DE1643265A1 - Alpha-substituted 2-aminomethyl-benzyl alcohols and process for their preparation - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Assmann Dr. R. Koonigsbarger - Dipl. Phys. R. Holzhauer

p y

1 /? Q7 ^Dr * ^F * ^Zürns * ⁶ⁱⁿ » ^un ·

J- / ^ y t Ρ α t η t α η ν / α I t

8 Munich 2, BräuhauMtroö 4/111

New requirements for registration. ·

CH. BOEHRINGER SOHN, INGELHEIM AM RHEIN

g-Substituted 2-Αΐηίΐιο-πΐθ ^ γ1 · -Τ3θηζ7 ^ 11;: ο1ιο1θ and method

for their manufacture

The invention relates to new α-substituted 2-amino-methylbenzyl alcohols the general porniel

(D

and their acid addition salts and processes for their preparation.

In this formula mean:

R ^., Hydrogen or an alkyl radical with 1-4 carbon atoms, 109831 / 2U4

New documents

R _{2 is} hydrogen, an alkyl Iret with 1 - 4 carbon atoms, an aoyl or alkoxyoarbonyl radical,

R- is hydrogen, an alkyl or hydroxyalkyl radical with 1-5 carbon atoms, an aminoalkyl, alkylaminoalkyl, dialkylaeinoalkyl, aoylaminoalkyl, aoylalkylaminoalkyl or H-alkyl or Η, ΙΓ-dialkylhydrazinoalkyl group or a cycloalkyl or benzyl group, where at least one of the radicals R ₂ or R ~ must be hydrogen,

Rj is hydrogen, an alkyl or aoyl group,

Rc

, the oyolohexenyl or the

Benzyl radical, which is substituted by halogen fgfv6, R _{5 is} hydrogen, a halogen atom or the frifluoromethyl group

and Rg hydrogen, a halogen atom or the methyl group

The new compounds have a pronounced appetite-suppressing effect - the undesirable one in the known ones Appetite suppressants j · do oh mostly quite strong stimulants The effect on the central nervous system is only weakly pronounced in the compounds obtained according to the invention. To the Two processes have proven to be particularly beneficial for the production of the new compounds:

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ORIGINAL

a) Rin ^ opening of a phthalide with an amine and then Reduction of the resulting acid amide according to the following equation

Ό 4 HH

X ^R 2

• R,

III

CH - OH IV

wherein R2 is hydrogen or an alkyl radical having 1-4 C atoms

means.

In this reaction , a phthalide of the general formula II is first dissolved in an inert solvent, for example an alcohol, benaol, toluene or xylene, and an amine of the general formula III is added. If the amine of the formula III is a liquid, the reaction can also be carried out without an additional solvent. In some cases, the reaction already takes place at room temperature, but it is generally more advantageous at higher temperatures, possibly at the reflux temperature of the solvent used to work.

The corresponding aminocarbonyl * is obtained in this way. Compounds of the formula IT whose carbonyl group is customary Manner, for example with suitable complex hydrides, such as lithium aluminum hydride, is reduced to the C ^ group.

109831/2144 ORIGINAL BATHROOM

Compounds of the general formula I in which R _{1 is} hydrogen) R _{2 is} hydrogen or an alkyl radical having 1-4 carbon atoms and R. hydrogen can be obtained by these processes. For the preparation of compounds wherein Rg and / or R. represents an acyl group, then an excess (for R ₂ and R. = Aoyl) wjrd with the calculated amount (for R ₂ = acyl) or "a carboxylic acid anhydride or a Carbonsäurehalogenida Preferably _y in the presence of an organic base.

A compound of the formula I in which R _{2 is} an alkoxycarbonyl group can be obtained by reacting the corresponding compound in which R ₂ = hydrogen with a

Haloformic acid ester.

An alkyl group can also be introduced into a compound of the formula I in which R _{2 or R 1 is} hydrogen by customary methods, for example by reaction with an alkyl halide or a dialkyl sulfate.

A compound in which R. is an alkyl group can also be obtained by conventional etherification of the free hydroxyl group, for example by reaction with the corresponding one Alcohol in the presence of a hydrohalic acid.

109831/2144 _t originally inspected

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ΪΜ3295

- can alla Gewünschtenf "us a connection 4p formula I wherein R _{f 5} to Benzylreafc 1>ny" tet _f this residue will removed by hydrogenation "·

b) Ring opening of isoindoline! * by means of an acyl anhydride and, if desired, saponification of the resulting Ulacyl- » Connection according to the following scheme;

.CH ₂ - N

Ac

+ (Ac) ₂ O

«3

In these formulas, Ae denotes an acety group, preferably the acetyl group.

In this process, a compound of the general formula V in the relevant anhydride or, together with the anhydride dissolved in a suitable solvent and preferably heated under reflux. The response time is depending on the reaction components used and can take between a few minutes and several days vary. When the reaction is over, the diaoyiate becomes Compound of Formula I a Isolated; for the preparation of non-acylated end products of the formula I, the compound

109831/2144

ORIGINAL

of formula Ia in a suitable inert solvent dissolved and after adding a strong base, preferably of an alkali hydroxide, heated · After completion of the estacylation is the benzyl alcohol of the general formula I. isolated by customary methods

The compounds of the formula I obtained in the de * eylation, in which R ₉ and R * are hydrogen, can also be etherified, esterified or alkylated as indicated in a).

The end products obtained by one of the processes mentioned of the general formula I can if desired converted into their acid addition salts in the usual way * Acids suitable for salt formation are, for example, inorganic acids such as hydrohalic acids, P sulfuric acid, nitric acid, phosphoric acid or perchloric acid; also organic acids such as formic acid and acetic acid s, propiolic acid, oxalic acid, succinic acid, tartaric acid, Citric acid, maleic acid, ascorbic acid, salicylic acid, methanesulfonic acid or toluenesulfonic acid.

According to the method explained above in more detail, for _o example, the following end products - becoming obtained - preferably with the acids mentioned above in the form of their salts

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2-methyl-a-phenyl-benzyl alcohol, 2-methyl-a-dino-methyl-α-phenyi-bentyl-alcohol, 2-methyl-a-methyl-a- (4-fluoropheny 1) -benzyl alcohol, 2-methylaainoffiethyl-α- (2-chlorophenyl) - benzyl alcohol, 2-methylaneinoE! ethyl-a- (3-chlorophenyl) -benzyl alcohol, 2-methylaainoBethyl-α- (4-chlorophenyD-tenzyl alcohol, 2-methylaainomethyl-a- {4-broB> phenyl) -beneyl alcohol _t 2-Me thy Ians I nca ethyl-α- (4-iodophenyl) -benzyl alcohol, 2-methyIaitinoaethyl-a- (3-trifluoroethyl) phenyl) -b en ty lalcohol, 2-methylaajinoisethyl-a- (3-trifluoro- _1- ethyl -4-chlorophenyl) -bentyl alcohol ₍ 2-ithylaBinoiaethyla-U-chlorophenyl) -benyl alcohol, 2-n ^ Butylaainontthyltt- (4-chlorophenyl) -benxyl alcohol _y 2-Teobutylaninooethyla- (4-chlorophenyl} -benzyl alcohol thy Ιο- (4-chlorophenyl) -beney lalkchiol, 2-Bensy laisinoBe thylo- (4-chlorophenyl) -ben «yl alcohol, 2-DieethylaiBinorDethyI-a- (4-chlorophenyl) -beneyl alcohol _t 2- (2-HydroxylthyD- ajiino-ethyl-o- (4-chlorophenyl) -benxyl alcohol, 2- (2-afflinoethyl) -amino methyl-a- (4-chlorophenyl} -benzyl alcohol, 2- (2-methylaainoethyl) -aainoBethyl-c- (4-chlorophenyl) -benxyl alcohol, 2- (2-di-methyl-methyl-benzyl) -aaino-ethyl-a- {4-chlorophenyl ) - _;

benzyl alcohol »2- (2-methylacetylanino-ethyl) -« ainoBethyla- (4-chlorophenyl) -benzyl alcohol, 2- [l- (MethylaBlno) -ethyl] -: ο- (4-chlorophenyl) -benzyl alcohol , 2- [1 - (Methylaoino) -butylΙα- (4-chlorophenyl) -benzyl alcohol _y 2- (N-Methy 1-lf-ethoxycarbonyl aminomethyl-a- (4-chlorophenyl) -benzyl alcohol, 2- (N-methyl-H-ether heicy- carbony 1) -anincBe thyl-o- (4-f Iu or phenyl) -b emyl alcohol , 2-methylamino-methyl-a- (4-chlorobenzyl / -benzyl alcohol, 2-methrl-

109931 / 21A4 aBinoBethyl-a-cyclohexen-dJ-yl-benzyl alcohol,

ORIGINAL INSPSCTED i

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2- (H-Mithyl-N-aoe tyi) -aainoraethyl-a- (4-chlorophenyl) -O-ao · ty1-benzyl alcohol, 2- ("I-Hethyl-N-acetyl) -aminomethyla- (4 -f Iuophenyl)> «- 0-acetyl-benzyl alcohol, 2-methylamino- ■ ethyl-a- (4-chlorophenyl) -benzyl * ethyl ether, 2- (N-methyl- H-aoetyl) -aainonethyl-a- (3-trifluorDethyl-4-chlorophenyl) -O-acetylbenzyl alcohol, 2- [2- (N, N-Dinethylhydrazino) -ethyl] -aminoB · thyl-a- ( 4-chlorophenyl) benzyl alcohol

The ale starting materials compounds of the general formula II * used common j can according to known encryption. \ are used, for example by treating an O-acylbemsoic acid with zinc dust in acetic acid under | Heat·

Isoindolines of the general formula V are produced, for example, by the incorporation of a phthalimide with a compound Z-Mg-Hal and subsequent reduction of the resulting l-hydroxy-3-oxoisoindoline.

for use in therapy are preferred suitable acid addition salts of the new compounds with customary pharmaceutical PUIl- or carriers, extenders,. Disintegrants, binders, lubricants, thickeners3 or thinners,. ». Solvents or solubilizers or agents for Achieving a depot effect mixed tea, which is an enteral

• ·

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ORlGtNALlNSPSCTED '

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/.;-:■■■■. · -9-

or parenteral · Allow use. All pharmaceutical preparation forums could carry eB tablets, coated tablets, pills, capsules, solutions, suspensions or emulsions, whereby, in addition to the new active ingredients, preservatives or stabilizers, emulsifiers, buffer substances and other therapeutic agents such as laxatives can be added Pharmaceutical preparations should generally contain 10-100 ng, preferably 20-50 mg of active substance per dose. *

The following examples serve to provide a more detailed explanation the invention! '

Example 1 (method A)

2-Methylaainoa eth yl-a ~ (4-ohlorphe n yl) -benzyl alcohol hydrochloride

12.3 g (0.05 mol) of 3- (4-chlorophenyl) phthalide were dissolved in 500 ml of benzene saturated with methylamine. The mixture was left in a flask fitted with a calcium chloride tube for 48 hours at room temperature and then evaporated to dryness under a water jet vacuum. The remaining 2-methylaminocarbonyl-a- (4-chlorophenyl) -benzyl alcohol was recrystallized from ethano ^ btroläther. Pp. 150-152 ⁰ C, yield 3.2 g (97 #).

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Bine τοη solution 15.2 g (0.048 koi) of 2-cbigen Hethylaeinocarbonyl compound in 100 ml of tetrahydrofuran and 50 »1 of ether was added to a refluxing suspension τοη 5.8 g (0.1 koi) Llthiunfaluminiuahydrid in 2CO» 1 Ether added. The mixture was refluxed for 3 hours. After cooling, the excess lithlira aluminum hydride was destroyed with excess potassium hydroxide solution. The solid constituents were removed by filtration and the ether phase was dried over magnesium sulfate and then filtered. The ether was removed in a jet vacuum. The residue was dissolved in ethanol and hydrogen chloride was passed in with cooling until the reaction was weakly acidic. The material crystallized on addition of clay to ether.

The 2-methylaminomethyl-a- (4-chlorophenyl) -benzyl alcohol-

Ii '
hydrochiorid was encircled from AthanaMfther "

Bp 224-27 ° C; Yield 9.3 g (71 #). Example la

phenyl) benzyl alcohol

5.1 g of 2-methylaminonethyl-α ~ (4-chlorophenyl) benzyl alcohol were dissolved in 50 ml of dry iyridine and 2.1 g of Ϊ

Ethyl chloroformate was added with external cooling. The mixture was then left at tree temperature for 24 hours and then left to dryness

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ORIGINAL

The residue was dissolved in ethyl acetate and the solution was washed first with dilute hydrochloric acid, then with water, then with sodium carbonate solution and finally dried over magnesium sulfate. The solvent was removed in vacuo · The oily residue crystallized on trituration from Cyolohexan-petroleum ether (40 - 60 ⁰ C)

Pp. 87 - 88 ⁰ Cj yield 3.6 g (55 5t)

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Example 1 b

benzyl alcohol hydrochloride

A solution of 6 g of 2-methylaraincmethyl-a- (4-chlorophenyl) -benzyl alcohol hydrochloride in 200 ml of ethanol was saturated with hydrogen chloride at room temperature and the mixture was then refluxed for one hour. The solution was left at ⁰ ° C. for 12 hours . The crystalline precipitate was filtered off and recrystallized from water.
. Mp 231 ⁰ O; Yield 4.5 g (69 #)

Example 2 (method A)

2 ~ methylaminomethyl - a- (4-brpmphenyl) -benzy! Alcohol · » hydrochloride

a) 17 g of 3- (4-bronphenyl) phthalide were dissolved in 500 ml of benzene. ^{Methylamine was passed in at 10 °} C. for 1 1/2 hours through a sintered glass frit. The mixture was left at room temperature for 3 days. Most of the solvent was removed in vacuo and the remainder was recrystallized from ether / petroleum ether. £ to give 2-methylaminocarbonyl-a- (4-bromophenyl) benzyl alcohol by Pp. 144-145 ⁰ C in a yield of 18.5 g (98 56).

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ORIGINAL INSPSCTED

rs 4 * 326

b) A solution of 18.5 g of the 2-methylaminocarbonyl compound in 100 ml of tetrahydrofuran and 50 ml of ether was added to a refluxing suspension of 3.8 g of lithium aluminum hydride in 200 ml of ether. The mixture was refluxed for 3 hours. After cooling, the excess lithium aluminum hydride was destroyed with excess potassium hydroxide solution. The solid constituents were removed by filtration, the ether phase was dried over magnesium sulfate and filtered. The ether was stripped off in vacuo. The residue was taken up in ethanol and hydrogen chloride was passed in until a weakly acidic reaction occurred with cooling. After recrystallisation from methano ^ ther is l-bromophenyl ^ -benzyl alcohol hydrochloride 206- 207 ⁰ C received a 2-methylaminomethyl-a- ^ from Pp. In a yield of 12.7 g (65 #).

Example 3 (method A)

2-Cyclohexylaminomethyl-a- (4-chlorophenyl) benzyl alcohol hydrochloride

g of 3- (4 ~ chlorophenyl) phthalide were mixed with 17 g of cyclohexylamine 6 hours at 180 ⁰ C heated. After cooling down. The mixture was reduced to excess 4N hydrochloric acid / you. (^ poured and extracted with ether. The combined ethereal

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'BAD ORIGINAL

'T643265

extracts. were dried over sodium sulfate and evaporated to dryness. The residue (15 g) was dissolved in 150 ml of tetrahydrofuran and this solution was added to a refluxing suspension of 5 g of lithium aluminum hydride in 500 ml of tetrahydrofuran. The mixture was then refluxed for 3 hours. After cooling, the excess lithium aluminum hydride was destroyed with excess potassium hydroxide solution. The solids were removed by filtration and washed several times with tetrahydrofuran. The filtrate and wash solutions were combined and evaporated to dryness in vacuo. The residue was partitioned between 2N hydrochloric acid and chloroform. The aqueous phase was made alkaline with saturated sodium carbonate solution and the base was extracted with chloroform. The chloroform extracts were dried over sodium sulfate and evaporated to dryness. The substance was taken up in ethanol and converted into the hydrochloride with ethereal hydrochloric acid. To give the Z-Cyclohexylaninomethyl-a-C4-chlorophenyl) -benzylalkoholhydrochlorid after recrystallization from ethanol / petroleum ether, mp. 198 "201 ⁰ C in a yield of 9.6 g (47 56).

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BATH

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Example 4 (Procedure_A)

2-Benzylam i nom et hy 1 ~ α ~ (4-ohle rpher.y 1) -b enz y 1 a lkohol · ·· hydrochlorld

A solution of 24.4 g of 3- (4 - '^ chlorophenyl) -ph * .halicl and 40 g of benzylamine in 150 ml of ethanol were left at room temperature for 10 days. The alcohol was in vacuo drawn off and the residue partitioned between ether and excess 4N hydrochloric acid. The ether extracts were dried and then evaporated to dryness in vacuo

The residue was crystallized from ethanol / petroleum ether to give 22.5 g of recrystallized · (64 £) of 2-Beazylaminocarbonyl-a- (4-chlorophenyl) -benzyl alcohol by Pp. 108-110 ⁰ C ·

11 g of the 2-benzylaminocarbonyl compound were in 150 al Dissolved tetrahydrofuran and added dropwise to a refluxing suspension of 5 g of lithium aluminum hydride in 500 ml of tetrahydrofuran added. The mixture was refluxed for 3 hours. The excess lithium aluminum hydride was destroyed with excess potassium hydroxide solution. The solid ingredients were through Filtration removed and washed several times with tetrahydrofuran « The filtrate and washing solutions were combined and evaporated to dryness in vacuo. The residue was chromatographed on silica gel. After elution with benzene / 20? C chloroform, the 2-benzylaminomethyl-a- (4-chloro * phenyl / benzyl alcohol hydrochloride from ethanol / petroleum ether

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after addition of ethereal hydrochloric acid with a melting point of EIEnnfUtxf in a yield of 4.9 g (42 #) isolated.

Example 5

8 g of the 2-benzylaminomethyl-α ~ (4-chlorophenyl) ~ benzyl alcohol prepared according to Example 4 were dissolved in 600 ml of ethanol, 2 g of palladium carbon (5 #) were added and. the mixture shaken in a hydrogen atmosphere at room temperature. When the uptake of hydrogen had ceased, which was the case after about 48 hours, the catalyst was filtered off and the solution was evaporated to dryness in vacuo. The residue obtained was chromatographed on silica with chloroform / methane chloride / ammonia (90 i 9.5: 0.5) as the eluent. The main fraction was converted into the hydrochloride and recrystallized from ether / ethanol. 216 ⁰ C to give the 2-aminomethyl-a-phenyl-benzyl alcohol hydrochloride mp. In a yield of 3 »5 g (59 ^).

Example 6 (method A)

2-Meth.YlaminoaethyI «-tt- (3-trifluoromethy! Phenyl) -benzyl alcohol ttvdrochlorid

15 g of 3-trifluoromethylphthalide were in with methylamine

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BATH ORIGINAL

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1-843265

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Dissolved saturated ethyl alcohol and ^{leave at 2O 0} C for one hour. The mixture was then evaporated to dryness and the residue was recrystallized from benzene / petroleum ether. The 2-methyl: dinomethyl-a- (3-trifluoromethylphenyl) -benzyl alcohol of melting point 99 was obtained in a yield of 15 g (90 36).

14.3 g of the 2-methylaminoearbonyl-a- (3-trifluoromethylphenyl) benzyl alcohol was dissolved in 100 ml of tetrahydrofuran and this solution was added dropwise to a cooled and stirred solution of 3.5 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. The mixture was stirred and refluxed for 3 hours and cooled. The excess lithium aluminum hydride was destroyed by the dropwise addition of water and the inorganic precipitate was removed by filtration. The filtrate was dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue was converted into the hydrochloride by adding ethereal hydrochloric acid and recrystallized from ethanol / ether / petroleum ether. To give the 2-methylaminomethyl-a- (3-trifluormeth.ylphenyl) -benzylalkoholhydrochlorid of mp. 160 - 162 ⁰ C, a yield of 8.0 g (53 *). ■

BAD OBlGtNAL

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Example 7 /

J? R / 2-Hydroxyä thy]) am incaig.thyl- α- (• i-chlorpheny j j ^ benzyl alcohol- h ydrochlorld

50 g of 3- (4 ~ | chlorophenyl) ~ phthalide and 100 ml of ethanoiamine were refluxed for 7 hours. The reaction mixture was taken up in ethyl acetate and the solution was successively cit water, 2% hydrochloric acid, and saturated sodium carbonate! washed, dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from Easigsäureäthyiester / Pexroläther.
Pp. 98 - 100 ⁰ C, yield 35 g (56 tf).

8 g of 2-Hydroxyäthylaminoearbonyl ~ a- (4-chlorophenyl) -benzylalkohols were dissolved in 200 ml dry) and tetrahydrofuran with stirring and in a StickstoffatmDsphäre w 3 g MthiumaiuminiJiEhydrid added. This was then refluxed with stirring for 17 hours. The excess lithium alanate was destroyed by the dropwise addition of water while cooling, the mixture was filtered and the inorganic residue was washed out several times with ether. The combined organic pilates were dried and in vacuo The oily residue was converted into the hydrochloride by the addition of ethereal hydrochloric acid and recrystallized from ethanol / / ether to give

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BAD OfHGiNAL.

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mp. 157-161 ⁰ C in a yield of 4.5 g (42 $>), Example b ( '(ji ^ ftmmufiih

2-methylamine i no e thy1-tt-pheny1-b e nzy lalkoho 1-hydrochloride 42 g of 3-phenylphthalide were dissolved in 1500 ml of ethanol. The solution was saturated with methylamine while being cooled with ice and left at room temperature for 4 days. The solvent was removed in vacuo and the 2-Methy1-aminocarbonyi-a-phenyl-tenzyl alcohol was recrystallized from Äthancl / petroleum ether. Yield 41.5g (£ 74.5).

The substance was dissolved in 150 ml of tetrahydrofuran and added dropwise to a refluxing suspension of 16 g of lithium aluminum hydride in 350 ml of tetrahydrofuran. The mixture was refluxed for 6 hours. The excess lithium aluminum hydride was replaced by excess Potassium hydroxide structure destroyed. The solid components were removed by filtration and repeated washed out with tetrahydrofuran. The FiItrat and the • Wash solutions were combined, dried over potassium carbonate and evaporated to dryness in a yakjflum. The residue was taken up in ethanol and passed in hydrogen chloride while cooling with ice. The separating Crystals were recrystallized from ethanol, the 2-MetT ylaminomethyl-s-phenyl-benzyl alcohol hydro-

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Chloride of Pp ₀ 224-225 ⁰ O was obtained in a yield of 28.7 g (73 %) .

Example 9 (method A) _f ^:

2- [2- (N.N-Dimethylhydrazine) ethyljaminoBethyl-α- (A-.

chlorphenyl) benzyl alcohol ~ hyarochloride : '

To a solution of 24.4 g of 3- (4-chlorophenyl) phthalide ■ * ^ in 100 ml of benzene were 15.5 g Ν, Ν-dimethylhydrazino

ethylamine added, the mixture 8 was at room temperature *. Leave / and then remove the solvent in vacuo. . [

j

The residue was taken up in 150 ml of tetrahydrofuran and added to a refluxing suspension of 16 g

Lithium aluminum hydride in 350 ml of tetrahydrofuran trains i

The mixture was refluxed for 9 hours

and then leave it at room temperature for 4 days. Bas About »

excess lithium aluminum hydride was mixed with excess [

Potassium hydroxide solution destroyed. The solid components'

* I

^ were removed by filtration and washed several times with tetra [

hydrofuaan washed out. The L

Wash solutions were washed 3 times with 100 ml of 2N hydrochloric acid each time

extracted. The sour extracts were made with an excess;

made alkaline in saturated sodium carbonate solution ^

and extracted several times with ether. The united.Ä-cher- ί

extracts were dried over potassium carbonate and then ^

"N

evaporated to dryness in vacuo. The residue was taken up in ethanol and, while cooling \\ hydrochloric

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ORiGfNAL INSPECTED

1843 * 265

- 21 -

initiated. After adding ether, crystals separated out and recrystallized from ethanol / ether became. The 2- [2- (N, N-dimethylhydrazino) ethyl] aminomethyl-a - ^ - chlorophenyl / benzyl alcohol hydrochloride was obtained

tr

from Pp "184-187 ⁰ C in a yield of 16.1 g (40 #). ^]

Example 10 (method A)
2-methylaminomethyl-a-cyolohexen- (l) -yl-benz ₍ yl alcohol- ' λ

hydrochloride

A solution of 50 g of 3- [cyclohexen- (l) ~ yl] phthalide in 750 ml of benzene and 500 ml of ethanol was saturated with methylamine while cooling with ice, the mixture was left at room temperature for 7 days, then the solvent was removed in vacuo and the Backing made of ether / petroleum [ _:

ether recrystallized.

Pp. 102 - 106 ⁰ C, yield 45 g (78 *).

36 g of the 2-methylaminocarbonyl-a-cyclohexen (1) -yl- benzyl alcohol were dissolved in 200 ml of tetrahydrofuran « and to a refluxing suspension of 17 g Γ

f. lithium aluminum hydride in 500 ml of tetrahydrofuran pulls- ';.

drips. The mixture was refluxed for 32 hours. * _R The excess lithium aluminum schüssiger with above '£ _# potassium hydroxide was destroyed. The pests were removed by filtration and washed out several times with tetrahydrofuran. Those united with the Piltrat

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1 "* 43 ^: 265

Wash solutions were evaporated to dryness in a vacuum. The residue was taken up in ethanol and hydrogen chloride was passed in while cooling with ice. The check on the addition of ether, crystals separated out were AU3 ethanol / ether to give the 2-umkristallisiertο MethylaminomethyΙα-cyalohexen- (l) -yl-benzyl alcohol hydrochloride mp. 161-163 ⁰ C in a yield of 28 g (72 #) .

Example 11 (method A)

2 ~ Methylaroinomethyl- »α- (4" -chlorbenz yl ) -benzyl alcohol A solution of 35 g of 3- (4-chlorobenzyl) phthalide in 1000 ml of ethanol was saturated with methylamine while cooling with ice, left for 3 days at room temperature, and again while cooling with ice The mixture was left to stand for a further week at room temperature and the solvent was then removed in vacuo. The residue was recrystallized from ethanol / petroleum ether. Yield 28.8 g (63.5 Si)

17 g of 2-methylaminocarbonyi-a- (4-chlorobenzyl) benzyl alcohol were dissolved in 200 ml of tetrahydrofuran and added to a refluxing suspension of 12 g of lithium aluminum hydride added dropwise in 600 ml of tetrahydrofuran. The • mixture was refluxed for 10 hours. The excess. Lithium aluminum hydride was used with excess

• 108831/2144 ' bad original

Potassium hydroxide solution destroyed. The solids were filtered off and washed repeatedly with tetrahydrofuran. The washing solutions combined with the filtrate were dried over potassium carbonate and then evaporated to Trookr.e. After recrystallization from ethanol / petroleum ether to give 10.2 g (63.5 $) of 2-methylaminomethyl-a- (4-chlorobenzyl) benzyl alcohol, mp. 98- 100 ⁰ C.

Example 12 (method B)

2- (N-Methyl "-N-acetyl) -aminomethyl-q- (4-chlorophenyl) -0- a cetyl-benzyl alcohol

66 g of l- (4-chlorophenyl) -N-methylisoindoline were dissolved in 700 ml of acetic anhydride and heated for 24 hours under reflux, the haup-teeil dea acetic anhydride is then evaporated in vacuo and the concentrated solution was left at ⁰ ° C. The compound which crystallized out was filtered off, washed with ether and dried. Mp. 135 ^° C., yield 17.5 g (81.6 #)

Example 13

2-Methylaminomethyl -α- (4-chlorophenyl; -benzyl alcohol-hydro chloride

187 g of the 2- (N-methyl-N-

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• cetyr) -aBinomethyl-a ^ 4-ehlophenyl) -0-acetyl-benzyl- • alcohols and 500 ml of 50% aqueous potassium hydroxide solution in 1200 ml of ethylene glycol were refluxed for 8 hours. After cooling, 3000 g of ice were added to the solution and the mixture was extracted 5 times with 500 ml of methyl acetate each time. The combined extracts were washed with Essigester-sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness to W The residue was taken up in ethanol and excluded by the addition of ethereal hydrochloric acid, the hydrochloride precipitates'.

After recrystallization from ethanol the Hydro-chloride had a melting point of 226-227 ⁰ C. Yield 135 g (84 i)

At spie1_14 . (Method B)

fe 2j ^ (jJ-Me t hyl-Na ο e ty 1) -.aminqmg: thv_l-a- · (4 «-f Iu ρ rpheny 1 λ -O-iacetylbengyl alcohol

50 g of 1- (4-fluorophenyl) -N-methylisoindoline were dissolved in 500 ml of acetic anhydride and refluxed for 16 hours. The main part of the acetic anhydride was drawn off in vacuo and the concentrated solution at ⁰ ° C. for crystallization. ditched. The diacetyl compound was filtered off with suction, washed with ether and dried. Yield 51.7 g (71.5 *); m.p. 106 ⁰ C

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ORIGINAL INSPECTED

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Example 15

2-methylaminomethyl-a- (4-fluorophenyl) benzyl alcohol hydrochloride

50 g 2- (N ~ methyl-N-acetyl) -aminomethyl-a- (4 - fluorophenyl) - · O-acetyl-benzyl alcohol and 125 ml of 50 # aqueous Potassium hydroxide solution was refluxed for one hour in 250 ml of ethylene glycol. After the Solution was diluted with 1000 g of ice and 5 times with each 200 ml of ether extracted. The combined ether extracts were washed with sodium carbonate solution over magnesium sulfate dried and evaporated to dryness. The residue was dissolved in ethanol and washed with ethereal Hydrochloric acid precipitated the hydrochloride.

After recrystallization from ethanol, the hydrochloride had

Chloride has a melting point of 231 ⁰ Co yield 31 _f 2 g

Example 15a

2- (N-methyl-N ~ ethoxy carbon ylamino) - »a- (4 ~ fluorophenyl) - benzyl alcohol

Starting from 5.8 g of 2-methylaminomethyl-a- (4-fluorophenyl) -benzyl alcohol 4 g of pure product (53 #H yield) were obtained by following the procedure of Example 1a. The oil did not crystallize, but showed the analogous to chlorine

appropriate

109831/2 UV ',

ORIGINAL INSPECTED

* β "

1 «* 3265

- 26 -

Infrared and NMR spectra. Example 16 (method B)

2 ~ methylaminomethyl-tt- (2-chlorophenyl) -benzyl alcohol hydrochloride

12 g l ~ (2-calorphenyl) -2-methylisoindoline and 100 ml Acetic anhydride was refluxed for 5 days. The acet-P anhydride was then removed in vacuo and the remainder with

diluted aqueous ammonia and treated 5 times with 50 ml of ether extracted each time. The combined ether extracts were successively washed with dilute brine, water and saturated sodium carbonate solution, dried and evaporated to dryness.

The residue consisting of 15 g of a dark oil was dissolved in 70 ml of ethylene glycol and 55 oil of 50 μg aqueous potassium hydroxide solution and refluxed for 2 hours. The mixture was then diluted with 200 g of Sis and extracted 3 times with 100 ml of ether each time. The combined ether extracts were washed with water, dried and evaporated to dryness. The residue was dissolved in ethanol and neutralized with ethereal hydrochloric acid. The precipitate was recrystallized from ether / petroleum ether. Yield 9 g (61 %) , pp. 205 ^° C.

109831/2144 ⁴

ORIGINAL INSPECTED

• 1W3265

Following the procedure of Example 16 (3-chlorophenyl) -2-methyliaoindolin obtain 25 g (29 f>) 2-methylaminomethyl-a- (3-chlorophenyl) -benzylalkoholhydrochlorid from Pp. 174 ⁰ C of 70 g l-.

Example 17 (method B)

2-n ~ butylamino-methyl-tt- (4-chlorohenyl-benzyl alcohol hydrochlorld

10 g of 1- (4-chlorophenyl) -2-n-butylisoindole and 100 ml

Acetic anhydride was refluxed for 30 hours. The acetic anhydride was then removed in vacuo and the Treated residue with water and dilute ammonia.

The organic matter was 3 times bit per 100 ml of ether extracted. The combined ether extracts were washed with dilute hydrochloric acid, water and saturated sodium carbonate solution, dried and dried to dryness evaporated. The dark brown, oily residue was attached to Kieaelgel in the usual way using of a chloroform-methanol-ammonia mixture (97: 3: 0.5 Vol. #) Chromatographed as the eluent. The main fraction consisted of 6 g of a light yellow oil, which for the following reaction was used as such.

109831/2144

6 g of the oil obtained by the above process, 30 μl of ethyl glycol and 15 μl of 50% aqueous potassium hydroxide solution were refluxed for 6 hours, cooled to room temperature and diluted with 100 ml of water. The mixture was extracted 3 times with 50 ml of Xther each time and the combined ether extracts were washed with water, dried and evaporated to dryness. The residue was converted into the hydrochloride by neutralization with ethereal hydrochloric acid and the crystalline precipitate was recrystallized from ether / ethanol. Yield 3.2 g (27 Ji), Pp. 102-105 ⁰ C.

Example 18 ( method B)

2-Isobutyl iinomethyl-a - (4-chlorophenyl) «benzyl alcohol hydrochloride

18 g of l- (4-chlorophenyl) -2-isobutylisoindoline were in 180 al acetic anhydride heated under reflux for 15 hours. The solution was concentrated to a volume of about 50 µl by evaporation under reduced pressure and then poured onto ice / ammonia. The diacetyl compound was extracted with ether, the combined ether extracts with Washed acid, water and saturated sodium carbonate solution, dried over magnesium sulfate and refllioh evaporated to dryness. The 17 g of the dark oil obtained were dissolved in 90 ml of ethylene glycol and after addition of 45 ml of 50% aqueous potassium hydroxide solution for 10 hours

.109831 / 2144

LOCAL

1 & 43265

the reflux is heated. After diluting with 200 g of ice, the material was extracted 3 times with 200 ml of ether each time, and the combined ether extracts were washed with 100 ml of water, dried and evaporated. The residue was chromatographed on 600 g of silica gel using a mixture of 90 parts of benzene and 10 parts of methanol as the eluting agent. The purified material was dissolved in ether and precipitated with ethereal salic acid. After recrystallization from ethanol / ether, 6 g (£ 28) of the hydrochloride of boiling point 154 ^° C. were obtained

Example 19

2- (N-methyl ~ N-acetyl) "- aminomethyl-a- (3 '* trifluoromethyl- 4-chlorophenyl) -0 ~ acetylbenzyl alcohol 10 g of 1- (3-trifluoromethyl-4-chlorophenyl) -2-methyliso indoline and 100 ml of acetic anhydride were 1 week on the back ι River heated .. The main part of the acetic anhydride was la

Removed vacuum and the residue with ice and ammonia

treated and extracted with ether. The ethereal solution was treated with water, dilute hydrochloric acid and sodium carbonate

Ib'sung washed and dried over magnesium sulfate. Obtained after removal of the solvent in vacuo.

one 12.5 g of the dark oily Ο, Η-Diacety! compound.

.1CUB31 / 2U *

Beleplel 20

2-methylaminomethyl1-g- (3-trifluoromethyl-4-chlorophenyl) - benzyl alcohol hydrochloride

12.5 g of the oily 2- (N-methyl-N-acetyl) -aminomethyl-a- (3-trifluoromethyl - ^ - chlorophenyl) -O-acetyl-benzyl alcohol, 40 ml 50 ml potassium hydroxide solution and 120 ml ethylene glycol were refluxed for 2 hours. Bas mixture was then diluted with 200 ml of water and concentrated with

Acidified hydrochloric acid. The crystallized hydrochloride

was recrystallized 2 times from ethanol / ether. Developed 7 g (69 Ji), pp. 253 ^° C

Example 21 (method B)

2- (N-methyl-N-acetyl) ~ aminoaethyl-g- (4-methylphenyl) -0-ac etyl-bensyl alcohol

36 g of 1- (4-methylphenyl) -2-methylisoindoline and 360 ml of acetic anhydride were refluxed for 30 hours. About 300 ml of acetic anhydride were distilled off under reduced pressure and the remainder on ice / conc. Poured ammonia. The diacetyl compound was extracted 5 times with 100 ml of ether each time, the combined ether extracts were washed successively with dilute hydrochloric acid, water and sodium carbonate solution and then dried over magnesium sulfate. the ether was stripped off and the crystalline residue was recrystallized from ethanol. Yield 33 g (63 Jt), p. 96 ^° C

30a 109831 / 2U4 '

ORIGINAL

· ■ "· -1949265

Example 22

2-Methylaainoi3ethyl-a- (A-methylphenyD - ber .. yl alcohol hydrochloride

20 g of 2- (N-methyl-N 'acetyl) -aminoaethyi-a- (4-inethylphenyl) * -O-acetyl-benzylaikohol were dissolved in a mixture of 120 ml Ä ⁴ .hyienglykol and 60 ml of 50 jtiger aqueous Kaliunfnydroxidlösung 2 hours aas refluxed. The solution was then diluted with 30 ml of water and extracted twice with ether. The ether extracts were washed with Waseer, 2 ¹ Ur dryness · "deducted ul ~ he magnesium sulfate and in vacuo The residue crystallized in the treatment;.?. With ätheri3 forth hydrochloric acid and the Hydrcchierid resultant was uxkristallisiert from Äthancl / ether yields 13 g (7? +) _t mp. 218- ⁰

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Claims (1)

Claims 1. α-Substituted 2-amino-methyl-benzyl alcohols of the general ϊοπηβΐ R _{1 is} hydrogen or an alkyl radical with 1-4 carbon atoms, R _{2 is} hydrogen, an alkyl radical with 1-4 carbon atoms, an aoyl or alkoxyoarbonyl radical, R, hydrogen, an alkyl or hydroxyalkyl radical with 1-5 carbon atoms, an aminoalkyl, alkylaminoalkyl, sialkylaminoalkyl, aoylaminoalkyl, aoylalkyla * inoalkyl or N-alkyl or ff, N-dialkylhydrazinoalkyl group or a cycloalkyl or benzyl group, where at least one of the radicals R ₂ or IU must be hydrogen, Rj is hydrogen, an alkyl or aoyl group, Z the remainder "Λ ^ /, the Cyolohexenyl- or the Rg Benzyl radical, which may be substituted by halogenation, R, - hydrogen, a halogen atom or the trifluoromethyl gnippe and 109831 / 2U4 M3 \ was unsuccessful ! Art. 11 1 Ats, l wt. L sentence 3 4e änderuneaaea. y. 4.3- -e- Hydrogen, a calcium atom or the methyl group mean and their acid addition salts. 2. Compounds of the general formula CH ₂ - NH - CH ₅ CH-OK * 6 f where t Rc is a halogenated or trifluoroethyl group and ' ι Rg hydrogen _v a halogenated or the methyl group \ mean and their acid additionasalee. i · 2-MethylajD inon ethyl-α- (4-chlorophenyl) -benzyl alcohol and its acid addition salts .. 4 x 2-methylamine oxyethyl-α- (4-fluorophenyl) benzyl alcohol and its acid addition salts. ORIGINAL INSPECTED 109831/2144. ■ I 5. Process but production of τοη α-substituted 2-aminomethyl-benzy! Alcohols of the general formula R _{1 is} hydrogen or an alkyl radical with 1-4 carbon atoms, R _{2 is} hydrogen, an alkyl radical with 1-4 carbon atoms, an aoyl or alkoxyoarbonyl radical, R _{5 is} hydrogen, an alkyl or hydroxyalkyl group with 1-5 carbon atoms, an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aoylaminoalkyl, aoylalkylaminoalkyl or H-alkyl or H, N-dialkylhydrazinoalkyl group or an oyoloalkyl or bensyl group , where at least one of the radicals R ₂ or R ₅ must be hydrogen, R _{4 is} hydrogen, an alkyl or aoyl group, Z the rest ~ "* C__p < 1 the Cyolohexenyl- or the Bensyl radical, which is optionally substituted by halogen, Rc is hydrogen, a halogen atom or the irifluoromethyl group and Rg is hydrogen, a halogen atom or the methyl group mean, daduroh marked that one * ^y * ^: - 109831/2144 " - * - le a) £ phthalide of the general formula in which Z has the meaning given above, - with an amine of the general formula HK in which R _{2 is} hydrogen or an alkyl radical having 1-4 carbon atoms and R, which has the meaning given above, converts and the compound of the formula thus obtained Il C-N CH - OH J- where B ^, R «and Z have the meaning given above have been converted into the end product of the general formula I in a manner known per se, for example by means of suitable complex hydrides, or 1Q9831 / 2144 original · 1β <3265 that he
b) an isoindoline of the general formula wherein R, and Z have the meaning given above, with an acyl anhydride in a * compound of general formula ^CH 2-H CH - OAq
Z where R, and Z have the meaning given above and Ac is an acyl group, converts, if desired, deacylated this compound by customary methods, and that optionally the end product thus obtained is converted into a physiologically acceptable acid addition salt Convicted. 109831/2144 ORIGINAL IHSPiQTED 6. The method according to claim 5, characterized in that that a compound of the formula I in which Rg Hydrogen means reacted with a halogen formic acid. 7. The method according to claim 5 _f, characterized in that in a compound of the formula Xi in which R ^ or R * denote hydrogen »by customary methods, for example by treatment with an alkyl halide / or a dialkyl sulfate, an alkyl group is introduced. 8 · The method according to claim 5, characterized in that dafl man »ine. Compound of the general formula I, in which R * Hydrogen means, in the usual way, for example by reaction with the corresponding alcohol in Presence with a hydrohalic acid, etherified. 9 »Method according to claim 5, characterized in that a compound of the formula I in which R 1 denotes the bensyl radical is hydrogenated. 10. Pharmaceutical preparations containing as active ingredient one or more compounds of the formula I or their physiologically acceptable acid addition salts in a dosage of 10-100 mg, preferably ZO- 50 mg per dose. 109831 / 2UA original inspected 3f 11 Method for combating obesity in warm-blooded animals One or more compounds of the general formula I, optionally in combination with a laxative. 109831/2144 ORIGINAL INSPECTED