DE1695628A1 - Process for the preparation of 3-aminopyrrolidines - Google Patents

Description

PATENT LAWYERS

DR. E. WIEGAND DIPL-ING. W. NIEMANN DR. M. KÖHLER DIPL-ING. C. GERNHARDT

MÖNCHEN HAMBURG

TELEPHONE: 555 476 8000 MONKS 15, ² ^ * March 1967

TELEGRAMS: KARPATENT NUSSBAUMSTRASSE 10

W. 15036/67

AH. Ro "bins Company, Incorporated Eichmond, Virginia (V.8t.A.)

Process for the preparation of 3-aminopyrrolidines

The invention "relates to the manufacture of new heterocyelincher organic compounds known as 3-aminorr / rrolidine referred to and can have valuable therapeutic properties.

The object of the invention is to create a freeze for the production of 3-aminopyrrolidines, especially! -substituted 3-IT-alkylanilinopyrrolidines, in a simple and technically more advantageous way.

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According to the invention, compounds of the general formula

- Η '

I, ^ ^Ar (D

in the

R is lower alkyl,

Il Il Il

-R -Ar ', -R -O-Ar or -H -Ar represents,

OH

R is lower alkylene,

Ar is phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl or trifluoromethylphenyl and

Ar is phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl, trifluoromethylphenyl or pyridyl,

as well as their acid addition salts.

The method according to the invention can be represented as follows:

MR

I!

._. 2i- Ar + Y ^ "N-Ar

(II) ^K (I)

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R ^{1 is} lower alkyl;

_r "-O-Ar or

Il

-R -Ar

OH means

R ^{11 is} lower alkylene;

Ar from phenyl, lower alkylphenyl, lower alkoxyplienyl, ^ alogenphenyl or Trifluoriaetliylphenyl consists;

Ar ¹ consists of phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl, trifluorine methyl phenyl or pyridyl;

Y is XR ^H -Ar, H ₂ C = CH-pyridyl, XR "-O-Ar or -R"'-Ar;

R "and Ar have the meaning given above; X is a replaceable halogen, such as, for example, chlorine or bromine

represents and
II "'means lower alkylene of 0-6 carbon atoms.

The 3-aminopyrrolidine of the general formula

^J '- ^Ar

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can be obtained by using a 1-benzyl-δ-aminopyrrolidine the general J-formula

* - ^Ar

Γ—

Benzyl

debenzylated by hydrogenolysis or that ina: -i kaleimide with an H-alkylaniline with a lower alkyl group dor general Formula IDJIlAr converts and the obtained Asparimiu (Aspartic acid imide) of the general formula

t 1- - ^N - ^

reduced with lithium aluminum hydride.

Practice compounds obtained in accordance with the invention a suppressive effect on the central nervous system from (depressants) and are railde sedatives. Other Compounds are useful as intermediates in the manufacture of other compounds, especially in manufacture of indole compounds as described in the patent application Ii 44 443 IVd / 12 ρ are described.

The compounds of the last-mentioned patent application are used for the treatment of convulsions, including the

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Parkinsonism suitable. Furthermore, certain compounds of the present invention can be used as a substitute for phenyl

piperazine are used in certain procedures.

The term "lower alkyl" as used herein, "inspects to straight and branched chain radicals of up to B carbon atoms, that is to say to groups such as methyl, ethyl, I ^J ropyl, isopropyl, butyl, sec-butyl, tert-TU.ityl, amyl, isoaniyl, hexyl, heptyl, octyl or the like.

The term "lower alkylene" refers to straight ver-sv / eictkettige ieste with up to 8 carbon atoms, rt.ii. on groups such as methylene, ethylene, propylene, Isopropylene, butylene, sec-butylene, tert-butylene, amylene, looai.r.len, liexylen, lioptyleii, octylen or the like.

"Lower alkoxy" has the formula "-O-lower alkyl". Suitable Haste Ar unu Ar ^f include unsubstituted phenyl or those phenyl radicals which are uituced by one or more .le.'jte ;;: iljs, which are not reactive or in any other way under the reaction conditions at dor U: "i: -letting participate, such as lower alkoxy, lower alkyl, trifluorine, ethyl or halogen.

ide substituted phenyl radicals preferably do not have my * ul :; 1 "to 3 substituents of the specified type; furthermore, these substituents can be at different,

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for available sites of the phenyl nucleus and, if more than one substituent is present, these can be the same or different and can occupy different combinations of positions relative to one another. the have lower alkyl and lower alkoxy substituents preferably 1 to 4 carbon atoms in straight or branched beds can be arranged.

The free basic compounds according to formula (I) can be converted into acid addition salts, preferably are kept as such and can be used many times over. Salts of this kind also have a better / barrel solubility.

Purely to be used as pharmaceutical products the non-toxic salts are preferred, but any salt can be used produced and as a chemical intermediate product »as for Example in the production of another, but non-toxic acid addition salt, can be used.

The free basic compounds according to formula (I) can easily be converted into the corresponding acid addition salts by reacting the free base with the chosen acid, preferably in the presence of an organic solvent which is compatible with the jieaktionateilnehnern under the reaction conditions and the reaction product is inert.

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Suitable acid addition salts are those derived from mineral acids, such as hydrochloric, hydrobromic, hydroiodic iodine. Nitric, sulfuric, sulphamic or phosphoric acid, or derived from organic acids such as acetic, citric, lactic, lumaric or v / anic acid. The IHxmerat is the preferred acid addition as.

The acid addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid eii.thält and separation of the sals through Evaporation of the solution or by reaction of the free base with the chosen acid in an organic solvent manufactured. In the latter case, the salt either separates out immediately or it can pass through in the usual way Concentration of the solution or similar procedure can be obtained.

Conversely, the free base can be obtained in a conventional manner by treating the acid addition salt with a suitable base such as ammonia, ammonium hydroxide, sodium carbonate or the like. Neutralized, the released base so claim with a suitable solvent, such as ethyl acetate or benzene extracted, the extract dried and evaporated to complete dryness, or fractionated distilled, or in some other conventional manner and './ I connect it.

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According to the method according to the invention, in particular g ':. I 3- (N-Alkylanili.no) -pyrrolidine with lower alkyl substituents, which is not substituted in the 1-position, reacted with an aralkyl compound, dia a reactive atom or a reactive group in its alkyl moiety possesses, such as a phenoxy-alkyl halide, e.g. l-bromo-2-phenoxyethane, a phenyl-alkyl halide, e.g. i-bromo-2-phenylethane, a vinyl pyridine or a tJ-epoxyphenylalkane, e.g. styrene oxide, the reaction using a suitable reaction process, e.g. in the presence of an "aprotic" (unable to To absorb protons) solvent, and under suitable conventional heaction conditions, such as 2. under reflux listed in the solvent chosen for the reaction will. These procedures are explained in more detail in the following examples.

Process for the preparation of g- (N-methylanilino) pyrrolidine Procedure A I? -Carbarnoylmaleamic acid

500 g of potassium anhydride (5.10 hol) and 300 r; (5.0 LoI) urea with 1000 g ice egg; mixed. The solution is ^{heated to 50 °} C. for 15 hours. Ifach ^ M-Sti

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Standing "at room temperature, the deposited solid is collected, washed with 125 ml of acetic acid and" dried at 50 ⁰ O iia vacuum oven.

Yield: 391 g (49.5 ^); Melting point 156-159 ° G.

H- G'arbaino.ylrjal e irüid

900 ml of acetic anhydride are stirred magnetically and heated to 90 ° C., li-uarbanoylinaleamic acid is added in portions. After the last portion has been added, the oil temperature is increased to 97-102 ° C. for 45 minutes. The hot mixture is filtered under gravity, the filtrate is cooled thoroughly, the product is collected and dried in a vacuum oven. Aur; oeube: 196.0 g (69.2? I); Pivot point 156-160 ⁰ G ₀

ο (3 »56 Iiol) ll-carbamoyl maleimide v / earth in portions iiu 11:.; Jiiusohylformamide is added at 90-95 ° C. with stirring, after the addition of the solid is complete the mixture is stirred at 90 ° -95 ° C. for 1.5 hours. The rtbgeläilil'Le HiGcnung (20 ⁰ G) is stirred for 2 hours, uü'j UIO 'Jy.uriur-uliure is then filtered off. The Piltrat. '/ Ιϊ-ΐΊ j'Jt, r-ji ^ Mj,. ;; i :: r; orpur: iperivakuum concentrated, and the, .Ci ei:;, t; and becomes ι Δ. t distilled quickly in an oil pump vacuum, Hierboi v / er (ien 133 g (53 / -J) of crude maleimide with a melting

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- ίο -

point receive from 84 to 93 ⁰ G. The crude halimide is crystallized from ethyl acetate.

Yield: 159 g ($ 46) of maleiraid; Melting point 90-93 ⁰ C.

U-methyl-IT-phenylasparimide

286.4 g of maleimide (2.95 mol) and 326 g (2.95 mol) of IT-methylaniline (97 $ reagent grade) are mixed together and heated for 3.5 hours at a container temperature of 150-160 ° C. As soon as the container ^{temperature has dropped to 120 °} C., isopropanol is slowly introduced into the mixture in order to bring the finely divided product to precipitate. The weight of the dried crude product is 377 g ($ 62.8). The rolling stock is recrystallized from 6 liters of boiling isopropanol and gives 303 g ($ 50.5) of a white, crystalline substance with a melting point of 161-164 C ₀

3 - (II-methylanilino) -pyrrο lidine

40.8 g of N-IIethyl-IT-phenylasparimide (0.20 mol) are partially to a vigorously stirred slurry of 16.4 g (0.43 mole) lithium aluminum hydride in 250 ml dry A'ther added. The mixture is refluxed with stirring for 2 hours and then cooled; then 200 L dry tetrahydrofuran and 5 g lithium aluminum hydride were added and the mixture was allowed to continue for 3.5 hours Refluxed. The reaction mixture is mixed with water

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deterred. The organic phase is separated off, dried and concentrated to a Cl. The oil \ tfird distilled to yield 17.4 g (49,5 ^) of a colorless solid with a boiling point of 101-102 ⁰ G at a pressure of 0.10 mn.

Failure B

1-1- ensyl-3-pyrrolidinol-p-methylb eng oil sulfonate ester 35'Ig l-3 _p nzj ^r l-3-pvrroldinol (2.0 mol) weep drop by drop while stirring to a suspension of 73 g ( 2.0 moles) of Iatriuinaniu in 1 liter of dry toluene were added. The addition

is set so that a vessel temperature

of 35 ° G is maintained. After stirring for one hour becomes a solution of 381 g (2.0 KoI) p-IIethylbenzenesulfonyl chloride in 2.5 liters of dry toluene added, the vessel temperature being kept below 30 ° C. with the aid of an ice bath will. The reaction mixture is stirred for 2.5 hours and then 500 ml of water is carefully added to decompose unregulated sodium alumina. The Ilish is washed twice with one liter of water each, the organic Layer is separated off, dried over sodium sulfate, filtered, and the volume of the filtrate is brought to 3 liters.

I ₁ -BeUSyI-P- ('.'-methylanilino) -pyrrolidine

300 r: il of a tolluene solution of the l-eensyl-3-pyrrolidinol-p -... ethylbene sulfate ester (about 0.2 Hol 3u} .fonate ^ ter)

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are concentrated on a rotating evaporator. The residue is mixed with 150 ml of N-methyl anil in. The mixture is then heated until 1.5 hours at 120 to 140 ⁰ C, for 2 hours at 18O ⁰ C. The cooled mixture is divided between 200 ml of dilute sodium hydroxide and 200 ml of toluene. The toluene layer is dried over sodium sulfate, filtered and concentrated with the aid of a water pump. The oily residue is distilled to yield 30 g of l-benzyl-3- (N-methylanilino) pyrrolidine with a boiling point of 170-185 ⁰ C at a pressure of 0.01 mm.

3- (N-methylanilino) pyrrolidine

92g of l-benzyl-3- (N-methylanilino) pyrrolidine (0.345 mol) in 750 ml of ethanol with an addition of 3 g of 10 ^ -igem Palladium on charcoal are shaken at 55 ° C in a hydrogen atmosphere. Then another 3 g TO ^ -iges palladium on charcoal added · The solution is acidified with concentrated hydrochloric acid and hydrogen is released to a moderate extent, i.e. about 4.5 liters in 6 hours, recorded. The reaction mixture is left to stand overnight, then another 3 g of catalyst are added added, and the reaction st eilii elin he will be another 15 Shaken for hours.

The reaction product is filtered, concentrated and partitioned between 400 ml of dilute sodium hydroxide

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and 200 ml of benzene. The benzene solution will about liapSO. dried, concentrated and made to the desired Distilled product. Yield: 39 g ($ 64); Boiling point 108-112 ° Ö at a pressure of 0.2 ram. Related raw materials with other lower alkyl (R ') groups from N and substituted phenyl radicals (Ar) are selected by the same procedure by using the IT lower Alkyl aniline as a starting material in the corresponding stage in either of the two above-described Procedures A and B made.

The invention is explained in more detail below with the aid of examples.

example 1

3 -K-IIe thylanilino-1- (2-phenoxyethyl) pyrrolidine The free base is obtained by reacting 3- (N-methylanilino) pyrrolidine (0.057 mol) with l-bromo-2-phenoxyethane (0.057 mol) in ethanol (150 ml) with the addition of 5 g of sodium bicarbonate. Other solvents such as isopropanol can be used and the use of sodium bicarbonate is optional.

The measurement will take several hours Reflux boiled, cooled and a partition between Ether and a dilute aqueous solution of potassium

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subject to hydroxyd. The ether layer is dried and concentrated, and the residue is purified by fractional distillation "at reduced pressure. Here is 3-N-methylanilino-l- (2-phenoxyethyl) pyrrolidine in 75 ^ -iger yield with a boiling point of 183-188 G at obtained a pressure of 0.15 mm.

Analysis: ⁰ Iq ^ ₄ N ₂ 0 0 H N Calculated:
Found : 76.99
76.87 8.16 9.54
8.03 9.24 Example 2 3-N-methylanilino-1- (2-phenylethyl) pyrrolidine

Using the method according to Example 1, equimolar amounts of 3- (N-methylanilino) pyrrolidine and 1-bromo-2-phenylethane are mixed and reacted. The product is purified by fractional distillation under reduced pressure, and 3-N-methylanilino-1- (2-phenylethyl) pyrrolidine is obtained in 53% yield. Boiling point; 164-168 ⁰ C at a pressure of 0.1 mm.

Analysis: O ₁₉ H ₃₄ N ₂ O HN

Rewarded: Found:

81 , 38 8th, 63 9 , 99 81 M. 8th, 68 9 , 91

1 0 9 8 1 7/2 U 7

Example 3

3 -N-Methylanilino-1- (3-phenylpropyl) -pyrrolidine Using the procedure of Example 1, equimolar amounts of 3- (II-methylanilino) -pyrrolidine and 1-bromo-3-phenylpropane are mixed and reacted. The product is purified by reduced pressure distillation and 3-N-methylanilino-1- (3-phenylpropyl) pyrrolidine is obtained in 48% yield. Boiling point: 194-197 ⁰ C mm at a pressure of 0.2.

Analysis: ° 20 ^H 26 ^N 2 - - -

Calculated: 81.58 8.90 9.52

Found: 81.35 8.60 9.32

Example 4

3 -IT-Me thylanilino-1- (1-methyl-2-phenylethyl) -py rr ο 1 id in Using the method according to Example 1, equimolar amounts of 3- (N-methylanilino) pyrrolidine and i-bromine are used -l-methyl-2-phenylethane mixed and implemented. The product is purified by fractional distillation under reduced pressure and 3-H-methylanilino-1- (1-methyl-2-phenylethyl) pyrrolidine is obtained in a yield of 21%. Boiling point: 155-165 ° C at a pressure of 0.05 mm.

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"Analysis: C ₂ Q ^H 26 ^li 2 G H S. 52
81 Calculated:
Found : 81.58
81.65 8.90
8.90 9,
9, Example 5 pyrrolidine 3-ff-metharlanilino-l _f2- (2-pyridyl) ethyl 7

A mixture of 2-vinylpyridine (0.1 mol) and 3- (N-methylanilino) pyrrolidine (0.1 mol) is reacted in 50 ml of ethanol with the addition of 4 g of acetic acid. The reaction mixture is refluxed for several hours (18 hours), cooled and partitioned between chloroform and a dilute aqueous solution of sodium hydroxide. The chloroform layer is dried, concentrated, and the residue is subjected to fractional distillation under reduced pressure. It is 3-N- ^ ^{-ethyl-anilino-l-r} 2- (2-pyridyl) pyrrolidin--äthylJ obtained. Boiling point: 185-19O ⁰ C at a pressure of 0.05 mm.

Analysis: C ₁₈ H ₃₅ N ₅ 9th EE

Calculated: 76.83 8.24 14.93

Found: 76.53 8.09 15.18

Example 6

3-I'i-methylanilino-l- ^r ₁ 2- (4-pyrjdyl) ethyl "/ -pyrrolidine Using the method of Example 5 -reraäii wei'den equimolar amounts of 4- ^v inylpyridin and 3- (lT-L ^r ethylanilino) -

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pyrrolidine mixed and reacted. Bs becomes 3-N-methylanilino-1- £ 2- (4-pyridyl) -ethyl | "-pyrrolidine obtain.

Boiling point: 175-18O ⁰ O at a pressure of 0.5 mm.

Analysis: ^ i 8 ^ 23% - - -

Calculated: 76.85 8.24 14.93

Found: 76.89 7.96 14.99

Example 7

1- (2-Hydroxy-2-phenylethyl) -5- (H-methylanilino) pyrrolidine A mixture of 3- (N-methylanilino) pyrrolidine (0.1 mol) and styrene oxide (0.1 mol) with a small one Addition of water (3 drops) is implemented in the course of several hours at room temperature. The reaction mixture is then heated to 70 ⁰ O for 10 hours. Upon cooling the reaction product, which is recrystallized from ligroin (60-110 ⁰ C) crystallized.

Yield: 1- (2-Hydroxy-2-phenylethyl) -3- (N-methylanilino)

pyrrolidine ($ 68).

Melting point: 87-90 ⁰ O.

Analysis: ( H 1 Calculated:
Found: COCO , 16 9.45
, 23 9.23 3- (li-methyl- 2-phenoxyethyl) pyrrolidine D ₁₉ H ₂₄ N ₂ O 0 76.97
77.15 Example 8 -4-methylanilino) -l- (

Using the procedure of Example 1 are

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equimolar amounts of 3- (N-methyl-4-methylanilino) pyrrolidine and l-bromo-2-phenoxyethane mixed and reacted. It becomes 3- (lY-methyl-4-methylanilino) -1- (2-phenoxyethyl) pyrrolidine obtain.

Example 9

3- (N-Methyl-4-ethoxyanilino) -1- (2-phenoxyethyl) pyrrolidine Using the procedure of Example 1, 3- (N-methyl-4-ethoxyanilino) pyrrolidine is made with 1-bromo-2-phenoxyethane implemented. 3- (N-methyl-4-ethoxyanilino) -1- (2-phenoxyethyl) pyrrolidine is obtained,

Example 10

3- (U-Methyl-3-chloroanilino) -l- (2-phenoxyethyl) -pyrrolidine Using the procedure according to Example 1, equimolar amounts of 3- (N-methyl-3-chloroanilino) -pyrrolidine and l-bromo 2-phenoxyethane mixed and implemented. 3- (N-methyl-3-chloroanilino) -1- (2-phenoxyethyl) pyrrolidine is obtained.

Example 11

3- (N-methyl-4-trifluoromethylanilino) -1- (2-phenoxyethyl) pyrrolidine

. Using the procedure of Example 1 are equimolar amounts of 3- (N-methyl-4-trifluoromethylaniliono) -

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pyrrolidine and l-Broia-2--ph.enoxyath.an mixed and reacted. 3- (N-methyl ~ 4-trifluoromethylanilino) -l- (2-

phenoxyethyl) pyrrolidine obtained

Example 12

1-r2-hydroxy-2- (4-methylphenyl) ethyH-3- (N-ethylanilino) pyrrolidine

Using the method according to Example 7, equimolar amounts of 3- (N-ethylanilino) pyrrolidine and 4-methylstyrene oxide mixed and reacted. It will 1- £ 2-hydroxy-2- (4-methylphenyl) ethyl] -3- (N-ethylanilino) pyrrolidine obtain.

Example 13

1-f2-hydroxy-2- (4-methoxyphenyl) ethyl] -3- (N-propylanilino) ■ pyrrolidine

Using the procedure of Example 7, equimolar amounts of 3- (N-propylanilino) pyrrolidine and 4-kethoxystyrene oxide mixed and reacted. It will 1- | ~ 2-Hydroxy-2- (4-methoxyphenyl) -ethyij -3- (li-propylanilino) ■ get pyrrolidine

Example 14

1 -f2-Hydroxy-2- (4-chlorophenyl) ethyl] -;> - (H-methylanilino) pyrrolidine

Using the procedure of Example 7 are

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equimolar amounts of 3- (IT-methylanilino) pyrrolidine and 4-Chlörsytroloxyd mixed and reacted »It is l-f" 2-Hydroxy-2- (4-ehl or phenyl) -äthylj -3- (N-methylanilino) pyrrolidine obtain.

Example 15

l - / "2-Hydroxy-2- (4-trif luorme thylphenyl) -ethyll -3 - (fl-methylanilino) -pyrrolidine Using the procedure according to Example 7 v / ground equimolar amounts of 3- (ϊΤ-methylanilino) Pyrrolidine and 4-trifuluoromethylstyrene oxide are blurred and reacted, giving 1,2-hydroxy-2- (4-trifluoromethylphenyl) ethyl] -3- (N-methylanilino) pyrrolide.

Example 16

3- (H-methylanilino) -l- ^ _i 2- (4-iaethyl phenoxy) ethy 3 ^ - pyrrolidine Using the procedure according to Example 1, equimolar amounts of 3- (H-methylanilino) pyrrolidine and l-bromine -2- (4-methylphenoxy) -ethane mixed and implemented. 3- (1-methylanilino) -1 - [_ 2- (4-methylphenoxy) ethyl] pyrrolidine is obtained.

Example 17

3- (H-methylanilino) -1- '2- (4-ethoxyphonoxy) - ».h.ylj -pyj ' rolidine Using the procedure described in Example 1 ground

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equimolar amounts of 5- (N-methylanilino) pyrrolidine and l-IJrom-2- (4-äthoxyphenoxy) -äth mixed and implemented. It becomes 3- (lI-methylanilino) -l-f 2- (4-ethoxyphenoxy) -ethyl2 ~ pyrrolidine obtained.

Example 18

3- (N-Methylanilino) -l- [£ - (4-chlorophenoxy) ethy! U -pyrrolidine Using the method according to Example 1, equimolar amounts of 3- (N-methylanilino) pyrrolidine and l-3rom-2 - (4-chlorophenoxy) -ethane mixed and implemented. 3- (H-ethylanilino) -1- £ 2- (4-chlorophenoxy) ethyl pyrrolidine is obtained.

Example 19

3- (H-ethylanilino) -l- Ü2- ( 4-trifluoromethylphenoxy) ethyI] pyrrolidine

Using the method of Example 1, equimolar amounts of 3- (li-methylanilino) pyrrolidine and l-bromo-2- (4-trifluoromethylphenoxy) -ethane mixed and unset. It is 3- (II-methylanilino) -l- [2- (4-trifluoromethylpehnoxy) ethyl] -pyrrolidine obtained.

Example 20

3- (ii'-Eth, yl-4-methylanilino) -pyrrolidine Using the procedure of Example 1 become

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equimolar amounts of N-ethyl-4-methylaniline and maleic acid imide mixed and implemented. The product obtained in the process is in ethyl ether-tetrahydrofuran as a solvent reduced with lithium aluminum hydride · It becomes 3- (M-ethyl-4-methylanilino) -pyrrolidine obtain·

Example 21

3- (H-Isopropyl-4-methoxyanilino) -pyrrolidine Using procedure "A", equimolar amounts of iT-isopropyl-4-methoxyaniline and maleic acid imide are prepared and reacted accordingly. The product obtained in this way is reduced in an ethyl ether-tetrahydrofuran solution containing lithium aluminum hydride. 3- (F-isopropyl-4-methoxy-anilino) -pyrrolidine is obtained,

Example 22

3- (IT-Butyl-3-chloroaniline) pyrrolidine Using the procedure ¹¹ A ", equimolar amounts of N-butyl-3-chloroaniline and maleic acid imide are mixed and reacted. The reaction product is then placed in an ethyl ether-tetrahydrofuran Solution containing lithium aluminum hydride reduced, giving 3- (N-butyl-3-chloroanilino) pyrrolidine.

Example 23

3- (N-methyl-4-trifluorme thylanilino) -pyrrolidine Using the procedure ¹¹ A "are equimolar

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Amounts of N-methyl-4-trifluoromethylaniline and maleimide mixed and implemented. The reaction product is then in an ethyl ether-tetrahydrofuran solution with a "Lithium aluminum hydride content is reduced. It is 3_ (H-methyl-4-trifluoromethylanilino) -pyrrolidine obtained

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Claims (1)

Claim 1. Process for the preparation of 3-aminopyrrolidines the general formula in the E is lower alkyl, R one of the remainders -F ^ -Ar ¹ >> -R "-O-Ar or -E ¹¹ -Ar., ι OH R "is a lower alkylene radical, Ar is phenyl, lower alkylphenyl, lower alkoxyphenyl or trifluoromethylphenyl and Ar phenyl, lower alkylphenyl, lower alkoxyphenyl, Represents halophenyl, trifluoromethylphenyl or pyridyl, as well as their acid addition salts, characterized in that one l-benzyl-3-aminopyrrolidine debenzylated by hydrogenolysis or a maleic acid 10 9 8 17/2147 imide with an N-alkyl aniline with a lower alkyl group Reacts the general formula HIRAr and reduces the obtained Aspariaiid with lithium aluminum hydride and that obtained 3-aminopyrrolidine of the general formula Ar \
H in which E and Ar have the meaning given above, is reacted with a compound which consists of X - R "- Ar» H _fl 0 = OH - pyridyl, X - R "- 0 - R or H ₀ O.- pH -R " ¹ -Ar consists, where R, R" and Ar have the meanings given above, X is a replaceable halogen and E ¹ "is a lower alkylene radical having 0 to 6 carbon atoms and, if desired, the base obtained with an acid in its acid addition salt convicted. 109817/2147