potassium, calcium, magnesium and barium methylate. :

d) For tetramethylation: molar ratio 1: 4: 8, otherwise; as under c). :.

Reaction medium ■ yield

j methanol 6% of theory

Water .... 6% -

Example 2

3-isoamyl-phloracetophenone

OH

(C Hg) 2 CHCH2CH2

HO-L

4 g of phloracetophenone, 1.64 g of sodium (3 equivalents), dissolved in 20 ecm of absolute methanol, and 23 g of isoamyl iodide (3 mol) are reacted with one another as in Example 1 and, after standing for 5 days at room temperature, worked up as follows: The clear red reaction mixture (p _H about 9) is acidified,

, covered with 100 ecm warm petroleum ether (bp. 40 to 60 °), diluted with 40 ecm water, shaken and the petroleum ether layer separated quickly. The aqueous-methanolic layer is extracted twice with 100 ecm petroleum ether each time and then diluted with 20 ecm water. After standing in the refrigerator for a few hours, the crude 3-isoamyl-phloracetophenone is separated off; Yield 0.32 g (5.7 ° / ₀ of theory); after recrystallization from dilute methanol or benzene, pale yellowish prism clusters with a mp of 188 °.

Example 3
3, 5-dimethyl-phloracetophenone

OH

CH ₃ . ,.

In addition to 3-methyl-phloracetophenone (Example 1), this compound is isolated from the soda-soluble fractions of the corresponding methylation batches, Example 1, a) to c). The crude product obtained by acidification is boiled with an insufficient amount of water to dissolve, 3-Methyi-phioracetophenone going into solution; which are difficult to dissolve in water. Residue was crystallized several times from 3O ° / ₀ methanol, thus obtaining pure 3, 5-dimethyl-phloracetophenon in the form of long needles with a mp 220 °; Yield 3% of theory.

Example 4

i-Acetyl-3,3-dimethyl-c.yclohexa-1,5-diene-2, 6-diol-4-ori -. . (= »Filicic acid ethanone«)

OH

CH ₃ , CH ₃ .... ■■ ^: ■. '..

From a lot of hot things. Water colorless intergrown octahedra, also from dilute methanol; F. 174 to 176 °. ^: \ _;

Example 5

i-acetyl-3, 3, S-trimethyl-cyclohexa-i, 5-diene

2,6-diol "4-one (=" methylfilicinic acid ether ") ^ _go

OH

COCH ₃ OH

CH ₃ CH ₃

From dilute ethanol or methanol, coarse, colorless, long prisms; fused from benzene Prisms; from a lot; hot water, fine prisms united in tufts; F. 160 to 16 °. . '

■ Example 6 · ', ■'. ■. ■■ ■; ·,

i-acetyl-3, 3. 5. 5-tetramethyl-cyclohex-i-en-2-0I-4, 6-dione

O '

CH ₃

CHq

From diluted ethanol, colorless, glittering, irregular leaves; F, 37 ^0; from dilute methanol, as a dimorphic form, long flat prisms with a mp of 54 °. ■ '■■'"■ lao

The methylated phlofacylophenones listed in Examples 4> 5 ^and 6 can be isolated as byproducts and main products next to one another from the bicarbonate-soluble fractions of the Kernmethylierungsaüsätze according to Example 1, a) to d), z. B. from 'the trimethylation approach:

609 5Φ8 / 546

R 13691 IVb / 12 q

20 g of phloracetophenone are dissolved in 150 ecm of methanol dissolved and added with cooling to a solution of 8.21 g (3 equivalents) of sodium in 50 ecm of methanol. 101.5 g of methyl iodide are added with further cooling (6 equivalents) and leave the red-brown solution for 5 days (with exclusion of moisture and air) stand at room temperature. Excess methyl iodide and methanol are then distilled off (last in vacuo), and the residue is with each

250 ecm of water and ether brought into solution. After acidification with dilute sulfuric acid to congo acid reaction, shaking the aqueous solution twice with 50 cc of ether and extracted the combined red-colored ether extracts with 8 χ 30 cc of saturated aqueous potassium bicarbonate solution (then with io ° / ₀ sodium carbonate solution [cf. . Example 1]). When the bicarbonate solution, which has been washed once with ether, is acidified, a red-brown precipitate is formed; Yield 14.08 g (55.2% of theory); long skewers and prisms from 140 to 150 °. This amount is digested with 4 × 50 ecm benzene in the cold, and the combined filtered benzene extracts are evaporated; of this residue is recrystallized from 3O ° / ₀ methanol and 0.28 g (1.1% of theory) of i-acetyl-3, 3, 5, s-tetramethyl-cyclohex-i-en ^ -ol-4 , 6-dione obtained from F. 54 ⁰ . The residue remaining undissolved from cold benzene is recrystallized from 110 ecm of 30% methanol and gives 10.2 g (40.8% of theory) of i-acetyl-3, 3, 5-trimethylcyclohexa-i, 5-diene-2, 6-diol ~ 4-one of the F. 160 °.

When the mother liquor of the latter compound is diluted with about 100 ecm of water, it crystallizes i-acetyl-3, 3-dimethyl-cyclohexa-i, 5-diene-2, 6-diol-

4-one from, yield 1 g (4.3% of theory) from F.169 ⁰ .

If you work with such trimethylation approaches in a more concentrated or less concentrated manner methanolic solution and if potassium methylate is used instead of sodium methylate, see above essentially the same yields are obtained, which fluctuate within the following limits:

yield
Example 4 2.5 to 6.0 ° / ₀ of theory

5
6th

40.0 - 60.0% 1.0 - 10.0 ° / ₀ -

If one works with such trimethylation approaches in different reaction media, one obtains the following yields are obtained:

Reaction medium

Methanol (repeat) ........

Ethanol

tert-butanol

acetone

benzene

ether

Yield (% of theory)
in the examples
6th

4.3
track
track
track

40.8
41.2
20.0
I5, o
track
track

ι, ι
3.0
23.5
17.8
track
track

Finally, if you change the molar ratio of phloracetophenone to sodium methylate to methyl iodide from to ι: ι: 2 (= »monomethylation«), 1: 2: 4 (= * dimethylationff) and 1: 4: 8 (= »tetramethylation«), the following yields are obtained under otherwise similar conditions:.

Molar ratio

Yield (° / ₀ der 4th Theory' 6th at track the examples 5.3 5 5.4 track 4, o 35.8 25.2 30.8

Example 7

l-phenacetyl-3, 3, S-trimethyl-cyclohexa-i, 5-diene-2, 6-diol "4-one

OH

COCH ₀
I-OH

CH ₃

Example 8

i-Phenacetyl-3, 3, 5-triethyl-cyclohexa-i, 5-diene-2, 6-diol "4-one

OH

COCH,

5 g of phlorphenacetophenone, 1.41 g (3 equivalents) of sodium, dissolved in 25 ecm of methanol, and 17.5 g of methyl iodide (6 mol) are reacted and worked up as is customary in the above methylation batches. A brownish oil is obtained from the bicarbonate fraction during acidification, which is then extracted with ether. After the ether has evaporated, 3.42 g of a reddish resin remain, which is dissolved in 10 ecm hot benzene and mixed with 20 ecm petroleum ether (b.p. 40 to 60 °) crystallizes out in colorless prisms; Yield 2.49 g (42.5% of theory); 135-138 °; after recrystallization from dilute methanol or benzene, F. 143 ⁰ .

OH

4 g phlorphenacetophenone, 1.13 g sodium (3 equivalents) , dissolved in 20 ecm of absolute methanol, and 15.32 g of ethyl iodide (6 mol) are reacted with one another and worked up. The main part of the above compound is only found in the soda fraction; Bicarbonate and soda fraction are united and acidified; the precipitated brown oil is extracted with ether and the resinous residue (3.34 g) remaining after evaporation of the ether was dissolved in 4 ecm of benzene and on »silica gel, active, standardized according to Riedk (in

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R 13691 IVb / 12 q

Benzene suspension) (manufacturer: E. Merck, Chemische .Fabrik, Darmstadt) chromatographed: Column height 6.5 cm, diameter 2 cm, development with 130 ecm absolute benzene. The eluate (134 ecm) is evaporated and taken up in hexane; the The above compound, which precipitates out as an oil, solidifies to coarse crystals when standing in the refrigerator; Yield 1.64 g (3 °> 5% of theory); 94 to 96 °; after recrystallization from dilute methanol or hexane, F. ioo °.

Examples 9-15

Following the same procedure and using the usual methods, the following are also made Compounds of type (D) (or tautomeric forms) are given:

OH

example
No. ethyl Gross formula F. yield
(° / o the n-propyl Theory) 9 n-butyl QuH ₂₀ O ₄ 148 ° 43 IO Isobutyl Ci ₇ H ₂₆ O ₄ 107 ° 54 II n-amyl ^ 20- ^ 32 ^ 4 122 ° 43 12th n-hexyl ^ 20 ^ 32 O ₄ 157 ° 42 n-hexadecyl ^ 23 ^ 38 O ₄ 101 ° 30th ^ 2 6 H ₄₄ O ₄ 8 ₄ ° 41 15th COeH ₁₀₄ O ₄ 73 ° 28

Example 16
i-acetyl-3, 3, 5-triisoamyl-cyclohexa-i, 5-diene

2,6-diol "4-one
(= »Hexahydro-aceto-lupuphenonec)

OH

(CHg) ₂ CHCH ₂ CH ₂ - ^
O =

COCH ₃
OH

(CHg) ₂ CHCH ₂ CH ₂ CH ₂ CH ₂ CH (CH ₈ ) ₂

a) 23 g of isoamyl iodide (6 mol) are added with cooling to a solution of 4 g of phloracetophenone and 1.64 g of sodium (3 equivalents) in 20 ecm of absolute methanol. After standing 5 days at room temperature, the clear red solution is about p _H 9 The mixture is acidified with 6 cc η 2-hydrochloric acid and the methanol is evaporated and the excess Isoamyljodid from (last in vacuum). The remaining oil is dissolved in 50 ecm of methanol, 100 ecm of warm petroleum ether (b.p. 40 to 60 °) is added and the mixture is diluted with 50 ecm of 2% sulfuric acid. It is shaken quickly and the petroleum ether layer is separated off, the above compound already largely crystallizing out. The aqueous methanolic layer is extracted twice with 100 ecm warm petroleum ether each time. The combined petroleum ether extracts separate on standing 2.96 g (33% of theory) colorless fine prisms with a mp of 154 to 157 °; after recrystallization from 8o ° / ₀ methanol F. 161-162 °. . - _,; .,:.: ..

b) The analog approach using the still less reactive Isoarnylbromids also leads to the above compound at a yield of 13.3 ° / ₀ of theory. _: . ■ ■. ■ !.

Example 17

i-acetyl-3, S-dimethyl-s-ethyl-cyclohexa-i, 5-diene-2, 6-diol "4-one

OH

CH ₃ C ₂ H ₅ ⁸ S

5 g of anhydrous 3, 5-dimethyl-phloracetophenone are dissolved in 50 ecm of absolute methanol and, with cooling, added to a solution of 0.586 g (1 × 25.5 milliequivalents) of sodium in 10 ecm of methanol. With further cooling, 8 g of ethyl iodide (2 × 25.5 millimoles) are added and the deep red-brown solution is left to stand for 10 days at room temperature with the exclusion of moisture and air. Then the methanol and the excess methyl iodide are distilled off in vacuo at 40 °, and the residue is taken up with 40 ecm of water and ether. After acidification with 40 cc of 2 ° / _o sulfuric acid by shaking the aqueous solution is still twice with 30 cc of ether and extracted the combined colored ether extracts deep red successively with, first, a saturated aqueous sodium bicarbonate solution (4 χ 30 cc), second io ° / ₀ iger aqueous soda solution (4 Χ 30 ecm) and thirdly 2 N sodium hydroxide solution (3 X 30 ecm). When the bicarbonate solution is acidified, a brown precipitate forms; Yield 2.1 g (36.8% of theory); F. 135 to 138 ⁰ . After recrystallization from 100 3O ° / ₀ methanol ECM gives the above compound in the form of long, flat prisms, mp 141 °. no

Example 18

i-Acetyl-3-methyl-3, 5-diethyl-cyclohexa-i, 5-diene-2,6-diol "4-one

OH

COCH ₃
OH

CH

In an analogous approach to Example 17, 5 g of 3-methyl-phloracetophenone, dissolved in 30 ecm Methanol, with a solution of 1.26 g of sodium

548/5 «

R 13691 IVb / 12 q

(2 X 27.4 milliequivalents) in 15 ecm of methanol and reacted with 17.1g ethyl iodide (4 X 27.4 millimoles) and worked up. From the bicarbonate-soluble fraction one obtains the above connection; Yield 2.8 g (43% of theory), in square, long prisms from 115 ° (from dilute methanol).

Claims (1)

Claim ·. Process for the preparation of ring-alkylated phloracylophenones by reacting the metal compounds of the phloracylophenones or of their nucleus-alkylated derivatives with alkyl halides in strongly dissociating solvents, characterized in that one inert alkyl halides used. Considered publications:
German patent application K 11340 IVc / I2q
(now Patent No. 899 198).