DE2264903C3 - Piperidine derivatives and their preparation - Google Patents

Description

The invention relates to piperidine derivatives of the formula Z '

(D O-CHa-iCH ^ -CHj-O-A

in which:
RH or benzyl,

X = Cl, trifluoromethyl, methoxy or methyl mercapto,

B = H or methyl,
Z '= H or C, - to Cio-Aikyi,
A = H or a group R, —CO with R = Ci- to da-alkyl

and
n = 0, 1 or 2,

which are described in DE-PS 22 22 931 and for their part due to their neuroleptic, analgesic, spasmolytic and antihistamine effects, especially in represent valuable pharmaceuticals in human medicine.

To prepare these compounds, the intermediates according to the invention are made with 10- (O) -haloalkyl) -phenothiazines of formula X

Z 'H or a group Z

with Z = linear or branched C _r to C | ₀ -alkyl, AH or a group Ri-CO-

with Ri = C, - to C ₁₈ -alkyl

and
η 0, 1 or 2.

These connections are e.g. B. Intermediates the production of Piparidinoalkylphenothiaziaen der formula

O —CH ₂ - (CH ₂ ) ,, - CH ₂ -Ο —Α

The process for the preparation of the compounds of the formula I according to the invention is indicated by

- Implementation of a cyclic acetal of N-benzylpiperidone the formula

C ₆ H ₅ -CH ₂ -N

CH ₂

CH ₂ -CH-CH ₂ -Y

implemented with X as above and Y = CI or Br.

O -CH ₂

with η as above

in an anhydrous medium,

(a) if TJ equals H,

with lithium alanate in the presence of a Lewis acid or,

(b) if TJ is Z, ie is Ci- to do-alkyl,

with an alkyl magnesium halide of the formula

Z-Mg-X

with Z = linear or branched Cr bis Cio-alkyl and X = CI, Br or J

to a compound of the formula Ia

/ - \ / C ₆ H ₅ -CH ₂ -N χ

O -CH ₂ - (CH ₂ ) ,, - CH ₂ -OH

with Z 'and η as above,

optionally with an acid chloride

Ri-CO-CI

with Ri as above

to a compound of the formula Ib

CiH ₅ -CH ₂ -N

with Ri, Z 'and η as above
is implemented,

Z '

O - CH ₂ - (CH ₂ ) ,, - CH ₂ - O - CO - R ₁

and if necessary

- Hydrogenation of the compound of formula la or Ib in the presence of a palladium catalyst to the corresponding compound of formula Ia 'or Ib '.

Η —Ν

Z '

0-CHj- (CH ₃ ) ,, - CH ₃ -OH (Ia ')

Η —Ν

Z '

O —CH ₃ - (CH ₂ ) ,, - CH ₃ -O —CO —R, (Ib ')

Aluminum chloride or zinc chloride, for example, are suitable as Lewis acids.

The preferred procedure for the preparation of the compounds according to the invention is as follows:

In case a)

The cyclic acetal of benzylpiperidone becomes added to a mixture of lithium alanate and aluminum chloride suspended in anhydrous ether and at a temperature between 15 ° C and the boiling point of the reaction mixture reacted for 1 to 5 hours. After that, the complex formed is through Adding water hydrolyzes the reaction mixture with sodium hydroxide and hydrolyzes the compound of the formula Ia with Z '= H isolated in the usual way ei wa by extraction and subsequent distillation.

In case b)

First there is an alkylmagnesium compound of the formula Z-Mg-X with Z = C, - to do-alkyl and X = Br by reaction of the corresponding alkyl bromide made with magnesium in a solvent such as water-free ether in the presence of iodine. This alkyl magnesium bromide is then dissolved in an anhydrous solvent such as benzene cyclic acetal of benzylpiperidone added; after the first solvent has been separated off, the The mixture was refluxed for 10 to 24 hours. The solution is then cooled and the complex formed with an aqueous saturated ammonium chloride solution hydrolyzed. The resulting compound of the formula la with Z '= Z is in the usual way, for example by extraction and subsequent distillation isolated.

The hydrogenation of the products of the formulas Ia and Ib with hydrogen in the presence of a palladium catalyst is preferably carried out by suspending the compounds in absolute ethanol and then stirring or shaking this suspension in a hydrogen atmosphere in the presence of palladium deposited on carbon (palladium content between 1% and 10%) . In this case, preferably hydrogenated at a hydrogen pressure between atmospheric pressure and IO bar and at a temperature between 30 and 70 ⁰ C. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off from the organic phase and the compound of the formula Ic is isolated therefrom in the customary manner. For this purpose, for example, the ethanol can be separated off and the residue rectified.

The implementation ο .r compound of the formula hi mil

2 » the acid chloride R, -CO — Cl is preferably carried out as follows:

The compound of the formula Ia and triethanolamine are dissolved in benzene and mixed in drops with the Acid chloride is added while the reaction vessel is kept in an ice bath. The solution then becomes 24 Leave at room temperature for up to 48 hours and then remove the precipitate formed by suction bzv. Separated by centrifugation. The benzene filtrate obtained is treated with an aqueous sodium hydrogen carbonate solution and then washed with water. Finally, the benzene is steamed Solution and distilled the residue. The compound of formula Ib obtained in this way is from the Distillate isolated.

The cyclic acetals of N-benzylpiperidone used in the process according to the invention can if they are not known, by reaction of a corresponding diol of the formula

HO-CH ₂ - (CH ₃ ) "- CH ₂ -OH

with η as above

with l-benzylpiperidone- (4) in the presence of hydrochloric acid be produced by methods known per se.

example 1

Production of 2- (piperidyl-4.oxy) ethanol a) 2- (1-Benzylpiperidyl-4-oxy) ethanol

106.8 g (0.8 mol) of Given aluminum chloride and then mixed with 800 ml of anhydrous ether with good cooling. To Stirring for 30 min, a suspension of 7.6 g (0.2 mol) of lithium alanate in 200 ml of anhydrous ether is added.

After stirring for 30 minutes, a solution of 93.2 g (0.4 mol ) of e-benzyl-l ^ -dioxa-S-aza-spiro [4.5] decane in 400 ml of anhydrous ether is added dropwise. After the addition is complete, stirring is continued for a further 2 hours at room temperature. Then it is chilled very carefully and water is added very carefully; the mixture is then ^{made alkaline by the addition of (} 10 g of sodium hydroxide biscuits.

The ether is decanted off and the aqueous phase is extracted again with ether. After drying the combined ethereal phases, the ether is evaporated and the residue is distilled. You get so 6Jg 2- (1-benzylpiperidyl-4-oxy) ethanol in the form of a clear oil: distributed 67%.

Kp = 140X70.133 mbar.

η = - 1.633.

Analysis:
Sum formula: Cu

Calculated: N 6.0%;

found: N 5.9%.

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

48 g (0.204 mol) of 2- (l-benzylpiperidyl-4-oxy) ethanol are dissolved in 500 ml of absolute ethanol. The solution is ^{hydrogenated with hydrogen at 50 °} C. in the presence of 5 g of palladium carbon (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.

Kp = 110 ° C / 0.133 mbar.

The product is recrystallized from cyclohexane.

Fp = 7 T C.

Analysis:

Voice formula: C: ENT>

Calculated: C 57.9. H 10.4. N 9.7%:

found: C 57.5. H 10.5. N 9.8%.

c) 8-Benzyl-1.4-dioxa-8-aza-spiro- [4.5] -decane

The cyclic used as starting material Acetal can be obtained as follows:

In a 2 l three-necked flask with a gas inlet tube and Dean-Stark attachment, 68.3 g (I.I mol) ethylene glycol and I I anhydrous benzene are mixed.

The mixture is heated to the boil to separate any water that may be present and then with it 189 g (1 mol) of I-Ben /> lpiperidon- (4) are added. the The mixture is then further heated to boiling, with in the solution is passed in a stream of dry gaseous hydrogen chloride until 18 ml (1 mol) of water are separated, which takes about 6 hours.

After cooling, the precipitate obtained is separated off, washed with benzene and then recrystallized from absolute ethanol. This gives 213 g of 8-benzyl-1,4-dioxa-P azaspiro- [4.5] decane hydrochloride in the form of white crystals. Mp = 262 ^c C: yield 79%.

This compound is suspended in 1 l of anhydrous ether, through which a stream of ammonia is passed for 4 hours is directed. The remaining solid is filtered off and the ether evaporated. 178 g are obtained 8-Benzyl-1,4-dio \ a-8-aza-spiro- [4.5] -decane in the form of a light amber colored oil. that in the fridge crystallized. Mp <50 C: yield 76%. based on 1 -Benzylpipcridon- (4).

Analysis:

Molecular Formula: C ^ H jNO;

Calculated: N 6.0%:

found: N 6.0 ° r>.

B e i s ρ i e! 2

Production of 3- (Pipendyl-4-o \ y) propanol
a) 3- (l-Benz> lpiperid \ I-4-oxy) propanol

With the same procedure as in example l (a). however, using 98.8 g (0.4 mol) of 9-benzyl-1.5-dioxa-9-aza-spiro- [5.5] -undecane. 48 g of 3- (1-benzylpiperidyl-4-ox-propanol are obtained in the form of a pale oil.

.nusucuic to- ■■! '.

Kp = 160 "CO. 133 mbar.
π = 1,531.

Analysis:

Molecular formula: C15H2JNO2

Calculated: N 5.6%;

found: N 5.7%.

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- (1-benzylpiperidyl-4-oxy) propanol 22.2 g of 3- (piperidyl-4-oxy) propanol are obtained in the form of a colorless oil. Yield 73%.

Kp = 112 * C / 0.0133 mbar.

η = 1,488.

Analysis:

Molecular formula: C11H17NO2

Calculated: C 60.3. H 10.8, N 8.8%;

found: C 60.4. H 10.7. N 9.0%.

c) 9-Benzyl-1,5-dioxa-9-aza-spiro- [5.5j-undecane

This compound can be obtained as in Example 1 (c) using 83.6 g (1.1 mol) of propanediol- (1.3) will. 180 g of g-benzyl-IS-dioxa-9-aza-spiro- [5,5] -undecane are obtained in the form of a light amber-colored oil. that crystallizes in the refrigerator.

Mp <50 ° C; Yield 73%. based on I-Benzylpipericion- (4).

Analysis:

1.1 Molecular formula:
Calculated
found:

N 5.7%:
N 5.6%.

Example 3

Γι Production of 4- (piperidyl-4-oxy) butanol

a) 4- (N-Benzylpiperidyl-4-oxy) butanol

With the same procedure as in example l (a). but using 110 g (0.421 mol) of 10-benzyl-4, i 1.6-dioxa-10-aza-spiro- [5.6] -dodecane. 71.5 g of 4- (N-benzylpiperidyl-4-oxy) butanol are obtained in the form of a clear oil: yield 65%.
Kp = l65 ° C / O.O67 mbar.

Analvse:

Molecular formula: CieH ^ NO:

Calculated: N 5.3%:

found: N 5.6%.

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

With the same working method as in example 1 (b * but

using 82.9 g (0.314 mol) 4- (N-benzylpiperidyl-4-oxy) -butanol. 34.1 g of 4- (piperidyl-4-oxy) butanol are obtained in the form of a colorless oil: yield

v, 61% '.

Kp = 120 = C / 0.067mbar.

η = 1,486.

Analysis:
_{r0 Molecular} formula: C ^ HiciNO:

Calculated: C 62.4. H 11.1. N 8.1%:
found: C 61.9. H 11.2. N 8.0%.

c) 10-benzyl-1.6-dioxa-10-aza-spiro- [5.6] -dodecane
ri This compound can be obtained as in Example l (c) nVIUVII. iy \ JXJ ^ l ^ t. \ J ζ. \ VV-f lllUlj UUtUIlUlUl \ * * '/ "W" are obtained. 139.6 g of 10-benzyl-l-dioxy-10-aza-spiro- [5.6] -dodecane are obtained in the form of a clear, amber-

stone-colored oil. that crystallizes in the refrigerator. Instant melting point: m.p. = 52 ° C; Yield 92%, based on l-benzylpiperidone- (4).

Analysis:

Molecular Formula: Cis ^ iNO?

Calculated: N 5.4%;

Pounds: N 5.2%.

Example 4

Production of 2- (piperidyl-4-oxy-ethyl acetate
a) 2- (N-Benzylpiperidyl-4-oxy) ethyl acetate

To a solution of 47 g (0.2 mol) of the according to Example l (a) prepared 2- (l-benzylpiperidyl-4-oxy) ethanol and 20.2 g (0.2 mol) of triethylamine in 300 ml Benzene is added dropwise to 20 ° C. while cooling with an ice bath, 15.6 g (0.2 mol) of acetyl chloride. One lets the reaction mixture stand for 48 h at room temperature and then suck or centrifuge the formed Precipitation from. The benzene filtrate is with an aqueous sodium hydrogen carbonate solution and then washed with water. After drying and evaporation of the benzene solution, the residue is distilled; 36.5 g of 2- (N-benzylpiperidyl-4-oxy) ethyl acetate are obtained in the form of a clear oil; Yield 66%.

Kp = 160-170 ^? C / 0.133 mbar.

π = 1.512.

Analysis:

Voice formula: CibH. ^ NO)

Calculated: C 69.3. H 8.4. N 5.1%;

found: C 68.7, H 8.4, N 4.9%.

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

36.4 g (0.131 mol) of 2- (N-benzylpiperidyl-4-oxy) ethyl acetate are dissolved in 200 ml of absolute ethanol. then is hydrogenated at 50 ° C in the presence of 3.5 g of palladium carbon (5%) until the theoretical amount of hydrogen is absorbed.

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

Kp = 102 ° C / 0.133 mbar.

π) = 1.4665.

Analysis:

Molecular formula: C9H1-NO3

Calculated: C 57.7, H 9.2, N 7.5%;

found: C 57.5. H 9.2, N 7.5%.

Example 5
Production of 2- (piperidyl-4-oxy) ethyloctanoate

To a solution of 47 g (0.2 mol) of the 2- (l-benzylpiperidyl-4-oxy) prepared according to Example l (a) - bo ethanol and 20.2 g (0.2 mol) of triethylamine in 300 ml of benzo! is added dropwise while cooling with an ice bath to 20 ⁰ C 32.4 g (0.2 mol) Octanoyichlorid. The reaction mixture is left to stand for 24 hours at room temperature and the precipitate formed is then filtered off with suction or centrifuged. The collected benzene filtrate is washed with an aqueous sodium hydrogen carbonate solution and then with water. After the benzene solution has been dried and evaporated, the residue obtained is dissolved in 300 ml of absolute ethanol. The mixture is then hydrogenated at 50 ° C. in the presence of 4.5 g of palladium carbon (5%) until the theoretical amount of hydrogen has been absorbed. After filtering off the catalyst, the ethanol is evaporated and the residue is distilled. 35.5 g of 2- (piperidyl-4-oxy) ethyloctanoate are obtained in the form of a clear oil; Yield 64%.

Bp = 150-156 ° C / 0.133 mb? R.

n-: = 1.464.

Analysis:

Molecular formula: Ο, Κ'ίΝΟ)

Calculated: C 66.4. H 10.8. N 5.2%;

found: C 66.0. H 10.7. N 5.3%.

Example 6

Production of 2- (4-methylpiperidyl-4-oxy) ethanol
a) 2- (N-Benzyl-4-methylpiperidyl-4-oxy) ethanol

150 ml of ether are placed in a flask, which is cooled to about -10 ° C. and mixed with 40 g of methyl bromide is added and mixed.

9.6 g of magnesium turnings, 50 ml of ether and an iodine crystal are placed in another flask, and the methyl bromide solution is added dropwise to this mixture. When the addition is complete, a solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4.5] decane in 1 l of anhydrous benzene is added.

After the ether has evaporated, the mixture is refluxed for 16 h. After that, the received Solution cooled and hydrolyzed with a saturated ammonium chloride solution. The benzene is decanted off and the aqueous phase extracted with ether. The organic phase is dried over sodium sulfate, the solvents are evaporated off in vacuo and the residue is rectified under reduced pressure. You get so 42.8 g of 2- (N-benzyl-4-methylpiperidyl-4-oxy) ethanol in the form of a colorless oil.

Bp = 136-140 ° C / 0.133 mbar.

n? = 1.527.

Analysis:

Molecular formula: C5H21NO2 (M = 249.3)

Calculated: C 72.25. H 9.30. N 5.62%;

found: C 72.4. H 9.2, N 5.9%.

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

51.5 g of the 2- (N-benzy! -4-methylpiperidyl-4-oxy) ethanol obtained according to a) are dissolved in 500 ml of absolute ethanol and at 50 ° C in the presence of 5 g Palladium carbon (5%) hydrogenated until the theoretical amount of hydrogen is absorbed. which is about 3.5 h requires. After filtering off the catalyst, the ethanol is evaporated off and the residue under reduced pressure Pressure rectified. This gives 24 g of 2- (4-methylpiperidyl-4-oxy) ethanol in the form of a colorless Oil.

Kp = 80-86 ° C / 0.0133 mbar.

ri; = 1,481.

Analysis:

Molecular formula: C ₃ Hi-NO ₂ (M = 159.2)

Calculated: C 6034. H 10.76%:

found: C 59.6. H 10.5%.

Example 7

Production of 2- (4-ethylpiperidyl-4-oxy) -ethanol
a) 2- (N-BenzyI-4-ethylpiperidyl-4-oxy) ethanol

19.2 g of magnesium and 100 ml of ether are placed in a flask and then refluxed 87.5 g of ethyl bromide must be added dropwise to 100 ml of ether. The addition takes place over about 30 minutes.

After cooling, 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4.5] decane are obtained added in 250 ml of benzene. The ether is evaporated off, 250 ml of benzene are added and the mixture is refluxed for 20 hours. The reaction mixture is then cooled and hydrolyzed with a saturated ammonium chloride solution. The benzene phase is then decanted off and the aqueous phase is extracted with methylene chloride; the combined organic phases are washed with water until neutral and over sodium sulfate dried; after the solvents have been evaporated off under reduced pressure, the residue is rectified. 37.6 g of 2- (N-benzyl-4-ethyl-piperidyl-4-oxy) -ethanol are obtained in the form of a colorless oil.

Kp = 152-156 ° C / 0.67 mbar.

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

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

37 g of 2- (N-benzyl-4-äthylpiperidyl-4-oxy) ethanol are dissolved in 300 ml of absolute ethanol and in 50 ° C in the presence of 4 g of palladium carbon (10%) hydrogenated until the theoretical amount of hydrogen is absorbed, which takes about 3 hours.

After filtering off the catalyst and evaporation of the ethanol, the residue is rectified. 19.2 g of 2- (4-ethylpiperidyl-4-oxy) ethanol are thus obtained in the form of a colorless oil.

Kp = 102-106 ° C / 0.67 mbar.

Analysis:

Molecular formula: G) Hi ₁ ) NO ₂ (M = 173.26)

Calculated: C 62.39, H 11.05, N 8.08%;

found: C 62.4, H 10.8, N 8.0%.

Example 8
Production of 2- (4-propylpiperidyl-4-oxy) ethanol

a) 2- (N-Benzyl-4-propylpiperidyl-4-oxy) ethanol
and its hydrochloride

19.2 g of magnesium and 100 ml of ether are placed in a flask and then refluxed dropwise mixed with 108 g of propyl bromide in 250 ml of ether. 5i

Then gradually 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4.5] decane added in 500 ml of benzene. After the ether has evaporated, the reaction mixture is refluxed for 24 hours.

The resulting solution is cooled and hydrolyzed with a _b o saturated ammonium chloride solution. The benzene phase is then decanted off and the aqueous phase is extracted with ether. The organic phase is washed with water until neutral and dried over sodium sulfate. After the solvent has been evaporated off under reduced pressure, the residue is rectified ( ^{boiling point = 129 G} C / 0.133 MB ^). Are thus obtained 28 g of 2- (N-benzyl-4-propyipiperidyl-4-oxy) ethanol are of a yellowish oil, which confused dissolved in 250 ml ether ¹ To the solution in the form of 13 ml of a 5 N solution of hydrochloric acid in Ether added; the hydrochloride obtained is filtered off with suction and recrystallized from isopropanol.

After drying in vacuo, 12.9 g of 2- (N-benzyl-4-propyipiperidyl-4-oxy) -ethanol hydrochloride are added obtained in the form of colorless crystals; Mp. 196 ° C.

Analysis:

Molecular Formula ·. C ₁₇ H ₂ SCINO ₂ (M = 313.87)

Calculated: C 65.06, H 8.99, N 4.46, Cl 11.30%;

found: C 65.1, H 8.9, N 4.1, Cl 11.6%.

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

10.7 g of 2- (N-benzyl-4-propylpiperidyl-4-oxy) ethanol are dissolved in 200 ml of absolute ethanol; was, and ^{hydrogenated at 50 0} C in the presence of 1 g of palladium carbon (10%) until the theoretical amount of hydrogen is absorbed.

After the catalyst has been filtered off, the ethanol is evaporated off: 6.1 g of 2- (4-propylpiperidyl-4-oxy) ethanol are obtained in the form of yellowish crystals; Mp. 72 ° C.

For the analysis, the product is recrystallized from cyclohexane. The product obtained in this way is in shape of white crystals soluble in chloroform; M.p. 76 ° C.

Analysis:

Molecular formula: CmH ₂ INOj (M = 187.28)

Calculated: C 64.13, H 11.30, N 7.48%;

found: C 63.8, H 11.6, N 7.3%.

Example 9

Production of 2- (4-heptylpiperidyl-4-ox> y-ethanol a) 2- (N-Benzyl-4-heptylpiperidyI-4-oxy) ethanol

9.6 g of magnesium shavings, 50 ml of ether, an iodine crystal and 3 drops of ethyl iodide are placed in a flask. Then a solution of 101.5 g of n-heptyl bromide in 300 ml of ether is added under nitrogen within 1 hour added and stirred for a further 1 h.

46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4.5] decane are added to the solution obtained added in 1 l of anhydrous benzene; after evaporation of the ether, the mixture is refluxed for 16 hours. To cooling the solution, 20 ml of water and then 400 ml of a saturated ammonium chloride solution are added with stirring admitted.

After the organic phase has been decanted off and the solvent has been separated off under reduced pressure The residue is rectified under pressure. This gives 40 g of 2- {N-Benzy! -4-hepty] piperidyl-4-oxy) ethanol, the is used for the next stage without further purification; 150-20O = C.

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

40 g of 2- (N-Benzy! -4-heptylpiperidyI-4-oxy) ethanol are dissolved in 300 ml of absolute ethanol and in

13 14

10 ° C in the presence of 0.4 g of palladium carbon (5%) of colorless oil.

hydrogenated until the theoretical amount of hydrogen decreases. Kp = 110-130 ° C./0.133 mbar.

sorbiTt is what takes about 5 hours. After filtering

trating of the catalyst and evaporation of the ethanol Molecular formula: C ₁₄ H _n NO ₂ (M = 243.4)

the residue is rectified. You get 10.6 g -. Calculated: N 5.53%:

2- (4-Heptylpiperidyl-4-oxy) -ethanol found in the form of: N 5.8%.

Claims (2)

Patent claims:
1. Piperidine derivatives of the formula I N-benzylpiperidones of the formula _Z 'O -CH ₃ (DC ₆ H ₅ - CH, - O-CH ₂ - (CH ₂ ) "- CH ₂ -OA _| O O -CH ₂ in which mean: ™ ¹ " ^{as in} claim 1 in anhydrous Medium, R H or benzyl,,> _,,. , ". Z 'H or a group Z _I5 ^ if Z' equals H .st, with Z = linear or branched C ₁ - bis ^with .L'thiumalanat in the presence of e.ner Co-alkyl, ... Lewis acid or. AH or a group R ₁ -CO- ^ ^if . ^{z is} equal to z. with R ₁ -C, - to C _ie -alkyl ^{mlt ei} " ^em alkylmagnesium halide and 20 ^formula η 0, 1 or 2. Z-Mg-X 2. Process for the preparation of the Piperidinderi- with Z = linear or branched C ₁ - bis Vate according to claim 1, characterized by C ₁ O-alkyl and X = Cl, Br or J - Implementation of a cyclic acetal des 25 to a compound of formula Ia Z ' C ₆ H ₅ -CH ₂ -N ^ X ^ da) O-CH ₂ - (CH ₂ J _n -CH ₂ -OH with Z 'and π as in claim 1, optionally with an acid chloride R ₁ -CO-CI with Ri as in claim 1 to a compound of the formula Ib Z ' C ₆ H ₅ - CH ₂ - N ~ ^> / (Ib) O-CH ₂ - (CH ₂ ) "- CH ₂ -O- CO- R ₁ Reacted with R ₁ , Z 'and η as in claim 1 Ib in the presence of a palladium catalyst becomes, to the corresponding compound of the formula and if necessary la 'or Ib' - Hydrogenation of the compound of formula la or ίο Z ' II —N V '(Ia') O -CH ₂ - (CH ₂ J _n -CH ₂ -OH Z ' Η --Ν V (Ib ') O - CH ₂ - (CH ₂ ), - CH ₂ - O - CO - R ₁