DE1198364B - Process for the N-alkylation of primary amines to secondary amines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07c

C07d

German class: 12 ο - 27

Number: 1198 364

File number: C 28895IV b / 12 ο

Filing date: January 12, 1963

Opening day: August 12, 1965

The invention relates to a new process for the N-alkylation of primary amines to form secondary ones Amines.

It has been found that primary amines can be alkylated to secondary amines if the primary amines R ₂ - NH ₂ are converted into N-substituted imino ethers of the formula in a known manner

R -c;

₅ NR ₂ OR ₁

converted, in which R is a lower alkyl or aralkyl radical and R _{1 is} a lower alkyl radical or R and R ₁ together with the imino carbon atom and the imino ether oxygen atom represent a tetrahydrofuran ring and R _{2 represents} the radical of a primary amine after deduction of the NH ₂ group who have favourited Iminoethers with a compound of the formula

R ₃ -X

in which R _{8 is} a lower alkyl radical and X is the radical of a strong inorganic or organic acid, is quaternized in a manner known per se and the quaternary compound is hydrolyzed in a manner known per se.

The implementation of the imino ethers with the quaternizing agents is in a known manner, advantageously in the presence of diluents, such as halogenated Hydrocarbons, e.g. methylene chloride or chloroform, acetonitrile, ether, dioxane or Tetrahydrofuran and the like. The hydrolysis is also in a known manner, alkaline or sour, made, z. B. by means of alkali hydroxides, carbonates, bicarbonates or dilute acids, in particular mineral acids such as hydrochloric acid or sulfuric acid, or organic acids such as acetic acid, or aqueous solutions of acidic salts of polybasic acids, ζ. B. Citrate buffer solutions.

The quaternizing agents to be used according to the invention for the reaction are esters of lower ones Alkanols with strong inorganic or organic acids, preferably hydrohalic acids, such as chloric, bromic or hydroiodic acid, sulfuric acid or organic sulfonic acids, especially arylsulfonic acids, such as benzene or toluenesulfonic acid.

The new method is generally applicable. It can be carried out with any N-substituted iminoetheme. The imino ethers can be open-chain or processes for the N-alkylation of primary
Amines to secondary amines

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr.-Ing. Dr. jur. F. Redies,
Dipl.-Chem. Dr. rer. nat. B. Redies
and Dr. T. Türk, patent attorneys,
Opladen, Rennbaumstr. 27

Named as inventor:

Dr. Albert Eschemnoser, Zollikon (Switzerland);

Dr. Jakob Schreiber, Bethesda, Md.

Dr. Heinrich Peter,

Mountain View, Calif. (V. St. A.)

Claimed priority:

Switzerland of January 18, 1962 (600)

be cyclic. In the latter case they are internal imino ethers of the γ-oxybutyric acid of the structure

The substituent R _{2 of} the imino ethers is an aliphatic, aromatic, araliphatic or heterocyclic radical, ζ. B. a lower alkyl radical, such as methyl, or a cycloalkyl radical, such as cyclopentyl or a cyclohexyl, or a mono- or dicyclic aryl radical, such as phenyl, naphthyl, or an araliphatic radical, such as benzyl, / S-phenylethyl, or a monocyclic heterocyclic radical, such as pyridyl, piperidyl; preferably is

509 630/433

3 4

R _{2 is} the residue of a natural α-amino acid or 2.734 g (7.8 mmol) of solid silver fluoroborate di-benone of its esters, e.g. B. a lower alkanol ester, after zolat is dissolved in 50 ml of absolute methylene chloride deduction of the amino group. Such residues are for example and filtered the cloudy solution. At 0 °, the remainder of the glycine or a glycine ester, excluding moisture and with stirring, a solution of the alanine or an alanine ester, of the serine or 5 of 1.580 g (7.8 mmol) of y-chloro-N-cyclohexyl-buttereines serine ester, in particular an aromatic or acid amide in 20 ml of absolute methylene chloride added dropwise to heterocyclically substituted natural "amino". A precipitate of acids such as phenylalanine, tyrosine, histidine or silver chloride forms immediately. After stirring for 2 hours at 0 °, tryptophan or its ester becomes. With particular advantage sucked off by the silver chloride, part of the methylene is used the new method in such io chlorides evaporated and the solution in ether on-cases, where secondary amines are taken by conventional methods, whereby the hydrofluoroborate of iminonur is difficult or impossible to obtain. Here it goes down. It is now possible by shaking out with 2N soda solution; the imino ether is released from the salt according to the method according to the invention. To make such amines. The ether extract is washed three times with less saturated

This is of particular interest in the area of 15 saline, drying it with sodium sulfate and peptide chemistry, where the problem of exchange evaporates the ether. An acyl radical is obtained from the residue against an alkyl radical which is optionally substituted by distillation in a high vacuum 2-cyclohexyl radical, which is of considerable importance. Imino-tetrahydrofuran, _{b.p. Ojl} = 76 °, nf = 1.4939. The method according to the invention offers new possibilities here. So you can z. B. Peptides Forming an Aliphatic 20 Example2
Have acylamino group, the acyl radical in y-position

treatment carries a reactive esterified oxy group, 287 mg of N-tetrahydrofuranylidene- (2) -L-tryptophan

alkylate intramolecularly, whereby the carbamylsauer- methyl ester (1 mmol) are in 10 ml absolute

substance atom reacts in the enol form; acetonitrile is thus obtained, dissolved with excess methyl iodide

to iminotetrahydrofurans. 25 (0.5 ml) added as reactive ester and left to stand at 20 ° for 70 hours,

In particular, those of halogenated water can be used. Then the liquids are at 30 ° am

chemical acids, sulfuric acid or organic sulfonic rotary evaporator removed, with a yellowish

acids such as arylsulfonic acids, e.g. B. toluenesulfone foam remains, which with 10 ml of 2N potassium

acids, use. The cyclization can be mixed with bicarbonate solution and 4 hours with the

more comfortable, expediently at an elevated temperature, 30 magnetic stirrer is stirred. The

if necessary using catalysts, yellow solution after a short time. For work-up

in particular silver salts, such as silver tetrafluoroborate, the reaction mixture is dissolved in methylene chloride.

Silver nitrate, silver perchlorate. taken and the reaction product with 2N salt

The thus obtained, a cyclic imino ether acid extracted. The sour extracts are made with

Grouping-containing peptides can then be made alkaline and made in a concentrated soda solution

duly extracted again with methylene chloride with reactive esterified alcohols. After this

implemented and hydrolyzed. Wash neutral with saturated saline solution

The imino ethers used as starting materials, the extract dried over anhydrous sodium sulfate

are known or can net in a known manner and the solvent at low temperature

or won as shown. You can vaporize them in 40. 197 mg (84.5%) remain slightly yellow

Use the form of free bases or salts. You return the oil. The raw IR spectrum shows the

can also be produced in the course of the process and bands of a secondary amine and the N-methyl

do not need to be isolated. group on.

The invention is illustrated in the following examples. The oil is dissolved in absolute ether and drier

described in more detail. The temperatures are initiated in Celsius-45 hydrogen chloride. The failing hydro

degrees indicated. chloride is made off after decolorization with activated charcoal

Recrystallized methanol and absolute ether. It

Example 1 are 211 mg (78%) N-methyltryptophan-methyl-

ester hydrochloride as fine, colorless needles

3.0 g «-Cyclohexyh'mino-tetrahydrofuran will hold 50, soft melting at 170.5 to 172 °. That

Doused with 15 g of methyl iodide, then the mixture of the analysis product melts after being converted six times.

diluted with 50 ml ether and crystallized for 14 hours at 171.5 to 172 ° (corrected). [« F

temperature left to stand. The resulting iodine = + 47.2 ° (c == 2.03 in methanol),

methylate is separated off by filtration. The imino ether used as the starting material is obtained

5.3 g of crystals with a decomposition point of 182 ° to 185 °. 55 can be produced in a manner known per se as follows

This can be dissolved in 50 ml without further purification:

saturated sodium bicarbonate solution, still diluted a) 5.20 g (20.4 mmol) L-tryptophan methyl ester

with 40 ml of water and the mixture is allowed to be dissolved in 50 ml of methanol and the mixture for 14 hours

stand at room temperature. Now one brings the with 2.14 g (2ImMoI) anhydrous triethylamine

Sodium hydroxide solution is added to pH 10 and 60. After being left standing in the room

extract them with ether. After careful distillation temperature, the methanol is

letting the ether, the residue is gently sucked off at normal pressure.

distilled. The N-methylcyclohexylamine is obtained in this way. The free methyl ester is then dissolved in methylene chloride

KP-72 »- 140 to 143 °, n * § - 1.4540, melting point added and the insoluble triethylammonium

of the 3,5-dinitrohenzoate 151 to 152 °. 65 chloride filtered off. The solution is poured into a cylinder

The imino ether used as the starting material is filled with a vibromixer and an ice can Salt mixture prepared in a manner known per se as follows, cooled to -20 °. Then will become: 1.82 g (23 mmol) pyridine and 3.25 g (23 mmol)

5 6

y-chlorobutyric acid chloride in 30 ml of a small amount of absolute ether. The first yellow ether methylene chloride added dropwise. The reaction mixture fractions turn dark brown when left to stand, is overnight at -20 to -15 ° and then the acidic yellow solution is made with solid soda

Stirred for 4 hours at room temperature. made alkaline until the color turns reddish

For work-up, the methylene chloride layer 5 is beaten. They are then extracted with five portions each with three portions of ice-cold 2N soda solution, each of 100 ml of chloroform. The combined chloro-2N hydrochloric acid and distilled water are extracted by shaking the form extracts with two small portions of one and dried over anhydrous sodium sulfate. The saturated sodium chloride solution is washed neutral, the yellow solution of the crude product is washed with activated charcoal. After drying over sodium sulfate, it is decolorized and concentrated. After adding hexane to solvent sucked off. 1.890 g of γ-chlorobutyryl-L-tryptophan-methyl- (9.05 mmol) of a light yellow oil crystallizes, which after ester out in the form of fine, colorless needles, which crystallize for 2 hours. Crude yield: 82.7% form spherical drusen. After the first three frac- N-methyl-L-tyrosine methyl esters. Hydrochloride: F. 141 tions (4.586 g) from 113 to 113.5 ° are still up to 142 °, · [«]? = + 35.3 ° (c = 3.04 in methanol), two further fractions (0.846 g) with a melting point of 112 to 112.5 ° obtained (yield 87.5%) · can prepared in a manner known per se as follows After recrystallizing twice from methylene:

chloride-hexane, 5.54 g (84.2%) crystals are obtained, a) 4.38 g (18.9 mmol) of L-tyrosine-methyl-

which as the analysis product from the first ester hydrochloride in 200 ml of methanol and neutral batch melt at 113 to 113.5 ° (corrected). 20 siert the solution with 2.407 g (23.8 mmol) of triethylamine. b) 5.100 g (15.78 mmol) γ-chlorobutyryl-L-trypto- The solvent and the excess triethylphane methyl ester are in about 200 ml of absolute amine are removed in vacuo. The white reverse methylene chloride dissolved, cooled to -20 ° and stood in 300 ml of absolute methylene chloride 62 ml (18.00 mmol) of O.29N silver fluoroborate solution were taken up and the mixture was placed under nitrogen. After stirring for one hour at -20 to -15 ° C, rinsed with an ice-salt mixture and cooled. it is left for 1 hour at 0 ° and 1/2 hours at room temperature. A solution of 2.830 g is then slowly added dropwise react to temperature. The excess silver (20.1 mmol) γ-chlorobutyric acid chloride in 30 ml of ether fluoroborate in the reaction mixture is added by vibrating vigorously, gives 2.06 g (20.4 mmol) Addition of 350 mg of triethylammonium chloride and triethylamine in 30ml of ether removes the subsequent fibrillation decomposed for 15 minutes. 30 cooling and vibrating the solution overnight. The precipitated, slightly violet colored silver after suctioning off the methylene chloride on

chloride is filtered off and the oily residue is taken up in ether with 2N soda solution and vacuum washed with methylene chloride. The methylene on. Formed by adding a little 2N hydrochloric acid chloride extracts are two clear layers with 2N soda solution. One shakes the ethereal layer and extracted three times with saturated saline solution, each with three portions totaling 100 ml ice-cold and dried over sodium sulfate. The slightly cloudy 2N hydrochloric acid and 50 ml of 2N potassium bicarbonate solution Solution (finely divided silver chloride) is passed through and washes the extract with four small portions Celite column filtered and the solvent neutral with an ice-cold, saturated sodium chloride solution lower. Temperature sucked. After drying over sodium sulfate, the

During the crystallization from methylene chloride-hexane 40 ether sucked off in a vacuum. The last water becomes a total of 4.51 g of N-tetrahydrofuranylidene (2) -3> traces are removed azeotropically with the addition of benzene, tryptophan methyl ester as needle-shaped crystals. After drying for 18 hours, keep in a high vacuum (100% = 4.52 g). After another um- (10 ~ ⁸ mm), 5.685 g (18.9 mmol) of N- (γ-chlorine crystallization from methylene chloride-hexane and dry-butyryl) -L-tyrosine methyl ester are obtained in the form of a slightly under high vacuum 3 , 84 g of crystals of the yellow oil that nucleates on -F after 24 hours. 171.5 to 172 ° and 0.530 g, which points at 171 to 172 °. Crude yield: 100%.

melt (96.6%). The analysis product melts 2.403 g (8.01 mmol) of the oil in little

after four recrystallization at 171.5 to 172 °. Dissolve methylene chloride and add hexane to begin-es contains between 0.15 and 0.18 mol of methylene ends in turbidity. With a preliminary approach

chloride. 50 crystals obtained are inoculated. It is formed

. · 1, slightly yellow colored crystals, which you can with activated charcoal

ΰ e 1 s ρ 1 e I 5 _{decolorized in} methylene chloride. After another change

2.64 g of freshly produced N-tetrahydrofuranylidene crystallization are 1.913 g (6.39 mmol) of N- (y-chlorine-

(2) -L-tyrosine methyl ester are dissolved in 160 ml of absolute butyryl) -L-tyrosine methyl ester from a melting point of 76 to 77 ° Acetonitrile added. Obtained under a nitrogen atmosphere 55. Yield + 79.7%.

20.7 g (146 mmol) of methyl iodide are added. According to b) 3.282 g (10.9 mmol) are carefully dried

38 hours of stirring with a magnetic stirrer with Zimneten N- (γ-chlorobutyryl) -L-tyrosine methyl ester in mertemperature under a nitrogen atmosphere is the 200 ml of absolute methylene chloride and cools the Excess methyl iodide drawn off in vacuo. Solution with ice-table salt mixture. Under Stick-Das Acetonitrile removed at the same time becomes again a substance atmosphere and vigorous vibration is given replaced. 70 ml of a 20 ml (12.5 mmol) 0.626 molar silver-saturated sodium bicarbonate solution are added to the solution, and the tetrafluoroborate solution is vibrated. The hour is at -6 ° for 2 hours at room temperature. Vibrated for 2 hours at room temperature, the yellow solution immediately becomes colorless, and the subsequent addition of 0.503 g (3.65 mmol) voluminous, white precipitate. The largest 65 triethylammonium chloride and vibrating for 15 minutes Part of the acetonitrile is now drawn off. The excess silver tetrafluoroborate is destroyed with 2N salt. acid is set to a pH of. 1 to 2 and the precipitated silver chloride is filtered off and extracted the y-ButyroIactön formed twice with extracted the methylene chloride solution with two "An * - ·

7 8

Divide a total of 90 ml of ln potassium bicarbonate 2.15 g (21 mmol) of triethylamine in 20 ml of ether solution with the addition of ice and twice with a little ice cold. The reaction mixture is poured into room-saturated saline solution. The aqueous extracts are allowed to warm to temperature and stirred overnight, are mixed with two small portions of methylene chloride after gently evaporating the solvent

rewashed. The combined organics are dried under reduced pressure, taken up in ether, niche solutions are extracted over sodium sulfate and the solution is extracted three times with 2N hydrochloric acid and three times with 1N sodium carbonate solvent in a high vacuum at room temperature with ice cooling and extracted with four. The N-tetrahydrofuranylidene- (2) -L-tyrosine-methyl- portions of ice-water were washed neutral. The light ester (2.640 g) is obtained as a bubbled, light yellow oil, brown-yellow ether solution is thinned with a little activated charcoal. Crude yield: 91.5% · ^10, decolorized over anhydrous sodium sulfate

left and evaporated. It remains a clear, whole

Example 4 back slightly yellowish oil, which does not turn into a crystal

lization can be brought. Yield: 5.5 g

6 mmol of N-tetrahydrofuranylidene- (2) -L-phenyl- (92.5%) (y-chlorobutyryty-L-phenylalanine ethyl ester. Alanyl ethyl ester are, as described in Example 2, 15 turns in absolute ethanol: [<x ] V = -2.7 ° methylated with methyl iodide, then with 50 ml (c = 3.71).

O ^ n-sodium bicarbonate solution at room temperature b) 1.80g (6.04mMol) of oily (y-chlorobutyryl) -phenyl-

hydrolyzed overnight. After working up in methyl alanine ethyl ester, as described in Example 2, lene chloride, 1.092 g of N-methyl-L-phenylalanine with 27 ml of O.245N silver fluoroborate solution (6.6 mmol) ethyl ester obtained as a practically colorless oil (cyclized from 20 and the excess silver ions with Yield: 87%, based on γ-chlorobutyryl-phenyl-140 mg (1 mmol) triethylammonium chloride as silver alanine ethyl ester). chloride precipitated. By washing the methylene

0.875 g of the crude N-methylamino acid ester are chloride solution with ice-cooled 2N sodium carbonate 150 ml of absolute ether dissolved and dried solution and saturated sodium chloride solution, dry hydrochloric acid gas initiated. Fine white crystals immediately fall over sodium sulfate and the solution crystals are evaporated from, which is filtered off, dried in vacuo by means of which the free imino ether base is obtained, and weighed: 0.990 g.

After one recrystallization from absolute example 5

Alcohol and absolute ether are 0.920 g fine

Needles with a mp of 129.3 to 129.8 ° obtained. A solution of 3 g of p-toluene-sulfonated product (0.87 g) melts at 129.6% of the analytical ether to 1 g of N-ZS-phenylethylphenylessigsaure-athyliminoreine and dried for 3 days in a high vacuum up to 129.8 °. methyl acid ester in 30 ml of ether and the mother liquors leave 90 mg of needles of the mixture to stand for 16 hours at room temperature. F. 130.3 to 130.8 ° obtained. Then the precipitate is filtered off and stirred in water: [ot] * ¹ / = + 9.9 ° (c = 3.67). 35 overnight with 50 ml citrate buffer (pH 3.4). That

The picrate of the N-methyl-L-phenylalanine-ethyl ester mixture is made basic with sodium hydroxide solution, with After recrystallizing twice from sodium chloride, it melts saturated and extracted with 300 ml of ether. Chloroform-hexane at 136 °. After drying over sodium sulfate, the

The imino ether used as the starting material is distilled off in vacuo. The residue can be prepared in a manner known per se as follows. The methyl (β-phenylethyl) amine has a _{boiling point of 2o} : = 105 °.

a) 95 ml of ethanol are in a cylinder vessel The N- / 5-phenyl used as starting material

from 200 ml contents to -10 ° and under ethyl-phenylacetic acid-ethyliminoether can as follows Vibrate slowly 6.8 ml of thionyl chloride added dropwise. getting produced:

In this mixture 12.45 g of L-phenyl-45 1.245 g of phenylacetic acid-zS-phenylethylamide are added alanine entered, the mixture is dissolved with cooling in 10 ml of methylene chloride and 1.16 g shifted to -10 ° for half an hour and with triethyloxonium fluoroborate. After 3 hours Stirred at room temperature overnight. Eventually standing at room temperature will result in the reaction warmed to 70 ° for 3 hours, the mixture running on ice-cold sodium bicarbonate solution half an hour a clear solution obtained 50 pour, extracted with ether, with sodium sulfate will. dried and freed from solvent. You get

The solvent completely changes the imino ether as a colorless oil in a vacuum. sucked off, the residue taken up in a little absolute ethanol and with absolute ether up to example 6 permanent cloudiness. In two factions 55

16.2 g (94%) of fine needles of L-phenyl-0.5g. 2-benzylimino-tetrahydrofuran are in 10 ml

alanine ethyl ester hydrochloride with a melting point of acetonitrile dissolved, 2 g of dimethyl sulfate in 20 ml of ether 147 to 148.5 ° obtained. added and 24 hours at room temperature

4.6 g (20 mmol) of L-phenylalanine-ethyl ester-hydro- allowed to stand. The precipitate is then filtered off from chloride in 130 ml of absolute dioxane and stirred for 6 hours with 5% phosphorus. Acid while cooling with ice and stirring. After 2.25 g (22 mmol) of triethylamine in 20 ml of ether have been added alkaline with sodium hydroxide solution, the solution is saturated with sodium chloride, added dropwise. After stirring for 272 hours, it is extracted with ether, the ether solution is dried over the precipitate of triethylammonium chloride sodium sulfate and the solvent is removed. It is filtered off and washed with ether. The filtrate 65 receives methylbenzylamine as a colorless liquid, which is cooled with an ice-common salt mixture and _{boiling point 72o} = 179 to 182 °.

vigorous stirring 3.1 g (22 mmol) γ-chlorobutyric acid- The imino ether used as starting material

chloride in 20 ml of ether and then a solution of can be obtained by reacting 761 mg of N-benzyl-

Prepare y-bromobutyric acid amide with 505 mg silver nitrate in acetonitrile.

Example 7

A solution of 0.5 g of N-cyclohexyl acetic acid ethylimino ether in 5 ml of acetonitrile with 2.5 g of ethyl bromide in 20 ml of ether is allowed to stand for 14 hours at room temperature. The precipitate is then separated off and stirred for 8 hours at room temperature with 20 ml of Ο, ΐη hydrochloric acid. Then it is made alkaline with sodium hydroxide solution, the solution is saturated with sodium chloride, extracted with ether, the ethereal solution is dried over sodium sulfate and the ether is distilled off in vacuo. The residue contains N-ethylcyclohexylamine, which has a boiling point of _72O = 159 to 163 °.

The imino ether used as the starting material is obtained by adding 5 mmol of N-cyclohexyl-acetic acid amide and 7.5 mmol of triethyloxomum fluoroborate in 20 ml of methylene chloride for 5 hours at room temperature lets stand, shaken with concentrated potassium carbonate solution and the methylene chloride removed in vacuo.

Claims (2)

Patent claims: 1. Process for the N-alkylation of primary amines to secondary amines, thus characterized draws that the primary amines R ₂ -NH ₂ in a known manner in N-substituted imino ethers of the formula OR ₁ converted, in which R is a lower alkyl or aralkyl radical and R _{1 is} a lower alkyl radical or R and R ₁ together with the imino carbon atom and the imino ether oxygen atom represent a tetrahydrofuran ring and R _{2 represents} the radical of an amine after subtracting the NH ₂ group with imino ether a connection of the primary
stands that
formula R ₃ -X in which R _{3 is} a lower alkyl radical and X is the radical of a strong inorganic or organic acid, quaternized in a manner known per se and the quaternary compound is hydrolyzed in a manner known per se. 2. The method according to claim 1, characterized in that the primary amine is a natural α-amino acid or a peptide is used. 509 630/433 8.65 © Bundesdruckerei Berlin