DE2264903A1 - PIPERIDINE DERIVATIVES - Google Patents

Description

226A903

! • «tentenwlUt · DfpT.-fng. R. B E K T Z sea DlpWng. K. LAMPiTiCHT

Dr.-lng. Γί. L2 ϊϊ ETZ Jr. 501-23. 727P ^- E. Mönchen22, Steinsdorfstr. 10

P 22 6k 903.2 April 28, 1975

ROUSSEL UCLAP, Paris (France)

Piperidine derivatives

The invention relates to new piperidinoalkylphenthiazines of the general formula 1:

-N-CH ₀ -CH- (CH _n ) -NK (1)

2'p

'"0-CH- (CH ₂ J _n -CH-OA

R R

in which X is a hydrogen or chlorine atom or a trifluoromethyl, Is methoxy or methyl mercapto;

B and R, which can be the same or different, represent a Hydrogen atom or an alkyl radical with no more than

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Carbon atoms;

Z ¹ denotes a hydrogen atom or Z, where Z is a linear or branched alkyl radical having not more than 10 carbon atoms;

ρ can be 0 or 1;

η can take the values 0, 1 or 2 and

A is a hydrogen atom or a R.CO radical in which FL is a polymethoxyphenyl radical or an alkyl radical with not more than 18 carbon atoms, which can contain a double bond or an oxygen bridge (-0-), or A is an RpOOC group, where R _{2 is} a linear alkyl radical with not more than 15 carbon atoms and its acid addition salts formed with organic or mineral acids.

The new piperidinoalkylphenthiazines of the formula 1 and their pharmaceutically acceptable organic or Mineral acids are formed by addition salts because of their neuroleptic, antihistamine, analgesic and spasmolytic Effectiveness in human therapy of benefit.

The invention also encompasses a process for the preparation of the piperidinoalkylphenthiazines of the formula (1) as well their addition salts formed with organic or mineral acids, which is characterized in that one 10- (a> -haloalkyl) -phenthiazine of the general formula 2:

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N-CH _p -CH- (CH _p ) -Y (2)

in which X, B and ρ have the meaning already given and Y is a chlorine or bromine atom, with a piperidine derivative of the general formula 3 '.

H-N

O-CH- (CH _{2) n} -CH-OA (3) RR

in which A, Z ¹ , R and η have the meaning already given, converts and either

a) the product of the formula (1) obtained is isolated and, if necessary, reacted with an organic or mineral acid to form the salt; or

b) in the event that a product of the formula (1) has been prepared in which A is a hydrogen atom, this Product either

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-lieinem acid chloride of the formula Cl-CO-R, in which R. has the meaning already given, and then the product of the formula (1) thus obtained, in which A is an R ₁ CO radical, isolated and optionally with a converting organic or mineral acid to form the salt; or

with an alkyl chloroformate of the formula Cl-COOR, in which R _{2 has} the meaning already given, and then the product of the formula (1) thus obtained, in which A is an RpOOC radical, is isolated and optionally with an organic or mineral acid Formation of the salt converts.

Under the preferred conditions for practicing the invention, there will be the manufacturing process described above carried out in the following way:

a) A solution of the compound of the formula (2) in an inert organic solvent is equimolar Amount of an organic base such as triethylamine that can take on the function of a hydrogen acid acceptor and then adding an equimolar amount of the compound of formula (3). Besides, it is especially when Y is a chlorine atom, particularly advantageous when an equimolar amount of sodium iodide is present. The received Mixing is for about 10 to 100 hours at a temperature between room temperature and the boiling point the reaction mixture held. After the reaction has ended, the triethylammonium salt formed is filtered off and isolating the compound of formula (1) from the filtrate.

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b) The reaction of a compound of the formula (1) in which A is a hydrogen atom with an acid chloride of Formula Cl-CO-FL or with an alkyl chloroformate of the formula Cl-COO-R- is preferably carried out at room temperature in a solvent such as benzene and in the presence of an organic base such as triethylamine, which is responsible for trapping the hydrochloric acid formed during the reaction is suitable.

c) The compounds of the formula (1) have basic properties and according to the invention their acid addition salts by the action of corresponding organic or mineral acids based on these compounds of the formula (1) are prepared, preferably in a solvent is used. In particular, anhydrous solvents such as benzene, ethyl ether, Ethanol and acetone were chosen. The salts can be prepared without prior isolation of the appropriate bases will.

These acid addition salts can, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, Nitric acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, Citric acid, oxalic acid, alkanesulfonic acid or arylsulfonic acid.

The new piperidine derivatives of the general formula 3 also belong to the overall complex of the invention

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HN

0-CH- (CH ₀ ) -CH-OA t ^ ^η »

R R

in which A, Z ¹ , R and n have the meaning already given.

The invention further comprises a process for the preparation of these new piperidine derivatives of the formula 3, which is characterized is that a cyclic acetal of N-benzylpiperidone- (4), that of the general formula U

^CH 2> n

O-CH

corresponds, in which R and η have the meaning already given, in an anhydrous medium with an anions delivering Reagent converts the lithium aluminum hydride in the presence of a Lewis acid such as aluminum chloride or zinc chloride or by an alkyl magnesium halide of the general formula 5:

Z-Mg- Shark (5)

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in which Hal is a chlorine, bromine or iodine atom and Z is the one Has given meaning, can be formed and on the product of the general formula 6 thus obtained

No. ¹

^c 6 ^H 5 ~ ^CH 2 "\ __ / \ RR (6)

0-CH- (CH ₀ ) -CH-OH ά η

in which R, Z ¹ and η have the meaning already given, either

a) Hydrogen can act in the presence of a palladium-based catalyst to obtain a product of the formula (3), in which A is a hydrogen atom, or

b) an acid chloride of the formula Cl-CO-R, in which R _{1 has} the meaning already given, to obtain a compound of the general formula 7

R R (7) O-CH- '"

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in which R, R ₁ , Ζ · and η have the meanings already given, and the product of the formula (7) is treated with hydrogen in the presence of a palladium-based catalyst to obtain a product of the formula (3) in which A is R. Is -OC radical; or

c) a chloroformate of the formula ClCOORp, in which R _{p has} the meaning already given and the resulting product is treated with hydrogen in the presence of a palladium-based catalyst to obtain a product of the formula (3) in which A is an RpOOC radical.

Finally, the overall complex of the invention also includes the N-benzylpiperidyl-4-oxyalkanols of the general formula 8:

^C 6V ^CH 2- \ Λ RR

O-CH- (CH ₂ ) _n -CH-OA (8)

in which R, n, Z 'and A have the meaning already given.

The piperidine derivatives of formula (3) are very useful compounds, especially as secondary amines for Manufacture of new substances, especially for human and veterinary therapy.

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Preferred conditions for carrying out the manufacturing process described above are as follows:

a) The compound of the formula (4) is added to a mixture of lithium aluminum hydride and aluminum chloride suspended in anhydrous ether and left in contact for one to five hour (s) ^{at a temperature between 15 ° C. and the boiling point of the reaction mixture.} The complex formed is then hydrolyzed by adding water, the reaction mixture is made alkaline with sodium hydroxide and the compound of the formula (6) in which Z ¹ = H is isolated by conventional means such as extraction with subsequent distillation.

b) First, an organomagnesium compound of the formula (5), in which Hai is a bromine atom and Z is an alkyl radical, is prepared by reacting the corresponding alkyl bromide with magnesium within a solvent such as anhydrous ether in the presence of iodine. A compound of the formula (4) dissolved in an anhydrous solvent such as benzene is then added to this alkyl magnesium bromide and, after the first solvent has been separated off, the mixture is refluxed for 10 to 24 hours. The solution is then cooled and the complex formed is hydrolyzed with an aqueous saturated ammonium chloride solution. The compound of the formula (6) obtained, in which Z ¹ = Z, is prepared by conventional means

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isolated like extraction and subsequent distillation,

c) The hydrogenation of the products of the formulas (6) or (7) with hydrogen in the presence of a palladium-based catalyst is preferably carried out by suspending these products in absolute ethanol and then stirring or agitating this suspension in a hydrogen atmosphere in the presence of palladium deposited on carbon (Palladium content between 1 % and 10 Jt). In this case, preferably with a hydrogen pressure zwisehen atmospheric pressure and 10 kg / cm worked and at a temperature between 30 and 70 ⁰ C. After the theoretical amount of hydrogen has been absorbed, the catalyst is separated off from the organic phase by filtration and the compound of the formula (3) is isolated from this organic phase by conventional means. For this purpose, for example, the ethanol can be separated off or driven off and the residue can be rectified.

d) The reaction of the compound of the formula (6) with the acid chloride Cl-COR. can preferably be carried out as follows will:

The compound of the formula (6) and triethylamine are dissolved in benzene and the acid chloride Cl-COR _{1 is} added dropwise, the reaction vessel being kept in an ice bath. The solution is then left for 2k to M8 hours at room temperature and the precipitate formed is then removed by suction or suction.

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226A903

- αϊ -

Separated throwing off. The benzene oil obtained was obtained is washed with an aqueous sodium bicarbonate solution and then with water. After all, you vape the benzene solution and the residue is distilled. The compound of formula (7) thus obtained is made from Distillate isolated.

The compounds of the formula (4) necessary for carrying out the process according to the invention can, insofar as they are not known, by reaction of a diol of the general formula 9:

HIGH

HIGH

^ Vn (9)

in which R and η have the meaning already given, with l-benzylpiperidone- (4) in the presence of hydrochloric acid be prepared by methods known per se.

As already stated above, the new piperidinoalkylphenthiazines of the formula 1 and their phar-

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pharmaceutically acceptable organic and mineral acids Adhesion salts useful in human therapy. They can be used in treating disorders of the neuro-vegetative Balance, character disorders, behavior disorders, various allergic manifestations, algias and spasmodic Digestive tract complaints are applied.

The usual dose may vary depending on the compound used, the person treated and the condition being treated in the case of oral administration in humans, for example, be 10 mg to 1 g per day.

The invention finally relates to pharmaceutical agents containing piperidinoalkylphenthiazines of formula 1 and / or their pharmaceutically acceptable salts as active ingredients.

These pharmaceutical agents can be solid or liquid and in the ones commonly used in human medicine pharmaceutical forms such as simple or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, pomades, creams or gels, and they can be prepared using conventional methods.

Thus, the active ingredient (s) can be used with excipients customarily used in such pharmaceutical compositions be mixed like with talc, gum arabic, lactose, starch,

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Magnesium stearate, cocoa butter, aqueous or non-aqueous Carriers, fats of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing agents or emulsifiers and preservatives.

Of the compounds that can form the active ingredient of such pharmaceutical agents according to the invention, in particular the 1O-J3-Rl- (2-hydroxyethoxy) -piperidinoJ-propyl? · -Phenthiazine hydrochloride should be mentioned, which is particularly noteworthy as having a Antihistamine effect has been shown to have, for example, the effect of histamine on the isolated guinea pig intestine (hay) at a dose of
nized.

sis of 5 x 10 g / l (determined according to the Magnus technique) antagonistic

Likewise, the 2-trifluoromethyl-10-j3 - [_ ⁱ i- (2-hydroxyethoxy) -4-methyl-piperidinoJ-propylv-phenthiazine hydrochloride should be mentioned, which has been shown to be endowed with remarkable neuroleptic properties, for example in the traction test, a 50 % effective dose (DE ₅₀ ; ie the dose which prevents 50% of the animals from returning to their normal position in less than 5 seconds) of 0.85 mg / kg (administered intraperitoneally) is found.

The following examples serve to illustrate the invention without, however, restricting it in any way.

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-IH-

Example 1: Preparation of 2- (piperidyl-4-oxy) -ethanol a) 2- (1-benzyl-piperidyl-4-oxy) -ethanol

In a 2 l three-necked flask, Iü6.8 g (0.8 mol) Brought aluminum chloride and then added 800 ml of anhydrous ether with vigorous cooling. After 30 minutes A suspension of 7.6 g (0.2 mol) of lithium aluminum hydride in 200 ml of anhydrous ether is added with stirring.

After stirring for 30 minutes, it is added dropwise a solution of 93.2 g (0.4 mol) of 8-benzyl-1,4-dioxa-8-aza- -spiro - (_ Add 4,5j-decane in 400 ml of anhydrous ether. After When the addition is complete, stirring is continued for a further 2 hours at room temperature. Then it is vigorously cooled and very carefully added 1 liter of water. The mixture is made alkaline with 90 g of sodium hydroxide cookies.

The ether is decanted off and the aqueous phase is extracted again with ether. The combined ethereal phases are dried, the ether is evaporated and the residue is distilled. 63 g (67 %) of 2- (l-benzyl-piperidyl ⁱ l-oxy) -ethanol are thus obtained in the form of a clear oil.

Kp _{0> 1} = 140 ⁰ C 20th
in _D = 1.63: 5 6th N Molecular formula: I ₂₁ NO ₂ 5 , 0 calculated (%) : , 9 found (%):

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b) 2- (piperidyl-4-oxy) ethanol

48 g (0.204 mol) of 2- (l-benzyl-piperidyl-4-oxy) ethanol are dissolved in 500 ml of absolute ethanol. The solution is ^{treated with hydrogen at 50 °} C. in the presence of 5 g of palladium on charcoal (5%) until the theoretical amount of hydrogen has been absorbed. The catalyst is then filtered off, the ethanol is evaporated and the residue is distilled. This gives 22 g (74 %) 2- (piperidyl-4-oxy) ethanol in the form of a colorless oil which crystallizes on cooling.

^Κρ ο, οι - ^{110 c}

The product is recrystallized from cyclohexane.

* p (K) - ^{72 C.}
Molecular formula: C ₇ H ,,, -NO ₀

(Ip c-

C HN

calculated (%): 57.9 10.4 9.7 found (%): 57.5 10.5 9.8

c) The 8-benzyl-1,4-dioxa-8-aza-spiro- | 4,5j-decane can be obtained as follows:

68.3 g (1.1 mol) of ethylene glycol are placed in a 2 l three-necked flask with a gas inlet and a separator of the Dean & Stark type and 1 1 anhydrous benzene mixed.

The mixture is heated to the boil to separate any water that may be present and then with 189 g (1 mol) of 1-benzylpiperidone- (4) offset. The mixture is then further heated to the boil, whereby a stream of dry gas-

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shaped hydrogen chloride is introduced until 18 ml (1 mol) Collected water (which takes about 6 hours).

After cooling, the precipitate obtained is filtered off with suction or centrifuged and washed with benzene and then recrystallized from absolute ethanol. This gives 213 g (79 %) of e-benzyl-ljlJ-dioxa-e-aza-spiro-jJI ^ -decane hydrochloride in the form of white crystals. Pp (K) = 262 ⁰ C.

The above product is suspended in 1 1 of anhydrous ether, long a stream of ammonia is passed through the H hours. The remaining pesticide is separated by filtration and the ether is evaporated. This gives 178 g (76%, based on the 1-Benzylpiperidon- (O) 8-benzyl-l, ¹ * - dioxa-8-aza-spiro-L4,5j-decane in the form of a light-amber oil, which in the Refrigerator crystallizes (melting point < 50 ^° C.).

Molecular formula: C ₁ 4 ^H. 19 ^NO 2 6th N 6th , 0 calculated , 0 found

Example 2; Preparation of 3- (piperidyl-4-oxy) propanol a) 3- (1-benzyl-piperidyl-4-oxy) propanol

Using the same procedure as in Example 1 (a), but using 98.8 g (0.4 mol) of 9-benzyl-1,5-dioxa-9-aza-spiro- [5,5] -undecane, one obtains HQ g (48 %) 3- (l-benzyl-

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piperidyl-4-oxy-propanol in the form of a light oil

Kp _0fl = 160 ⁰ C, "20th
ⁿ D = 1 , 531 5 N Molecular formula: ^C 15 H ₂₃ NO ₂ 5 , 6 , 7 calculated {%) : found ( % ):

b) 3- (piperidyl-4-oxy) propanol

Using the same procedure as in Example 1 (b), but using 47.5 g (0.19 mol) of 3- (l-benzyl-piperidyl-4-oxy) propanol, 22.2 g (73 %) are obtained 3- (Piperidyl-4-oxy) propanol in the form of a colorless oil.

^κ Ρο, οι = (%): "20th
■ · ⁿ D = L C. 488 H ,8th 8th N ^C 8 ^H 11 _r N0 ₂ 60 10 , 7 9 ,8th Molecular formula: 60 10 , 0 , 3 calculated , 4 found

c) The 9 ~ benzyl-l, 5-dioxa-9-aza-spiro-Jj), 5l-undecane can be obtained in the same way as in Example 1 (c), but using 83.6 g (1, 1 mol) propanediol- (1,3): 180 g (73?, Based on the l-benzylpiperidone- (4)) of 9-benzyl-1,5-dioxa-9-aza-spiro- | _5,5j undecane as a light-amber oil, which crystallized in the refrigerator (mp <50 ⁰ C).

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Molecular formula: ^c i5 ^H 21 ^N0 2

calculated {%) : 5.7

found (%) : 5.6

Example 3: Preparation of 2- (piperidyl- ⁱ J-oxy) -l, 2-dimethyl- ethanol

a) 2- (N-Benzyl-piperidyl-4-oxy) -l, 2-dimethyl-ethanol

Using the same procedure as in Example 1 (a), but using 130.6 g (0.5 mol) of 2,3-dimethyl-8-benzyl-1,4-dioxa-8-aza-spiro- [4 , 5J-decane gives 83.3 g (63 %) 2- (N-benzyl-piperidyl- ⁱ J-oxy) -l, 2-dimethyl-ethanol in the form of a pale or clear oil.

^K ? 0.01 = 150 ° (it): - 155 ° C = 1 VJl • Molecular formula: C ₁₆ H. 5, N calculated 3 found 5 - ~ ²⁰
'» ^N D J ₅ NO ₂

b) 2- (piperidyl-4-oxy) -l, 2-dimethyl-ethanol

With the same procedure as in Example 1 (b), but using 83.3 g (0.315 mol) of 2- (N-benzyl-piperi dyl-4-oxy) -l, 2-dimethyl-ethanol is obtained after recrystallization from Cyclohexane 37.5 g (75 %) 2- (piperidyl-'4-oxy) -1,2-dimethyl-ethanol in the form of white crystals.

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Pp (K) = 88 ^° C

Molecular formula: C ₉ H ₁₉ NO ₂ C. 4th H ,1 8th N 62, 2 11 , 9 8th ,1 calculated {%): 62, 10 , 0 found (%):

c) The 2,3-dimethyl-8-benzyl-1,4-dioxa-8-aza-spiro- [4,5] - -decane can be obtained in the same manner as in Example 1 (c), but using of 99.1 g (1.1 mol) of butylene glycol: 200 g (77 % based on the 1-benzylpiperidone- (4)) 2, ^ - dimethyl-S-benzyl-1 ^ -dioxa-S-aza are obtained -spiro- [4,5j-decane in the form of a light amber-colored oil.

Molecular formula: C. 16 ^H 23 ^NO 2 N 5.4 calculated 5.6 found

Example 4: Preparation of 4- (piperidyl-4-oxy) -butanol a) 4- (N-benzyl-piperidyl-4-oxy) -butanol

Using the same procedure as in Example 1 (a), but using 110 g (0.421 mol) of 10-benzyl-1,6-dioxa- -10-aza-spiro- [5.6] -dodecane, 71.5 is obtained g (65 %) 4- (N- -Benzyl-piperidyl-4-oxy) -butanol in the form of a clear oil.

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Kp _{0 05} = 165 ⁰ C • N 3 Molecular formula: ⁰ IO ¹ • 5, 6th 5, calculated (5t) found (Ϊ)

b) 4- (piperidyl-4-oxy) butanol

Using the same procedure as in Example 1 (b), but using 82.9 g (0.3I ¹ * mol) 4- (N-benzyl-piperidyl-4-oxy) -butanol, 34.1 g (6l %) 4- (Piperidyl-4-oxy) -butanol in the form of a colorless oil.

Kp _{0 05} = 120 ⁰ C, n £ * = 1 *
• , 486 H ,1 N 1 Molecular formula: C ₉ H ₁₉ NO _{2 :} 11 , 2 8th, 0 C. 11 8th, calculated (51) 62.4 found (5t) 61.9

c) The 10-benzyl-1,6-dioxa-10-aza-spiro-j_5,6J-dodecane can be obtained in the same way as in Example 1 (c), but using 57.6 g (0.64 Mol) butanediol- (1,4): One receives 139.6 g (92 Jt, based on the 1-benzylpiperidone- (4)) 10-benzyl-1,6-dioxa-10-aza-spiro- [jj , 6j-dodecane in the form of a clear, amber-colored oil that crystallizes in the refrigerator. Instant melting point: 52 ⁰ C.

Molecular formula: 0./-H ₀ ^

Ib 2;

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2264303

calculated (%) : 5.4

found (%): 5.2

Example 5: Preparation of 2- (piperidyl-4-oxy) ethyl acetate

a) 2- (N-Benzyl-piperidyl-4-oxy) -ethyl acetate

To a solution of 47 g (0.2 mol) of the 2- (l-benzyl-piperidyl-4-oxy) -ethanol prepared according to Example 1 (a) and 20.2 g (0.2 mol) of triethylamine in 300 ml Benzene is added dropwise with cooling (with an external ice bath) to 20 ^° C., 15.6 g (0.2 mol) of acetyl chloride. The reaction mixture is left to rest for 48 hours at room temperature and the precipitate formed is then filtered off with suction or centrifuged. The benzene filtrate is washed with an aqueous sodium bicarbonate solution and then with water. After the benzene solution has been dried and evaporated, the residue is distilled and 36.5 (66 %) 2- (N-benzyl-piperidyl-4-oxy) -ethyl acetate are obtained in the form of a clear oil.

^Kp 0, l = ^l6 ° ° - W ° C; nj " ⁰ = 1.512

Molecular formula: Ο. ,, - Η, -, -. ΝΟ,

16 23 3

CHN

calculated (%): 69.3 8.4 5.1 found (%) : 68.7 8.4 4.9

b) 2- (piperidyl-4-oxy) ethyl acetate

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36.4 g (0.131 mol) of 2- (N-benzyl-piperidyl-4-oxy) -ethyl acetate are dissolved in 200 ml of absolute ethanol. Hydrogen is then allowed to act at 50 ^° C. in the presence of 3.5 g of palladium on charcoal (5%) until the theoretical amount of hydrogen has been absorbed.

The catalyst is then filtered off, the ethanol is evaporated and the residue is distilled. This gives 18.2 g (74 %) of 2- (piperidyl-4-oxy) ethyl acetate in the form of a clear oil.

Kp _{0 t} = 102 ° C; "20 _
ⁿ D - 1.4665 C. 9 H 7th N Molecular formula: Π IJ
C ₉ H 17 ^NO 3 57; 9 , 2 7th , 5 57, , 2 , 5 calculated (?) : 2- (piperidyl-4-oxy ) ethyloctanoate found (?) • Example 6: Manufacture from , 7 , 5

To a solution of 47 g (0.2 mol) of the 2- (l-benzyl-piperidyl-4-oxy) -ethanol prepared according to Example 1 (a) and 20.2 g (0.2 mol) of triethylamine in 300 ml benzene is added dropwise under cooling (with an external ice bath) at 20 ⁰ C 32.4 g (0.2 mol) of octanoyl chloride. The reaction mixture is left to stand for 24 hours at room temperature and the precipitate formed is then filtered off with suction or spun off. The collected benzene filtrate is washed with an aqueous sodium bicarbonate solution and then with water. After drying

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2264S03

and evaporating the benzene solution, the residue obtained is dissolved in 300 ml of absolute ethanol. The mixture is left out hydrogen at 50 ⁰ C in the presence of 4.5 g palladium on charcoal (5 JSig) act until the theoretical amount of hydrogen is absorbed. The catalyst is then filtered off, the ethanol is evaporated and the residue is distilled. 35.5 g (64 %) of 2- (piperidyl-4-oxy) ethyloctanoate are obtained in the form of a clear oil.

^κ Ρο, ι = ¹ 50 ° <*> - 156 •
• ⁰ C- η ²⁰ -
ο, n _D - C. 1.46 4th N 2 Molecular formula: (*) C ₁₅ H • 29 ^NO 3 66.4 5, 3 66.0 H 5, calculated 10, 8th found 10, 7th

Example 7: Preparation of 2- (4-methylpiperidyl-4-oxy) ethanol

a) 2- (N-Benzyl-4-methyl-piperidyl-4-oxy) ethanol

150 ml of ether are placed in a flask, which has been cooled ^{to about} C}
is mixed.

-10 ⁰ C cooled and mixed with 40 g of methyl bromide and

9.6 g of magnesium turnings, 50 ml of ether and an iodine crystal are placed in another flask. One then gives to this Solution dropwise the above methyl bromide solution. When this addition is complete, the resulting addition is added Mixture with a solution of 46.6 g of 8-benzyl-1,4-dioxa-8-azaspiro-jj_4,5j-decane in 1 1 anhydrous benzene.

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The ether is evaporated and the mixture is then 16 hours brought to reflux conditions for a long time. The resulting solution is cooled and saturated with ammonium chloride solution hydrolyzed. The benzene is decanted and the aqueous phase is extracted with ether. One dries the organic Phase over sodium sulfate, the solvents evaporated in vacuo and rectify the residue under reduced pressure. 42.8 g of 2- (N-benzyl-4-methyl-piperidyl-4-oxy) ethanol are obtained in this way in the form of a colorless oil.

^Kp 0, l ^{= 136} " ¹ ^ ⁰ ° ^{Ci n} D ^{6 = 1} ^ ²⁷ Sum formula: ^C i5 ^H 23 ^NO 2 ^{= 2} ^» 3

CHN

calculated (*): 72.25 9.30 5.62 found (Ϊ): 72.4 9.2 5.9

b) 2- (4-methylpiperidy1-4-oxy) ethanol

51.5 g of the 2- (N-benzyl-4-methyl-piperidyl-4-oxy) ethanol obtained by the process described above under a) are dissolved in 500 ml of absolute ethanol.

Hydrogen is allowed to act on this solution at 50 ^° C. in the presence of 5 g of palladium on charcoal (5%) until the theoretical amount of hydrogen has been absorbed. This reaction takes about 3.5 hours. The catalyst is then filtered off, the ethanol is evaporated off and the residue is rectified under reduced pressure. This gives 24 g of 2- (4-methyl-

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piperidyl-4-oxy) ethanol in the form of a colorless oil.

^Kp o, oi = 8 ° -δ ⁶ ° C; "d ^{4 = 1} ^

Molecular formula: CgH ₁₇ NO ₂ ; M = 159.2

C H

calculated (%): 60.34 10.76

found (,%): 59.6 10.5

Example 8: Preparation of 2- (4-ethylpiperidyl-4-oxy) -ethanol a) 2- (N-benzyl-4-ethyl-piperidyl-4-oxy) -ethanol

19.2 g of magnesium, 100 ml of ether and then 87.5 g of ethyl bromide in 100 ml of ether are added dropwise to a flask. The addition is continued over about 30 minutes of reflux conditions.

After cooling, 46.6 g of 8-benzyl-1,4-dioxa-8-azaspiro-jjj, 5l-decane added in 250 ml of benzene. Evaporate the ether, add 250 ml of benzene and keep the mixture Boiling under reflux for 20 hours. The reaction mixture is cooled and saturated with ammonium chloride solution hydrolyzed. The bensolic phase is decanted, the aqueous phase is extracted with methylene chloride, washes the combined organic phases with water until neutral, dried over sodium sulfate, evaporated the solvents under reduced pressure and rectify the residue. 37.6 g of 2- (N-benzyl-4-ethyl-piperidyl-4-oxy) ethanol are obtained in this way in the form of a colorless oil.

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= 152 - 156 ⁰ C.

This product is used for the next step without further purification.

b) 2- (4-ethylpiperidyl-4-oxy) ethanol

37 g of 2- (N-benzyl- -M-ethyl-piperidyl-Jj-oxy) ethanol are dissolved in 300 ml of absolute ethanol. The hydrogen solution is allowed to act at 50 ^° C. in the presence of 4 g of palladium on carbon (10 jig) until the theoretical amount of hydrogen has been absorbed. This reaction takes about 3 hours.

The catalyst is then separated off by filtration, the ethanol is evaporated off and the residue is rectified. Man thus receives 19.2 g of 2- (4-ethylpiperidyl-4-oxy) ethanol in the form of a colorless oil.

Kp _nc = 102-106 ⁰ C.

Molecular Formula: C ₉ H ₁₉ NO; M = 173.26

CHN

calculated (%): 62.39 11.05 8.08

found (*): 62.4 10.8 8.0

Example 9: Preparation of 2- (4-propylpiperidyl-M-oxy) - -ethanol

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a) 2- (N-Benzyl-4-propyl-piperidyl-4-oxy) ethanol and its Hydrochloride

19.2 g of magnesium and 100 ml of ether are placed in a flask and then dropwise 108 g of propyl bromide in 250 ml of ether Maintenance of reflux conditions.

You then continuously add 46.6 g of 8-benzyl-1,4-dioxa -8-aza-spiro-J3 »5] -decane in 500 ml of benzene was added. The ether is evaporated and the reaction mixture for 24 hours brought to the boil under reflux.

The resulting solution is cooled and hydrolyzed with a saturated ammonium chloride solution. The benzene phase is decanted and the aqueous phase is extracted with ether. The organic phase is washed with water until neutral and dried over sodium sulfate. After evaporation of the solvent under reduced pressure, the residue is rectified (b.p. _{Q ±} = 129 ⁰ C). This gives 28 g of 2- (N-benzyl-4-propyl-piperidyl-4-oxy) ethanol in the form of a yellowish oil, which is dissolved in 250 ml of ether. 13 ml of an ethereal solution of hydrogen chloride gas (5 N) are added to the solution and the hydrochloride obtained is suctioned off and recrystallized from isopropanol.

After drying in vacuo, 12.9 g of 2- (N-benzyl-4-propyl-piperidyl-4-oxy) ethanol hydrochloride are obtained in the form of colorless crystals which melt at 196 ⁰ C.

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Molecular formula: C (Z): 17 ^H 28 ^C 1 NO 2 ^; M = 313, 87 Cl 30th C. H N 11 6th calculated 65 , 06 8th , 99 4.46 11 found 65 ,1 8th , 9 4.1

b) 2- (! »- Propylpiperidyl-4-oxy) ethanol

10.7 g of 2- (N-benzyl-4-propyl-piperidyl-4-oxy) ethanol are dissolved in 200 ml of absolute ethanol (which, starting from the hydrochloride described above under a), is dissolved by passing a stream of ammonia into a suspension of the same in anhydrous ether). Hydrogen is allowed to flow ^{onto this solution at 50 °} C. in the presence of 1 g of palladium on charcoal
(10 Jtig) act until the theoretical amount of hydrogen
is absorbed.

The catalyst is then filtered off, the ethanol
evaporated, and obtained 6.1 g of 2- (4-Propylpiperidyl-4-oxy) ethanol in the form of yellowish crystals at 72 ⁰ C
melt.

For the analysis, the product is recrystallized from cyclohexane. The product thus obtained is in the form of white crystals before, which are soluble in chloroform and melted at 76 ⁰ C.

Molecular formula: ^C _1O H ₂₁ NO ₂ ; M = 187.28

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(Jf): 61 » C. H , 30 7th N calculated (*): 63 , 13 11 , 6 7th »48 found ,8th 11 , 3

Example 10: Preparation of 2- (4-Heptylpiperidyl-4-oxy) · -ethanol

a) 2- (N-Benzyl-Jl-heptyl-piperidyl-iJ-oxy) -ethanol

In a flask it will be 9.6. g magnesium shavings, 50 ml Ether, an iodine crystal and 3 drops of ethyl iodide. A solution of 101.5 g of n-heptyl bromide in 300 ml of ether is then added under nitrogen over the course of one hour then stir for 1 hour.

To the resulting solution kd _S 6 g of 8-benzyl-l, [4,53-decane added, 4-dioxa-8-aza-spiro in 1 1 of anhydrous benzene. The ether is driven off and the mixture is refluxed for 16 hours. After the solution has cooled, 20 ml of water are added with stirring and then 400 ml of a saturated ammonium chloride solution.

The organic phase is decanted, the solvent is separated off under reduced pressure and the residue is rectified. Are thus obtained 40 g of 2- ^(N-benzyl-1 l-heptyl-piperidyl-4-oxy) ethanol in the form of a distilled between 150 and 200 ⁰ C oil. This product is used for the next step without further purification.

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b) 2- (4-heptylpiperidy1-4-oxy) ethanol

40 g of 2- (N-benzyl-4-heptyl-piperidyl-4-oxy) -ethanol are added to 300 ml of absolute ethanol solved.

The hydrogen solution is allowed to act at 50 ^° C. in the presence of 0.4 g of palladium on charcoal (5 Jig) until the theoretical amount of hydrogen has been absorbed. This reaction takes about 5 hours. The catalyst is then filtered off, the ethanol is evaporated and the residue is rectified. This gives 10.6 g of 2- (4-heptylpiperidyl-1-oxy) ethanol in the form of a colorless oil.

Kp ₀ j = 110 - 130 ⁰ C Sum formula: ^c m ^H 29 ^NO 2 ^{JM =}

calculated (Ϊ): 5.53

found (Jl): 5> 8

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Claims (2)

Expectations ί '
IjX-; Piperidine derivatives of the general formula 7 '
/ it ^Ε Ο ( O-CH- (CH ₂ J _n -CH-OA RR in the E is a hydrogen atom or a benzyl group, R is a hydrogen atom or an alkyl radical having not more than k carbon atoms, Z ^{1 is} a hydrogen atom or Z is. where Z is a linear or branched alkyl radical having not more than 10 carbon atoms, and A is a hydrogen atom or an R ₁ CO-ReSt, in which R is a polymethoxyphenyl radical or an alkyl radical with not more than 18 carbon atoms, which can contain a double bond or an oxygen bridge (-0-), or is an RpOOC radical in which R_ is a linear alkyl radical with not more than 15 carbon atoms, and
η can have the values zero, 1 or 2. 2. Process for the preparation of the piperidine derivatives according to claim 1, characterized in that one is a cyclic Acetal of benzylpiperidone of the general formula 509835/0949 0-CH > ^CH 2> n O-CH in which R and η have the meaning already given, in anhydrous medium reacts with an anion-supplying reagent, which by lithium aluminum hydride in the presence of a Lewis acid, the aluminum chloride or zinc chloride, or by an alkyl magnesium halide of the general formula (5) Z-Mg-HaI (5) in which Hai is a chlorine, bromine or iodine atom and Z is the has already given meaning, can be formed, and on the product of the general formula (6) thus obtained "YY / X ti ^ \ 0-CH- in which R, Z ¹ and η have the meaning already given, either 509835/0949 (A) an acid chloride of the formula Cl-CO-R, in which R _{1 has} the meaning already given, to obtain a product of the general formula (7) R R (7) O-CH- (J. can act, in which R, R ₁ , Z ¹ and η have the meaning already given, and optionally this product of the formula (7) treated with hydrogen in the presence of a palladium-based catalyst to obtain a product of the formula (3) (3) 0-CH- (CH ₀ ) -CH-OA ι <· ⁿ t RR where A is an R ₁ -CO-ReSt, or (b) allows a chloroformate of the formula ClCOOR _{2 to} act, in which R _{2 has} the meaning already given, and optionally treats the resulting product in the presence of a palladium-based catalyst with hydrogen to obtain a product of the formula (3) in which A is a R ₂ OOC-ReSt 509835/0949 is, or optionally (c) Hydrogen can act in the presence of a palladium-based catalyst to obtain a product of Formula (3)> where A is a hydrogen atom. 509835/0949