DE1418529B - Process for preparing N-substituted amino acid derivatives - Google Patents

Description

The invention relates to a method for producing N-substituted amino acid derivatives of the general formula _D.

N - R ₇ CON

in which R is hydrogen, alkyl, alkoxy, alkyl-substituted carboxyl, halogen or hydroxyl, R _{1 is} acyl, alkyl-substituted aminoacyl, _{haloacyl or carbamyl, R 2 is} alkylene, R _{3 is} hydrogen or alkyl and R _{4 is} alkyl, which is characterized in that in in a manner known per se, the hydrogen atom which ^{is bonded to the nitrogen atom N + of} the following general formula

_R f \ ~ N ⁺ HR ₂ CONR ₃ R ₄

replaced by a group corresponding to the above definition for R _1.

All of these compounds are new and have not yet been described in the literature. This Compounds have antipyretic and analgesic activity. Most of the connections show good solubility in water and can be used commercially as medicaments.

In the case of carbamylation, compounds such as KNCO etc. are preferably used. Possibly it is appropriate to use more than two of the above implementation partners, e.g. B. use acetic anhydride and sodium acetate at the same time, as this is more convenient than just the use of acetic anhydride in acetylation.

The following list shows some pharmacological values for the compounds which can be prepared by the process according to the invention, namely LD ₅₀ , ED ₅₀ and the solubility of the compound in water

QH ₅ N ⁺ HCH ₂ CON (CHa) ₂

(I)

(Reference substance), from which by substitution of the hydrogen atom of the directly bound to the aryl nucleus The compounds (II), (III) and (IV) according to the invention are prepared with nitrogen. In the following List is the corresponding compound obtained by an aminoacetyl radical as (II), which by Substitution by means of a carbamyl residue as (III) and the compound obtained by substitution by means of an acetyl radical obtained compound identified as (I V):

connection LD ₃₀ ED ₃₀ LD ₃₁₎ / ED _5U solubility
(g / ml) (D 6.3 1.8 3.5 0.0031 (II) 8.5 2.0 4.3 2.7 (III) 21.4 2.2 9.7 0.21 (IV) 14th 0.5 28 2.3

Analogous studies were carried out using

PC ₂ H ₃ OC ₆ H ₄ N ⁺ HCH ₂ CON (CH ₃ J ₂ (V)

(Comparative substance) executed, with the same

As above, the Η atom of the nitrogen atom connected to the aryl nucleus through the acetylresi is replaced, whereby the compound (VI) prepared according to the invention is obtained. The comparative pharmacological values and solubilities are given in the following table:

connection
O LD ₅₀ ED ₃₀ LD _3O / ED _3O solubility
(g / ml) (V)
(VI) 7.3
7.9 1.8
1.2 4.1
6.6 0.0021
2.1

These results clearly show that the compounds which can be prepared by the process according to the invention not only have an improved therapeutic index (LD ₅₀ / ED ₅₀ ), but also a significantly higher solubility in water, which is known to be extremely important for intravenous administration. Furthermore, the compounds produced by the process according to the invention hardly lead to methaemoglobinaemia.
In the US Pat. No. 2,568,142, groups of substances are described for which the α-anilino-N, N-diethylacetamide listed there is a typical representative. This compound is distinguished by its analgesic properties. There were now using this compound as a comparison substance [Ver.

bond (VIII) of the table below] comparative pharmacological studies with regard to the analgesic effectiveness with two compounds prepared by the process according to the invention, namely N-carbamyl-N-phenyl-N'.N'-dimethylglycine amide and N-benzoyl-N-phenyl-N ', N'-dibutylglycine amide [compound (III) or (VII) of the table below] was carried out on mice of the dd breed with a body weight of 12 to 14 g, the corresponding compounds being injected intraperitoneally and the values for LD ₅₀ and ED ₅₀ according to the method of L ichfie 1 d — Wi 1 c ο χ ο η on the basis of the modified method according to Ha ff η er and related to the number of mice killed within 24 hours after administration.

connection LD ₃ ,, *) ED ₃ ,, *) Therapeutic index
(LD _3O / ED _3O ) (HD
(VII)
(VIII) 21.4
16.8
10.9 2.2
> 5
> 5 9.73
<3.36
<2.18

*) mg / 10 gi.p.

As can be seen from the table, the compound (VIII) used as a comparison substance has the lowest therapeutic index among the compounds tested. It was also found that after administration of 250 mg / kg of the comparison compound (VIII) the test animals fell asleep and could hardly walk. In addition, when a larger dose was administered a strong hypnotic effect without analgesic effect was found in the mice.

In contrast, the compounds prepared according to the invention are not only analgesic, but they also show a strong antipyretic

and anti-inflammatory effectiveness, and this without undesirable, especially without any hypnotic side effects.

Two of the compounds prepared according to the invention, namely N-acetyl-N-phenyl-N '^' - dimethylglycine amide (IV) and N-acetyl-N- (p-ethoxyphenyl) -Ν ', Ν'-dimethylglycine amide (VI) have proven to be particularly valuable in terms of their pharmacological effectiveness during their testing, the solubility, the clinical effects and the like. Shown and in control examinations in which the same Investigation method was used that-above The excellent results cited are essentially confirmed.

The door of the method according to the invention can be used starting compounds z. B. can be produced by the following implementation:

NH- R, COOR 'HNR ₃ R ₄

'- R ₂ CON

in which R 'denotes alkyl and the other symbols have the meaning described above.

example 1

N-acetyl-N-phenyl-N'.N'-dimethylglycine amide

(R = H, R ₁ = CH ₃ CO, R ₂ = CH ₂ ,

R ₃ = R ₄ = CH ₃ )

An equivalent amount of acetic anhydride is added to 7 g of N-phenyl-N '^' - dimethylglycine amide and ^{reacted at 100 to 130 °} C. for 1 hour. It is then cooled and water is added to decompose the acetic anhydride. It is then made alkaline, extracted with chloroform and the crystals obtained from the extract are recrystallized from a mixture of benzene and η-hexane, whereby a compound with a melting point = 95 to 96 ° C. or 100 to 10 ° C. is obtained. This phenomenon is based on polymorphism. Yield 7.6g (93.5%).

Values for C ₁₂ H ₁₆ O ₂ N ₂ = 220.26:
Calculated ... C 65.43, H 7.32, N 12.72%;
found .... C 65.50, H 7.48, N 12.90%.

B e i s ρ i e 1 2

N-acetyl-N- (4-ethoxyphenyl) -N ', N'-dimethylglycine amide

(R = 4-C ₂ H ₅ O, R ₁ = CH ₃ CO, R ₂ = CH ₂ ,
R ₃ = R ₄ = CH ₃ )

8 g of N- (4-ethoxyphenyl) -N \ N'-dimethylglycine amide are dissolved in chloroform and 8 g of potassium carbonate and 3.2 g of acetyl chloride are added. The mixture is then heated on the water bath for 30 minutes, cooled and the chloroform solution is washed with water. The solvent is evaporated and the residue is recrystallized from benzene-η-hexane, whereby a compound with a melting point = 80 ^° C. is obtained. The yield is 8.5 g (85%).

Values for C ₁₄ H ₂₀ O ₃ N ₂ = 264.32:
Calculated ... C 63.62, H 7.63, N 10.60%;
found .... C 63.43, H 7.55, N 10.59%.

Example 3

N- (4-carbethoxyphenyl) -N-acetyl-Ν ', Ν'-dimethylglycine amide

(R = 4-COOC ₂ H ₅ , R ₁ = CH ₃ CO, R ₂ = CH ₂ ,
R ₃ = R ₄ = CH ₃ )

A mixture of 20 g of N- (4-carbethoxyphenyl) -Ν ', Ν'-dimethylglycine amide, 40 g acetic anhydride

and 1 g of sodium acetate (anhydrous) is put on the oil bath Heated to 100 to 130 ° C. for 1 hour and treated further as in Example 1. The conversion product is recrystallized from a mixture of benzene and n-hexane, producing a compound with a Mp. = 80 to 80.5 ° C. is obtained.

Door Values C ₁₅ H ₂₀ O ₄ N ₂ = 292.33: ₂ , calculated ... C 61.63, H 6.90, N 9.58%; found .... H 6.91, N 9.97%.

Be i s ρ i e 1 4

N-chloroacetyl-N-phenyl-N'.N'-dimethylglycine amide (R = H, R ₁ = COCH ₂ Q, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

14.3 g of N-phenyl-N ^ N'-dimethylglycine amide will be dissolved in chloroform and added to this solution 16.6 g of anhydrous potassium carbonate. Then be 13.6 g of chloroacetyl chloride were added dropwise with stirring and refluxed for 30 minutes. One cools then wash off the chloroform layer with water. The solvent is evaporated and the residue obtained recrystallized from a mixture of benzene and η-hexane, whereby 17.7 g (88%) a compound with a m.p. = 90 to 92 ° C can be obtained.

Values for C ₁₂ H ₁₃ O ₂ N ₂ Cl = 254.72: Calculated ... C 56.58, H 5.94, N 11.00%; found .... C 57.14, H 6.06, N 10.73%.

Example 5

N-chloroacetyl-N- (4-ethoxyphenyi) -Ν ', Ν'-dimethylglycine amide

(R = 4-C ₂ H ₅ O, R ₁ = COCH ₂ Cl, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

15.5 g of N-4-ethoxyphenyl-N ', N'-dimethylglycine amide are dissolved in chloroform, 14.5 g of anhydrous potassium carbonate are added and then 12 g of chloroacetyl chloride are added dropwise with stirring. One then works as indicated in Example 4. Recrystallization from a benzene-n-hexane mixture, 20.4 g (93.5%) ^e i are ^ner compound with a mp. Obtain = 115-116 ° C.

Values for Q ₄ H ₁₉ N ₂ O ₃ Cl = 298.77: Calculated ... C 56.27, H 6.40, N 9.38%; found .... C 56.14, H 6.44, N 9.21%.

Example 6 Example 10

N-carbamyl-N-phenyl-N'.N'-dimethylglycine amide N-dimethylaminoacetyl-N- (4-ethoxyphenyl) -

(R = H, R ₁ = CONH ₂ , R ₂ = CH ₂ , N'.N'-dimethylglycine amide

R ₃ = R ₄ = CH ₃ ) ⁵ (R = 4-C ₂ H ₅ O, R ₁ = COCH ₂ N (CH ₃ ) ₂ , R ₂ = CH ₂ ,

10.7 g of N-phenyl-N'.N'-dimethyiglycinamide become R ₃ = R ₄ = CH ₃ )

dissolved in 140 ml of 50% acetic acid and a mixture of N- (4-ethoxyphenyl) -N ', N'-di-

Stirring at 20 to 30 "C. Potassium cyanate is added. One methylglycine amide, dimethylaminoacetic acid and

then reacts for 2 hours at 40 ° C. The conversion io phosphorus pentachloride is converted according to Example 4

solution is then made alkaline, with set, whereby a compound with a m.p. = 77

Chloroform extracted and which is obtained from the chloroform to 78 ° C,

layer obtained crystals from a mixture of values for C H O N = 307 38

Chloroform and benzene recrystallized, giving ^{16 25} ~ * Λ ~ " _ο '. _ηΜΠ ,, ₀ ,

12.9 g (97%) of a compound with a m.p. = 162.5 Calculated ... C 62.52, H 8.20, N 3.67 / ₀ ;

to 163 ⁰ C can be obtained. found .... C 62.30, H 8.12, N 13.88 / ₀ .

Values for C ₁₁ H ₁₅ O ₂ N ₃ = 221.25: Example 11

.. C 59.71, H 6.83, N 18.99%; *

.. C 59.58, H 6.9, N 18.75%. _20th

η. ■,, (R = H, R ₁ = QH ₅ CO, R ₂ = CH ₂ ,

^{Example 7} R ₃ = R ₄ = CH ₃ ) N-Carbamyl-N- (4-ethoxyphenyl) -

N'.N'-dimethylglycine amide ²⁰ S N- (phenyl) -N ', N'-dimethylglycine amide

25 dissolved in 200 ml of chloroform and then 15 g of benzoyl

(R = 4-C ₂ H ₅ O, R ₁ = CONH ₂ , R ₂ = CH ₂ , chloride added. It is 1.5 hours on the

H - j ^ _ CH ₃ ) heated water bath and then 20 g of potassium carbonate

added. Then heat for more than 1 hour,

11.1 g of N- {4-Äthoxyphenyl) -N ', N'-dimethyIglycin- sets water, and the separated chloroformamide are dissolved in 100 ml of 40% acetic acid, 30 layer is concentrated. 8 g of potassium cyanate are added to the residue obtained, and the procedure is then carried out in accordance with a mixture of benzene and η-hexane umspiel 6. The crystals thus obtained crystallize, whereby a compound with a is recrystallized from benzene, whereby 12 g of melting point = 120 to 121 ° C is obtained. The yield (94%) of a compound with a melting point = 133 ° C. is 28 g. will hold. 35 _{values for} Q ₇ H ₁₈ O ₂ N ₂ = 282.33: values for C ₁₃ H _n O ₃ N ₃ = 265.31: calculated ... C 72.32, H 6.43, N 9.92% ; Calculated ... C 58.85, H 7.22, N 15.84%; found .... C 72.64, H 6.43, N 10.10%. found .... C 58.94, H 7.22, N 15.88%.

"..," 40 Example2

Examples

.,. ,., ...,, "...." ... , N-Benzoyl-N- {4-ethoxyphenyl) -N ', N'-dimethyl-

N-Acetyl-N- (4-athoxyphenyl) -N \ N'-dimethyl- ³ ^ «lycinamide alaninamide

(R = 4-C ₂ H ₅ O. R ₁ = CH ₃ CO, R ₂ = CH (CH ₃ ), ^(R = ⁴ ^ HjO, ^ i = QH ₅ CO, R ₂ = CH ₂ ,

R ₃ = R ₄ = CH ₃ ) ⁴⁵ R ₃ = R ₄ = CH ₃ )

A mixture of IOg N- {4-ethoxyphenyl) -N ', N'-di- You start from 22.2 g of N- (4-ethoxyphenyl) -N', N'-di-

methylalaninamide and 20 g of acetic anhydride is made from methylglycine amide and proceeds according to Example 11,

according to the example! 1 implemented ,, whereby a compound whereby 20 g of a compound with a melting point = 94

dung with a bp = 170 ^c C at a pressure of 50 to 95 ^r C.

2 mm Hg is obtained. This compound crystalli- \ xj _orta r. \ _R t- υ η μ ivis.

•. . jr »■ · j ·. j values iur C ₁₉ M ₂₂ U ₃ IN ₂ = izo, ia.

sized after cleaning and then shows a ", ~, _ηΛ -, ,,, -," ν, ο, ""

Fd = 76 to 77 C tuf Calculated ... C 69.92, H 6.79, N 8.58V

l-p. found .... C 69.98, H 6.85, N 8.63 °.

B eis ρ ie I 9 _ss

N-Dimci h \ laminoacetyl-N-phcns 1-Example 13

N'.N -dimethylglycine amide N-propionyl-N-phenyl-N'.N'-dimethylglycine amide (R = H, R, COCH ₂ N (CH ₃ J _2. R ₂ = CH ₂ ,

R, = R ₄ = CH ₃ ) j «(R = a R ₁ = COCH ₂ CH ₃ , R ₂ = CH ₂ , A mixture of N-phenyl-N'.N'-dimethylglycine- R ₃ = R ₄ = CH ₃ ) amide, dimethylaminoacetic acid and phosphorus penta- 3d g of plienylglycine dimethylamide are reacted with 20.5 g of chloride according to Example 4, resulting in a propionyl chloride having a melting point of 83 ° C. using a potassium compound. carbonate as acid-binding agent for conversion values for CHO, N = "'63 33 · ^6s f? ^CDracnt - It was chloroform _.," ^u ■ '. ., .. ",, used as a solvent. One crystallized out of calculations. < W. 85. H 8.04. N Ix ^: _B , * _{H un} f _{wodmch ejnc} connection with pofundon. ■ (^) I. H 8.15. N IxSS ".

7 8

Example 14 ^{values for} Q ₅ H ₂₀ O ₄ N ₂ :

, .... ,,,., _XI , _XT ,,. .,, Calculated ... C 61.63, H 6.90, N 9.58%;

N-Acetyl-N ^ -cWorphenyO-N, N -d.methyl- _{found c} ^ _H ^ _N ^

(R = 4-Cl, R ₁ = COCH ₃ , R ₂ = CH ₂ , ⁵ examples.

R3 ⁼ R4 = CH ₃₎ N-chloroacetyl-N-phenyl-N ^ N'-dimethylalaninamid

15 g of 4-chlorophenylglycine dimethylamide are mixed with (r _ pj, R ₁ = COCH ₂ Cl, R ₂ = CH (CH ₃ ),

15 g of acetic anhydride heated and as usual to the 'r _ d _ ru)

Implementation brought about, creating a connection with 10 3 ¹ M 3J

a melting point = 133 to 134 ° C. (N-phenyl-N ', N'-dimethylalaninamide is recrystallized from benzene according to

siert) is obtained in almost quantitative yield. Example 4 chloroacetylated to give a compound

. ... is obtained. The connection so obtained is

Example 15 Syrupy and difficult to crystallize

Bring N-acetyl-N-phenyl-N ', N'-dimethylälaninamid 15. Hence, this connection is made by further

(R = H R = CH CO R = CH (CH) dimethylamination in N-dimethylaminoacetyl-

¹ '* ³ _' _ni l _χ N-phenyl-Ν ', Ν'-dimethylalaninamide (m.p. = 90 to

R ₃ -K ₄ - CH ₃ ) 9i ° C) converted.

N-phenyl-N ', N'-dimethylalanine amide is according to r ^- · 1? N

Example 1 acetylated to give a compound with 20 examples

a melting point = 98 to 99 ° C '(from benzene-η-hexane) N-acetyl-N- (4-propoxyphenyl) -

is obtained. Ν ', Ν'-dimethylglycine amide

Values for C ₁₃ H ₁₈ O ₂ N ₂ : (R = 4-OPr, R ₁ = CH ₃ CO, R ₂ = CH ₂ ,

Calculated ... C 66.64, H 7.74, N 11.96%; _{2 $} R ₃ = R ₄ = CH ₃ )

found .... C 66.87, H 7.95, N 11.90%. ■ _{N. (4.} P _r o _P oxyphenyl) - Ν ', Ν' - dimethylglycine amide

. . is acetylated according to Example 1, whereby a Ver

Example 16 bond with a m.p. = 63-65 ° C is obtained.

N-Dimethylaminoacetyl-N-phenyl _{values for c} H ₂₂ O ₃ N ₂ :

N, N-dimethylalanine amide 30. ",." Π-, _n -r vi mmo /

³ Calculated ... C 64.72, H 7.97, N 10.07%;

(R = H, R ₁ = COCH ₂ N (CH ₃ J ₂ , R ₂ = CH (CH ₃ ), found .... C 64.88, H 8.03, N 9.98%.

R ₃ = R ₄ = CH ₃ )

N- (Phenyl) -N ', N'-dimethylalaninamide is obtained according to B e 1 s ρ i e 1 21

Example 8 dimethylaminoacetylated, whereby a Ver 35 N-chloroacetyl-N- (4-ethoxyphenyl) -

Binding with a melting point = 90 to 91 ° C is obtained Ν ', Ν'-dimethylalaninamide

(from η-hexane). _{(R =} 4.OC ₂ H ₅ , R ₁ = COCH ₂ Cl, R ₂ = CH (CH ₃ ),

Example 17 R ₃ = R ₄ = CH ₃ )

N-acetyl-N- (2 ^ methylphenyl) -N ', N'-dimethyl- 40 N - (4 -ethoxyphenyl) - Ν', Ν '- dimethylalanine amide

glycine amide is chloroacetylated according to Example 4, whereby a

(R = 2-CH ₃ , R ₁ = CH ₃ CO, R ₂ = CH ₂ , syrupy compound is obtained.

R ₃ = R ₄ = CH ₃ ) Example 22

N- (2-methylphenyl) -N ', N'-dimethylglycine amide becomes 45 N-dimethylaminoacetyl-N- (4-ethoxyphenyl) -

acetylated according to Example 1, whereby a compound Ν ', Ν'-dimethylalaninamide

with a bp = 183 to 185 ⁰ C at a pressure m - α nr u ρ - rnu \ siru \

of 4 mm Hg is obtained. This was considered connects ^(R _ ~ _ ^ ^"5 'f ~ ^l _" _ ² JE? ^3/2'

some time to solidify. You ^Kz ~ ^ ^H \ ^ ^H 3h K ₃ -K ₄ - CH ₃ )

is then recrystallized from benzene-η-hexane, 5 ° N- (4-ethoxyphenyl) -Ν ', Ν'-dimethylalaninamide

whereby crystals with a melting point = 72 to 73 ° C he is dimethylaminoacetylated according to Example 9, where

will hold. 'is obtained by a syrupy compound.

Values for C ₁₃ H ₁₈ N ₂ O ₂ = 234.29: Example 23

Calculated ... C 66.64, H 7.74, N 11.96%; "N-acetyl-N- {4-methoxyphenyl) -

found .... C 67.03, H 7.97, N 12.25%. Ν ', Ν'-dimethylglycine amide

Example 18 (R = 4-OCH ₃ , R ₁ = CH ₃ CO, R ₂ = CH ₂ ,

N-acetyl-N- (2-carbethoxyphenyl) - R ₃ = R »= CH ₃ )

Ν ', Ν'-dimethylglycine amide 6 ° 20 g N- (4-methoxyphenyl) -N', N'-dimethylglycine-

amide are reacted with 13.4 g of acetic anhydride,

(R = 2-COOC ₂ H ₅ , R ₁ = CH ₃ CO, R ₂ = CH ₂ , whereby 20 g of a compound with a m.p. == 62

R = R ₄ = CH ₃ ) up to 64 ° C (from benzene-η-hexane).

The yield is 83.3%.

•! I ' ⁽² " ^C " a ^b n ^hO ^ rt ^enyl) " ^! ?'' ^N ' ^di % ^ethy !, ^GlyCina ^ ^{id 65} values for C ₁₃ H ₁₈ N ₂ O ₃ = 250.28:

is acetylated according to Example 1, whereby a ver _ V. «« ,,. _XT . _n n,

bond with a boiling point = 190-191 C at a calculated ... C 62.38, H 7.25, N, 19 / _0th;

Pressure of 0.08 mm Hg is obtained. found .... C 62.37, H 7.25, N, H, 29%.

10

Example 24

N-acetyl-N- (4-isopropoxyphenyl) -Ν ', Ν'-dimethylglycine amide

(R = 4-1-C ₃ H ₇ O, R ₁ = CH ₃ CO, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

7.0 g of N- (4-isopropoxyphenyl) -N ', N'-dimethylglycine amide are reacted with 5.0 g of acetic anhydride, whereby 7.0 g of a compound with a Melting point = 112 to 113 ° C. (from benzene-η-hexane) will. The yield is 85.3%

Values for C ₁₅ H ₂₂ N ₂ O ₃ = 278.34: Calculated ... C 64.72, H 7.97, N 10.07%; found .... C 64.99, H 7.97, N 10.46%.

Example 25

N-acetyl-N- (4-butoxyphenyI) -N ', N'-dimethylglycine amide

(R = 4-C ₄ H ₉ O, R ₁ = CH ₃ CO, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

10 g of N- (4-butoxyphenyl) -N ', N'-dimethylglycine amide are reacted with 6.7 g of acetic anhydride, as a result of which 10 g of a compound with a melting point of up to 61 ^° C. (from benzene-η-hexane) are obtained . The yield is 90%.

Values for C ₁₆ H ₂₄ N ₂ O ₃ = 292.37: Calculated ... C 65.72, H 8.27, N 9.58%; found .... C 65.83, H 8.28, N 9.63%.

Example 26

N-AcetyI-N- (4-isoamyloxyphenyl) -Ν ', Ν'-dimethylglycine amide

(R = 4-1-C ₅ H ₁₁ O, R ₁ = CH ₃ CO, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

10 g of N- (4-isoamyloxyphenyl) -N ', N'-dimethylglycine amide are reacted with 5.5 g of acetic anhydride, whereby 13 g of a compound with a melting point = up to 91 "C (from benzene — η-hexane). The yield is 90%

Values for C _n H ₂₆ N ₂ O ₃ = 306.36: Calculated ... C 64, H 8.55, N 9.14%; found .... C 67.14, H 8.55, N 9.24%.

Example 28

N-Acetyl-N- (2-methoxyphenyl) -Ν ', Ν'-dimethylglycine amide (R = 2-CH ₃ O, R ₁ = CH ₃ CO, R, = CH ,,

R ₃ = R ₄ = CH ₃ )

10 g of N- (2-methoxyphenyl) -N ', N'-dimethylglycine amide are reacted with 50 g of acetic anhydride, ίο whereby 6 g of a compound with a melting point = 103 to 104 "C (from η-hexane) are obtained.

Values for C ₁₃ H ₁₈ N ₂ O ₃ = 250.29: Calculated ... C 62.38, H 7.25, N 11.19%; found .... C 62.47, H 7.45, N 11.12%.

Example 29

N-acetyl-N- (2-ethoxyphenyl) -N ', N'-dimethylglycine amide

(R = 2-C ₂ H ₅ O, R, = CH ₃ CO, R ₂ R3 = R4 ⁼ CH ₃ )

CH

₂ ,

5 g of N- (2-ethoxyphenyl) -N ', N'-dimethylaminogiycinamide are reacted with 2 g of acetyl chloride, thereby obtaining 3 g of a compound with a bp = 166 to 167 "C at a pressure of 0.08 mm Hg ■ become. After the connection has stood for a while, it solidifies and then shows a melting point = 81 to 82 "C (from η-hexane).

Door values C ₁₄ H ₂₀ N ₂ O ₃ = 264.32: Calculated ... C 63.61, H 7.63, N 10.60%; found .... C 63.77, H 7.73, N 10.59%.

Example 30

N-acetyl-N- (2-propoxyphenyl) -Ν ', Ν'-dimethyl glycine amide

(R = 2-C ₃ H ₇ O, R ₁ = CH ₃ CO, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

10 g of N- (2-propoxyphenyl) -N ', N'-dimethylglycine amide are reacted with 50 g of acetic anhydride,' whereby 4.5 g of a compound with a melting point = 68 to 70 ° C. (from η-hexane) are obtained.

Values for C ₁₅ H ₂₂ N ₂ O ₃ = 278.34: Calculated ... C 64.72, H 7.97, N 10.07%; found .... C 64.97, H 8.24, N 10.18%.

Example 27

N-acetyl-N- (4-methylphenyl) -N ', N'-dimethylglycine amide

(R = 4-CH ₃ , R ₁ = CH ₃ CO, R, = CH ₂ , R ₃ = R ₄ = CH ₃ )

Example 31

N-acetyl-N- (2-butoxyphenyl) -Ν ', Ν'-dimethylglycine amide

(R = 2-C ₄ H ₉ O, R ₁ = CH ₃ CO, R ₂ = CH ₂ , R ₃ = R ₄ = CH ₃ )

41.5 g of N- (4-methylphenyl) -N ', N'-dimethylglycine- 6o 10 g of N- (2-butoxyphenyl) -N', N'-dimethylglycine-

amide are reacted with 40 g of acetic anhydride, amide are reacted with 50 g of acetic anhydride,

whereby 44 g of a compound with a m.p. = 129 whereby 7 g of a compound with a b.p. = 180

are obtained to 13O ⁰ C (from benzene-η-hexane). to 184 ° C at a pressure of 0.09 mm Hg

The yield is 87%.

Values for C ₁₃ H ₁₈ N ₂ O ₂ = 234.29: Calculated ... C 66.64, H 7.74, N 11.96%; found .... C 66.54, H 7.58, N 12.27%. Values for C ₁₆ H ₂₄ N ₂ O ₃ = 292.37: Calculated ... C 65.72, H 8.27, N 9.58%; found .... C 65.52, H 8.54, N 9.70%

Example 32

N-acetyl-N- (4-carbethoxyphenyl) -Ν ', Ν'-dimethylalaninamide

(R = 4-COOC ₂ H ₅ , R ₁ = CH ₃ CO, R ₂ = CH (CH ₃ ), R ₃ = R ₄ = CH ₃ )

5 g of N- (4-Carbäthoxyphenyl) -N ', N'-dimethylalaninamid are reacted with 1.6 g of acetyl chloride to give 3 g of a compound with a boiling. = 193-194 ^C' C at a pressure of 0.09 mm Hg obtained will. The yield is 69%

Values for C _1n H ₂₂ N ₂ O ₄ = 306.35: Calculated ... C 62.72, H 7.24, N 9.14%; found .... C 62.89, H 7.38, N 8.89%.

Example 33

N-acetyl-N- (2-carbethoxyphenyl) -Ν ', Ν'-dimethylalaninamide

(R = 2-COOC ₂ H ₅ , R ₁ = CH ₃ CO, R ₂ = CH (CH ₃ ), R ₃ = R ₄ = CH ₃ )

20 g N - (2-carbethoxyphenyO-Ν ', Ν'-dimethyl alaninamide are reacted with 8 g of acetyl chloride, whereby 8 g of a compound with a boiling point = 160 to 162 "C at a pressure of 0.02 mm Hg.

Values for C ₁₆ H ₂₂ N ₂ O ₄ = 306.35: Calculated ... C 62.72, H 7.24, N 9.14%; found .... C 61.27, H 7.58, N 9.06%.

Example 34

N-acetyl-N- (4-ethoxyphenyl) -N ', N'-diethylglycine amide

(R = 4-C ₂ H ₅ O, R ₁ = CH ₃ CO, R, = CH ,, R ₃ = R ₄ = C ₂ H ₅ )

10 g of N- (4-ethoxyphenyl) -N ', N'-diethy! Glycinamide are reacted with 5 g of acetyl chloride, whereby 3.5g of a compound with a bp = 180 to 182 "C at a pressure of 0.01 mm Hg.

Values for C ₁₆ H ₂₄ O ₃ N ₂ = 292.37: Calculated ... C 65.72, H 8.27, N 9.58%; found .... C 65.80, H 8.25, N 9.71%.

Example 35

N-acetyl-N- {4-a! Lyloxyphenyl) -N ', N'-dimethylglycine amide

(R = CH ₂ = CHCH ₂ O ₅ R ₁ = CH ₃ CO, "

R .. = CH ₂ , R ₃ = R ₄ = CH ₃ )

9 g of N- (4-allyloxyphenyl) -N ', N'-dimethylglycine amide are reacted with 5.5 g of acetic anhydride,

ίο making 5.5 g of a compound with one Bp = 190 C at a pressure of 1 mm Hg. The yield is 51%. Man believes that the low yield of this reaction is due to molecular rearrangement in the Distillation is caused.

Values door C ₁₅ H ₂₀ N ₂ O ₃ = 276.33:
Calculated ... C 65.19, H 7.30, N 10.14%;
found .... C 64.83, H 7.43, N 10.47%.

.

Claims (1)

Claim: Process for making N-substituted amino acid derivatives the general formula N-RXON in which R is hydrogen, alkyl, alkoxy, alkyl-substituted carboxyl, halogen or hydroxyl, R _{1 is} acyl, alkyl-substituted aminoacyl, _{haloacyl or carbamyl, R 2 is} alkylene, R _{3 is} hydrogen or alkyl and R _{4 is} alkyl, characterized in that in per se as is known, the hydrogen atom connected to the nitrogen atom N ^{+ of} the compound of the general formula N ⁺ -R ₂ CON replaced by a group corresponding to the above definition for R _1.