DE1048589B - Process for the production of xanthene derivatives - Google Patents

Description

The invention relates to a process for the preparation of new xanthene derivatives and their acid addition salts, which is characterized in that optionally by alkyl, aralkyl, aryl, alkoxy, Aralkoxy, aryloxy, alkylthio, aralkylthio, arylthio, halogen, protected acyl, protected amino, protected Xanthones or thioxanthones substituted by hydroxyl or protected carboxyl groups in a manner known per se reacts with non-aromatic tertiary aminopropyl metal compounds, hydrolyzes the reaction products, splitting off any protective groups present and, if desired, those obtained. Xanthenols or Thioxanthenols converted into acid addition salts. As organometallic compounds are preferred by a dialkylamino, e.g. B. the dimethylamino group, * 5 propyl metal compounds substituted for the morpholino, pyrrolidino or piperidino group are used.

The invention also includes the preparation of the acid addition salts of the aforementioned xanthene and thioxanthene compounds. Such salts are e.g. B, those with inorganic acids, such as hydrochloric acid, Hydrobromic acid or sulfuric acid, or with organic acids such as oxalic acid, citric acid, acetic acid, Lactic acid or tartaric acid.

The preparation of the starting materials required for the process according to the invention takes place in accordance with itself known methods.

For carrying out the first reaction stage of the process according to the invention, in particular Use magnesium, lithium and organozinc metal compounds. In a preferred embodiment, the xanthones or thioxanthones are either in solid, finely powdered form or in an inert organic solvent, such as. B, absolute ether, Benzene or tetrahydrofuran, to that in such an organic inert solvent Magnesium compound of a tertiary aminopropyl halide was added. After the implementation is complete, the Reaction product; subjected to hydrolysis. Particularly advantageously designed, the decomposition of the resulting organic metal compound under practically neutral conditions, e.g. B, by hydrolysis in aqueous Ammonium chloride solution. In this way, the resulting xanthene containing basic groups or thioxanthene compounds directly in free form and can be obtained immediately by treatment with suitable, water-immiscible organic Solvents such as B. ether, ethyl acetate, chloroform or methylene chloride, of the by-products: the reaction are separated and isolated.

Any acyl,. Amino, hydroxyl and carboxyl groups must be before the. Sales; protected with the organometallic compound, to a. Reaction of these groups with the organometallic process for their production
of xanthene derivatives

Applicant:

F. Hoffmann-La Roche & Co.

Corporation,

Basel, Switzerland)

Representative: Dr. G. Schmitt, lawyer,
Loerrach (Bad.), Friedrichstr. 3

Claimed priority:
Switzerland from June 12 and June 29, 1956

Dr. Karl Doebel, Dr. Gerald Rey-Bellet,
Dr. Reinhard Schläpfer and Dr. Hans Spiegelberg,

Basel, Switzerland),
have been named as inventors

To prevent reagent. These protective groups are usually split off at the same time as the hydrolytic one Breakdown of organic metal compounds.

The obtained in the 9-position by a basic Side chain substituted 9-xanthenols and 9-thioxanthenols and their acid addition salts are varied by Excellent effects on the nervous system. So are narcosis-potentiating, adrenolytic, sedative, antihistamine, antipyretic and hypothermic effects have been noted, these effects depending can vary according to the substituents. The new compounds are intended to be used as remedies.

Compared to the known /? - (9-Thioxanthy, l) -äthyltrimethylammoniumchlorid, 9- (ß- Diethylaminoäthyl) -thioxanthene and 9 - (/ 3-Dimethylaminoäthyl) -thioxanthene (US Pat. Nos. 2,368,006 and 2,676,971) have the Process products, in particular 9- ( γ-dimethylaminopropyl) -thioxanthenol- (9), 9: - {γ -dimethylaminapropyl) -xanthenoL · (9), 9- (γ-piperidinopropyl) -xanthenol- (9)., 2-methoxy -9- (γ-dimethylaminopropyl) -thioxaiithenol- (9) i, 2-bromo-9- (7-dimethylaminopropyl) -thioxanthehol- (9) and 1-methoxy-4-chloro-9- (γ-dimethylaminopropyl-tMeH xanthenol- (9), significantly stronger: anesthetic potency. '''* _:

. . -. I 809729/288

3 4

Example!. shaken twice with 200 ecm of ether each time, and the

In a 1-1 flask equipped with a stirrer, dropping funnel and combined portions of ether are poured over sodium sulfate Is provided with a reflux condenser, 2.5 g of Gilmansche are dried and evaporated. The residue delivers Alloy covered with 10 ecm dry ether and dissolving from ethyl acetate colorless crystals of 9- (y-Pimit 0.5 ecm of methyl iodide added. After the lively 5 peridinopropyl) -xanthenol- (9), which at 144 to 145 ° C If the reaction has waned a little, they will suddenly melt. !

7.5 g of magnesium shavings are added, and a solution, B _e j _s i _e l 4

of 40 g of freshly distilled ω-dimethylaminopropyl

chloride in 180 ecm dry ether in the course of one hour 2.0 g of activated Gilman's alloy and 1.6 g not

added dropwise. The copper-magnesium alloy activated under reflux for 5 hours at 40 ° C. is boiled in a cooler and then placed overnight at room temperature. The following day, a suspension of and dropping funnel is fitted, and 20 g of finely powdered xanthone in 400 ecm of dry ether is poured over it. Furthermore, a trace of iodine is gradually added to the ether with continued stirring. given. Now 10 to 12 drops of ethyl bromide are added. The whole thing is stirred for another 20 hours at 20 to 25 ° C. * 5 and waited until a vigorous reaction has developed - then the reaction mixture is cooled with ice water. As soon as the same has set in, a solution of 16 g of ω-dimethylamino is slowly added dropwise and a solution of 16 g of ω-dimethylamino is slowly added to a cold saturated ammonium chloride solution. The organic layer is separated off and the propyl chloride in 30 ecm of absolute ether is added, the aqueous solution being moved twice with 100 ecm of ether each time, and the stirrer is only moved from time to time. As soon as it shakes and the combined portions of ether slow down the reaction, the reaction vessel is dried over sodium sulphate and evaporated. The immersed a heating bath of 50 ⁰ C, the stirrer delivers in ■ residue, set after recrystallization from high motion and continued for 4 hours he stirred to boiling petroleum ether, colorless crystals of 9- (y-Di- the reaction completely lead end be methylaminopropyl) -xanthenol- (9) grams at 109-110 ⁰ C 6.0 thioxanthone portionwise in solid form is melt. thereto. 25 wear and ^{stirred at 50 0} C until the yellow color

Example 2 ^ ^it thioxanthones has disappeared and the reaction

mixture has colored gray-white. Now the room

Cooled the reaction mixture in a well with a cooler, stirrer and dropping funnel provided 1-1-round-bottom beri are 2.5 g Gilmansche cooled solution of 20 g ammonium chloride in 300 ecm Alloy covered with 20 ecm dry ether and poured 3 ° water, add 200 ecm ethyl acetate 0.5 ecm of methyl iodide added. Once the lively joined and well stirred. The entire mixture is from Reaction subsides somewhat, 7.5 g of a little undissolved sludge are freed all at once by suction filtration, Magnesium shavings are added, and a solution of 40 g freshen up the organic layer in a separatory funnel distilled co-dimethylaminopropyl chloride in separates, dried with sodium sulfate and in vacuo 180 ecm of dry ether is freed from the solvent in the course of one hour. The residue will be off added dropwise. It is recrystallized for a further 5 hours at 40 ° C. on re-high-boiling petroleum ether. You get River cooler and then boiled overnight at room 7.2 g of coarse, yellow-white crystals of 9- (γ-dimethyl temperature touched. The following day, a suspension aminopropyl) thioxanthenol (9) with a melting point of 147 sion of 23.5 g finely powdered 2-chlorxanthone in up to 148 ° C.

400 ecm of dry ether little by little while stirring 40 Beist> iel5

admitted. The whole thing is stirred for another 20 hours

20 to 25 ° C. Then the reaction mixture with ice 1.0 g activated Gilman's alloy and 1.0 g not

water-cooled and with a cold saturated ammonium-activated copper-magnesium alloy are in one chloride solution added. The organic layer is discharged from the 250 cc three-necked flask equipped with a stirrer, condenser separately, the aqueous solution is equipped twice with 100 ecm 45 and a dropping funnel, and with 10 ecm abso ether shaken, and the combined ether portions covered with pure ether. A trace of iodine will also be added dried over sodium sulfate and evaporated. joined. Now 5 drops of ethyl bromide are added, The residue yields after dissolving from ethyl acetate - and then you wait until a vigorous reaction occurs Petroleum ether has developed colorless crystals of 2-chloro-9- (y-dimethyl-. When this has set in, one drips aminopropyl) -xanthenol- (9), which slowly melts a solution of 9.0 co-dimethylaminopropyl at 129 to 130 ° C 50. chloride in 20 ecm of absolute ether, with the

Example 3 stirrer is occasionally moved by hand. As soon as the

Reaction slows down, the reaction vessel is turned into one

Immersed in a 50 ° C heating bath with a cooler, stirrer and dropping funnel, the stirrer in motion 5 g Gilmansche 55 are placed on the 2-1 round bottom flask and the mixture is stirred for a further 4 hours in order to remove the reac alloy Covered with 20 ecm of dry ether and carried out completely. Thereupon 4.0 g mixed with 1.0 ecm of methyl iodide. After the lively 2-chloro-thioxanthone in portions in solid form to reaction Has subsided, 50 g are added all at once and stirred at 50 ° C until the yellow Magnesium shavings were added, and a solution of 70 g of color of the 2-chloro-thioxanthone has disappeared and freshly distilled co-piperidinopropyl chloride in 360 ecm 60 the reaction mixture assumed a gray-white color dry ether is added dropwise over the course of an hour. Has. Now it is cooled to room temperature, that The reaction mixture is poured into a well-cooled solution of 15 g in a reflux condenser for a further 6 hours at 40.degree boiled and then poured ammonium chloride into 200 ecm of water overnight at room temperature, 150 ecm touched. The following day a suspension of 40 g of ethyl acetate is added and it is stirred well, finely powdered xanthone in 800 ecm dry ether 65 The entire mixture is made of little undissolved gradually added with stirring. The whole thing stirs sludge 'freed by suction, the organic the mixture is kept at 20 ° C. for a further 20 hours. The reaction layer is then separated off in a separatory funnel with a sodium mixture cooled with ice water and dried with a cold sulfate and removed in vacuo from the solvent saturated ammonium chloride solution added. The or- freed. The residue is made from high-boiling organic petroleum The layer is separated off and the aqueous solution 70 is recrystallized in ether. Prismatic needles are obtained

5 6

of 2-chloro-9- (γ-dimethylaminopropyl) -thioxanthenol- (9) Example 12

from melting point 148 to 150 ⁰ C. Starting from 4-methoxy-thioxanthone, according to the

. procedure described in Example 5, the 4-methoxy

tf eispiei 6 9- (y-dimethylaminopropyl) -thioxanthenol- (9), melting

In a manner analogous to Example 5, 4.66 g of 5 point 119 to 121 ^° C. are produced,

activated Gilman alloy and 1.0 g inactive. .. ,,

fourth copper-magnesium alloy with ω-dimethyl. - ^. Example. Io

aminopropyl chloride and 4-chloro-thioxanthone implemented. Starting from 3-methoxy-thioxanthone, according to the procedure described in Example 5, the 4-chloro-9- (y-dimethylaminopropyl) formed in this way melts after recrystallization 10 9- (y -dimethylaminopropyl) -thioxanthenol- (9), melt from a mixture of benzene and high boiling point 108 to HO ⁰ C, made.

Petroleum ether at 129 ° C.

Example 14

^els P ^le Starting from 1-methoxy-thioxanthone is after the

Starting from 3-chloro-thioxanthone, the 1-methoxy-

the procedure described in Example 5, the 3-chloro-9- (y-dimethylaminopropyl) -thioxanthenol- (9), melting

9- (γ-dimethylaminopropyl) thioxanthenol- (9); Melting point 126 to 128 ⁰ C obtained.

point 104 ⁰ C.. . ■

Example 15

20 Starting from l-chloro-4-methoxy-thioxanthone is

After the procedure described in Example 5 according to the procedure described in Example 5 the 2-bromo-9- (y-di- l-chloro-4-methoxy-9- (y-dimethylaminopropyl) thioxanemethylaminopropyl) is obtained from 2-bromothioxanthone - thioxanthenol - (9); Melting point thenol- (9), melting point 96 to 98 ° C.

139 to 140 ° C. '"··, <*

Example 16 Example 9 ²⁵

Starting from l-methyl-4-methoxy-thioxanthone is

Starting from 2-fluoro-thioxanthone, the procedure described in Example 5 is followed Example 5 described procedure the 2-fluoro-9- (y-di- l-methyl-4-methoxy-9- (y-dimethylaminopropyl) -thimethylaminopropyl) - thioxanthenol - (9); Melting point oxanthenol- (9), melting point 133 to 134 ° C.

171 to 172 ° C. 30th

Example 17

Example 10 Starting from 1-methyl-4-chlorothioxanthone becomes

4.66 g of activated Gilman's alloy and 3.75 g according to the procedure described in Example 5

unactivated copper-magnesium alloy are converted into the l-methyl ^ -chlor ^ -fy-dimethylaminopropy ^ -thioxan-

brought a 750 ccm ground joint three-necked flask containing 35 thenol- (9), melting point 150 ° C.

Equipped with stirrer, reflux condenser and dropping funnel. .

is. The ingress of air humidity is controlled _{through CaCl 2 pipes}

activity prevented. The copper-magnesium alloy Starting from l-chloro-4-methyl-thioxanthone is

is now covered with 30 ecm of absolute ether and carried out according to the procedure described in Example 5

Addition of 25 drops of ethyl bromide, the reaction causes the l-chloro-4-methyl-9- (y-dimethylaminopropyl) -thio-

starts. A solution of 37.5 g of xanthenol- (9), melting point 137 ° C., is then slowly obtained.

ω-Dimethylaminopropyl chloride in absolute ether back _.

added, the stirrer only slowly from time to time. Example 19

is moved. As soon as the reaction slows down, starting from 2-chloro-7-methoxy-thioxanthone will be

the reaction vessel is immersed in a heating bath of 5O ⁰ C, 45 according to the procedure described in Example 5 that

the stirrer is set in motion and 2-chloro - 7 - methoxy - 9 - (y-dimethylaminopropyl) - thio-

kept stirring to complete the reaction. xanthenol- (9), melting point 162-164 ° C.

Then a solution of 20 g of 2-methyl-thioxanthone

Example 20 is added dropwise in absolute benzene over the course of 10 minutes and the mixture is stirred at 50 ^° C. for a further 12 hours. Then 50 starting from 2,7-dibromothioxanthone, the mixture is cooled to room temperature, the procedure described in Example 5 2,7-dibromine reaction mixture in a well-cooled solution of 100 g of 9- (γ-dimethylaminopropyl) - thioxanthenol- (9), melting ammonium chloride poured into 500 ecm water, 500 ecm point 209 to 210 ⁰ C, produced. . Ethyl acetate are added and it becomes

well stirred. The entire mixture is of little unsatisfactory 55 Example 21

freed dissolved sludge by suction filtration, the organic to a Grignard solution, which is activated from 4.66 g

Layer separated in a separatory funnel and the copper-magnesium alloy (according to Gilman) and 3.75 g

aqueous phase extracted several times with ethyl acetate. non-activated copper-magnesium alloy and 37.5 g

The combined ethyl acetate extracts are prepared with sodium ω-dimethylaminopropyl chloride

sulfate well dried and after filtration in vacuo 60 an absolute benzene solution of 15 g of 2-acetyl-thio-

freed from solvent. The crystalline residue xanthone monoketal is added dropwise. After finished

is recrystallized from high-boiling petroleum ether. The mixture is allowed to stir for a further 4 hours at 40 ^° C. and

receives 18 g of 2-methyl-9- (γ-dimethylaminopropyl) - then poured into an aqueous ammonium chloride solution.

thioxanthenol- (9) from melting point 118 to 119 ° C. The condensation product is extracted by using

. 65 ethyl acetate separated, the ethyl acetate extracts are with

eispie 11 dried sodium sulfate and evaporated in vacuo.

Starting from 2-methoxy-thioxanthone after the The residue in the form of a golden oil is in

the procedure described in Example 5, the 2-methoxy. high-boiling petroleum ether dissolved cold, by a few

'9- (y-dimethylaminopropyl) -thioxanthenol- (9), melting flakes freed by filtration and the filtrate again in the

point 117 to 118 ° C. 70 evaporated vacuum. The residue is dissolved in methanol

dissolved, treated with 200 mg of p-toluenesulfonic acid and refluxed for 1 hour. It is then evaporated in vacuo, the residue is taken up in 1N hydrochloric acid and extracted once with ethyl acetate. The red, aqueous phase is made alkaline with sodium hydroxide solution while cooling well with ice, extracted again with ethyl acetate, the extracts are dried with sodium sulfate and evaporated in vacuo. 18.0 g of oil remain, which crystallizes on trituration with low-boiling petroleum ether. After recrystallization from high-boiling petroleum ether, 2-acetyl-9- (γ-dimethylaminopropyl) -thioxanthenol- (9) is obtained in the form of beautiful rosettes with a melting point of 93 to 94 ° C.

Claims (3)

Claims; 1S 1. Process for the production of xanthene derivatives or their acid addition salts, characterized in that optionally by alkyl, Aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkylthio, aralkylthio, arylthio, halogen, protected Acyl, protected amino, protected hydroxyl or protected carboxyl groups substituted xanthones or thioxanthones in a manner known per se with non-aromatic tertiary aminopropyl metal compounds converts, hydrolyzes the reaction products, splits off any protective groups present and optionally the xanthenols or thioxanthenols obtained are converted into acid addition salts. 2. The method according to claim 1, characterized in that the organometallic compounds Dialkylaminopropyl metal compounds can be used. 3. The method according to claim 2, characterized in that the organometallic compounds Dimethylaminopropylmagnesium compounds can be used. Considered publications:
U.S. Patent Nos. 2,368,006, 2,676,971;
Journal of the American Chemical Society, 48, pp. 1752-1954 (1926). © 809 '729/288 1.59