JPS6153252A - P-aminosalicylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is amino which may be substituted with lower alkoxy or lower alkyl R2-R4 are H or methyl; R5 and R6 are H, lower alkyl, lower alkenyl or together with adjacent N form a ring; n is 0 or 1) and its acid addition salt. EXAMPLE:2-Methoxy-4-piperidinoacetylaminobenzoic acid methyl ester. USE:It has excellent antiarrhythmic action and local anesthetic action, and is useful as a remedy and preventive for extra-sistole, ventricular arrhythmia, paroxysmal tachycardia, etc., and a preventive for arrhythmia accompanying to opration and anesthetic. PREPARATION:The compound of formula I can be prepared by reacting the halide of formula II (X is halogen) with the amine of formula III in the absence or presence of solvent (e.g. water, methanol, etc.) at room temperature -200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to a novel para-aminosalicylic acid derivative that has excellent antiarrhythmic effect and local anesthetic effect, and its pharmacologically acceptable salt. Definition of the Invention To be more specific, the present invention relates to the general formula (Seal) (wherein R1
R2+ R3 and R4 are the same or different and represent a hydrogen atom or a methyl group;
5 and R6 may be the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, or R5 and R6 may form a ring together with the nitrogen atom to which they are bonded, and n is 0 or Represents an integer of 1. ) and its pharmacologically acceptable acid addition salts.

In the general formula of the present invention, the lower alkoxy group represented by R1 is, for example, methoxy.

Examples of the amine 7 group in which an ethoxy, propoxy, butoxy group, etc. may be substituted with a lower alkyl group include amino, methylamino, dimethylamino, ethylamino, diethylamino; , for example, Amino.

Methylamino, dimethylamino, ethylamino.

diethylamino, propylamino, isopropylamino/l butylamino, tert-butylamino 7, inbutylamino, 5ea-butylamino, vinylamino, allylamino, dipropylamino, dibutylamino,
diallylamino, methylbutylamino.

Examples include pyrrolidino, piperidino groups, etc. The compound represented by the general formula (seal) of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or the generated acid addition salt can be converted into a pharmacologically acceptable acid addition salt. Bases can also be liberated from salts.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula (1) of the present invention include mineral salts such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Acid acid, or acetic acid, maleic acid, hexamaric acid, citric acid, oxalic acid, tartaric acid.

Examples include organic acid salts such as malic acid.

The novel para-aminosalicylic acid derivative represented by the general formula (1) of the present invention can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the preceding two general formulas (1) is produced by the following general formula (
II) A halide represented by the following general formula (Ill) (wherein Rlr R21R3+ R4 and n have the same meanings as above, and X represents a halogen atom) and the following general formula (Ill) (wherein R5 and R6 have the same meanings as above.) can be produced by reacting F without a solvent or in the presence of a solvent.

Solvents used in this reaction include Toba, water + methanol, ethanol, propatool, butanol, 3-methoxybutanol, isoamyl alcohol,
Examples include ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, a7ton, dioxane, a7tonitrile, and tetrahydrofuran.

In addition, the reaction is carried out in the range from room temperature to 2,000 °C. All of the 10-genides represented by the above general formula (1), which are the starting materials in the production method of the present invention, are new compounds, and regarding their production, is described in the reference example. According to the second mode of the method for producing the compound according to the present invention, the compound represented by the general formula (+) can be represented by the following general formula (
A para-aminosalicylic acid derivative represented by the following general formula (V
) (In the formula, R3, R4, R5, R6 and n have the same meanings as above, and A represents a halogen atom.) by reacting with an aminoalkylcarbonyl halide derivative represented by the formula in the presence of a solvent. can be manufactured.

Any solvent may be used in this reaction as long as it does not inhibit the reaction, such as acetone,
Methanol, chloroform, dioxane, benzene, toluene, etc. are used.

Further, the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably at room temperature.

According to the third mode of the method for producing a compound according to the present invention, in the general formula (+), R4 is a hydrogen atom, and n is 1
The para-aminosalicylic acid derivative represented by the following general formula (Ma1) Co-R1 (wherein, R1+ R2, R3+, R5 and R6 have the same meanings as above) is a para-aminosalicylic acid derivative represented by the following Co-
R.

(In the formula, R1, R2 and R3 are 0 representing the same meanings as above.
) and a propenamide derivative represented by the general formula (Ill
) in the presence of a solvent. Examples of solvents used in this reaction include methanol, acetone, dioxane, benzene, toluene, chloroform, Examples include dimethyl sulfoxide.

The propenamide derivatives represented by the general formula (M11), which are the starting materials in the production method of the present invention, are all new compounds, and their production is described in Reference Examples.〇Production of compounds related to the present invention. According to the fourth mode of the method, a compound in which R2 in the general formula (1) is a methyl group,
By demethylation in an inert organic solvent, the following general formula (M1!1) in which R2 in the above general formula (1) is a hydrogen atom
) (In the formula, R1+ R3, R4+ R5+ R6 and n represent the same meanings as above.) Examples of the agent for producing the para-aminosalicylic acid derivative include hydroiodic acid, hydrobromic acid, concentrated hydrochloric acid,
Pyridine hydrochloride, boron tribromide, aluminum chloride, etc. are used.

Any inert organic solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as 7-cetone and chloroform.

Benzene, methylene chloride, bigne, etc. are used.

In addition, the reaction is carried out from room temperature to reflux F.
Preferably, it is carried out at room temperature.

Effects of the Invention The novel pateaminosalicyl # derivative represented by the general formula (1) and its pharmacologically acceptable acid addition salt produced in this manner have excellent antiarrhythmic and local anesthetic effects. and premature contractions.

The present invention will be described below with reference to Examples, as it is useful for the treatment and prevention of ventricular arrhythmia paroxysmal tachycardia and the like, and for the prevention of arrhythmia associated with surgery and anesthesia.

Reference Example 1 Methyl 4-chloroacetylamino-2-methoxybenzoate 10°OOI
To 100 g/solution of acetic acid, add 6.0.1 of chloroa-7tyl chloride while stirring under water cooling, and stir for 30 minutes.The reaction mixture is poured into ice water, and the precipitated crystals are collected. Crystals are water;
Washing successively with an aqueous potassium carbonate solution yields light brown crystals 12.
Obtain 4'l. Recrystallize from ethyl acetate, melting point 113.
Colorless prismatic crystals of ~115° are obtained.

Elemental analysis value C1IH12CINO4 Theoretical value C, 51, 27iH, 4, 69; N, 5.4
4 Experimental values C, 51, 20iH, 4, 92N, 5.8
1 Example 1 4-Chloroacetylamino-obtained with 2-methoxy-4-piperidino-heptylami7benzoic acid methyl sulfate = jHFII l
Methyl 2-methoxybenzoate 2.00,9. A mixture of 2.0 ml of piperidine and 2 (Jul) of methanol is heated and stirred at 100° for 2 hours in a sealed tube. After the reaction, the solvent is distilled off and the residue is dissolved in ethyl acetate. The p liquid is extracted with an aqueous hydrochloric acid solution.The aqueous layer is made alkaline with potassium carbonate and then extracted with ethyl acetate.The ethyl acetate layer is washed with water and then dehydrated.

The solvent was distilled off to obtain an orange liquid 2.86F.

IR spectrum y (film)cw4-1:17
00.178O (C tonnage 0) Converted to hydrochloride using a conventional method. Recrystallized from ethanol,
Colorless needles with a melting point of 165-168° are obtained.

Elemental analysis value C16J2N204 ・HCl ・7/4
H, 20 theoretical value C, 51, +7 iJ 7.18;
N, 7.49 Experimental value C, 51,51iH, 6,9
2iN, ? L49 Example 2 Methyl 4-butylaminoacetylamino-2-methoxybenzoate Methyl 4-chloroacetylamino-2-methoxybenzoate obtained in Reference Example 1 2.00. L Butylamine 8.0
ml and 20 zt of ethanol to obtain 2.261 ml of yellow liquid.

Construct the hydrochloride using a conventional method. Recrystallized from ethanol,
Colorless needles with a melting point of 173-176° are obtained.

Elemental analysis value C15H2C15H2・HC1 theoretical value C
,54,46iH,? , 01 ; N, 8.47 Experimental value C, 54,45iH, 7J2 ; N, 8.18 Reference example 2 Methyl 4-(α-chlorobu-a-pionylamino)-2-methoxybenzoate 4-amino-2-methoxybenzoic acid To a solution of 6.00 g of methyl chloride in 6CJnl of acetic acid, 5.5 (l) of α-chloropropionyl chloride was added while stirring under water cooling, and the mixture was stirred for 30 minutes.

The reaction mixture was poured into ice water and extracted with ether. The ether layer is an aqueous solution of hydrochloric acid and water.

Wash sequentially with potassium carbonate aqueous solution and water. Distill the solvent and leave an orange liquid? , obtains 05.9.

IR spectrum v (film)3-1:1705
(C-0) Example 8 4-(2-diethylaminopropionylamino)-2-
Methyl methoxybenzoate 4-(α-chloropropionylamino) obtained in Reference Example 2
-A mixture of 2.00.9° methyl 2-methoxybenzoate, 7.0 ml of diethylamine and 20 ml of methanol is heated and stirred at 1oo0 for 56 hours in a sealed tube.Hereafter,
Treated as in Actual IfFA Example 1, orange liquid 1, T'll
/ get.

IR spectrum '(filt!+)oM-1゜1
700, 1710 (C=0) Converted into hydrochloride using conventional method. Recrystallized from ethanol,
Colorless prismatic crystals with a melting point of 190-192° are obtained.

Elemental analysis value C16H24N204・HCI theoretical value C
,55,71iH,7J1 ;N, 8.12 Experimental value
C,55,60iH,7,51;N,8.11 Example 4 Methyl 2-methoxy-4-(2-piperidinopropionylamino)benzoate 4-(α-chloropropionylamino) obtained in Reference Example 2 )
-Methyl 2-methoxybenzoate 4,oo,y.

A mixture of piperidine 6,5 ytl and methanol 40aI is heated and stirred at 100° for 16 hours in a sealed tube.

Thereafter, the same procedure as in Example 1 is carried out, and ether is added to the residue. The precipitated crystals were collected to obtain pale yellow crystals with a melting point of 96-97°. Colorless needles are obtained.

Elemental analysis value C1? H24N204・3/2C4H40
4 Theoretical value C155°87; H, 6,11iN, 5.
67 experimental value C, 55, 87; H, 6, 25; N, 5
．． 57 Reference Example 3 Ethyl 4-(α-chloropropionylamino)-2-methoxybenzoate 4-amino-2-methoxybenzoic m-hydrochloride 20, OI
250g of ethanol7! In the suspension, thionyl chloride 17
After adding Mt dropwise and heating under reflux for 2 hours, the solvent was distilled off, water was added to the residue, and the mixture was made alkaline with potassium carbonate. Separate the precipitated crystals and add water.

After successive washing with ether, 17.89 g of ethyl 4-amino-2-methoxybenzoate was obtained as colorless crystals. Recrystallization from benzene gives colorless platelet crystals with a melting point of 132-188°.

Elemental analysis value Cl0H13NO3 Theoretical value C, 61, 53; H, 6, 71i, N, 7
．． 17 Experimental values C, 61,58; H, 6,78; N,
7.044-Amino-2-methoxybenzoate ethyl 4.
00Il α-chloropropionyl chloride 2.4 y
Treat in the same manner as in Reference Example 2 using tl and 20 ml of acetic acid. Add inpropyl ether to the residue and remove the precipitated crystals.
Take 4.64 colorless crystals! / get. Recrystallization from ethanol gives colorless platelet crystals with a melting point of 101-102°.

Elemental analysis value C13H15CINO4 Theoretical value C,54,65iH,5,64iN, 4.9
0 Experimental value C, 54,49; H, 5,78; N, 4.
85 Example 5 Ethyl 2-methoxy-4-(2-piperidinopropionylamino)benzoate 4-(α-chloropropionylamino) obtained in Reference Example 3
Ethyl-2-methoxybenzoate 4.20 F.

A mixture of 8.50.9 piperidine and 50 xl of ethanol is heated to reflux for 23 hours. Thereafter, the treatment was carried out in the same manner as in Example 1, and a yellowish brown liquid 4. 'OIR spectrum to obtain 1 OIi v (film) cm l: 1710.1
700 (C=0) Recrystallize from a mixture of ethanol and ether to obtain 7-malate salt using a conventional method to obtain colorless plate crystals with a melting point of 161-162°0 Elemental analysis value CIBH16N204・3/2C4H40
4 Theoretical value C, 56,69iH, 6,84iN, 5.
51 experimental value C, 56, 63; H, 6, 52: N, 5
．． 41 Example 6 4-(2-diallylaminopropionylamino)-2-
4-(α-chloropropionylamino) obtained with ethyl methoxybenzoate reference Na
-2-7-) Ethyl xybenzoate 2. OO,F.

Diallylamine 7,50.9 and ethanol 80txl
The mixture is heated to reflux for 4 days. Thereafter, the treatment was carried out in the same manner as in F1 Example 1, and a yellowish brown liquid 2.20. OIR spectrum to obtain F l' (film)5-1.

1725.1695 (C=O) Example 7 Ethyl 2-hydroxy-4-(2-piperidinopropionylamino/)benzoate 2-methoxy-4-(2-piperidinopropionylamino) obtained in Example 5 ) benzoin a2 x + le 1.60g
0.9 ml of boron tribromide is added to the methylene chloride Rod solution under water-cooling and stirring, and the mixture is stirred at room temperature for 1 hour. Add water to the reaction mixture, make alkaline with potassium carbonate, and extract with lyqloform.The organic layer is washed with water and then dehydrated.
The solvent is distilled off to obtain a pale yellow liquid 1.40F.O IR spectrum y (film) as 1:1
700.1670 (C=0) Converted to hydrochloride using a conventional method. Recrystallization from a mixture of ethanol and ether gives pale yellow plate crystals with a melting point of 210-212°.

Elemental analysis value C1tH24M204・HCI・l/2H
20 Theoretical value C, 55, 81; H, 7-16; N, 7
．． 66 experimental value C, 55, 73iH, 7, 1? ;N,
From 7.45, the compounds of Reference Examples 4 to 7 are obtained by the method described in Reference Example 1. Reference Example 4 4-chloroacetylamide/-2-methoxybenzoic acid amide colorless needles Melting point 193-195° (Ethanol) Elemental analysis value C
1ol (llcIN203 theoretical value C, 49, 50; H
,4,57;N, 11.54 experimental value C,49,+3
iH, 4,77; N, 11.39 Reference Example 5 4-(α-chloropropionylamine)-2-methoxybenzoic acid amide colorless needle crystals Melting point 192-194° (ethano-/I/) Elemental analysis &
J C41H13CIN203 Theoretical value C, 51, 4
7;I(,5,10;N, IQJI experimental value C,51
, 44; H85, 34; N, IO to It Reference Example 6 4-Rintro-7thyl-amino-N-ethyl-2-methoxybenzoic acid amide colorless needle crystals Melting point 189-191' (ethanol) Elemental analysis value C
1,2H15CIN203 theoretical value C,5124iH,
5,58iN, 10J5 experimental value C,53,00;H
, 5,97iN, 10.20 Reference Example 7 4-(α-chloropropionylamino)-N-ethyl-
2-Methoxybenzoic acid amide colorless needle crystals Melting point 134-135° (benzene) Elemental analysis value C13H17CIN203 Theoretical value C,5
4,84iH, 6,02iN, 9.84 experimental value C,
55,09; H, 6,19; N, 9.56 Example 8 4-Diethylaminoacetylamino-2-methoxybenzoic acid amide 4-chloroacetylamino-2-methoxybenzoic acid amide obtained in Reference Example 4 2. 00.9. diethylamine 5
．． A mixture of Otnl and 20 ml of ethanol is heated in a sealed tube at 100° for 3 hours. The reaction wave solvent is distilled off and the precipitated crystals are collected. The crystals were washed with water and the melting point was 19.
0-191' colorless crystals 2.08F are obtained.

IR spectrum v (KBr) cm-1-:17
00.1660 (C=0) Converted to hydrochloride using a conventional method. Recrystallized from ethanol,
Obtain colorless prism crystals with a melting point of 208-211°〇Elemental analysis value C14H21N303・HCI theoretical value C
,53,25;H,7,01N, 13.31 experimental value
C,52,89;H,? , 15 ; N, 13.07 Example 9 2-methoxy-4-(2-piperidinopropylonylamino)benzoic acid amide 4-(α-chloropropionylamino) obtained in Reference Example 5
A mixture of -2-methoxybenzoic acid amide 2.019° piperidine 3.0 ml and ethanol 20 ml is heated and stirred at 100-1100 for 6 hours in a sealed tube. below,
Processed in the same manner as in Example 8, melting point 139.5-140.5
Colorless crystals of 1.59.9° are obtained.

IR spectrum　　　(KBr　)　cm-1.

1700.1660 (C=O) Converted to hydrochloride using conventional methods. Recrystallized from ethanol,
Colorless crystals with a melting point of 179-182° are obtained.

Elemental analysis value C161 (23N303・MCI・l/4
H20 theoretical value C, 55, 49iH, 7, 1a; N,
12.13 Experimental value C, 55, 39iH, 7, 44i
N, 11.95 or less. Using the compound of Reference Example 6.7 as a raw material, the same operations as in Examples 1 to 9 were carried out to obtain the compounds of Examples 10 to 16.

Example 10 4-diethylaminoacetylamino-N-ethyl-2-
Methoxybenzoic acid amide yellow liquid technology R spectrum v (film) cll-1.

1690.1640 (C=0) Example 11 N-ethyl-2-methoxy-4-piperidinoacetylaminobenzoic acid amide colorless needle crystals Melting point 108-109° (ethyl acetate) Elemental analysis value C
17H25N303 Theoretical value C, 61, 98; H,? , 89; N, 13
．． 16 experimental values C, 64,05; H, 7,96; N,
12.82 Example 12 4-(2-dimethylaminopropionylamino)-N-
Ethyl-2-methoxybenzoic acid amide pale yellow liquid IR spectrum y (film) m-1:1695
．． 1640 (C=0) Example 18 4(2-diethylaminopropionylamino>-W-ethyl-2-methoxybenzoic acid amide orange liquid film R spectrum l' (film) cB-1:16
95.1640 (C-0) Example 14 N-ethyl-2-methoxy-4-(2-pyrrolidinopropionylamino)benzoic acid amide yellow liquid IR spectrum k v (film) cm l:1
690.1640 (C 0) Fumarate: colorless needle crystals Melting point 176-177° (ethanol) Elemental analysis value C
17H2, N303・C4Ha04 theoretical value C, 57,
92iH, 6, 71; N, 9.65 Experimental value C, 57
,74; H, 6,95; N, 9.65 Example 15 N-ethyl-2-methoxy-4-(2-piperidinoprobionylamino)benzoic acid amide orange liquid IR spectrum v (film) 3 1 :1695
．． 1645(C-0) Example 16 4-(2-7′ thylaminopropionylamino)-N-
Ethyl-2-methoxyben, alpha aromatic acid amide colorless needles Melting point 42-46° (ether-isopropyl ether) Elemental analysis value 017H27N303'H20 Theoretical value C
, 60, 16; H, 8, 61; ) Methyl benzoate 4-amino-2-methoxybenzoate 3.0 (19
,) Chloroborum 301 of ethylamine 1.80.9
11 into a solution, under water cooling and stirring, mecryloyl chloride 1
．． Add 7tttl and stir at room temperature for 8o minutes.

The reaction mixture is washed successively with an aqueous potassium carbonate solution, water, an aqueous hydrochloric acid solution, and water, then dehydrated, and the solvent is distilled off.

Column chromatography (silica gel) of the residue.

Elution with chloroform) yielded colorless crystals at 3°19
Recrystallization from isopropyl ether gives colorless needles with a melting point of 96-97°.

Elemental analysis value C13H15NO4 Theoretical value C, 62,64; H, 6,07; N, 5.6
2 Experimental value C, 62, 81iH, 6, 08; N, 5.
69 Reference Example 9 Ethyl 2-methoxy-4-(2-methyl-2-propenoylamino)benzoate 8.0OF,
) Diethylamine 4.30.9. Chloroform 80tt
tt and methacryloyl chloride 4.1 txl to m-
Then, the same procedure as in Reference Example 8 was carried out to obtain light brown crystals of 8.901. Recrystallization from 0 ethanol gave a melting point of 155 to 156.
° pale yellow needles are obtained.

Elemental analysis value C14H17NO4 Theoretical value C,61,87;H,6,51iN, 5J2
Experimental value C, 63,89; H, 6,61; N, 5.1
0 Example 17 Ethyl 4-(3-diethylamino-2-methylpropionylamino)-2-methoxybenzoate 2 obtained in Reference Example 8
-Methyl-methoxy-4-(2-methyl-2-propenoylamino)benzoate 1.60.9. Diethylamine5.
A mixture of 40.9 g/methanol and 40 ag/methanol is heated to reflux for 3 days. After the reaction, the solvent is distilled off and the residue is dissolved in a mixture of ethyl acetate and ether. The solution was extracted with an aqueous hydrochloric acid solution, and the aqueous layer was made alkaline with potassium carbonate. The ether layer was washed with water, dehydrated, and the solvent was distilled off. Isopropyl ether l [I, t
, take one of the precipitated crystals to obtain 1.46 F colorless crystals.

Recrystallized from isopropyl ether, melting point 88-89
° colorless needles are obtained.

Original 1 analytical value C17H26N204 Theoretical value C, 63, 31iH, 8, 13; N, 8.6
9 Experimental values C, 6a, 25 iH, 8, 21iN, 8
．． 42 Example 18 2-Methoxy-4-(2-methyl-3-piperidi/propionylamino)an 5 is the 2-methoxymethyl compound obtained in Reference Example 8.
Methoxy-4-(2-methyl-2-propenoylamino) methyl benzoate 1°60, L piperidine 1.60
A mixture of 40 g of methanol and 40 g of methanol is heated to reflux for 23 hours. Thereafter, the same treatment as in Example 17 was carried out, and colorless crystals 2.
0 G, get 9. Recrystallization from isopropyl ether λ gives colorless plate-like crystals with a melting point of 99-100°.

Elemental analysis value C16H26N2o4 Theoretical value C, 64, 65;)I, 7.84;M,
8.88 Experimental value C, 64, 88; H,? , 81 iN
, 8.17 Example 19 Ethyl 2-methoxy-4-(2-methyl-3-piperidi/propionylamino)benzoate 2-methoxy-4-(2-methyl-2-propenoylamino) obtained in Reference Example 9 )
Sabbath 1M ethyl 5゜50#, pipet IJ gin 5.30j
Proceed as in Example 18 using 10 Oxl of 7 and ethanol to obtain a tan liquid 7.20.9.

IR spectrum v (fllm) tri-1:1
780.1700 (C=0) Example 20 Ethyl 2-hydroxy-4-(2-methyl-3-piperidinopropionylamino)benzoate 2 obtained in Example 19
-methoxy-4-(2-methyl-8-piperidi/propionylamino)benzoic acid x+l 5.2011. Treat as in Example 7 using methylene chloride 7oIR1 and boron tribromide 3.0tttt. The residue was treated with column chromatography (silica gel, eluted with chloroform) to give pale yellow crystals with a melting point of 110-111°.
! ◇IR spectrum ν(KBr) cm
-L H1700,1660 (C=0) Constructed into hydrochloride by conventional method. Recrystallized from ethanol,
Obtain colorless acicular crystals with a melting point of 180-181° O Elemental analysis value Cl8H26N204・F (C1 theoretical value
C, 58, 29; H, 7, 14iN, 7.55 experimental value C, 58, 11iH,? , 60 iN, 7.49 Example 21 Ethyl 4-(2-butylamino-2-methylpropionylamino)-2-methoxybenzoate To a solution of 1.60 g of ethyl 4-amino-2-methoxybenzoate in 20 grams of chloroform While stirring at room temperature, a solution of 1.80.9 ml of 2-butylamino-2-methylpropionyl chloride hydrochloride in 15 #I of chloroform is added, and the mixture is stirred at room temperature for 4 hours. After sequentially washing the reaction mixture with an aqueous hydrochloric acid solution, an aqueous potassium carbonate solution, and water, the chloroform layer was dehydrated, the solvent was distilled off, and the residue was purified by column chromatography (alumina).

Eluted with chloroform) to produce a yellow liquid 1゜oo
, i9 is obtained.

IR7, Pect” L’ (film) (711
1.

1710.1695 (C=0)

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R_1 is a lower alkoxy group or an amino group which may be substituted with a lower alkyl group, R_2, R
_3 and R_4 are the same or different and represent a hydrogen atom or a methyl group, R_5 and R_6 are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, or R_5 and R_6 are the nitrogen atoms to which they are bonded. It may form a ring together with atoms, and n represents an integer of 0 or 1. ) and its pharmacologically acceptable acid addition salts.