JPH02138160A - N-substituted amide compound - Google Patents

Abstract

NEW MATERIAL: A compd. represented by formula I (wherein R¹ is a lower alkyl; R² is H, methyl or ethyl; X¹ is a lower alkoxy, a halogen, nitro or phenyl; and Y¹ is H or a lower alkyl).

EXAMPLE: N-(4-Fluorophenacyl)-N-methylformamide.

USE: A liver disease preventing and treating agent.

PROCESS: An α-halogenoacetophenone compd. represented by formula II (X is a halogen) is reacted with an amine represented by the formula R¹NH₂ to obtain an amino compd. represented by formula III. Reaction is performed by using a solvent such as an ethanol or ethanol. Subsequently, this compd. is acylated by using an acid anhydride represented by formula IV (R⁵ is R² other than H) or formula V or an acid halide as an acylating agent to obtain the compd. represented by formula I. It is favorable to perform reaction in the presence of a base such as Na₂CO₃ or K₂CO₃.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel N-substituted amide compounds useful in the field of medicine, particularly in the prevention and treatment of liver diseases.

Conventional technology The liver is damaged acutely or chronically due to various causes such as viruses, alcohol, nutritional deficiencies, and hepatic circulation disorders.
It causes liver diseases such as fatty liver, jaundice, and cirrhosis. Recently, malotylate and the like have been reported as therapeutic agents for these liver diseases. However, symptomatic treatments such as dietary therapy, steroid drugs,
Truly effective treatments and therapeutic agents, including drug therapy using immunostimulants and the like, have not yet been found.

Problems to be Solved by the Invention As mentioned above, there is still no satisfactory solution for liver diseases, especially those that are prolonged or chronic.

Furthermore, drug therapy using steroids, immunostimulants, etc. has the problem of serious side effects.

Means for Solving the Problems The present inventors synthesized various N-substituted amide compounds and investigated their effects in order to develop therapeutic agents for liver diseases that solved the above problems. As a result, the present inventors discovered that the compound of the present invention exhibits a remarkable hepatic damage-suppressing effect in an experimental liver damage model, and completed the present invention.

The present invention is based on the following formula I (wherein R1 represents a lower alkyl group, R1 represents a hydrogen atom, a methyl group, or an ethyl group, Xl represents a lower alkoxy group, a halogen atom, a nitro group, or a phenyl group, and Y ' represents a hydrogen atom or a lower alkyl group).

In addition, another aspect of the present invention is the following formula ~17 alkenyl group or a lower alkenyl group substituted with a phenyl group, Xt represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, or a halogen atom, Y2 represents a hydrogen atom or a lower alkyl group, and n is 1 or 2 ) is an N-substituted amide compound represented by

In the present invention, a lower alkyl group has 1 to 4 carbon atoms.
is an alkyl group, which may be linear or branched. These include, for example, a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, and the like. The alkyl group having 3 to 18 carbon atoms may be linear or branched, and examples thereof include methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group. , normal pentyl group,
These include normal hexyl group, normal heptyl group, normal decyl group, normal hexadecyl group, normal heptadecyl group, etc. A lower alkoxy group has 1 carbon atom.
-4 alkoxy groups, such as methoxy, ethoxy and propoxy groups. Number of carbon atoms: 2~
The alkenyl group of 17 may be linear or branched, and examples thereof include vinyl group, 1-propenyl group, 2-butenyl group, 8,11.14-hebutade group, etc. Such as trienyl group. The halogen atom represented by xl or xl is a fluorine, chlorine or bromine atom.

The compound of the present invention can be produced, for example, by the method shown below.

Method 1: (1) An α-halogenoacetophenone compound represented by the following formula (wherein, Xl and Y' have the same meanings as above, and X is a halogen atom) is mixed with (2) R'NH,IV ( (wherein, R1 has the same meaning as defined above) to form an amino compound of formula (1) (wherein, X'Y' and R' have the same meaning as defined above). As the solvent for this reaction, alcohol solvents such as methanol and ethanol, ether solvents such as ethyl ether, dioxane, and tetrahydrofuran, as well as acetone and benzene can be used. The reaction temperature is from -10°C to the boiling point temperature of the solvent, preferably from O'C to room temperature.The reaction is completed instantaneously, but may be stirred for about 0.5 to 2 hours.

2) Next, the obtained amino form of formula V is converted into formula
CO)! O or R'COX VI (wherein,
The compound of the present invention of formula I can be obtained by an acylation method using an acid anhydride or an acid halide as an acylating agent. can.

In this reaction, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, ethyl ether, benzene,
Toluene or the like can be used as a solvent. Also,
This reaction is conveniently carried out in the presence of a base. These bases include sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, pyridine, triethylamine, and the like.

The reaction temperature, reaction time, etc. may be the same as those for a normal acylation method.

The compound of the present invention of formula I in which R1 is a hydrogen atom can be produced in the same manner as in (2) above, using acetic formic anhydride in place of the compound of formula (1).

(2') Instead of the acid anhydride or acid halide in (2), a carboxylic acid represented by the formula % (in the formula, R' is <R'' excluding a hydrogen atom) is used, and a dehydrating agent ( For example, the compound of the present invention can also be obtained by reacting in the presence of dicyclohexylcarbodiimide, etc.).

Ether, tetrahydrofuran, dioxane, dichloromethane, pyridine, etc. are used as the reaction solvent.

On the other hand, the compound of the formula (1) of the present invention can be produced in the same manner as in Method 1 using the corresponding starting compounds, acid anhydrides, acid halides, carboxylic acids, etc.

Method 2: The compound of the present invention can also be produced by the method shown below. The method for producing the compound of the present invention of formula (1) will be described below, but the same applies to the method of producing the compound of the present invention of formula (2).

That is, the compound of the present invention of formula I has the following formula (i) (where x
l yl and R1 have the same meanings as above. ) is reacted with the same acid halide (R'C0X) as in Method 1 in the presence of a base to produce an amide of formula (1) (wherein, xi yl R1 and Rs have the same meanings as above). The compound of the present invention can be produced by converting the compound into a compound and then oxidizing it. In this reaction, bases include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, pyridine, triethylamine, and the like. The reaction temperature is from -10°C to the boiling point temperature of the solvent, preferably from 0°C to room temperature. The reaction is completed in about 1 hour.

Oxidation may be carried out by a conventional method of oxidizing alcohol to ketone. These include, for example, chromic acid-pyridine oxidation, dimethyl sulfoxide-acetic anhydride oxidation, and the like.

In addition, in the compound of the present invention of formula (■), X! A compound in which is a lower alkoxy group can be obtained by further reacting a compound of the present invention in which xt is a hydroxyl group with a lower alkyl halide (eg, methyl iodide, etc.) in the presence of a base such as potassium carbonate.

Effects of the Invention The compound of the present invention significantly suppressed serum GPT activity in a D-galactosamine-induced experimental liver injury model (rat), and exhibited a significant liver injury-suppressing effect. Therefore, the compounds of the present invention are useful as preventive or therapeutic agents for liver diseases.

The usefulness of the compounds of the present invention will be shown below in Test Examples.

Test Example 1 [Effect on D-galactosamine-induced acute liver injury] Male Wistar rats (8 weeks old, weight 200 g)
) Six animals were made into one group and used for the test. The compounds obtained in the examples were suspended in a 0.2% sodium carboxymethylcellulose aqueous solution, and the 0.2% sodium carboxymethylcellulose aqueous solution was used as a control group. Test drug 200mg/
kg body weight was administered orally to individual animals, followed 30 minutes later by intraperitoneal administration of D-galactosamine 300 mg/kg body weight. After being left for 24 hours, blood was collected from the −0 animal under ether anesthesia, and after centrifugation, the serum GPT value was measured. The inhibition rate (%) was calculated from the serum GPT values of the test drug and the control group.

The results are shown in Table 1.

Table 1 (note) a; N-methyl-N-phenacylbutanamide b:
N-(2-methoxyphenacyl)-N-methylacetamide c; N-(4-fluorophenacyl)-N-methylhexanamide d; N-(4-fluorophenacyl)-N-methylpentanamide JL EXAMPLES Next, the present invention will be explained in more detail with reference to Examples.

Example I Preparation of N-(4-fluorophenacyl)-N-methylformamide To 10 g of potassium hydroxide was added 1 part of a 40% aqueous methylamine solution.
Drop 0ml to generate methylamine as a gas,
A solution of 5 g (0,029 mol) of 4-fluorophenacyl chloride in 40 ml of dioxane was bubbled through at 30°C. After stirring for an additional hour at room temperature, excess methylamine was removed under reduced pressure and 7.7 units (0,087 mol) of acetic formic anhydride were added.
was added dropwise at 10-15°C. The reaction solution was brought to room temperature and left overnight, then poured into ice water and extracted with dichloromethane.
The extract was washed with water, dried, and concentrated, and the resulting oily substance was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 2.6 g of the title compound.

m, p, 101-103°C (recrystallized from n-hexane-ethyl acetate) NMR (
CDC4)3) δ (ppm): 3.08 (3H,
s), 4.75 (2tLs).

7, 1-7.3 (2H, m), 7.96-8.07
(2H, m>.

8, 22 (IH, s> M S <rs/e>: 195 (M''), 44 (base) The following compounds were obtained by the same method.

N-(2-methoxyphenacyl)-N-methylborumamide m, p, 58-60°C (recrystallized from n-hexane-ethyl acetate) NMR(
CDCρ3) S (ppm): 3,05 (3H,s)
, 3.95(3H,s) , 4.74(2H,s
).

6.96-7.12 (2H, m), 7.48-7.
62 (LH, m).

7, 84-7.94 (LH, m), 8.21 (LH
, s) MS (m/e): 207 (M”), 135 (base) N-(4-bromophenacyl)-N-methylformamide m, p, 80.5-82°C (recrystallized from ether) N M R(CDCρ3) ippm): 3,07<
38. s), 4.75 (28, s).

7.62-7.74 (2H, m>, 7.80-7.
90 (2H, m).

8.23(1)1. ! 9) MS (m/e): 255 (M”), 72 (base) Example 2 40% methylamine aqueous solution 1 in 15 g of potassium hydroxide
5ml was added dropwise to generate methylamine as a gas,
7.5 g of 3-methoxyphenacyl bromide (32,8
millimoles) of dioxane in 60 mQ at 10°C. After stirring for a further hour at room temperature, excess methylamine was removed under reduced pressure, 10.4 g (131.2 mmol) of pyridine were added and 10.0 g (98.4 mmol) of acetic anhydride was added at 5 °C. dripped. The reaction solution was returned to room temperature and left overnight, then poured into ice water and extracted with chloroform. The extract was washed with water, dried, and concentrated. The resulting oil was subjected to silica gel column chromatography (eluent: ethyl acetate).
Purification was performed to obtain 2.17 g of the title compound.

NMR(CDCj?3) δ(ppm):2,
19 (3H, s), 3.09 (3H, s), 3
．． 85 (38, s).

4.83 (2H, s), 7.1~7.6 (4H, m
) MS (m/e): 221 (M"), 135 (base) The following compound was obtained by a similar method.

N-<2-methoxyphenacyl)-N-methylacetamide b, p, 160-163°C 70.43 mml (gN
M R (CDCΩ3> δ (ppm): 2.17 (3
H,s), 3.08(3)1. s), 3.92
(3H, s).

4,76(2H,s), 6.9~7.2(2H,m
).

7, 4~? , 7(1)1. m), 7.8-8.
0 (IH, m) M S (m/e): 221 (M”), 135 (base) N-(4-methoxyphenacyl)-N-methylacetamide N M R (CD (ff3 > S (ppm) :
2, 19 (3H, s), 3.10 (3H, s),
3.87 (3H, s).

4,80(2H,s), 6.9~7.1(2H,m
).

7, 9-8.1 (28, m) MS (m/e): 221 (M”), 135 (base) N-(4-fluorophenacyl)-N-methylacetamide m, p, 102-103 °C (recrystallized from n-hexane-ethyl acetate) NMR (
CD (J'3) l; (ppm): 2, 19 (3
H,s), 3.10(3H,s), 4.81(
2H,s).

7.1-7.3 (2H, m), 7.95-8.05
(2H, m) MS (m/e): 209 (M”), 86 (base) N-(4-chlorophenacyl)-N-methylacetamide m, p, 118.5-120.5°C (n - Recrystallized from hexane-ethyl acetate) NMR (CDCΩ3)
8 (ppm): 2, 19 (3H, s), 3
．． 10 (3H, s), 4.80 (2H, s).

7.4-7.6 (2H, m), 7.8-8.0 (2
H, m) MS (m/e): 225 (M”), 86 (base) N-(4-bromophenacyl)-N-methylacetamide m, p, 105.5-1075°C (n-hexane-ethyl acetate recrystallized from)NMR(
CDCI+3) δ (ppm): 2, 19 (3)
(,s), 3.10(3H,s>, 4.79(
2H,s).

7, 58-7.73 (2H, m), 7.79-7.
91 (2H, m) MS (m/e): 269 (M”), 44 (base) N-(4-nitrophenacyl)-N-methylacetamide ff1., 125-128°C (n-hexane- recrystallized from ethyl acetate)NMR(
CDCΩ3) S (ppm): 2.21 (3H, s)
, 3.15(3H,s) , 4.84(
2H,s).

8.1-8.2 (2H, m), 8.3-8.4 (2
H, m) MS (m/e): 236 (M”), 44 (base) N-(4-phenylphenacyl)-N-methylacetamide m, p, 143-144.5°C (n-hexane- Recrystallized from ethyl acetate)N M
R (CDCR3) S (ppm): 2, 21
(3H,s), 3.14(3)1. s), 4.
88 (2B, s).

7, 3 to 8.1 (9H, m) MS (m/e): 267 (M"), 181 (base) Example 3 To 40 ml of a 5 mol dioxane solution of ethylamine, α
-Chloro-p-bromopropiophenone 5g (0,02
mol) was added at 5-10°C, followed by stirring at 10°C for 12 hours. After the reaction, concentrated hydrochloric acid was added at 10°C or lower to adjust the pH to 2, unreacted propiophenone was dissolved in ether and removed, and the precipitated white precipitate was collected by filtration and dried to give α-ethylamino-p. -bromopropiophenone hydrochloride 4.8
8 g was obtained.

The α-ethylamino-p-bromopropiophenone hydrochloride obtained above was dissolved in 10 mQ of water, and 40%
The pH was adjusted to 10 by adding sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with saturated brine, dried and concentrated to obtain 4.05 g of α-ethylamino-p-bromopropiophenone. After adding 5 ml of acetyl chloride to 1.0 g of α-ethylamino-p-bromopropiophenone and refluxing for 2 hours, the remaining acetyl chloride was distilled off, and the residue was poured into ice water and extracted with ether.

The ether layer was washed successively with 1.5N hydrochloric acid, a saturated aqueous sodium hydrogen oxide solution and saturated brine, dried and condensed, and the resulting solid was recrystallized from ethyl acetate-petroleum ether to yield the title compound. 237 g was obtained.

m, p, 104-106°C NMR (CDCI23) δ (p
pm): 1, 16 (3H, t), 1.47 (3H,
d), 2.20 (3H, s).

3, 16 (2H, q), 6.18 (18, q),
7.94 (2H, d).

8, 03 (2H, d) MS (m/e): 297 (M''), 72 (base) The following compound was obtained by the same method.

NMR(CDCI23)S(ppm):
1.28 (3H, d), 2.04 (3H, s),
2.76 (38,s).

6, 10 (LH, q>, 7.60 (2H, d),
7.88 (2H, d) MS (m/e): 284 (M”+1), 58 (base) Example 4 To 5 g of potassium hydroxide, 5 m of 40% methylamine aqueous solution
1 is added dropwise to generate methylamine as a gas, and α-
Bromo-O-methoxypropiophenone 2.2g (9
, 05 mmol) in 18 ml of dioxane.
Aerated at °C. After stirring for an additional hour at room temperature, excess methylamine was removed under reduced pressure and 2.86 g of pyridine (
36.2 mmol) and 2.77 g (2.3 mmol) of acetic anhydride were added.
7.2 mmol) was added dropwise at 5°C. The reaction solution was brought to room temperature and left overnight, then poured into ice water and extracted with chloroform. The extract was washed with water, dried, and concentrated. The resulting oily substance was purified by silica gel column chromatography (eluent: ethyl acetate). 1.13 g of the title compound was obtained.

NMR (CDCR3”) S (ppm): 1
, 36 (3H, d), 2.02 (3H, s),
2.88 (3H, s).

3.89 (3H, s>, 5.87 (18, q).

6, 91-7.10 (2H, m), 7.39-7.
64 (28, m) MS (m/e): 235 (M”), 58 (base) Example 5 α-
Chloro-p-bromopropiophenone 5.0 g (0
, 02 mol) was added at 5-10°C, followed by stirring for 6 hours. While cooling with water, hydrochloric acid was added to adjust the pH to 2, unreacted α-chloro-p-bromopropiophenone was removed by ether extraction, and the aqueous layer was concentrated to obtain 7 g of white crystals. This was recrystallized to obtain 4.5 g of α-methylamino-p-bromopropiophenone hydrochloride.

To a solution of 1.1 g (12.6 mmol) of n-butyric acid in 15 mQ of anhydrous dichloromethane was added 2.6 g of dicyclohexylgarbodiimide at 0 to 5°C and stirred for 30 minutes to obtain the α-methylamino-p obtained above. - A solution of 3.07 g (12.6 mmol) of bromopropiophenone hydrochloride in 5 mQ dichloromethane was added at 0-5 °C and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was added to 20 ml of water. The organic layer was washed successively with cooled 2N hydrochloric acid, saturated aqueous sodium hydrogen blown acid solution, and saturated brine, dried, and concentrated to obtain 3.5 g of an oily substance.This was subjected to silica gel column chromatography (eluent; ether: Petroleum ether = 1:1
) to obtain 1.98 g of the title compound.

NMR(CDC1)3>l; (ppat):
0,92(38,t), 1.34(3H,d),
1.68 (2H, dq).

2, 26 (2H, t), 2.76 (3H, s),
6.08 (IH, q).

7, 40-7.64 (3H, m), 7.84 (2H
, d) The following compounds were obtained by the same method.

N-<1-benzoylethyl)-N-methylbutanamide NMR(CD(J+3) f; (ppm)
:0,95(3H,t), 1.38(3H,d)
, 1.66 (2H, dq).

2, 26 (2H, t), 2.84 (3) 1. s)
, 6.26 (LH, q) 7, 40-7.72 (3H,
m>, 8.08 (2H, d) M S (m/e)
: 234(M”+1), 58(base)N-(1-
Benzoylethyl)-N-ethylbutanamide NMR(CDCff3)S (ppm):
0,90(3H,t), 1.06(3H,t),
1.38 (3H, d).

1.66 (2H, tq), 2.32 (2H, t
＞ , 3.24(21(, q＞.

6,02(IH,q), 7.32~7.60(3H,
m＞.

7, 92(2)1. d) M S (m/e): 247 (M"), 72 (base) Example 6 40% methylamine aqueous solution 2 in 20 g of potassium hydroxide
Drop 0ml to generate methylamine as a gas,
A solution of 5.0 g (22 mmol) of 2-bromobutyrophenone in 40 ml of dioxane was bubbled through at 10-15°C.

After stirring for a further 2 hours at room temperature, excess methylamine was removed under reduced pressure, 7.0 g (88 mmol) of pyridine was added, and 10.4 g (66 mmol) of n-butyric anhydride was added to 10
It was used at °C. The reaction solution was brought to room temperature and left overnight, then poured into ice water and extracted with chloroform. The extract was washed with water,
After drying and concentration, the resulting oily substance was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate-3:2) to obtain 3.4 g of the title compound.

b, p, 131~b NMR (CDCff3) δ (ppm): 0
．． 86-0.98 (6H, m), 1.56-2.0
6 (48, m).

2, 23-2.36 (2H, m), 2.78 (3H
,s).

6,09(18,dd), 7.36~7.62(3
H, m).

8,00-8.08 (2H, m) MS (m/e): 247 (M"), 72 (base) The following compound was obtained by the same method.

NMR (CDCff3) 8 (ppm):
0.86 (3H, t), 1.36 (3H, d).

1, 46-1.72 (2H, m), 2.16-2.
40 (2H, m).

2.88 (3H, s), 3.88 (38, s),
5.81 (IH, q).

6.89~7.09 (2H, m), 7.37~
7.62 (2H, m) M S (m/e): 263 (M”), 58 (base) b, p, 1
33-135℃/1.1mmHgNMR(CDC
R3) 8 (ppm): 0, 93 (3H, t),
1.34 (3H, d), 1.66 (2H, m)
.

2, 29 (2H, m), 2.79 (3H, s),
6.16 (IH, q).

7, 06-7.20 (2H, m), 8.00-8.
(
ppm): 0, 89 (3H, t), 1.20-1.
46 (2H, m) 1, 35 (38, d), 1.49
~1.72(2H, m>2, 23~2.42(2G,
m>, 2.79 (3H, s) 6.18 (LH, q>
, 7.40-7.64 (3H, m) 7, 94-8.
04 (2H, m) M S (m/e): 247 (M"), 58 (base) Example 7 112.5 mQ of normal aqueous sodium hydroxide solution was added.

Further, 37.5 d of a 2N aqueous sodium hydroxide solution and 75 d of a chloroform solution containing 12.1 g (0.09 mol) of hexanoyl chloride were added dropwise, and the dropping rate was adjusted so that the additions were completed at the same time. Subsequently, it was stirred for 2 hours under water cooling, and
75 rd of normal hydrochloric acid was added, and the mixture was further stirred for 1 hour.

The precipitated solid was collected by filtration, washed with water, and then mixed with 95% ethanol:water (
2:1) to obtain 11.9 g of the title compound.

m, p, 113-114°C NMR (CDC#3) 8 (ppm): 0, 90 (
3H,t), 1.1-1.9(6H,m).

2,56(2H,q), 3.18(3H,s),
4.2 (28,br).

4,78(2H,s), 6.90-7.46(31
(, m) MS (m/e); 279 (M"), 44 (base) Example 8 16.32 g (0,075 mol) of atrenalone hydrochloride was added to 15 ml of chloroporm, and the atmosphere was replaced with nitrogen.
1.4 g of 2N-hexanoyl adrenalone at 2°C (
1.75 g (0,013 mol) of anhydrous potassium carbonate and 5 g (0,035 mol) of methyl iodide were added to a 15 mQ solution of 0,005 mol) in acetone, and the mixture was refluxed for 4.5 hours. After cooling, it is filtered, the filtrate is concentrated, the residue is dissolved in dichloromethane, the insoluble materials are removed by filtration, the filtrate is washed with water, dried, and concentrated. The obtained oily substance is recrystallized from a small amount of ether to obtain the title compound. 0.91 g was obtained.

m, p, 47-48℃ NMR (CDCp3)S (ppm): 0, 94 (
3H,s), 1.1-1.9(6H,m>.

2, 50 (2H, q>, 3.12 (3H, 2s)
, 4.00 (6H, d).

4.86 (2H, 2s), 6.98-7.64 (3
1,m) M S (m/e): 307 (M''), 44 (base) The following compound was obtained by the same method.

m, p, 104-105°C (recrystallized from ethanol-water) NMR (CDCp3) 8 (ppm): 1.00
(3H,t), 1.76(2H,m>, 2.5
0(2H,t).

3, 14 (3H, 2s), 4.00 (6H, d)
, 4.88 (2H, 2s).

7,00-7.70 (3H, m) MS (m/e): 279 (M”), 44 (base) Example 9 Ethoxyacetic acid 2.066 g (19,87 mmol)
4.09 g (19.87 mmol) of dicyclohexylcarbodiimide was added to the chloroborum 25ynQ solution under water cooling, and after stirring for 15 minutes, 2-hydroxy-N
-Methyl-2-phenylethylamine 3 g (19,
87 mmol) and stirred at room temperature for 1.5 hours. The reaction solution was filtered, and the filtrate was washed successively with 3N hydrochloric acid, saturated aqueous sodium carbonate solution, and saturated brine, dried, and concentrated to obtain 5.12 g of a white solid.

This was recrystallized from ether to yield N-(β-hydroxyphenethyl)-N-methyl-2-ethoxyacetamide 3.11
I got g.

3.11 g of ethoxyacetamide obtained above (13,
1 mmol), dimethyl sulfoxide (35 mQ), and acetic anhydride were mixed and allowed to stand at room temperature for 48 hours. The reaction solution was poured into ice water and extracted with ether. The ether layer was washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated, and the residue was subjected to silica gel column chromatography (after eluting dimethyl sulfoxide with petroleum ether, Purification by eluting with ether) gave 1.4 g of the title compound.

NMR(CD(J13)S(I)Pm):
1.04, 1.30 (3H, 2t), 3.07.3
．． 16 (3H, 2s).

3.48.3.67 (2H, 2q), 4.12.4
．． 32 (2H, 2s).

4.86.4.94 (21(,2s), 7.60~
8.02<514. m).

The following compounds were obtained in a similar manner.

N-methyl-N-phenacylbutanamide m, p, 7
2 to 73°C (recrystallized from ether) NMR (CDCR3) s (ppm): 1.00
(3H, t), 1.74 (2H, m), 2.46<2H
,t＞.

3.04, 3.12 (3H, 2s), 4.81.4
．． 88 (2H, 2s).

7.60-8.04 (5H, m) N-methyl-N-phenacyl-5ee-pentanamide NMR (CDCN3) δ (ppm): 0, 92
(3H, t), 1.16 (3H, d), 1.6
0(2t(,m).

2, 72 (LH, m>, 3.12 (3H, s).

4, 77, 4.80 (2H, 2s), 7.46~7
．． 88 (5H, m) N-methyl-N-phenacylcrotonamide m, p, 99-100°C (recrystallized from ether) NMR (CDCR3) S (ppm): 1, 92 (
38, 2d), 3.08.3.20 (3H, 2s)
.

4,92(2H,s), 6.40(LH,d) 7
．． 00(LH,m).

7, 60-8.04 (5) 1. m) Example 1O Preparation of N-methyl-N-phenacylcinnamic acid amide 2-human bioxyN-methyl-2-phenylethylamine Ig (6,s mmol) was dissolved in 20 mQ of benzene.
2 g (14.5 mmol) of anhydrous reconstituted potassium dissolved in
, cinnamic acid chloride (6,6 mmol) in benzene 5m
Q solution was added, and the mixture was stirred at room temperature for 2 hours, and then refluxed for an additional 2 hours. After cooling, the reaction solution was washed with water, dried, and concentrated to obtain 1.83 g of a pale yellow solid. This was subjected to silica gel column chromatography (eluent: chloroform: methanol =
98.5:1.5) and further recrystallized from benzene to obtain 1.1 g of N-(β-hydroxyphenethyl)-N-methylcinnamic acid amide.

m, p, 135-137℃ Prepare 8 g (80 mmol) of chromic anhydride in 8 m of water in advance.
This solution was added to 72 ml of pyridine under cooling and mixed uniformly, and this solution was added to 72 ml of pyridine.
It was added to a solution of Og (14.2 mmol) in 20 ml of pyridine and stirred at room temperature for 12 hours. 200 ml of water was added and extracted with ether, the extract was dried and concentrated, and the residue was recrystallized from benzene to obtain the title compound 2. 6g was obtained.

m, p, 133-137°C NMR (CDCR3) δ (ppm): 3.23 (3
t(,s), 4.92(28,s),
6.94 (IH, d).

7, 68 (LH, d), 7.20-8.04 (IO
H, m) MS (m/e): 279 (M"), 131 (base) Example 11 40% methylamine aqueous solution 2 in 25 g of potassium hydroxide
Drop 0 mQ to generate methylamine as a gas,
2-fluorophenacyl chloride 12.9g (0,0
75 mol) 30-35 to Nosioxa/100+uQ solution
Aerated at °C. After stirring for a further 2 hours at room temperature, excess methylamine was removed under reduced pressure and 17.8 g of pyridine (
0,225 mol) and 27.9 g of n-valeric anhydride.
(0.15 mol) was added dropwise at 5°C. The reaction solution was returned to room temperature and left overnight, then poured into ice water and extracted with chloroform. The extract was washed with water, dried, and then concentrated. The resulting oily substance was subjected to silica gel column chromatography (eluent: n-hexane: Purification was performed using ethyl acetate (3:2) to obtain 10.8 g of the title compound.

b, p, 152-154℃/1, OmmHgN
M R (CDCR3) 8 (ppm): 0, 9
4 (3H, t), 1.2-1.5 (2H, m).

1,5-1.8 (2H, m), 2.45 (2H, t
).

3, 10 (3H, s), 4.80 (2H, s).

7, 1-7.3 (2H, m), 7.9-8.1 (2
H, m).

MS (m/e): 251 (M”), 123 (base) The following compounds were obtained in the same manner.

N-(4-fluorophenacyl)-N-methylhexanamide m, p, 71-73°C (recrystallized from n-hexane) NMR (CDCR3) 8 (ppm): 0,
82-1.02 (3H, m), 1.21-1.48
(4H, m).

1, 56-1.79 (2H, m), 2.44 (2H
,t).

3, 10 (3H, s), 4.80 (2H, s).

7, 09-7.18 (2H, m), 7.96-8.
09 (2H, m) MS (m/e): 265 (M"), 142 (base) N-(4-fluorophenacyl)-N-methylhebutanamide NMR (CDCff3) δ (ppm): 0 ,
78-1.78 (IIH, m), 2.45 (2H,
t).

3, 10 < 3H, s), 4.80 (2H, s).

7, 08-7.28 (2H, m), 7.96-8.
10(28,m)MS (m/e): 279(M”), 44(base)N-(2-methoxyphenacyl)-N-methylpentanamide NMR(CDCR3)S (ppm): 0,
94 (3H, t), 1.20-1.52 (2H, m
).

1.54-1.76 (2H, m), 2.44 (2H
,t).

3.09 (3H, s), 3.93 (3H, s)
, 4.77 (2H, s).

6, 94-7.16 (2H, m), 7.44-7.
64 (IH, m).

7, 84-7.94 (IH, m) M S (m/e): 263 (M"), 135 (base) N M
R(CDC4)3) S (ppm): 0, 94
(3H, t), 1.24-1.52 (2H, m)
.

1, 54-1.78 (2H, m), 2.46 (2H
,t＞.

3.11 (3H, s), 4.85 (2H, s).

7.42-7.70 (3H, m), 7.96-8.
04(2H,m)MS(m/e): 233(Ms, 105(base)N-methyl-N
-Phenacylhexanamide NMR (CDCff3
) S (ppm): 0, 80-1.02 (3H,
m), 1.18-1.47 (4H, m).

1, 55-1.84 (2H, m), 2.45 (2H
,t).

3, 11 (31 (, s), 4.86 (2H, s)
.

7, 40-7.72 (3H, m), 7.93-8.
14(2H,m)MS (m/e): 247(M”), 142(base)N-methyl-
N-Phenacylhebutanamide NMR (CD(J)
3) δ (ppm): 0, 80 to 1.78 (11H
, m), 2.45 (2H, t).

3.10 (3H, s), 4.85 (2H, s).

7, 42-7.73 (2H, m>, 7.94-8.
06 (2H, m) M S (m/e): 261 (M"), 44 (base) Example 12 40% methylamine aqueous solution 2 in 25 g of potassium hydroxide
Drop 0 mQ to generate methylamine as a gas,
4-fluorophenacyl chloride 12.1g (0,0
7 mol) dioxane 100TnQ solution at 25-30°
Aerated with C. - After stirring for an additional hour at room temperature, excess methylamine was removed under reduced pressure and triethylamine 21.
2 g (0.21 mol) was added thereto, and 25.1 g (0.083 mol) of stearic acid chloride was added dropwise at 5°C. The reaction solution was returned to room temperature and left overnight, then poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated. The resulting oily substance was subjected to silica gel column chromatography (eluent: n-hexane-acetic acid). Ethyl = 3:
2) to obtain 15.4 g of the title compound.

m, p, 69-70°C (recrystallized from n-hexane) NMR (CDC1)3') S (ppffl
): 0, 8 to 0.94 (3H, m), 1.1-1
．． 4 (28H, m).

1,5-1.75 (2H, m), 2.24 (2H,
t).

3.11<3H,s), 4.80(2H,s).

7, 06-7.24 (28, m), 7.94-8.
08 (2H, m) MS (m/e): 433 (M''), 44 (base) The following compounds were obtained in the same manner.

7.12-7.25<2)1. m), 7.99
~8.12 (2L ni) M S (m/e): 249 (M”), 83 (base) NMR (CD
C4) 3) δ (ppm): 2.37 to 2.62 (
4tt, m), 3.11 (3H, s).

4.82 (214,s), 4.96-5.17 (2
Lm＞.

5.82-6.02 (1B, m), 7.08-7.
24 (2H, m).

7.96-8.10 (2H, m) MS (m/e): 249 (M"), 44 (base) m, p, 6
0 to 62°C (recrystallized from n-hexane-ethyl acetate) NMR (
CDCQ3) δ (ppm): 1, 10 (31, t
), 2.20-2.38 (2H, m).

3, 18 (3H, s), 4.86 (2H, 9).

6, 30-6.44 (IH, m), 6°94-7.
10(1)1. m).

N M R (CDCρ3) S <ppm)
:0,98(3)1. t>, 1.2 to 1.5 (8
1(, m>.

1.5-1.5 (2H, m), 2.0-2.2 (4
H, m).

2,44(2H,t), 2.7~2.9(4H,m
).

3.10 (3H, s), 4.81 (2H, s).

5, 2-5.5 (6H, m), 7.1-7.24 (
2H, m).

7, 97-8.10 (2H, m).

MS (m/e): 427 (M”), 168 (base)

Claims (2)

[Claims] (1) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a lower alkyl group, R^2 represents a hydrogen atom, methyl group, or ethyl group, and X^1 represents a lower alkoxy group. , a halogen atom, a nitro group, or a phenyl group, and Y^1 represents a hydrogen atom or a lower alkyl group. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 represents a lower alkyl group, and R^4 represents a lower alkyl group substituted with an alkyl group having 3 to 18 carbon atoms or a lower alkoxy group. It represents an alkyl group, an alkenyl group having 2 to 17 carbon atoms, or a lower alkenyl group substituted with a phenyl group, X^2 represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, or a halogen atom, and Y^2 represents a hydrogen atom or (represents a lower alkyl group, and n represents 1 or 2).