JPS6030671B2 - spiro compounds - Google Patents

Description

[Detailed description of the invention]

The present invention relates to spiro compounds. More specifically, the present invention is based on the general formula [1] [where RI and R2 are the same or different and represent a hydrogen atom, a halogen, a lower alkyl group, or a lower alkoxy group, and Z is [1-hydrogen atom, '21 lower alkoxy] Substituted phenyl group, halogen-substituted penzoyl group, hydroxyl group, one CON(
C is a lower alkyl group optionally substituted with a rubber moyl group or a di-lower alkyl group represented by m [in the formula, m represents an integer of 4 to 6], {3}R3CO-(
In the formula, R3 is a hydrogen atom, a di-lower alkylamino group, or a lower group optionally substituted with a substituted amino/group represented by -N(C)n [wherein n represents an integer of 4 to 6]. represents an alkyl group, a lower alkoxy group or a phenyl group substituted with a halogen), {4-R4S02- (wherein R4 represents a lower alkyl group or a phenyl group substituted with a lower alkyl), and { 5) (in the formula, R5
, R6 are the same or different and represent a hydrogen atom or a lower alkyl group)] and salts thereof. These compounds are novel compounds described in the literature, and exhibit excellent gastric acid secretion suppressing, anti-inflammatory, and analgesic effects, making them useful as pharmaceuticals or veterinary drugs for humans or other warm-blooded animals (e.g., mice, rats, guinea pigs, etc.). It is useful as In the general formula [1], examples of the halogen represented by RI and R2 include fluorine, chlorine, and bromine. Specific examples of the lower alkyl group represented by RI and R2 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and s-butyl.
Examples of lower alkoxy groups include those having 1 to 4 carbon atoms, such as ec-butyl, and methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-phthoxy, sec-butoxy, etc. Items 1 to 4 are listed. Specific examples of the lower alkyl group represented by Z include methyl, ethyl, n-propyl, isopropyl, n-
Examples include those having 1 to 4 carbon atoms, such as -butyl, sec-butyl, t-phthyl, and isobutyl. This alkyl group may be substituted with one substituent, and examples of such a substituent include the following. ■
Phenyl stem. This phenyl group can further be exemplified by methoxy, ethoxy,
It is substituted at an appropriate position with a lower alkoxy group having 1 to 4 carbon atoms such as n-propoxy. ■ Penzoyl group. This penzoyl group is further substituted with a halogen (chlorine, bromine, etc.), such as p-halogenobenzoyl group. ■ Hydroxyl group. (2) A carbamoyl group represented by the formula [wherein m represents an integer of 4 to 6]. (iii) di-lower alkylamino group (preferably the alkyl group has 1 to 4 carbon atoms, e.g. monomethylamino, diethylamino, etc.) In the above general formula, when Z is R3CO-, R
Examples of the lower alkyl group of 3 include those having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and sec-butyl.
Examples of lower alkoxy groups include those having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and sec-butoxy. This lower alkyl group is, for example, a di-lower alkylamino group (e.g. dimethylamino group, etc.) or a formula -N(C
As a phenyl group substituted with a halogen, which may be substituted with a substituted amino group (e.g., 1N(CH2)5, etc.) represented by H2)n [in the formula, n is an integer of 4 to 6] is, for example, a 4-chlorophenyl group. In the above general formula, when Z is R4S02, examples of the lower alkyl group for R4 include those having 1 to 4 carbon atoms as exemplified in the section for R3CO-. Examples of the phenyl group substituted with a lower alkyl group for R4 include a 4-methylphenyl group. In the above general formula, when Z is represented by, the lower alkyl group of R5 and R6 is
Examples include those having 1 to 4 carbon atoms as exemplified in the section of 3CO-. Spiro [cyclopropane-1, represented by general formula [1]
2'-indoline]-3'-ones may form salts. Examples of such salts include inorganic acid addition salts such as hydrochloride, sulfate, hydrobromide, nitrate, maleate, fumarate, oxalate, and p-toluenesulfone. Examples include so-called pharmacologically acceptable salts such as organic acid addition salts such as acid salts, methanesulfonate salts, and malate salts. The target compound of the present invention has the general formula

[0] [In the formula, R1, R2, I and Z have the same meanings as the above provisions]
4,5-dihydrospiro [furan-3 (pan)
・Produced by subjecting 2-indoline]-2,3-diones to a decarboxylation reaction. This decarboxylation reaction is usually carried out in the presence of a catalyst that promotes decarboxylation, such as metal halogen compounds (e.g., sodium chloride, sodium bromide, sodium iodide, potassium bromide, etc.). , potassium chloride, potassium iodide, etc.), and quaternary ammonium salts (eg, tetramethylammonium bromide, etc.) are preferably used. The amount of catalyst used is about 0.1 to 10 equivalents based on compound [b]. The reaction temperature is usually about 1
About 0pi to 200℃, more preferably 140o to 16
000 is preferred, but lower or higher temperatures are of course possible. However, the reaction rate is slow at low temperatures, and decomposition reactions may occur at too high temperatures. Furthermore, substituting the reaction vessel with an inert gas such as nitrogen or argon may suppress side reactions and improve the yield. The reaction is usually preferably carried out in a suitable solvent, and any solvent may be used as long as it does not inhibit the reaction. However, solvents with boiling points higher than the reaction temperature, ie, above about 140°C, are particularly preferred. Suitable solvents include N.N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide. Furthermore, the object compound of the present invention can be produced by spiro[cyclopropane-1,2-indoline]-3 represented by the general formula [m] [where RI and R2 have the same meanings as defined above].
Spiro[cyclopropane-1,2-indoline]-3-one represented by the general formula [W] can be obtained by introducing a substituent represented by Z' below into the imi/group of the -ones by means known per se. It may also be carried out by manufacturing a similar product. The definition of Z' in general formula [W] is general formula [1] and

[0]
It is exactly the same as the definition of Z excluding the hydrogen atom. Means for introducing the group represented by Z' into an imino group are conventionally well known to those skilled in the art as alkylation means and acylation means, and the method of the present invention can be carried out according to such per se known means. As the alkylation means, Z'-x (wherein Z' is the same as defined above, x means halogen, preferably iodine, chlorine, or bromine) or ZS04 [wherein Z'' is the same as defined above] As a representative example, a method for reacting an alkyl sulfuric acid represented by the following formula with a compound represented by the general formula [blood] can be cited. The reaction temperature in this case is usually about 0 to 100q
Any solvent can be used as long as it does not inhibit the reaction, but preferred examples include dimethyl sulfoxide and dimethyl formamide. In this case, the reaction usually completes in about 5 minutes to 1 hour. do. The reaction is preferably carried out in the presence of a deoxidizing agent, such as sodium, alkoxide, sodium, hydride, alkyl lithium (
Examples include strong bases such as methyllithium.
Introduction of the acyl group represented by Z' is also carried out by means known per se. Typical examples thereof include acid ZOH itself corresponding to an acyl group, etc., or its reactive derivatives (e.g., acid halides, acid anhydrides, active esters such as pentachlorophenol ester and P-nitrophenol ester, azide, etc.). ) and a compound represented by the general formula [m] are reacted as a representative example. This method is Z
This is particularly effective when ' is an organic carboxylic acid residue or an organic sulfonic acid residue. When ZOH itself is used, the reaction is usually carried out in the presence of a dehydrating agent such as N.N'-dicyclohexylcarpodiimide. The reaction temperature is usually about 0 to 50°C, and suitable solvents include benzene, toluene, ethyl ether, pyridine, chloroform, methylene chloride, and the like. When using an acid halide, e.g. sodium bicarbonate
The reaction is preferably carried out in the presence of an inorganic base such as triethylamine or an organic base such as triethylamine or pyridine. The reaction is usually completed within one hour. When Z' is a carbamic acid residue represented by the above formula (wherein R5 and R6 are the same as defined above), the compound represented by the general formula [m] may be, for example, x is a halogen) to obtain a compound represented by the general formula [V] [wherein R1, R2 and X are the same as defined above], and the compound represented by the formula R
5R6NH (in the formula, R5 and R6 are the same as defined above)
It can be obtained by reacting the amine represented by The first step is usually carried out in a solvent of about 0 to 50 q○, such as benzene, toluene, ethyl ether, carbon tetrachloride, etc., which does not inhibit the reaction, and the second step is usually carried out in a solvent of about 0 to 50 q○.
It is preferable to carry out the reaction in the solvent used in the first step at a concentration of about 0 qo. Both steps include an inorganic base such as sodium bicarbonate, e.g. triethylamine, as a deoxidizing agent,
Preferably, this is carried out in the presence of an organic base such as pyridine. Furthermore, the compound represented by the general formula [m] has the formula R5
It can also be obtained by reacting a compound represented by R6NCOX (wherein R5 and R6 are the same as defined above, and X is a halogen). This reaction is usually carried out with an inorganic base such as sodium bicarbonate, e.g. triethylamine,
In the presence of an inorganic base such as pyridine, in a solvent that does not inhibit the reaction, such as benzene or toluene, oo ~ 1
It is preferable to carry out at about 00qo. Furthermore, when Z' is a carbamic acid residue represented by the formula R5RWCO- and one of R5 and R6 is a hydrogen atom and the other is a lower alkyl group, the compound represented by the general formula [m] and the formula R7
This is conveniently carried out by reacting with an isocyanate of the formula NC0, in which R7 is a lower alkyl group. This reaction is usually carried out at about 0 to 100 qo, and the reaction is completed in a short time (usually within 2 hours). In addition, when the lower alkyl group represented by Z has an ami/group as a substituent, prior to the introduction of the substituent, the group is protected with an appropriate protecting group such as penzyloxycarbonyl, and then the group is introduced into the ami/group. It goes without saying that, after introduction, it is preferable to remove the protecting group by means such as catalytic reduction. In addition, when the lower alkyl group represented by Z has a hydroxyl group as a substituent, the hydroxyl group is protected with an appropriate protecting group such as acetyl or tetrahydropyranyl prior to the introduction of the substituent, and then the group is introduced into the imino group. After introduction, the protecting group may be removed by means such as hydrolysis. The object of the present invention is usually produced in the form of a free base, but if desired, it may be converted into a non-toxic salt by means known per se. The thus produced compound can be separated and purified by conventional separation means such as distillation, recrystallization, column chromatography, etc. These compounds have gastric acid secretion suppressing action, anti-inflammatory action, and analgesic action, and are useful as medicines for warm-blooded animals such as humans, rats, mice, and guinea pigs. For example, when used as an anti-inflammatory agent or analgesic, about 1 to 30 doses/k9/y of ship may be orally administered to the host. At this time, the target compound is usually administered after being made into a tablet or powder together with a known excipient such as starch. In addition, it can also be administered parenterally in the form of injections, suppositories, etc. The raw material compound [D]** used in the method of the present invention includes a new compound, and can be easily produced, for example, by the following method or a method analogous thereto. {5' A group Z' is introduced into the compound represented by the single-pronged formula by the above-mentioned alkylation or acylation method. t6) A substituent is introduced into the benzene ring of the compound represented by the general formula to obtain the general formula. Spiro [cyclopropane-1,2-indoline]-3'
-one and 4,5-dihydro [furan-3 (dark blue)]
The numbering of 2-indoline]-2,3-dione is shown below. Example 1 4.5-dihydro 1'-spiro[furan-3 (3H
)・2'-indoline] 12.2 parts of 12,3-dione were dissolved in 100 parts of dimethyl sulfoxide, 3.86 parts of sodium chloride was added, and the solution was dissolved under argon gas.
React at 60°C for 5 hours. After wrapping, ice water is added and extracted with chloroform. The extract is washed with water and dried over magnesium sulfate. The chloroform was removed, and the residue was purified by silica gel column chromatography and purified with 1'H-sp. [Cyclopropane-1,2'-indoline]-3'-one was obtained in an amount of 8.91 g. Melting point 110
-11100 Elemental analysis value C, Pan-9 NO C day N Calculated value 75.4 fu 5.70, 8.80 Actual value 75.235.498.54 Example 2 4.5-dihydro 1' day-spiro [furan-3 (3H
), 2'-indoline]-2, 3-dione, dissolved in 50 parts of dimethyl sulfoxide, 3 parts of sodium bromide.
．． Adding 4 nights, 16,000 yen while passing argon gas.
, 1. Parent time to react. After treatment in the same manner as in Example 1, 4.36 g of 1'-spiro[cyclopropane-1,2-indoline]-3'-one was obtained. The melting point and elemental analysis values of the 1'H-spiro[cyclopropane-1,2-indolin]-3'-one obtained here completely matched those obtained in Example 1. Example 3 1'-Acetyl-4,5-dihydro rH-spiro[furan-3 (fine), 2-indoline]-2,3-dione 0.491 g was dissolved in 2 parts dimethyl sulfoxide, and sodium chloride 0.129 g was dissolved. and react at 1550-160°C for 2 hours while passing nitrogen gas. After cooling, add ice water and extract with chloroform. The extract is washed with water and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.38 g of 1'-acetyl-1'H-spiro[cyclopropane-1,2-indoline]-3'-one. Recrystallize from ethanol. Melting point 156-157
0. Elemental analysis value C, 2 days. C day N as N02 Calculated value 71.62, 5.51, 6.96 Actual value 71
．． 335.556.68 Example 4 1'-formyl-4,5-dihydro-1'-spi
Dissolve 1.50% of furan-3 (2-indoline)-2,3-dione in 6.5% of dimethyl sulfoxide, add 0.736% of sodium bromide, and heat at 150°C for 2 hours while passing argon gas. Make it react. After cooling, ice water is added and extracted with chloroform. The extract is washed with water and dried over magnesium sulfate. The chloroform was removed and the residue was purified by silica gel column chromatography to obtain 1.102 spiro[cyclopropane-1,2'-indoline]-3'-one per 1' day. obtain. Recrystallize from ethanol. Melting point 122-12
Wow. Elemental analysis value C,. Day 9N02C Day N Calculated value 70.5 & 4.8fu 7.48 Actual value 70.634.837.33 Example 5 1'(4-chlorobenzoyl)-4,5-dihydro-1
'H-spiro [furan-3 (pan)/2-indoline]-
Dissolve 0.684 mm of 2,3'-dione in 5 mm of dimethyl sulfoxide, add 0.227 mm of sodium bromide, and react for 160 mm while passing argon gas. After cooling, ice water is added and extracted with chloroform. The extract is washed with water and dried over magnesium sulfate. After removing the chloroform, the residue was purified by silica gel column chromatography to obtain 1'-(4-chlorobenzoyl), 1', and 1', spiro[cyclopropane-1,2-indoline], 3
- Get 0.511 hours on. Recrystallize from ethanol. Melting point 118-119qo. Elemental analysis value C, 7 days, 2
C day N calculated value as N02CI 68.5 & 4.004
．． 70 Actual measurements 68.74, 4.10, 4.39 Example 6 4,5-dihydro-1'-methyl-1'-spiro[furan-3(9H)/2-indoline]-2,3'-dione 0 Dissolve 0.435% of dimethyl sulfoxide in 1.5% of dimethyl sulfoxide, add 0.129% of sodium chloride, and react for 150-155% while passing nitrogen gas. After cooling, add ice water. Extract with loform, wash the extract with water, and dry with magnesium sulfate. The chloroform was removed and the residue was purified by silica gel column chromatography to obtain 0.319 g of 1'-methyl-1'-spiro[cyclopropane-1,2-indoline]-3'-one, diisopropyl. Recrystallize from ether.Melting point 73-75oo Elemental analysis value C,.day,.NO as CdayN Calculated value 76.27, 6.40, 8.09 Actual value 76
．． 456.19, 8.15 Example 7 1'-acetyl-4,5-dihydro-5'-methoxyrH-spiro [furan-3(3H)/2-indoline]
0.551 g of -2,3-dione was dissolved on 5 portions of dimethyl sulfoxide, 0.129 g of sodium chloride was added, and the mixture was reacted for 160 g03 hours while passing argon gas. After cooling, ice water is added and extracted with chloroform. The extract is washed with water and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.396 g of 1'-acetyl-5'-methoxy-11'-day spiro[cyclopropane-1,2-indoline]-13'-one. get. Recrystallize from ethanol.
Melting point 169-17○ Elemental analysis value C, 3 days, 3N03
As C day N Calculated value 67.52, 5.67, 6.06 Actual value 67
．． 61, 5.556.05 Example 8 1'-acetyl-4,5-dihydro-5',6-dimethoxy-1'H-spiro [furan-3 (group), 2-indoline]-12,3-dione 1.22 was dissolved in 10 parts of dimethyl sulfoxide, added with 0.257 parts of sodium chloride, and heated to 160°C while passing argon gas. React to song time. After wrapping, ice water is added and extracted with chloroform. The extract is washed with water and dried over magnesium sulfate. Chloroform was removed, and the residue was purified by silica gel column chromatography to obtain 1'-acetyl-5,6-dimethoxy-1'H.
- Spiro [cyclopropane-1,2-indoline]-3
'-on gets 0.79 yen. Recrystallize from ethanol. Melting point 174-17600 Elemental analysis value C, 4 days, 5N
04 as C day N Calculated value 64.36, 5.79 5.36 Actual value 64
．． 305.745.32 Example 9 1'-acetyl-5'-chloro 4,5-dihydro 1
Dissolve 2.52 parts of spiro[furan-3(SH), 2'-indoline]-2,3-dione in 30 parts of dimethyl sulfoxide, add 0.58 parts of sodium chloride, and add 0.58 parts of sodium chloride, and add 0.58 parts of sodium chloride for 155 qol while passing argon gas. Make it react. After cooling, ice water was added, and the precipitated crystals were taken out in a furnace, washed thoroughly with water, dried, and 1'-acetyl-6-chloro-1'H-spiro[cyclopropane-1,2-indoline]-13-one was obtained. Obtained 2.02 evening. Recrystallize from ethanol. Melting point 188-189qo. Elemental analysis value C, 2nd, Bu02C
I as C day N Calculated value 61.154.28 5.94 Actual value 61.184.31, 6.16 Example 10 1'H-spiro[cyclopropane-1,2-indoline]-3-one 1.12 pm Dissolve in 21 parts of 99% formic acid and add 7 parts of acetic anhydride while stirring under ice cooling. After stirring for 1 hour under ice-cooling and 4 hours at room temperature, ice water was added and extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 1'
-formyl-rH-spiro[cyclopropane-1,2-
[indoline]-3'-one obtained 1.027 times. Recrystallize from ethanol. Melting point: 122-123o○. The 1'-formyl-1'H-spiro[cyclopropane-1,2-indoline]-3'-one obtained here is completely different from that obtained in Example 4 based on elemental analysis values, infrared absorption spectrum, etc. matched. Example 11 Dissolve 0.319 g of 1'H-spiro[cyclopropane-1,2'-indoline]-3-one over dry pyridine and add 0.525 g of 4-chlorobenzoyl chloride while stirring under ice. Add and stir at room temperature for 1.5 hours. Ice water is added to the reaction solution, extracted with ethyl acetate, and the extract is washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography to give 1'-(4-chlorobenzoyl)-1'H-spiro[cyclopropane-1,2-indoline]-3-one 0.279 Get the evening. The 1'-(4-koo benzoyl)11'-spiro[cyclopropane-1,2'-indoline]-3'-one obtained here has a melting point, elemental analysis value, and the same as that obtained in Example 5. The infrared absorption spectra showed complete agreement. Example 12 1'H-spiro[cyclopropane-1,2-indoline] was prepared by stirring a mixture of 0.144 g of 50% oily sodium hydride and 5 g of dry dimethyl sulfoxide under ice cooling while passing argon gas through the mixture. -3'-on 0.319
Add a solution of water dissolved in three sides of dry dimethyl sulfoxide. After stirring at room temperature for 30 minutes, a solution of 0.47 g of 4-methoxybenzyl chloride dissolved in 3 g of dry dimethyl sulfoxide was added while stirring again under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ice water is added to the reaction mixture and extracted with chloroform. The extract is washed with water and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 1'-(4-methoxybenzyl)-1'H-spiro[cyclopropane-1
・2-indoline]-3'-on 0.57% is obtained. Recrystallize from diisopropyl ether. Melting point 66-67
0 elemental analysis value C, 8 days, C day N as 7NQ Calculated value 77.396.135.01 Actual value 77.136.154.92 Example 13 50% oily sodium hydride while passing nitrogen gas 0.
A solution of 0.319% of 1'-spiro[cyclopropane-1,2-indoline]-13'-one dissolved in 3M of dry dimethyl sulfoxide was stirred under ice-cooling. Add. After stirring at room temperature for 20 minutes, a solution of 0.487 g of 3-dimethylaminopropyl chloride dissolved in 3 parts of dry dimethyl sulfoxide was added, and the mixture was stirred at room temperature for 30 minutes.
React at 0o0 for 75 minutes with stirring. Add ice water to the reaction solution, extract with chloroform, wash the extract with water,
Dry with magnesium sulfate. Chloroform was distilled off, and the residue was purified by alumina column chromatography to obtain 0.58 g of 1'-(3-dimethylaminopropyl)-rH-spiro[cyclopropane-1,2'-indoline]-3-one. is obtained as an oil. Dissolve this oily substance in 5 parts of ethanol, add a solution of 0.18 parts of oxalic acid dissolved in 5 parts of ethanol, collect the precipitated crystals in a furnace, wash them with ethanol, and dry them. propyl) - 1' day - spiro [cyclopropane - 1.
2-indoline]-3'-one oxalate (1:1)
Get 0.505 evenings. Recrystallize from ethanol. Melting point 173-174 0 (decomposition) elemental analysis value C, 7 days 22
C day N as N205 Calculated value 61.066.638.38 Actual value 60.936.70, 8.45 Example 14 50% oily sodium hydride 0.00% while passing nitrogen gas.
A solution of 0.319 g of 1'H-spiro[cyclopropane-1,2-indoline]-13'-one dissolved in 3 g of dry dimethyl sulfoxide was prepared while stirring a mixture of 144 g and dry dimethyl sulfoxide 3 g under ice cooling. Add. After stirring at room temperature for 30 minutes, while stirring again under ice-cooling, a solution of 0.735 ml of 4'-chloro-4-fluorobutylphenone ethylene acetal dissolved in 3 parts of dry dimethyl sulfoxide was added, and the mixture was stirred at room temperature for 2 hours. 50
-5y0 and react with stirring for 5 hours. Add ice water to the reaction solution, extract with chloroform, wash the extract with water,
Dry with magnesium sulfate. Distill the chloroform,
The residue was purified by silica gel column chromatography to obtain 1'-[3-(4-fluorobenzoyl)propyl]11'd spiro[cyclopropane-1,2'-indoline]-3'-one-ethylene acetal. 0.734
Get the evening. Recrystallize from diisopropyl ether. Melting point 96-970 Elemental analysis value C22 days C days N as 22N03F Calculated values 71.92, 6.043.81 Actual values 71.886.093.85 1'-[3-(4-fluorobenzoyl) obtained above ) propyl]-1'H-spiro[cyclopropane-1.
2-indoline]-3-one-ethylene acetal 1.
Dissolve 47% in 10% ethanol and add a solution of 85% phosphoric acid and 25% water with stirring under ice cooling. Stir for 3 hours under ice-cooling and 1 hour at room temperature, and concentrate the reaction solution under reduced pressure. Ice water is added to the residue, extracted with chloroform, and the extract is washed with water and dried over magnesium sulfate.
Chloroform was distilled off, the residue was purified by silica gel column chromatography, and 1'-[3-(4-fluoro
1.25 hours of benzoyl)propyl-rH-spiro[cyclopropane-1,2-indoline]-3-one are obtained. Recrystallize from diisopropyl ether. Melting point 87.
5-88.5qo elemental analysis value C2 rainbow, C day N as 8NQF Calculated value 74.28 5.61, 4.33 Actual value 74
．． 295.47, 4.33 Example 15 A mixture of 50% oily sodium hydride (0.144 g) and dry dimethyl sulfoxide (5 g. A solution of 0.319 g of 2-indoline-3-one dissolved in dry dimethyl sulfoxide is added. After stirring at room temperature for 2 minutes, add a solution of 0.536 ml of 2-(3-chloropropoxy)tetrahydropyran dissolved in 3 parts of dry dimethyl sulfoxide, and stir at room temperature for 2 hours and at 50 qo for 1.5 hours. . Ice water is added to the reaction solution, extracted with chloroform, and the extract is washed with water and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 1'-[3-(2-tetrahydropyranyloxy)propyl]-1'-spiro[cyclopropane-1,2-indoline]-3. '-on 0.576 yen is obtained. 1'-[3-(2-tetrahydropyranyloxy)propyl]11'-spiro[cyclopropane-1] obtained above
・Dissolve 0.30% of 2-indoline]-3-one in methanol, add 3% of acetic acid, and heat under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 1'-(
0.12 spiro[cyclopropane-1,2-indoline]-3-one per day is obtained as an oil. Infrared absorption spectrum (liquid film) 3400 ka-1 (hydroxy) 1670 skin-1 (ketone) Example 16 A mixture of 50% oily sodium hydride 0.72 g and dry dimethyl sulfoxide 15 g was cooled on ice while passing through argon gas. While stirring, add 1'H-spiro[cyclopropane-1,2'-indoline]-3'-one 1.59
Add a solution of 15% of dry dimethyl sulfoxide. After stirring at room temperature for 1 hour, a solution of 2.505 ml of ethyl furomoacetate dissolved on 10 ml of dry dimethyl sulfoxide is added while stirring again under ice. After stirring at room temperature for 5 hours, ice water was added to the reaction solution, extracted with chloroform, and the extract was washed with water and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 1'H-spiro[cyclopropane-1,2-indoline]-3-one-1'
- 1.98 ml of ethyl acetate are obtained. Infrared absorption spectrum (Nujol) 1735 Hada-1 (ester) 168 Shuei-1 (ketone) 1'H-spiro[cyclopropane-1] obtained above
2-indoline]-3'-one-r-ethyl acetate 0.4
Dissolve 91 parts of methanol in 10 parts of methanol, add 2 parts of 10% potassium hydroxide aqueous solution while stirring under ice, and stir at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, a small amount of water is added, and while cooling in ice water, IN hydrochloric acid is added to make it acidic. The precipitated crystals were collected in a furnace, washed with water, and then recrystallized from 50% aqueous ethanol to give 0.413 g of 1'-spiro[cyclopropane-1,2-indoline]-3'-one-1'-acetic acid monohydrate. obtain. Melting point 154qo (decomposition) elemental analysis value C, 2 days, 3
C day N as N04 Calculated value 61.27, 5.57, 5.96 Actual value 61
．． 535.32, 5.93 Example 17 While stirring a mixed solution of 30% phosgene in carbon tetrachloride solution of 9.9% and 30% of carbon tetrachloride under ice cooling, r-spiro[cyclopropane-1.2' -Indoline]-3-
Add a solution of 2.39 ml of triethylamine, 1.897 ml of triethylamine, and 50% of dry benzene. After stirring at room temperature for 2 hours, the reaction solution was concentrated to dryness under reduced pressure. 100 g of dry benzene was added to the residue, and ammonia gas was blown in for 1 hour while stirring under ice cooling. Benzene is removed under reduced pressure, water is added to the residue, extracted with chloroform, the extract is washed with water, and then dried over magnesium sulfate. Chloroform was removed, ethanol was added to the resulting crystalline residue, the crystals were collected in an oven, washed with ethanol, and dried for 1 day. ' - 2.25 mg of ruboxamide is obtained. Recrystallize from ethanol. Melting point 210-2120 (decomposition). Elemental analysis value C,. Day,
C day N as bu202 Calculated value 65.334. 13.86 Measured value 65.034.91, 13.82 Example 18 Dissolve 0.478 1'-spiro[cycloproban-1,2-indoline]-3'-one in 10 parts of dry benzene, and dissolve 0.478 parts of methyl isocyanate. .343 evenings added,
Stir at room temperature for 3 hours, then heat to reflux for 6.5 hours. Add 0.343 g of methyl isocyanate and heat to reflux for an additional hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
N-methyl-1'-spiro[cyclopropane-1,2
-indoline]・1-3-one-1'-carboxamide 0
．． Obtain 616 evenings. Recrystallize from methanol. Melting point 1
15-11 is ○ Elemental analysis value C, 2 days, C day N as 2N202 Calculated value 66.6fu 5.59 12.96 Actual value 66
．． 4-5.54 12.82 Example 19 1'-acetyl-4,5-dihydro-5-methyl-rH
- Spiro [furan-3 (thin), 2-indoline]-2.
3-dione 9.08% dimethyl sulfoxide 40 [
2.25 kg of sodium chloride was added, and the mixture was reacted for 2 hours at 155 kg of nitrogen gas. After cooling, add ice water, collect the precipitated crystals in a furnace, and recrystallize from ethanol to obtain 1'-acetyl-5'-methyl-1'
Hiichi Spiro [cyclopropane-1,2-indoline]-
Get 3'-on 6.55 pm. Melting point 137-13800
Elemental analysis value C, 3 days, C days N as 3N02 Calculated value 72.54, 6.096.51 Actual value 72.80 6.296.53 Example 20 4,5-dihydro-1'-propionyl-1'H - Spiro [furan-3 (spot)/2'-indoline]-2/3-
Dissolve 3.12 parts of dione in 12 parts of dimethyl sulfoxide, add 0.78 parts of sodium chloride, and react at 155-160 parts for 2 hours while passing nitrogen gas. After cooling, add ice water, collect the precipitated crystals in a furnace, and recrystallize from ethanol to obtain 1'-propionyl-1'H-spiro[cyclopropane-1,2-indoline]-3'-one 2.0 ml. get. Melting point 172.5 - 173.500 Elemental analysis value C, 3 days, C days N as 3N02 Calculated value 72.546.096.51 Actual value 72.686.11, 6.41 Example 21 r day - Spiro [cyclopropane -1.2-indoline]
Dissolve 1.91 μl of isobutyl chloride in 40 μl of chloroform, add 3.65 μl of triethylamine, and while stirring under ice-cooling, drop a solution of 3.84 μl of isobutyl chloride dissolved in 20 μl of chloroform over 40 minutes. do. Stir on ice for 40 minutes and at room temperature for 2 hours, then leave overnight. Ice water is added to the reaction mixture to separate the chloroform layer, and the aqueous layer is extracted twice with chloroform. Combine the chloroform layers, wash with water, and then dry with magnesium sulfate. The chloroform was removed and the residue was purified by silica gel column chromatography to obtain 1.068 g of 1'-isobutyryl-1'H-spiro[cycloproban-1,2-indoline]-3'-one. Recrystallize from ethanol. Melting point 90-91℃ Elemental analysis value C, 4
Calculated value 73.346.596.11 Actual value 73.296.506.02 Example 22 1'H-spiro[cyclopropane-1,2'-indoline]-3'-one 1. Dissolve 12 parts of chloroform over 30 parts of chloroform, add 3.78 parts of triethylamine, and chlorinate 3.17 parts of chloroacetyl chloride while stirring under ice cooling. A solution dissolved in 20 ml of Form was added dropwise over 30 minutes. After stirring for 30 minutes under ice cooling, ice water is added to separate the chloroform layer, and the aqueous layer is extracted twice with chloroform. Combine the chloroform layers, wash with water, and then dry with magnesium sulfate. The total amount of chloroform extract is about 5
Concentrate to 0' and pass dimethylamine gas through the residue for 20 minutes. Then at room temperature 1. Stir briefly, add ice water to the reaction mixture, separate the chloroform layer, and extract the aqueous layer twice with chloroform. Combine the chloroform layers, wash with water, and then dry with magnesium sulfate. The chloroform was removed and the residue was dissolved in ethyl acetate for 30 minutes.
Dissolve 0.813 ml of maleic acid in 3 ml of ethyl acetate.
Add the solution dissolved in [0]. The precipitated crystals were collected in a furnace to obtain 2.30 g of 1'-dimethylaminoacetyl-rH-spiro[cyclopropane-1,2-indolin]-3-one maleate. Recrystallize from ethanol. Melting point: 162.5 - 163.5 qo (decomposed). Elemental analysis value C, 8 days 2bu 206 C days N Calculated value 59.935.597.77 Actual value 59.505.607.71 Example 23 1 synthesized on exactly the same scale and same operation as Example 22
'-Chloroacetyl-1'-spiro[cyclopropane-1,2-indoline]-13-one in chloroform 50
[While stirring the solution at room temperature, a solution of 5.96 g of piberidine dissolved in 20 g of chloroform was added dropwise between the two powders. After leaving it overnight, add ice water and separate the chloroform layer.
Extract the aqueous layer twice with chloroform. Black. The form layers were combined, washed with water, and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 1'-piberidinoacetyl-1'-spiro[cyclopropane-1.
Crystals of 2'-indoline]-3'-one were dissolved in ethyl acetate 2
A solution of 0.557 g of maleic acid dissolved in 30 g of ethyl acetate is added. The precipitated crystals are collected in a furnace to obtain a 2.0-molecular acid salt of 1'-piberidinoacetyl-1'H-spiro[cyclopropaso-1,2'-indoline]-gon. Recrystallize from ethanol. Melting point 148-149qo Elemental analysis value C2, day 24
C day N as N206 Calculated value 62.996.047.00 Actual value 62.33, 6.00, 6.80 Example 24 1' day-spiro [cyclopropane-1,2'-indoline]-3'-one 1 Dissolve 59% of 2-bromopropionyl bromide in 50% of chloroform, add 8.1% of triethylamine, and stir under ice cooling to dissolve 13.0% of 2-bromopropionyl bromide.
A solution prepared by dissolving water in 50 parts of chloroform was added dropwise to each of the four females. After stirring for 1 hour at room temperature under ice-cooling, ice water is added to separate the chloroform layer, and the aqueous layer is extracted twice with chloroform. Combine the chloroform layers, wash with water, and then dry with magnesium sulfate. The chloroform extract was concentrated to a total volume of about 100 ml, and dimethylamine gas was passed through the residue for 40 minutes under ice cooling. Thereafter, the mixture was stirred at room temperature for 1 hour, chloroform was distilled off, ice water was added to the residue, and the mixture was extracted three times with ethyl acetate. Wash the ethyl acetate extract once with water and once with saturated brine, and dry over magnesium sulfate. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography to obtain 1'-(2-dimethylaminopropionyl)-1'H.
-Spiro[cyclopropane-1.2'-indoline]-13'-one is dissolved in 30 parts of ethyl acetate, and a solution of 1.16 parts of maleic acid dissolved in 5 parts of ethyl acetate is added. The precipitated crystals were collected in a furnace and converted into 1'-(2-dimethylaminopropionyl)-rH-spiro[cyclopropane-1
・2-indoline]-13'-one maleate 2.4
Get 9 evenings. Recrystallize from ethanol. Melting point 160-16100 (decomposition). Elemental analysis value C, Rainbow 22N206
As C day N Calculated value 60.95 5.92, 7.48 Actual value 60
．． 91, 6.00, 7.54 Example 25 1'H-spiro [Sik. Propane-1,2'-indoline]-3-one 0.47
Dissolve 150% of n-butyllithium in 15% of dry tetrahydrofuran, cool to -70% in an argon stream, and dissolve 11% of n-butyllithium.
．． Add 92 (15% hexane solution) and stir for 5 minutes. To this, add a solution of 0.651 g of ethyl chlorocarbonate dissolved in 5 g of dry tetrahydrofuran, and add 17 g of ethyl chlorocarbonate.
Stir for 30 minutes at 0qo. Add water to the reaction solution,
Extract with ethyl acetate. Wash the extract once with water and once with saturated saline, and dry over magnesium sulfate. Ethyl acetate was removed, the residue was purified by silica gel column chromatography, and 1'-day-spiro [cyclopropane-1
-0.565 ml of 2'-indoline]-3'-one-1'-ethyl carbonate was obtained. Recrystallize from cyclohexane.
Melting point 87.5-88.5q0. Elemental analysis value C, 3 days,
C day N as 8N03 Calculated value 67.52, 5.67, 6.06 Actual value 67
．． 435.635.92 Example 26 Dissolve 0.478 g of 1'H-spiro[cyclopropane-1,2-indoline]-3'-one in 5 parts of pyridine, and dissolve 0.688 g of methanesulfonyl chloride in 3 parts of pyridine.
Add the solution dissolved in the water, stir at room temperature for 6 hours, and then leave to stand for 2 days. Ice water is added to the reaction mixture and extracted with ethyl acetate. The extract is washed twice with water and once with saturated brine, and dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.64 g of 1'-mesyl-1'-spiro[cycloproban-1,2-indoline]-3'-one. Recrystallize from ethanol. Melting point 142-14*○. Elemental analysis value C,. Day,. C day N as N03S Calculated value 55.634.67, 5.91 Actual value 55.594.695.88 Example 27 1' day-spiro [cyclopropane-1,2-indoline]-3'-one 1.44 night Dissolved in 15M pyridine,
A solution of 2.58 g of p-toluenesulfonyl chloride dissolved in 9 g of pyridine is added and left to stand for 2 days. Ice water is added to the reaction mixture and extracted with ethyl acetate. The extract is washed twice with water and once with saturated brine, and dried over magnesium sulfate. Ethyl acetate was removed, and the residue was purified by silica gel column chromatography to obtain 2.5 g of 1'-tosyl-1'-spiro[cyclopropane-1,2-indoline]-13-one. Recrystallize from methanol. Melting point 125-12600. Elemental analysis value C, 7 days,
Assuming 03, C day N Calculated value 65.17, 4.82, 4.47 Actual value 65
．． 37, 4.64, 4.31 Example 28 A mixture of 50% oily sodium hydride 0.576 g and dry dimethyl sulfoxide 10 ml was stirred at room temperature under argon gas for 1'-spiro[cyclopropane-1. 2-indoline]-3'-one 0.478
Then add a solution of dimethyl sulfoxide 5 dissolved in dry dimethyl sulfoxide. After stirring at room temperature for 30 minutes, a suspension of 0.865 mg of 2-dimethylaminoethyl chloride hydrochloride in dry dimethyl sulfoxide was added, and the mixture was stirred at room temperature for 3 minutes at 5 ml.
Stir for 1 hour. Ice water is added to the reaction solution, extracted with chloroform, and the extract is washed with water and dried over magnesium sulfate. Remove the chloroform, dissolve the residue in 30 ml of ethanol, and add 0.27 ml of oxalic acid to 30 ml of ethanol.
Add the solution dissolved in the secretion. The precipitated crystals were filtered, washed with ethanol and ethyl ether, and 1'-(2-dimethylaminoethyl)-1'H-spiro[cyclopropane-
Oxalate of 1,2'-indoline]-3'-one 0.
Get 795 evenings. Recrystallize from 95% aqueous ethanol. Melting point 183qo (decomposed). Elemental analysis value C, 6 days 2N2
Calculated value 59.996.298.75 Actual value 59.836.358.96 Example 29 A mixture of 1.16% 50% oily sodium hydride and 20% dry dimethyl sulfoxide was added under argon gas. While stirring at room temperature, a solution of 1.28 g of 1'H-spiro[cyclopropane-1,2-indoline]-13'-one in 10 g of dry dimethyl sulfoxide is added. After stirring at room temperature for 30 minutes, 2.07 g of 2-diethylaminoethyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Add ice water to the reaction solution, extract with ethyl acetate,
After washing the extract with water, it is dried with magnesium sulfate. Ethyl acetate was distilled off, the residue was dissolved in 40 parts of ethanol, and a solution of 0.72 parts of oxalic acid dissolved in 40 parts of ethanol was added. The precipitated crystals were collected in a furnace and washed with ethanol and ethyl ether to obtain 1'-(2-jethylaminoethyl)-1'-spiro[cyclopropane-1,2'-indoline]-3'-one oxalate. 2. Obtained the 14th evening. Recrystallize from ethanol. Melting point 15600 (decomposition)
. Elemental analysis value C, 8 days 24N205 C days N Calculated value 62.056.948.04 Actual value 61.82, 6.9f 8.05 Example 30 50% oily sodium hydride while passing argon gas 0.216 While stirring a mixture of 10 parts of dry dimethyl sulfoxide at room temperature, 0.47% of 1'H-spiro[cyclopropane-1,2'-indoline]-13'-one was added.
Add a solution of 8 parts dissolved in 10 parts of dry dimethyl sulfoxide to the skin. After stirring for 20 minutes at room temperature, 0.582 g of 2-chloroacetopiveridine was added to 10 g of dry dimethyl sulfoxide.
1. Add the solution dissolved in the secretion and incubate at room temperature. Stir current time. Ice water is added to the reaction solution, extracted with ethyl acetate, and the extract is washed with water and dried over magnesium sulfate. Ethyl acetate was removed, and the residue was purified by silica gel column chromatography to obtain 1'-day-spiro[cyclopropane-
0.637 g of 1,2'-indoline)-3'-1'-acetopyvelizide is obtained. Recrystallize from benzene. Melting point: 148.5 - 149.5 pm. Elemental analysis value C,
C day N as 7 days 2bu 202 Calculated value 71.80, 7.09 9.85 Actual value 71
．． 897.1 S9.82 Example 31 While passing argon gas, add 0.216 g of 50% oily sodium hydride and 10 g of dry dimethyl sulfoxide.
While stirring the mixture, add a solution of 0.478 g of 1'H-spiro[cyclopropane-1,2-indoline]-3-one in 5 g of dry dimethyl sulfoxide. The mixture is stirred at room temperature for 20 minutes, then a solution of 0.823 g of isobutyl bromide in 5 g of dry dimethylformamide is added. Stir the mixture at room temperature for 6 hours. Add ice water and extract with chloroform. Wash the chloroform extract with water and dry with magnesium sulfate. After chloroform was distilled off and the residue was purified by silica gel column chromatography, 1'-isobutyl-
1'-spiro[cyclopropane-1,2-indoline]-3-one is obtained as an oil. Infrared absorption spectrum (liquid film) 1685ka-1 (ketone), 1615ka-1 (aromatic hydrocarbon) nuclear magnetic resonance spectrum (CDC13 medium, chest),
0.90 (double line, thin), 1.20 (single line, 'H),
1.6-2.4 (multiple line, IH), 2.92 (double line,
), 6.6-7.8 (multiplet, 4H) Reference example 1 Asotranilic acid 68.6%, Sodium carbonate 132.2%
In the evening, a mixture of 400 g of water was stirred at room temperature for 1 hour, and then 103.2 g of Q-bromo-butyrolactone was added dropwise under ice-cooling. After stirring under ice cooling for 5 hours and at room temperature for 24 hours, the mixture was made acidic by adding hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. Ethyl acetate was removed, ethyl ether was added to the residue to crystallize it, and the precipitated crystals were collected in a furnace to give Q-[(2-carboxyphenyl)amino].
- Obtain butyrolactone. Melting point: 197-198. ○
Elemental analysis value C,. Day,. C day N as N04 Calculated value 59.72, 5.01, 6.33 Actual value 59
．． 32, 4.996.18 Reference Example 2 In the method of Reference Example 1, N-
Reaction with methylanthranilic acid yields Q1[(2-carpoxyphenyl)methylami/]y-butyrolactone. Melting point 112.5-114℃ Elemental analysis value C, 2 days, 3N
04 as C day N Calculated value 61.27, 5.57, 5.96 Actual value 61
．． 37, 5.595.85 Reference Example 3 In the method of Reference Example 1, 5-methoxyanthranilic acid was reacted instead of anthranilic acid to produce Q1[(2-methoxybenyl)amino]-y - Obtain butyrolactone. Melting point 206.5-20800 (decomposition). Elemental analysis value C
, 2 days, 3NQ as C day N Calculated value 57.31, 5.22, 5.58 Actual value 57
．． 22, 5.37, 5.50 Reference Example 4 In the method of Reference Example 1, instead of anthranilic acid, 4
・React with 5-dimethoxyanthranilic acid to form Q1 [
(2-carboxy4,5-dimethoxyphenyl)amino]-y-butyrolactone is obtained. Melting point: 214 pm (decomposition). Elemental analysis value C, 3 days, 5N
06 as C day N Calculated value 55.51, 5.384.98 Actual value 55.595.30, 4.97 Reference example 5 Q-(2-carboxyphenyl)amino]y-butyrolactone 2.22 days Dissolve over 1 ow of trifluoroacetic anhydride and stir at room temperature for 4 hours. Concentrate the reaction solution under reduced pressure, and add 20% of acetic anhydride to the resulting residue.
115 oo
Stir for 2 minutes. Add cold water to the reaction solution, extract with chloroform, wash with water, and dry with magnesium sulfate.
After removing the chloroform, the residue was purified by silica gel column chromatography to obtain 4.5-dihydro 1'
Japan Spiro [Fran 13 (ancestor), 2-Indoline] -2
・Obtain 3-dione. Melting point 136.5-137.5°C.
Elemental analysis value C,. Day 9N03 as C Day N Calculated value 65.02, 4.406.89 Actual value 64.684.336.81 Reference example 6 Q-[(2-carboxyphenyl)amino]-y-butyrolactone 6.64 evening, anhydrous A mixture of 90 parts of acetic acid and 18 parts of triethylamine was heated under reflux for 1 hour while passing nitrogen gas. Concentrate under reduced pressure, add ice water to the residue, collect the precipitated crystals in a furnace, wash thoroughly with water, dry, and dissolve 1'-acetyl-4.
5-dihydro 1' day-spiro [furan-3 (9H).
2-indoline]-2,3-dione 6.7 units are obtained. Recrystallize from ethanol. Melting point 159-16000. Elemental analysis value C. 3 days... C day N as N04 Calculated value 63.67, 4.52, 5.71 Actual value 63
．． 704.435.63 Reference example 7 Q-[(2-carboxyphenyl)methylamino]-y
- Butyrolactone 0.471 ml, a mixture of 5 ml of acetic anhydride and 1 ml of triethylamine was heated under reflux for 30 minutes while passing nitrogen gas. Concentrate under reduced pressure, add ice water to the residue, collect the precipitated crystals in a furnace, wash well with water, dry, and give 4,5-dihydro-1
'-Methyl-1'H-spiro [Furan-3 (thin)・2'
-Indoline] 12.3-dione 0.363 yen is obtained.
Recrystallize from ethanol. Melting point: 184-185oo.
Elemental analysis value C, 2 days. C day N as N03 Calculated value 66.3fu5.1u6.45 Actual value 66.3 & 4.71, 6.30 Reference example 8 In the method of Reference example 6, Q1 [(2-carboxyphenyl)-amino]- Q-[(2-carpoxy-4-methoxyphenyl)amino] instead of y-butyrolactone
-Y-butyrolactone is reacted to obtain 1'-acetyl-4,5-dihydro-5-methoxy-1'-spiro[furan-3(fine).2-indoline]-2,3-dione. Melting point 136-13800. Elemental analysis value C, 4 days, 3N
Calculated value 61.094.705.09 Actual value 61.134.604.96 Reference example 9 In the method of Reference example 6, Q-[(2-carboxyphenyl)amino]-y-butyrolactone Q1 instead of
(2-carboxy4,5-dimethoxyphenyl)amino]1y-butyrolactone is reacted to produce 1'-acetyl-4,5-dihydro-5,6-dimethoxy1'-spiro[furan-3(3H).2- Indoline〕-2・3
- Obtain dione. Melting point 226-228q0. Elemental analysis value C, 5 days, 5N
06 as C day N Calculated value 59.01, 4.9 4.59 Actual value 58. Salmon fish 4.744.55 Reference example 10 4.5-dihydro rH-spiro [furan-3 (pan),
2'-indoline]-2,3-dione 0.61 99
Dissolve in 9% formic acid and add 3% acetic anhydride while stirring under ice cooling. After stirring under ice for 30 minutes and at room temperature for 2 hours, ice water was added and the precipitated crystals were collected in a furnace. After washing with water, the obtained crude crystals were recrystallized from ether/al to obtain 1'-formyl-4.・5
-dihydro-1'H-spiro [furan-3 (thin), 2-
[indoline]-2.3-dione 0.461 yen is obtained. Melting point 198.5-200.5°C. Elemental analysis value C, 2 days 9
C day N as N04 Calculated value 62.343.92, 6.06 Actual value 62.503.87, 5.96 Reference example 11 4,5-dihydro 1'H-spiro [furan-3 (group)
・2-indoline]-2,3-dione 0.61 yen, sodium bicarbonate 0.375 yen, 4-chlorobenzoyl chloride 1.05 yen, zinc chloride 0.01 yen, chloroform 1 yen
0' mixture was heated to reflux for 4 hours. (Add 0.01 g of zinc chloride after 2 and 3 hours.
) After cooling, add ice water to the reaction mixture, extract with chloroform, wash the extract with saturated aqueous sodium bicarbonate solution, and dry over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 1
'-(4-chlorobenzoyl)-4,5-dihydro-r
H-spiro [furan-3 (thin)/2-indoline]-2
・Obtain 0.829 3-dione. Recrystallize from ethanol. Melting point: 151-152.5q○. Elemental analysis value C
, 8th, 2N04CI, C day N calculation value 63.20
3.54, 4.10 Actual value 63.31, 3.504.06 Reference example 12 1'-acetyl-4,5-dihydro 1'-spiro [
Dissolve 4.91 g of furan-3(2'-indoline)-2,3-dione in 50 g of acetonitrile, and add 80 g of a 3.7% w/v chlorine acetonitrile solution dropwise under ice cooling. . After stirring for 2 hours under ice-cooling and 16 hours at room temperature, it was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to give 1'-acetyl-5-chloro-4,5-dihydro 1.
'Japan Spiro [furan-3 (general), 2-indoline]-
2,3-dione is obtained. Melting point 178.5-180°C. Elemental analysis value C, 3 days, C day N as 04CI Calculated value 55.833.60, 5.01 Actual value 55.933.495.03 Reference example 13 In the method of Reference example 1, instead of anthranilic acid' This 5-methylanthranilic acid is reacted to obtain Q1[(2-carboxy-4-methylphenyl)amino]-y-butyrolactone. Melting point: 199-200 pm. Elemental analysis value C. 2nd, 3N
04 as C day N Calculated value 61.27, 5.57, 5.96 Actual value 61
．． 135.61, 5.99 Reference Example 14 In the method of Reference Example 6, Q-[(
2-Carpoxy 4-methylphenylated amino]-y-
By reacting butyrolactone, 1'-acetyl-4.5
-dihydro-5'-methyl-1'H-spiro[furan-3(3H).2-indoline]-2.3'-dione is obtained. Melting point: 176-1770○. Elemental analysis value C, 4 days, 3N
04 as C day N Calculated value 64.805.055.40 Actual value 64.604.955.43 Reference example 15 Q1[(2-carboxyphenyl)amino]y-butyrolactone 6.64%, propionic anhydride 25 In the evening, a mixture of 10 parts of triethylamine was stirred at 140°C for 1 hour under argon gas. Add ice water to the reaction mixture, extract with chloroform, wash the extract with water, and then dry over magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to obtain 4,5-dihydro-1'-propionyl-1'-spiro[furan-3(9H).2-indoline]-2,3-dione. 6.34 evening is obtained. Recrystallize from ethanol. Melting point 140-14100. Elemental analysis value C, 4 days, C day N as 3N04 Calculated value 64.805.0fu 5.40

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom, halogen, lower alkyl group or lower alkoxy group, is (1) a hydrogen atom, (2) a phenyl group substituted with a lower alkoxy group, a benzoyl group substituted with a halogen, a hydroxyl group, -CON(CH_2)_m [wherein m represents an integer of 4 to 6] A lower alkyl group optionally substituted with a carbamoyl group or a di-lower alkylamino group represented by (3) R^3CO- (wherein R^3 is a hydrogen atom, a di-lower alkylamino group or -N(CH_2 )
__n (in the formula, n represents an integer of 4 to 6) represents a lower alkyl group optionally substituted with a substituted amino group, a lower alkoxy group, or a phenyl group substituted with a halogen), (4) R^4SO_2- (in the formula, R^4 represents a lower alkyl group or a phenyl group substituted with a lower alkyl group) or (5) ▲There are numerical formulas, chemical formulas, tables, etc.▼ (in the formula, R^4 5, R^6 are the same or different and represent a hydrogen atom or a lower alkyl group)] [cyclopropane-1,2'-
Indolin]-3'-ones and their non-toxic salts.