DE1445891A1 - Process for the production of isopropanols - Google Patents

Description

RAN 4007/2

Po Hoffmann- La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Process for the production of isopropanols

The invention relates to a process for the preparation of new isopropanol derivatives of the general formula

in which X is a hydrogen atom, a halogen atom or a lower alkyl group, i.e. an alkyl group

Hof / Og / Br
Coil. Dn / Ah
February 27, 1964

809810/1316

- 2 - 14458S

with 1-6 carbon atoms, a lower alkoxy group or a lower alkyl mercapto group, and in which η represents the integer 1, but with the restriction that if X is present in the meaning of alkoxy η can also mean the number 3,
and acid addition salts of these compounds.

The inventive method is characterized in that a 4-Plcolyl metal compound with a Compound of the general formula

III

in the R ^! represents a halogen atom or an alkoxy, benzyloxy, or a phenoxy group and X and η have the meanings given above,

converts and, if desired, the compound obtained is converted into a salt, ζ "Β" by the action of hydrochloric acid _s sulfur

Nitric acid _s p-toluenesulfonic acid etc. -

In a preferred embodiment of the invention

809810./.1.316,. ORlSINAL! MSPECTED

according to the procedure, a 4-picolyl-metaH compound is used the general formula

CH ₂ M

II

in the M an alkali metal, such as sodium, Represents potassium or lithium, with a compound of the general formula

O-Hal

III (aj

in which Hai means a halogen atom and X has the meaning given above,

As compounds as defined by Formula IHa are., for example, are used? Benzoyl chloride, halogen-substituted benzoyl chlorides, such as, for example, 3-fluorobenzoychloride, 4-fluorobenzoyl chloride, 4-chlorobenzoyl- " Chloride etc. or lower alkyl-substituted benzoyl chlorides,

809810/1316

- ■■■ £ -

such as p ^ toluic acid chloride; etc ^, allsGs ^ ubj ^ tuated ^ Bgnzogr3 ~ chloaride, like methoxylaenzoylchlQrid or lower alkyJmer benzpylchloride, like W ^ h ^ lmero ^^ pyienZOYOLGTaloTtu .. If desired, instead of chlorides; other halides are used.

In another previous embodiment of the invention In the process, put the: ^ Ekeolyl-MetalJ ^ er. Mndxuig of the Bormel 1: 1: with ;, one c ¥ erbindiang / the general -

. GOOE '.

in (b)

in which R is a lower Alfcylgruppe, d _o ho is an alkyl group with 1-6 Eohlenst off atoms, such as methyl, ethyl ₉ propyl, isopropyl, butyl, isobutyl, pentyl or a hexyl or a benzyl group, and in which X and η the have the meaning given above,

around. As compounds, as defined by formula IIIb, to use alkyl esters of benzoic acid such as methyl benzoate, Ethyl benzoate, etc., alkyl esters of alkyl-substituted benzoic acids, such as methyl tolate,

0 ^ 98 10/1316

Ethyl toluate, etc., alkyl esters of halogen-substituted benzoic acids, such as methyl chlorobenzoate, ethyl chlorobenzoate, methyl fluorobenzoate, ethyl fluorobenzoate, etc; Benzylic acid esters, benzylic esters of alkyl-substituted benzoic acids such as benzylic acid toluic acid esters; Benzyl esters of halogenated benzoic acids such as benzyl chlorobenzoate e benzyl luobenzoate; Alkyl esters of lower alkoxy _t ζ . B ο jnethoxy-substituted benzoic acids, alloys e .3 äer of alkyl (eg methy3 -) - mercapto-substituted benzoic acids; Benzyl esters of methoxy-substituted benzoic acids or benzyl esters of methylmereaptosubstituted benzoic acids «,

In a further preferred embodiment of the inventive method, a compound of formula II is reacted with benzoic acid phenyl ester or with a low-substituted alkyl-benzoates ₉ a halogen-substituted phenyl benzoate an alkoxy, for example methoxy Phenylbenzoesäureester or an alkyl reacted mercaptobenzoesäurephenylester - (such as methyl -). Thus, for example, as a starting material Methylbenzoesäurephenylester, Aethylbenzoesäurephenylester, Propylbenzoesäurephenylester, Chlorbenzoesäurephenylester, Brombenzoesäurephenylester, methoxy benzoates _t Methylmercaptobenzoesaurephenylester etc. for the method to use.

809810/1316

In a further preferred embodiment of the process according to the invention is 4-picolyl magnesium bromide. Likewise a 4-picolyl metal compound for the purposes of this invention - with phenyl benzoate or with an alkyl-substituted, halogen-substituted, alkoxy-substituted or an alkyl mercapto-substituted phenyl benzoate of the same type as described in the previous paragraph, implemented.

When carrying out the method according to the invention a ratio of at least 2 mol; -4-picolyl metal compound is preferred per mole of those compound as they go through Formula III is defined is used. Leave if desired however, higher or lower concentrations also apply Use 4-picolyl metal compound o

The following is a preferred embodiment of the Described method according to the invention. First, a 4-picolyl metal compound, for example 4-picolyl magnesium bromide made in an organic solvent. In general, any organic solvent in which the 4-PiCOlyl metal compound is soluble, use. Particularly Solvents such as benzene, diethyl ether, toluene, TPicQlin, tetrahydrofuran, etc. have proven to be useful. Mixtures of these solvents can also be used.

. 809810/1316

_ ₇ 1445S81

Solution of the ^ !! icolyl metal compound in one, inert organic solvent is heated to a temperature ■ below room temperature, expediently to temperatures between -10 ° C and -60 ° C, cooled down »Then the reaction partner defined by formula III, dissolved in one suitable © solvents, to the cooled solution of the 4-picolyl metal compound added. For the preparation of the above solution, anything organic can be inert under the reaction conditions Use solvents «. Such solvents are z ", B" ethyl ether, n- ^ tylether, dioxane, tetrahydrofuran xiswo, either as such, odej? ipi mixture with each other "under the reaction conditions" inerteai solvent »

When giving the reactants a low temperature, preferably between -10 ° 0 and -60 ° C. After the two reactants have been given, cooling is continued until the reaction has ended for about one hour at a temperature between -10 ° C. and -60 ° C., then stirred for a further hour at room temperature. When the reaction is complete, the reaction mixture is worked up and the eyridyl compound thus produced is isolated. The crude product can be purified by the usual methods “Both the cleaning and the work-up methods are obvious to a person skilled in the art and a more detailed description is superfluous * sioho

809810/1316

The compounds of the general formula I and their acid addition compounds are suitable for combating pathological conditions which are characterized by the occurrence of a tremor. For example, a tremor caused by 1,4-dipyrrolidino-2-but, in is greatly reduced in animals or made to disappear entirely. In addition, the compounds which can be prepared according to the invention are suitable for the treatment of Parkinson's disease, since here too they either completely prevent or at least extremely greatly reduce the tremor, which is a characteristic symptom of this disease. It is noteworthy that, in contrast to conventional agents for the treatment of Parkinson's disease, the compounds according to the invention do not show any peripheral anticholinergic activity. The process products can be used as medicaments, for example in the form of pharmaceutical preparations, which they or their salts mixed with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as water, gelatin, lactose, starch, magnesium stearate, TaIk _{Contains 5} vegetable gels, gums, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions; -, wetting or emulsifying agents, salts to change the osmotic

809810/1318

Pressure or buffer. You can also do others therapeutically contain valuable substances

The following examples illustrate this inventive method, but do not limit it. All temperatures are given in degrees Celsius.

Example 1 ,

Its solution of 3.5 moles of phenyllithium in 1.89 liters of ether / benzene is added with stirring over a period of 3 1/2 hours to a solution of 326 g (3> 5 moles) of 4-picoline in 800 ml of tetrahydrofuran Given nitrogen. After completion of the addition witere 15 minutes stirring, then the reaction mixture cooled to about -2O ^0th 4-picolyl-lithium is obtained by transmetalation.

To the thus obtained 4-picolyl-lithium solution a mixture of 197 _g of benzoyl chloride (1.4 mol) in 100 ml of tetrahydrofuran over 50 minutes while the temperature is maintained at about -20 ** g. A pale green solution is obtained, which is stirred for a further 60 minutes at -20 °. The reaction solution is warmed to room temperature and stirred for a further 60 minutes. There are now added dropwise ml of water, then, with vigorous stirring, the reaction mixture is diluted with one liter of water and the resulting

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The solution is poured into a separating funnel. »It is acidified with 800 ml of 6N hydrochloric acid and the organic phase is separated, which in turn is extracted twice with 200 ml of 3N hydrochloric acid each time.» The acidic extracts are combined, 3 times with 500 ml each time Toluene and then washed again with 500 ml of ether. 5 g of ice are now added to the acidic extract and then made alkaline with ammonium hydroxide _Λ while maintaining a temperature of approx. 10 ° * When the acidic extract is treated with the base, a precipitate is formed The precipitate is then carefully digested with a mixture of 400 ml of methylene chloride and 600 ml of water. The insoluble residue is filtered off and twice with 200 ml of water each time, twice with 200 ml of methylene chloride each time and once washed with 200 ml of ether. The product is then dried at 50 and 20 torr for 15 hours, 2-phenyl-13-di (A-pyridyl) -2-propanol, which first melts at 92-99P, is obtained, and after solidification and reheating shows a melting point of 166-168 °.

Example 2

With stirring, 0.5 mole of 4-Picolyi-iithium at a temperature of -30 ° to -50 ⁰ to be 0.2 Möl p-toluic, geiöst in 100 ml tetrahydrofuran. This addition takes place under nitrogen and the dripping speed is adjusted in this way.

lierfc that all the acid chloride has dripped in after approx. 60 minutes. The reaction mixture is stirred overnight, then diluted with 100 ml of water and extracted three times with 150 ml of 6 η hydrochloric acid each time. The acidic extracts are combined and washed three times with 150 ml of ether each time. The desired product is precipitated by adding a mixture of 5 ° C. Sis and 300 ml of ammonium hydroxide to the acidic solution * while maintaining a temperature of approximately 0 °. The precipitate is filtered off in the form of a brown, semi-solid mass and then carefully digested with a mixture of 300 ml of methylene chloride and -300 ml of water. The residue is filtered off and recrystallized three times from a mixture of acetone and water. Colorless platelets of 1,3-di (4 ~ pyridyl} -2- (4-methyl-phenyl) -2-propanol are obtained, which melt at 100-110 ° and, after solidification, have a melting point of 160- when heated again. 16I ⁰ show.

Example "5

In this example the preparation of 2- (5-fluorophenyl) -1, 3-di (4-pyridyl) -2-propanol in analogy to the procedure in Example 1 described

In this case too, the reaction mixture is extracted with acid and the desired product is obtained by treatment with concentrated ammonium hydroxide solution, the red precipitated

' 809810/1316

semi-solid precipitate is stirred vigorously with a mixture of 3OO ml of water and 200 ml of methylene chloride and the residue is filtered off, recrystallized three times from a mixture of acetone / water to give 2- (3 ~ fluorophenyl} -l _a 3-di (4-pyridyl) -2-propanol is obtained, which melts at 108-112 °. After solidification and renewed melting, the compound has a pour point of 189-19I ⁰ »" ■ _.

Example 4

In this example, the preparation of 2- (4 = fluo-, orphenyl) -l _J , 3-di (4-pyridyl) -2-propanol is carried out in analogy to the procedure given in Example 2, by adding only 4-fluorobenzyl chloride instead of p-toluic acid chloride: used as starting material «.

The precipitate, which separates out when the acidic extract is treated with concentrated ammonium hydroxide solution, is filtered off and vigorously stirred with a mixture of 40 ml of methylene chloride and 400 ml of water , 3-ai (4-P2rridyl) -2-propanol _{Jf is obtained} in the form of colorless crystals, "is recrystallized from a mixture of acetone / water and colorless platelets are obtained, which first melt at 122-125, after solidification and again Melts show a pour point of 155.5 "15T«

9810/1316

144SfSt

Toil 35, Ö g {Ö _S 2 mol) p-chloro-benzoylönlorid in 25 AL anhydrous tetrahydrofuran is added slowly over a period of 20 minutes with stirring to an Oj 5 iööla # ent MSuiig of 4-picolyl-lithium «whereby one Temperature of -SICJ ^{0 is} maintained. After the addition matt ext-ärrafe is stirred at Ainet ¹ temperature of -20 ° for 30 minutes then stirred for at room temperature and for another hour. 800 ml of water are added to the reaction mixture, which is then acidified with 3 η hydrochloric acid. They form two layers. The organic phase is separated and zweiä & I Mt 200 ml 3 η hydrochloric acid shaken * The acids iöEferstMte are combined ^ gewasöhtn three times with 300 ml Äethör, wku then made alkaline with 10 η sodium hydroxide solution diluted to a volume of 4 liters of ice water. The mixture is left to stand for 18 hours, the precipitate which has separated out is filtered off, washed with 500 ml of water and then digested with a mixture of 200 ml of water and 50 ml of methylene chloride for about 30 minutes. The residue is crystallized from aqueous acetone and 2 - {4-chlorophenyl) -1,3-di {4-pyridyl) -2-propanol is obtained as pale yellow prisms, which are initially at 87-102 ° and after solidification and renewed melting show a flow point of 181-183 ⁰ »

“$ 9,810 / $ 131

g "t.G. * lX Hol) N-BEOmUSnZOyIeAlOrIXi, in 125 ml

tetrahydrofuran are dissolved; with stirring over a period of 75 minutes into a 0.5 molar solution of 4-Heo; lyl ^ litMuffi, the temperature of the reaction mixture being kept at -40 °, and after the addition at: i this temperature a further 60 minutes. The mixture is warmed to room temperature and stirred for a further 60 knuts. 800 ml of water are added to the reaction mixture and the same is acidified with 1N hydrochloric acid. Two layers are formed, the organic phase is separated off and extracted twice with 200 ml of 3 Å hydrochloric acid each time. The satirical figures are combined, washed three times with 500 ml of ether each time, then mixed with 10% atriamine hydroxide solution, cooled and extracted again three times with 200 ml of methylene chloride each time. The methylene chloride extracts are combined, washed three times with 200 ml of water each time and then evaporated. © as so erlialtene oil is digested three times with $ s ~ wells 25ο ml ^ water. The oily residue is then made to crystallize by rubbing with acetone.

-pyridyl) ⁱ -2-propanol in the form of colorless prisms,

which melt at 15Ä-157 ⁰

80

3 g of the product prepared according to the instructions given in the previous section become 100 ml Given methylene chloride and the solution with gaseous hydrogen chloride saturated. The solution is concentrated, and an oil is obtained which crystallizes on trituration with ethanol. Recrystallization from a mixture of ethanol and ether gives the dihydric chloride of 2- (3-bromophenyl) -1, 3-di (4-pyridyl) -2-propanol in the form of white prisms that melt at 211-212 °.

Example 7

Using dry nitrogen as a protective gas and with stirring, 0.5 mol of 4-picolyl-lithium are converted at a temperature of -30 ° to -50 ° to a solution of 34.12 g (0.2 mol) of p-methoxy-benzoyl chloride in 50 ml of tetrahydrofuran added dropwise over a period of 60 minutes. The mixture is warmed to room temperature, stirred for 17 hours and the reaction mixture is diluted with 50 ml of water. The solution is extracted three times with 150 ml of 6 η hydrochloric acid each time. The combined acidic extracts are shaken out three times with 150 ml of ether each time and added, with stirring, to a mixture of 500 ml of concentrated ammonium hydroxide solution and 50 g of ice. This gives 2- (4 ~ methoxyphenyl) -1, 3-di (4-pyridyl) ~ 2 ~ propanol in the form of a colorless precipitate, which is filtered off _a washed with 500 ml of water and from a mixture of acetone and

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144S8Sf

Water is recrystallized » Me compound first melts at 80 * 100 °, after solidification and renewed melting it shows a pour point of 130-133 ° · After three recrystallization from acetone / water one obtains the pure compound _? which now shows a melting point of 131-133 «

Example 9

To a solution of 34.6.4 g (1.25 mol) of 4-picoline in

290 ml of tetrahydrofuraia. will over a period of 3 1/2

2.28 mol of phenyllithium are added to a benzene / ether solution for hours at a temperature of 30. The mixture is stirred for 15 minutes , then cooled to a temperature of -20 ° and 116 g of a solution of trimethoxybenzoyl chloride are added in 260 ml of tetrahydrofuran added over a period of 40 minutes, the temperature being kept at approximately -20 °. The mixture is stirred for one hour> then 330 ml of water are added dropwise to the reaction mixture, while the temperature is kept at about 30.degree. The reaction mixture is then acidified and the aqueous phase is drawn off. The organic layer is extracted three times with 200 ml of cold hydrochloric acid each time. The combined acidic extracts are washed with 30 ml of ether and made alkaline with concentrated aramonium hydroxide solution, the temperature being kept below 12 °. The bodice that forms during the neutralization step is filtered off and mixed with a mixture of 600 ml of methylene chloride βθθ ml of water digested

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The insoluble residue is filtered off, washed first with 200 ml of cold water and then twice with 200 ml of methylene chloride each time. This gives 1.30i (4-pyridyl) -2- (3, l | -, 5-trimethoxyphenyl) -2-propanol _? that melts at 151-154 ° «. After recrystallization from ethanol, the compound has a melting point of 168-170 ° "

Example Q

With stirring and using dry nitrogen as protective gas, O ₃ 2 moles of p-methylmercaptobenzoyl chloride are dissolved in 150 ml of tetrahydrofuran / and over a period of 60 minutes at a temperature of -JO to -50 to form a solution of 0 ^ , 5 moles of 4-picolyl-lithium added dropwise. The mixture is stirred overnight, the reaction mixture is then diluted with 100 ml of water and extracted three times _? by using 150 ml of 6 η hydrochloric acid in each case. The acidic extracts are combined, extracted three times with 150 ml of ether each time and the acidic solution is treated at 0 ° with a mixture of 300 πΛ concentrated ammonium hydroxide solution and 500 g of ice, with 2- (4-methylmeroapto-pheny1) -1 _s 3-di (4-pyridyl) -2-propanol separates out as a precipitate. The heterogeneous mixture is treated with methylene chloride * the organic phase is separated off and dried over sodium sulfate. After concentration in vacuo, a gummy residue is obtained. This residue is washed with ether and continuously with hexane for 48 hours

809810/1316

1445894,

extracted. An insoluble product is thus obtained which, after three recrystallization, is obtained in the form of light yellow platelets which are at 164.5 to 16? ° melt. . . _;

Example 10

A solution of 39 * 6 g (O ₅ 2 mol) of phenyl benzoate in 100 ml of anhydrous tetrahydrofuran is slowly added with stirring to a solution of 0.5 mol of 4-picolyl-lithium, the reaction mixture warming to 40 »The reaction mixture becomes a Stirred for another hour, and then 806 ml of water are added. The aqueous phase is acidified by adding 350 ml of 3 η hydrochloric acid. The mixture is shaken in a separating funnel, the organic phase is separated off and extracted again twice with 200 ml of 3 η hydrochloric acid each time. The acidic extracts are combined, extracted three times with 500 nil of ether each time, then made alkaline with 10 η sodium hydroxide solution, and made up to a volume of 4 liters with ice water. The mixture is left to stand at room temperature for 10 hours and the precipitate which has separated out is filtered off. The precipitate is filtered off and washed with 500 ml of water. For purification, the product is carefully digested with a mixture of 200 ml of water and 50 ml of methylene chloride. It is filtered off and crystallized from aqueous acetone to give the 2-phenyl-1,3-di (it-pyridyl) -2 obtained in this way -propanol melts at 164-166 °.

, 809810/1310

Example 11

In the following regulation another way to Representation of 2-phenyl-1,3-di (4-pyridyl) -2-propanol are shown. 64.9 g (0.7 mol) of 4-picoline are added dropwise to a refluxing solution of ethyl magnesium bromide given in 350 ml of tetrahydrofuran. A solution of 4-picolyl magnesium bromide in tetrahydrofuran is obtained in this way.

A solution of 4-picolyl magnesium bromide in tetrahydrofuran (prepared as described above) is cooled to -6 ° and to a solution of 63.7 g (0.3 mol) of benzyl benzoate in 60 ml of tetrahydrofuran added, the temperature being kept at -4 to -6 °. After the addition of the benzyl benzoate, the reaction mixture is heated to room temperature and stir for 18 hours after · The G-rignard complex is decomposed by adding 375 ml of 2 η hydrochloric acid and the tetrahydrofuran removed in vacuo. The solution is made strongly acidic with hydrochloric acid and then four times with each 200 ml of ether shaken out. The aqueous phase will made alkaline by adding sodium hydroxide · The aqueous alkaline phase is filtered and the Piltrat four times with each Extracted 200 ml of methylene chloride. The organic phases are then combined and washed twice with 50 ml of water each time and finally dried with anhydrous sodium sulfate * The solution is filtered and concentrated, 2-Pheayl-

«09810/1316

l "3-di (4-pyridyl) - 2-propanol, which after recrystallization aqueous alcohol melts at 164-166 ° »

Example 12

20 g of 2-phenyl-l, 3-di (4-pyridyl) -2-propanol [prepared according to the instructions given in Example 1] are dissolved in 3000 ml of ethyl acetate and the mixture is saturated with dry hydrogen chloride gas. The precipitate is filtered off and dried in vacuo at 60 ° over concentrated sulfuric acid »For purification, the product is extracted for 30 minutes with 1,000 ml of boiling ethyl acetate» After filtering and drying in vacuo at 60 °, the 2 ~ Phenyl ™ l _i 3-di (4-pyridyl) is obtained ~ 2-propanol dihydrochloride which melts at 227-229 ° with decomposition.

Example 15

5.42 mol phenyllithium, dissolved in a mixture of ether / benzene, are dissolved to j 5 "42 mol of 4-picoline in 800 ml of tetrahydrofuran over a period of 3 hours under Eühren and using nitrogen as protective gas. After all the phenyllithium to the 4-picoline solution is added ,, the reaction mixture is stirred for a further 15 minutes ,, The Mischungj, which is further cooled in a · Sis-salt mixture to about "10 ° ₉ contains the resultant by transmetallation 4-picolyl lithiuBio '

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Over a period of 20 minutes, a mixture of 2.25 mol of benzyl benzoate and 75 ml of tetrahydrofuran is added to this 4-picolyl lithium solution. The temperature is kept below 25 °. A pale green colored solution is obtained, which is stirred for a further 60 minutes at room temperature. Then ice and 8 η hydrochloric acid are added alternately in portions until the two immiscible phases are clear. About 1 kg of ice and about 1 liter of hydrochloric acid (ß n) are required. The mixture is stirred for about 5 minutes and then poured into a large separating funnel. «The organic layer is separated off and shaken out twice with 200 ml of 3 η hydrochloric acid each time» The acidic extracts obtained are combined and washed three times with 500 ml of ether each time and then with ammonium hydroxide made alkaline »During the pouring out the temperature is kept at about 10» When the acidic extract is neutralized, a precipitate forms which is separated off by filtration »The precipitate washed out with water (5x1 liter) is mixed with 400 ml of methylene chloride and 600 ml Water digests. The insoluble residue is filtered off and washed twice with 200 ml of methylene chloride each time, then twice with 200 ml of water each time. "The residue is" dried at 20 torr and 90 ° for about three hours. 174 g of 2-phenyl-1,3-di are obtained (4-pyridyl) -2-propanol with a melting point of 80-102 °. Each solidification shows this product with a renewed melting point determination of a pour point of 145-163 ° »

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1445S91

The cleaning- of 2-phenyl-l, 3-di (4-pyridyl) -2-propänol prepared according to the above-described procedure was carried out as follows ι 375 g 2-phenyl-l, 3-di (4-pyridyl) -2-propanol are added to 3 liters of acetone and the mixture is heated to reflux. 50O ml of acetone are added in portions to the boiling solution at 15-minute intervals until complete dissolution has occurred. Then another 50O ml of acetone are added to the solution in order to prevent the product from crystallizing out during the filtering process. A total of 6 liters of acetone are required. The still hot solution is filtered. The filtrate is concentrated until about 2 liters of acetone have distilled off. Then 50 ml of water are added, the distillation is continued and each time 500 ml of acetone have distilled off, another 500 ml of water are added to replace the acetone that has distilled off The process, namely distilling off 500 ml of acetone each time and replacing it with 500 ml of water each time, is continued until about 5 liters of distillate have accumulated and about 3 liters of water have been added. The solution thus obtained is cooled to 50 and a further liter of water is added. In order to improve the crystallization that has already occurred, the mixture is stirred for three hours while cooling with an ice bath. The precipitated product is then filtered, washed twice with 200 ml of water andin 30 "and 90 Torr for 18 hours dried. • are thus obtained 352 g of 2-phenyl-l _i 3-di (i <pyridyl) -2-propanol in the form of colorless needles with a melting point of & ^Q

8098T0 / 1316

When working according to this rule, one Case get one product that is at 117-118 °, in another Case a product that melts at 126-127 °. Recrystallization from acetone / water resulted in what was described above in each case higher melting material obtained.

Example 14

In a 5 liter three-necked flask equipped with a stirrer, condenser, thermometer, dropping funnel and nitrogen inlet tube, 454 g of a 50 # -lgen dispersion of sodium in mineral oil are added to one liter of benzene. The apparatus is carefully flushed with dry nitrogen and the reaction is carried out under nitrogen. With vigorous stirring, 20 ml of bromobenzene are added and, after the reaction has started, a further 627 g of bromobenzene are added dropwise, the dropping rate being regulated so that the temperature of the reaction mixture ^{does not exceed 60-70 0} ; if necessary, the reaction mixture is cooled in an ice bath.

The phenyl sodium suspension shown in this way turns 30 Stirred minutes at room temperature. Then 404 g of diisopropylamine are added drop by drop over a tent room of 30 minutes added away to this suspension, and the temperature, des Reactions are held between JO and 33 °. The thus obtained viscous, blackened product is 1.5 liters

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Benzene diluted and the mixture stirred for 30 minutes. Thereafter 372 g of gamma-picoline are added dropwise over a period of about 30 minutes and maintaining the temperature of the reaction mixture at about 30-35 °. A green colored suspension of 4-Pieolyl Sodium, which is stirred for about 60 minutes. This suspension is cooled to about 20 ° and added 300 g of ethyl benzoate added, the temperature of the Solution is between 20 and 30 °. After the addition is complete, the mixture is stirred for two hours without external cooling, poured onto ice, and the 2-? enyl-l, 3-di (4-pyridyl) -2-propanol filtered off.

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Example 15

a) Capsules 10 mg of 2-phenyl-1,3-di (4-pyridyl) -2-propanol are mixed well with 165 mg lactose and 30 mg corn starch Bach adding 5 mg talc, is mixed well again “The The mixture is then filled into gelatine capsules

b) tablets; 5.10 mg of 2-phenyl-1,3-di (4-pyridyl) ~ 2- ~ per ~ panol are made with 84 »40 ^ g lactose» 10.0 mg corn starch and 0.5 mg magnesium stearate mixed well »The mixture is then pressed into lumps with the tablet machine, the latter are crushed again and sieved (sieve Ho * Ιο), the mixture is then compressed into tablets of 100 mg.

σ) Parenteral solution * 25 mg of 2-phenyl-1,3-di (4 ~ pyridyi) -2-propanol is slurried in a small amount of water to By slowly adding ί η hydrochloric acid, the slurry is brought to pH 3 »The solution is then filtered, left to stand for 24 hours and filtered through a filter candle. Finally, the filtrate is filled into ampoules under nitrogen, which are sealed and sterilized at 250 ° for 20 minutes

8098 1.0 / 1 3 18

Claims (13)

1445091 claims 1. Process for the »production of isopropanol derivatives, characterized in that one. a 4-picolyl-metaH compound with a compound of the general formula COR in which R is a halogen atom or an alkoxy, eenzyloxy or phenoxy group, X is hydrogen or Represents halogen atom or a lower alkyl, lower alkoxy or lower alkylmeroapto group, η means the whole number 1, with the restriction that when X is present in the meaning of alkoxy, η can also mean the whole number 3, converts, and if desired, the compound obtained in a Acid addition salt transferred * 2. The method according to claim 1, characterized in that ⁵¹ that one is a ^ -Picolyl-Metallverbinoisig of the general formula Ή2Μ 80J810 / 1318 in which M is an alkali metal, with a compound of the general formula OHaI (X) n in which Hai is a halogen atom and X and η have the meaning given in claim 1, implements. 3. The method according to claim 1, characterized in that that you have a 4-picolyl metal compound of the general formula H ₂ M in which M means an alkali metal, with a compound of the general formula COOR 809810/1316 in which R represents a lower alkyl, phenyl or benzyl group and X and η have the meaning given in claim 1,
implements. 4. The method according to claim 1, characterized that you have a 4-FIeölyl-magnesium bromidever. bond with a Compound of the general formula in which X and η have the meaning given in claim 1,
implements. 5. Method according to one of claims 1-4, characterized in that that you have at least 2 moles of the 4-picolyl metal "compound with one mole of the reactant. 6. The method according to any one of claims 1-5 *, characterized in that that one is a benzoic acid chloride or a benzoic acid ester used as a starting material and the obtained If desired, 2-phenyl-1,3-di (4-pyridyl) -2 ~ propanol in one • 809810/1316 Acid addition salt transferred. 7 · Method according to one of claims 1-5 * thereby characterized in that one p-toluic acid chloride or one p-toluic acid ester used as starting material » 8. The method according to any one of claims 1-5 * thereby characterized in that one is a halobenzoic acid chloride or a halobenzoic acid ester is used as the starting material * 9. The method according to claim 8, characterized in that that you have a ra-fluorobenzoic acid chloride or a m-fluorobenzoic acid ester used as starting material. 10. The method according to claim 8, characterized in, that one is a p-fluorobenzoic acid halide or a p-fluorobenzoic acid ester used as starting material « 11. The method according to claim 8, characterized in that > That one is a p-chlorobenzoic acid halide or a p-chlorobenzoic acid ester used as starting material. 12. The method according to claim 8, characterized in that that one is an m-bromobenzoic acid halide or an m-bromobenzoic acid ester used as starting material « 809810/1316 13. The method according to any one of claims 1-5 »characterized in that one is a p-methoxybenzoic acid halide or one p-methoxybenzoic acid ester used as starting material * 14. Method according to one of Claims 1-5, characterized in that that one is a 3,4,5-trimethoxy-benzoic acid halide or a 3,4,5-trimethoxy-benzoic acid ester as starting material used. -15. Method according to one of Claims 1-5, characterized in that that one is a p-methylmercapto-benzoic acid halide or a p-methylmercapto-benzoic acid ester as a starting material used « 16 β method according to claim 6, characterized in ₉
that the compound obtained is converted into a dihydrochloride ₀ 8098 10/13 1 6