JPH09157237A - N-lower alkyl-2-amino-3,3-dimethoxy-propanamide and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new N-lower alkyl-2-amino-3,3-dimethoxy-propanamide useful as a synthetic intermediate for heterocyclic compounds, etc. SOLUTION: This invention relates to an N-lower alkyl-2-amino-3,3-dimethoxy- propanamide expressed by formula I (R is a lower alkyl), e.g. N-n-pentyl-2- amino-3,3-dimethoxy-propanamide of formula II. The compound of formula I can be produced by reacting 2-bromo-3,3-dimethoxy-propionic acid methyl ester of formula III with a lower alkylamine and treating the produced N-lower alkyl-2-bromo-3,3-dimethoxy-propionamide with ammonia. The compound of formula I produced by this process may be separated and purified in the form of. e.g. oxalic acid salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to N-lower alkyl-
The present invention relates to 2-amino-3,3-dimethoxy-propanamide, a method for producing the same, and a method for producing a synthetic intermediate thereof. N-lower alkyl-2-amino-3,3-dimethoxy-propanamide is useful as a synthetic intermediate for heterocyclic compounds and the like.

[0002]

2. Description of the Related Art
As a method of synthesizing an amino-3,3-dialkoxy-propion derivative, for example, 2-amino-3,3-diethoxy-propionic acid (2-chloro-3,3-diethoxy-propionic acid aminated with aqueous ammonia ( Buternandt, Z,
physiol. Chem. 283 , 213 (1948)), N-
Formylglycine ethyl ester and ethyl formate are reacted in the presence of sodium methylate to synthesize ethyl 2-formamino-3-oxopropionate (Reuben G. et al.
Jones, J. Am. Chem. Soc. 71, 646 (194
9)) is known. Also 2-amino-
A method of reacting ethyl 3,3-diethoxy-propionate with hydrazine to synthesize 2-amino-3,3-diethoxy-propionic acid hydrazide (Adkins. J. Am.
Chem. Soc. 79 , 4544, 4554 (1957)) is also known.

The present inventors have used N-lower alkyl-2-amino-, which is useful as a synthetic intermediate for heterocyclic compounds and the like.
As a result of various studies on synthetic methods of 3,3-dimethoxy-propanamide, methyl 2-bromo-3,3-dimethoxy-propionate, which is easily obtained by bromination of methyl 3-methoxyacrylate, was used as a starting material, and N- We succeeded in producing N-lower alkyl-2-amino-3,3-dimethoxy-propanamide through lower alkyl-2-bromo-3,3-dimethoxy-propanamide.

That is, there is a difference in the reactivity of the lower alkylamine with respect to the bromine and ester groups of methyl 2-bromo-3,3-dimethoxy-propionate, that is,
It has been found that lower alkyl amines preferentially react with ester groups. The present invention has been completed based on such findings. Then, N-lower alkyl-2-bromo-3,3-dimethoxy-propanamide was heated with concentrated aqueous ammonia to obtain N-lower alkyl-2-amino-3,3-dimethoxy-propanamide.

[0005]

[Means for Solving the Problems] The following general formula:

Embedded image (Wherein R represents a lower alkyl group), N-lower alkyl-2-amino-3,3-dimethoxy-propanamide, and methyl 2-bromo-3,3-dimethoxy-propionate and lower alkyl Method for producing N-lower alkyl-2-amino-3,3-dimethoxy-propanamide and synthetic intermediate, N-lower alkyl-2-bromo, characterized by reacting amine and then aminating with ammonia The present invention provides a method for producing -3,3-dimethoxy-propanamide.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Lower alkyl or lower alkyl of lower alkylamine means a saturated linear or branched hydrocarbon residue having 1 to 6 carbon atoms, preferably 3 to 5 carbon atoms. . For example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, n-hexyl and the like are included. The lower alkylamine is preferably pentylamine, butylamine or propylamine.

For the description of the raw material of the present invention, 2-bromo-
Although described as the methyl ester of 3,3-dimethoxy-propionic acid, it may be the ethyl ester. Preferred is methyl ester. 2-bromo-
Methyl 3,3-dimethoxy-propionate can be easily synthesized by reacting methyl 3-methoxy-acrylate with bromine and methanol.

The reaction of methyl 2-bromo-3,3-dimethoxy-propionate with a lower alkylamine is carried out in the presence or absence of a solvent at 10 ° C to 50 ° C, more preferably 10 to 20 ° C, most preferably React at around 20 ° C. Examples of the solvent include hydrocarbons such as benzene and toluene, but it is preferable to react in the absence of solvent. The reaction time is 16 hours or more. After completion of the reaction, water is added for extraction and concentration to obtain crude N-lower alkyl-2-bromo-3,3-dimethoxy-propanamide. It is purified by recrystallization from an organic solvent such as hydrocarbon.

Further, N-lower alkyl-2-bromo-
Amination of 3,3-dimethoxy-propanamide with aqueous ammonia was carried out in an autoclave at 5 to 10 kg / cm ² ,
Preferably, the bath temperature is 100 to 13 under atmospheric pressure of 7 to 9 kg / cm ^2.
The reaction temperature at 0 ° C is 90 to 130 ° C, preferably 100 to 1
The reaction can be performed at 20 ° C., most preferably around 110 ° C., with a reaction time of 4.5 hours or more. After completion of the reaction, extraction with an organic solvent such as toluene and concentration are performed to obtain an N-lower alkyl-2-amino-3,3-dimethoxy-propanamide oily substance. The obtained oily substance is separated and purified in the form of, for example, oxalate.

[0010]

【Example】

Example 1 Nn-pentyl-2-bromo-3,3-dimethoxy-
Synthesis of propanamide (3a)

Embedded image Methyl 2-bromo-3,3-dimethoxy-propionate
(2) 11.4 g (0.05 mol) of n-pentylamine 22.
Add 0 g (0.25 mol) slowly, taking care of the exotherm (cool with ice if necessary). The solution becomes yellowish when stirred overnight at room temperature. 100 ml of toluene and 50 ml of water are added to the reaction solution to separate the layers, and the organic layer is washed with dilute hydrochloric acid.
Also at this time, pay attention to the heat generation, and perform a plurality of washing operations until the pH of the washing solution becomes weakly acidic (total 6N hydrochloric acid 40 ml + water 200 ml was used). It is washed with a dilute NaHCO ₃ solution to make the pH neutral, washed once with saturated NaHCO ₃ water, and dried with mirabilite. A yellow oil was obtained by concentrated degassing and solidified by standing overnight to give 11.7 g of crude product of 3a.
Yield 82.6% Recrystallization from a mixed solvent of 10 ml of toluene and 30 ml of hexane gave 7.6 g of purified 3a. Recovery rate 6
5.0% Nn-pentyl-2-bromo-3,3-dimethoxy-
Propanamide (3a) slightly yellowish white crystalline powder mp51-53.5 ° C IR (KBr, cm ^-1 ) 1651,1568,1119,10
67 NMR CDCl ₃ , δ (ppm); 0.67-1.77 (9 H, m),
3.20-3.40 (2H + 6H, q like + d like) *, 4.
21 (1H, d, J = 6Hz), 4.57 (1H, d, J = 6Hz),
6.05 (1H, brs) * ... 2H of carbon bonded to N of amide group and 6H of methoxy group overlap.

Example 2 Synthesis of Nn-butyl-2-bromo-3,3-dimethoxy-propanamide (3b)

Embedded image Methyl 2-bromo-3,3-dimethoxy-propionate
(2) 11.4 g (0.05 mol) to n-butylamine 18.3 g
(0.25 mol) is added slowly and stirred at room temperature. A little heat is generated due to the progress of the reaction and the solution becomes slightly yellow. After stirring overnight, 100 ml of toluene and 50 ml of water are added to the reaction solution to separate the layers, and the organic layer is washed with diluted hydrochloric acid. At this time, pay attention to heat generation and wash several times until the pH of the washing liquid (water layer) becomes weakly acidic.
(A total of 30 ml of 6N hydrochloric acid and 200 ml of water were used).
It is washed with a dilute NaHCO ₃ solution to make the pH neutral, and finally washed with saturated NaHCO ₃ water and dried with sodium sulfate. A light yellow oil was obtained upon concentration, but solidified after standing for a while to give 10.6 g of crude product 3b. Yield 78.7% Recrystallized from a mixed solvent of 10 ml of toluene and 30 ml of hexane and dried at 60 ° C to obtain 9.4 g of purified 3b. Recovery rate 88.7% Nn-butyl-2-bromo-3,3-dimethoxy-propanamide (3b) pale yellowish white crystalline powder mp 78.5-79.5 ° C IR (KBr, cm ^-1) ) 1651,1572,1134,10
69 NMR CDCl ₃ , δ (ppm); 0.70 to 1.70 (7 H, m),
3.23 + 3.53 (2H + 6H, q like + d like) *, 4.
23 (1H, d, J = 5Hz), 4.58 (1H, d, J = 5Hz),
6.38 (1H, brs) * ... 2H of carbon bonded to N of amide group and 6H of methoxy group overlap.

Example 3 Nn-propyl-2-bromo-3,3-dimethoxy-
Synthesis of propanamide (3c)

Embedded image Methyl 2-bromo-3,3-dimethoxy-propionate
(2) 14.3 g (0.05 mol) of n-propylamine 14.
Slowly add 4 g (0.24 mol) and stir at room temperature overnight (n
-A little heat is generated when propylamine is added). 100 ml of toluene and 50 ml of water are added to the reaction solution to separate the layers, and the organic layer is washed with dilute hydrochloric acid. At this time, pay attention to heat generation, and wash liquid (water layer)
Wash several times until pH becomes slightly acidic (total 6N hydrochloric acid 2
5 ml and 150 ml water were used). The pH is returned to neutral by washing with a dilute aqueous solution of NaHCO ₃ , washed with saturated aqueous solution of NaCl, and then dried with sodium sulfate. After concentrating and allowing to stand for a while, 7.1 g of crude 3c was obtained. Yield 56.1% Recrystallized from 8 ml of toluene + 21 ml of hexane and dried at 60 ° C. to obtain 6.7 g of purified 3c. Recovery rate 94.4% Nn-propyl-2-bromo-3,3-dimethoxy-
Propanamide (3c) slightly yellowish white crystalline powder mp 80.0-81.0 ° C IR (KBr, cm ^-1 ) 1651,1568,1124,10
59 NMR CDCl ₃ , δ (ppm); 0.97 (3H, t like), 1.
30-1.87 (2H, m), 3.21-3.46 (2H + 6H,
q like + d like) *, 4.27 (1H, d, J = 5Hz), 4.6
1 (1H, d, J = 5Hz), 6.60 (1H, brs) * ... 2H of carbon bonded to N of amide group and 6H of methoxy group overlap.

[Chemical 6] _{R: -CH 2 CH 2 CH 2} CH 2 CH 3 3a: -CH 2 CH 2 CH 2 CH 3 3b: -CH 2 CH 2 CH 3 3c

Example 4 Nn-pentyl-2-amino-3,3-dimethoxy-
Synthesis of propanamide oxalate (4a)

Embedded image Nn-pentyl-2-bromo-3,3-dimethoxy-
8.5 g (0.03 mol) of propanamide (3a) and 70 ml of concentrated aqueous ammonia are charged into the autoclave (at this time, 3a is not soluble in concentrated aqueous ammonia). Close the container and bath temperature ~ 120 ° C
The mixture is heated and stirred for 4 hours and a half or more (the solution changes from a suspension state to a yellow solution and further to a reddish orange solution as the reaction proceeds). After allowing to cool to room temperature, 150 ml of toluene is added and the mixture is stirred to separate the layers. 50 ml of saturated NaCl water was added to the aqueous layer and the mixture was extracted with 50 ml of toluene × 2 times. After drying with mirabilite and concentration, 7.4 g of a red-orange oil of Nn-pentyl-2-amino-3,3-dimethoxy-propanamide (1a) was obtained. To this, 16 ml of THF, 220 ml of ethyl acetate and 2.7 g (0.03 mol) of oxalic anhydride are added, and the mixture is stirred at room temperature (at the start of the reaction, a yellow solution becomes cloudy after 30 minutes to 1 hour). After stirring overnight, the precipitate was collected by filtration to give crude Nn-pentyl-2-amino-3,3-dimethoxy-.
6.9 g of propanamide oxalate (4a) was obtained. Yield 74.6% 4a purified by recrystallization from 48 ml of acetonitrile.
3 g was obtained. Reconstitution yield 91.3% Nn-pentyl-2-amino-3,3-dimethoxy-
Propanamide oxalate (4a) white crystalline powder mp99-101 ° C IR (KBr, cm ^-1 ) 1672 (719,498) NMR DMSO-d ₆ , δ (ppm); 0.60-1.66 ( 9
H, m), 2.80 to 3.29 (2H + 6H, m + s) *, 3.80
(1H, d, J = 5Hz), 4.55 (1H, d, J = 5Hz), 8.3
2 (1H + 4H, brs) *** ... 2H of carbon bonded to N of amide group and 6H of methoxy group overlap. ** ... 1H of amide group and 4H of oxalic acid + amino group overlap.

Example 5 Synthesis of Nn-butyl-2-amino-3,3-dimethoxy-propanamide oxalate (4b)

Embedded image An autoclave was charged with 8.0 g (0.03 mol) of Nn-butyl-2-bromo-3,3-dimethoxy-propanamide (3b) and 70 ml of concentrated aqueous ammonia, and the mixture was sealed and the bath temperature was -1.
Heat and stir at 20 ° C. for 4 and a half hours or more. After allowing to cool to room temperature, 150 ml of toluene is added, and the mixture is stirred and separated. Saturated N in the water layer
Add 50 ml of aCl water and extract with 50 ml of toluene twice. After drying with Glauber's salt, concentration under reduced pressure and N-n-butyl-2-
8.6 g of a red-orange oil of amino-3,3-dimethoxy-propanamide (1b) are obtained. To this are added 16 ml of THF, 220 ml of ethyl acetate and 2.7 g (0.03 mol) of oxalic anhydride and stirred overnight. The precipitate was collected by filtration, air-dried and then dried by heating at 60 ° C. to obtain 6.3 g of crude 4b. Yield 71.3% Recrystallized from 38 ml of acetonitrile and purified to give 6.2 g of 4b.
I got Recovery rate 98.4% N-n-butyl-2-amino-3,3-dimethoxy-propanamide oxalate (4b) white crystalline powder mp108-111.5 ° C IR (KBr, cm ^-1) ) 1676, (719,496) NMR DMSO-d ₆ , δ (ppm); 0.63 to 1.63 (7
H, m), 2.83 to 3.27 (2H + 6H, m + s) *, 3.83
(1H, d, J = 6Hz), 4.58 (1H, d, J = 6Hz), 8.2
4 to 8.53 (4H + 1H, brs + m) *** ... 2H of carbon bonded to N of amide group and 6H of methoxy group are overlapped. ** ... 1H of amide group and 4H of oxalic acid + amino group overlap.

Example 6 Nn-propyl-2-amino-3,3-dimethoxy-
Synthesis of propanamide oxalate (4c)

Embedded image Nn-propyl-2-bromo-3,3-dimethoxy-
Propanamide 7.7g (0.03mol) and concentrated aqueous ammonia 7
Charge 0 ml into an autoclave, seal tightly and bath temperature ~ 120
Stir for 4 hours or more at ℃. After allowing to cool to room temperature, 150 ml of toluene is added, and the mixture is stirred and separated. 50 ml of saturated NaCl water was added to the aqueous layer, and the mixture was extracted with 50 ml of toluene × 2 times. After drying with mirabilite and concentration under reduced pressure, 3.2 g of a red-orange oil of Nn-propyl-2-amino-3,3-dimethoxy-propanamide (1c) was obtained. 5 ml of THF, 70 ml of ethyl acetate and 1.5 g (0.017 mol) of oxalic acid are added and stirred overnight. The precipitate was collected by filtration, air-dried and then heat-dried at 70 ° C to give a crude 4
c 3.1 g was obtained. Yield 36.9% Purified by recrystallization from 30 ml of acetonitrile 4c 1.4g
I got Reconstitution yield 45.2% Nn-propyl-2-amino-3,3-dimethoxy-
Propanamide oxalate (4c) slightly yellowish white crystalline powder mp 115-120 ° C IR (KBr, cm ^-1 ) 1676 (721,500) NMR DMSO-d ₆ , δ (ppm); 0.85 (3H, t like),
1.17 ~ 1.66 (2H, m), 2.90 ~ 3.32 (2H + 6
H, m + s) *, 3.76 (1H, d, J = 5Hz), 4.55 (1H, d,
J = 5Hz), 7.63 (4H, brs), 8.37 (1H, m) * ... 2H of the carbon bonded to N of the amide group and 6H of the methoxy group overlap.

Embedded image _{R: -CH 2 CH 2 CH 2} CH 2 CH 3 4a: -CH 2 CH 2 CH 2 CH 3 4b: -CH 2 CH 2 CH 3 4c

Example 7 Nn-pentyl-2-amino-3,3-dimethoxy-
Synthesis of propanamide (1a)

Embedded image Nn-pentyl-2-amino-3,3-dimethoxy-
Propanamide oxalate (4a) 4.6g (14.9m)
mol) in 10% NaOH aqueous solution, then 10%
Adjust to pH 10 with NaOH solution. 50 ml of toluene
It is extracted twice with 25 ml × 2 times and dried with Na ₂ SO ₄ . After filtration, the filtrate was concentrated and degassed to obtain 3.2 g of Nn-pentyl-2-amino-3,3-dimethoxy-propanamide (1a) as a pale yellow oily substance. Yield 98.4% Nn-pentyl-2-amino-3,3-dimethoxy-
Propanamide (1a) 60 MHz NMR CDCl ₂ , δ (ppm); 0.66-1.
56 (9H, m), 1.66 (2H, brs), 3.06 ~ 3.38 (2
H + 1H + 6H, m + s) *, 4.63 (1H, d like), 7.2
1 (1H, brs) * ... 2H of carbon bonded to N of amide group, 1H of carbon adjacent to amino group and 6H of methoxy group overlap.

Example 8 Synthesis of Nn-butyl-2-amino-3,3-dimethoxy-propanamide (1b) Nn-butyl-2-amino-3,3-dimethoxy-propanamide oxalic acid The salt (4b) was treated in the same manner as in Example 7 to obtain an oily Nn-butyl-2-amino-3,3-dimethoxy-propanamide (1b). 60 MHz CDCl ₂ , δ (ppm); 0.73 to 1.60
(7H, m), 1.66 (2H, brs), 3.03 to 3.37 (2H +
1H + 6H, m + s) *, 4.60 (1H, d like), 7.33 (1
H, brs) * ... 2H of the carbon bonded to N of the amide group, 1H of the carbon adjacent to the amino group and 6H of the methoxy group overlap.

Example 9 Synthesis of Nn-propyl-2-amino-3,3-dimethoxy-propanamide (1c) Nn-propyl-2-amino-3,3-dimethoxy-
The propanamide oxalate salt (4c) was treated in the same manner as in Example 7 to give an oily Nn-propyl-2-amino-3,3-
Dimethoxy-propanamide (1c) was obtained. 60 MHz CDCl ₂ , δ (ppm); 1.93 (3H, t, lik
e), 1.27 to 1.60 (2H, m), 3.03 to 3.45 (2H
+ 1H + 6H, m + s) *, 4.66 (1H, d like), 7.16
(1H, brs) * ... 2H of the carbon bonded to N of the amide group, 1H of the carbon adjacent to the amino group and 6H of the methoxy group overlap.

Embedded image _{R: -CH 2 CH 2 CH 2} CH 2 CH 3 1a: -CH 2 CH 2 CH 2 CH 3 1b: -CH 2 CH 2 CH 3 1c

Production Example Synthesis of 2-bromo-3,3-dimethoxy-methyl propionate (2)

Embedded image 150 ml of toluene was added to 57.0 g (0.49 mol) of methyl methoxyacrylate and cooled to 10 ° C or lower. 87.2 g (0.55 mol) of bromine was added dropwise while keeping the temperature below 10 ° C. After the dropping is completed in about 30 minutes, the mixture is further stirred for 30 minutes at 10 ° C. or lower. Then, the reaction solution is concentrated under reduced pressure to remove toluene and unreacted bromine to obtain a slightly yellow liquid residue. This liquid was ice-cooled, and methanol was added while keeping the temperature below 10 ° C.
Add 0 ml dropwise. After dropping in about 20 minutes, potassium carbonate 3
3.9 g (0.245 mol) was added and the mixture was stirred for 1 hour or longer to remove insoluble matter by filtration, and the filtrate was concentrated under reduced pressure. If there was a precipitate, it was filtered once more, the filtrate was concentrated, and the concentrated residue was distilled under reduced pressure (3 mmHg, 73 to 75 ° C.) to obtain 99.5 g of a transparent oil 2. Yield 89.4%

Claims (3)

[Claims] 1. The following general formula: (In the formula, R represents a lower alkyl group), N-lower alkyl-2-amino-3,3-dimethoxy-propanamide. 2. A compound of methyl 2-bromo-3,3-dimethoxy-propionate and a lower alkylamine are reacted to form N-
Lower alkyl-2-bromo-3,3-dimethoxy-propionamide is obtained, which is then treated with ammonia. N-lower alkyl-2-amino-3,3-
Method for producing dimethoxy-propanamide. 3. N-lower alkyl-2-bromo-3,3, characterized by reacting methyl 2-bromo-3,3-dimethoxy-propionate with a lower alkylamine.
-Method for producing dimethoxy-propanamide.