KR810001073B1 - Process for preparing spirobenzofuranone compounds - Google Patents

Abstract

Title complds (I; A = alkyl, NO2, halo, amino, optionally substituted OH, acyl, sulfamoyl), useful as medicine, were prepd. by decarboxylic acid from II. Thus, 4',5'-dihydrospiro [benzo[b furan-2(3H),3'(2'H)-furan -2',3-dione 1.75 g, Nacl 552mg and dimethylsulfoxide 9ml were stirred for 2hr at 155oC under N2, poured in cold water, and the obtained precipitate was filtrated and recrystallized in EtOH-H2O(3:2) to give 1.21 g spiro[benzo[b furan-2(3H),1' -cyclopropan -3-one (m.p. 89-90.5oC).

Description

Process for the preparation of sprobenzofuranone compound

The present invention relates to a method for preparing a spiro compound having a novel skeletal structure useful as a pharmaceutical or pharmaceutical preparation intermediate. In particular, the present invention is a general formula

(In the above formula, Ring A represents a benzene ring or a naphthalene ring, and the benzene ring or naphthalene ring is unsubstituted, a lower alkyl group nitro group, a halogen atom, an amino group which may be substituted, or a substitution). May be substituted with at least one of hydroxyl, acyl and sulfamoyl groups).

Regarding the general formula (I), the benzene ring or the naphthalene ring represented by the ring A may not be substituted or may be substituted by any of the above-mentioned substituents. We will now describe such substituents in detail. Lower alkyl groups as substituents include alkyl groups having 1-6 carbon atoms (e.g., methylethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, n-hexyl , 2-methylpentyl, 2-ethylbutyl, etc.), and examples of the halogen element include chlorine, bromine, fluoro and iodine. As an amino group which may be substituted, an amino group, a mono- or di-alkylamino group, an acylamino group, a sulfonylamino group, a cycloamino group, etc. are mentioned. Such mono- or di-alkylamino groups are alkyl groups having 1 to 4 carbon atoms and are mono- or di-substituted amino groups, ie methylamino, ethylamino, n-propylamino-isopropylamino, n-butylamino, dimethyl Amino, diethylamino, di-n-propylamino, methylethylamino group, etc. are mentioned. Examples of the acylamino group include alkanoylamino groups having about 2-4 carbon atoms (eg, acetylamino, propionylamino, n-butyrylamino, isobutylylamino group, etc.). The sulfonyl amino group includes, for example, an alkanesulfonylamino group (eg, methanesulfonylamino, ethanesulfonylamino group, etc.) having about 1 to 4 carbon atoms. As a cycloamino group or 5- or 6-cyclic cycloamino group which may contain 0, for example, a pyrrolidinyl, a piperidino, a piperazinyl, a morpholino group, etc. are mentioned, A piperazinyl group is further its N atom at position 4 is an alkyl group having 1 to 4 carbon atoms (e.g., methyl or ethyl group), a phenyl-C _1-4 alkyl group (e.g., benzyl group) or an alkanoyl group having 2 to 4 carbon atoms (e.g., acetyl, propionyl group It may be substituted by).

Examples of the hydroxyl group which may be substituted include a hydroxyl group, an alkoxy group, an aralkyloxy group, an acyloxy group and the like. In particular, the alkoxy group preferably has 1-3 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy group), and the alkoxy group The group may be further substituted, for example, with mono- or di-C _1-4 alkylamino groups and the like (eg methylamino, ethylamino, dimethylamino, diethylamino). Aralkyloxy groups are, for example, phenyl-C _1-4 alkyloxy groups (eg benzyloxy, phenethylyloxy). The acyloxy group is, for example, an alkanoyloxy group (eg, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy group) having about 2-6 carbon atoms or a benzoyloxy group. The acyl group is, for example, an alkanoyl group having 2 to 6 carbon atoms (eg, an acetyl, propionyl, n-butylyl, isobutyryl group) or a benzoyl group. These substituents of the benzene ring or naphthalene as ring A mentioned above may be substituted from one to four identical or different at any position where the ring may be substituted. The benzene ring may be substituted at its 5- or 6-position (more preferably 5-position) by an amino group (particularly mono- or di-C _1-4 alkylamino group) which may be substituted or an acyl group (particularly C ₂ More preferably a _-4 alkanoyl group). The spiro compound (I) of this invention is manufactured by decarbonation-reacting the compound which has the following general formula (II), for example.

(Wherein A is as defined above)

This reaction is generally carried out in the presence of a catalyst which catalyzes the decarbonation reaction. Good catalysts for this purpose include metal halides (eg sodium chloride, sodium bromide, sodium iodide, potassium bromide, potassium chloride, potassium iodide, etc.) and quaternary ammonium salts (eg tetramethylammonium bromide, etc.). At the reaction temperature, if desired to control the reaction rate, the reaction is carried out at a higher or lower temperature but generally has a reaction temperature between about 100 ° C. and 200 ° C., in particular between about 140 ° C. and 160 ° C. Cleaning the reaction vessel with an inert gas (eg nitrogen or argon) is sometimes effective to suppress side reactions and increase yield. This reaction is customarily carried out in a suitable solvent. When using any solvent that does not interfere with the reaction, it is generally advantageous to use a solvent having a boiling point higher than the reaction temperature (eg dimethyl sulfoxide, N, N'-dimethylformamide, hexamethylphosphoamide). Among the spiro compounds (I) of the present invention, a compound having one or more substituents in ring A includes a compound (I) in which ring A is not substituted or a compound (I) having at least one hydrogen atom in ring A. It is prepared by subjecting the known alkylation reaction, nitration reaction, halogenation reaction, acylation reaction according to the kind of substituent to be used.

In addition, compound (I) in which the substituent (s) of A is an amino group (s) is catalytically reduced after nitrating compound (I) having hydrogen atom (s) at the position (s) to which amino group (s) are introduced. It is prepared by carrying out a reduction reaction such as a reaction. Furthermore, the substituent (s) of ring A of compound (I) may be changed to other substituent (s) by a known reaction. For example, compound (I) in which the substituent (s) of ring A is mono or di-alkylamino group (s) can react with compound (I) in which the substituent (s) are amino group (s), i.e., a carbonyl compound (e.g., It can be prepared by reducing with a metal hydride such as sodium cyanoborohydride in the presence of formalin acetaldehyde, acetone), by catalytic catalytic reduction, or by reacting with a halogenated alkyl to give mono or dialkylation. Compounds (I) having mono or dialkylamino group (s) can also be catalyzed by platinum or Raney-nickel in the presence of carbonyl compounds mentioned above for compounds (I) wherein the substituent (s) are nitro group (s). It can be prepared by catalytic catalytic reduction using. The preparation described above of compound (I) having a mono- or di-alkylamino group can be explained by way of example in the following scheme.

Wherein n is 1 or 2 and R ¹ is a mono- or di-alkylamino group as defined above.

The target compound (I) prepared in the same manner as described above can be separated and purified from the reaction mixture by ordinary separation and purification means (e.g., type, recrystallization, tube chromatography, etc.). Moreover, compound (I) may be isolate | separated into the pharmaceutically suitable salt according to the kind of substituent of ring A. For example, when the substituent is an amino group (e.g., an amino group, a mono or dialkylamino group, a cycloamino group), compound (I) is an acid addition salt (e.g. hydrochloride or hydrobromide, such as mineral salts, citrate, oxalic acid) Organic acids, such as salts), and the substituent may be separated as an alkali metal salt (eg, sodium salt, potassium salt, etc.).

Spiro compound (I) according to the present invention is a compound having a new skeletal structure, for example, gastric juice separation inhibitory action, anti-inflammatory action, analgesic action and the like for mammals (eg, humans, mice, mice, morphotes, dogs, pigs). For example, it is useful as an anti-ulcer agent, anti-inflammatory agent, analgesic agent for diseases such as duodenal ulcer, acute gastritis, low back pain and arthritis. When used as such a medicament, the compound (I) can be safely administered orally or parenterally as it is or in a convenient formulation such as tablets, powders, capsules, injections, drugs, etc. together with a known carrier or diluent. . The dosage varies depending on the subject to be administered, the serious injury, and the route of administration, but usually, as a therapeutic agent for stomach, duodenal ulcer or acute gastritis, oral administration of Compound (I) is about 1-20 mg./kg body weight daily. It is recommended to administer 1-3 times. The raw material compound (II) used in the method of the present invention can be produced by, for example, the following synthesis method or a method similar thereto.

1) hydrolysis, lactonation

2) (CH ₃ CO) ₂ O. (C ₂ H ₅ ) ₃ N

(A has the same definition as before).

Hereinafter, the present invention will be described in more detail according to pharmacological test examples, reference examples, examples and the like, but the scope of the present invention is not limited thereto.

Pharmacological test

The pharmacological activity of the compound (I) of the present invention was assayed in the gastric secretion inhibition test of rats as follows.

Gastric secretion inhibition was measured according to the method of Shay's "Gastrointestinal Disease" 5, 43 (1945).

Five male Sprague-Dawley rats (each body weight 110-130) were used for the control and test groups. During the 18 hours before the test, rats were not fed except water. The pylorus was tied under ether anesthesia, and 50 mg / kg of each test compound dose was administered in the duodenum at the time of entrainment. After 3 hours of binding, rats were killed, gastric secretions were collected, and centrifuged at 3500 r.p.m for 10 minutes. The results are shown in the table below.

Furthermore, these compounds were orally administered with 500 mg / kg of 5 ICR mice. No flock of mice died in seven days.

[table]

Gastric Secretion Inhibition in Rats

Reference Example 1

To a mixture of 15.2 g of methyl salicylate, 12 g of sodium hydroxide and 150 ml of N, N-dimethylformamide was added 25 g of α-bromo-r-butyrolacto under ice cooling, followed by stirring at room temperature for 28 hours. Dilute hydrochloric acid is added to the reaction mixture to make it acidic and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residue is dissolved in 30 ml of methanol, added with 150 ml of 20% aqueous sodium hydroxide solution and stirred at 55 ° C. for 30 minutes. 60 ml of concentrated hydrochloric acid is added to the reaction mixture to make it acidic, and the resulting precipitate (salicylic acid) is filtered off and the filtrate is extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residue was vacuum dried with phosphorus pentoxide for 24 hours and recrystallized from ethyl acetate-n-nucleic acid (2: 1) to give 8.0 g of colorless acicular crystal of α-[(2-carboxyphenyl) oxy] -r-butyrolactone. You get Melting point 113-115 ° C. (measured by Hot-Plate method and melting point is determined in the following examples in the same way)

Elemental Analysis Value, as C ₁₁ H ₁₀ O ₅

Calculated: C, 59.46; H, 4.54

Found: C, 59.21; H, 4.51

Reference Example 2

18.7 g of 5-chlorosalicylic acid methyl ester was obtained in the same manner as in Reference Example 1 to obtain 9.3 g of a colorless needle crystal of α-[(2-carboxy-4-chlorophenyl) oxy] -r-butyrolactone. Melting point 159-169.5 ℃

Elemental Analysis Value, as C ₁₁ H ₉ ClO ₅

Calculated: C, 51.48; H, 3.53; Cl, 13.82

Found: C, 51.22; H, 3.50; Cl, 13.70

Reference Example 3

To a 200 ml solution of 16.6 g of 3-methylsalicylic acid methyl ester of dimethylformamide, 5.3 g of sodium hydride (50% Bayol 85 suspension) was added, followed by 18.2 g of dimethylformamide a-bromo-r-butyrolactone under ice cooling. ML solution is added dropwise. The mixture is stirred at room temperature for 10 hours, and then a small amount of water is added to the reaction mixture, and the solvent is distilled off under reduced pressure.

60 ml of 20% aqueous sodium hydroxide solution was added to the residue, followed by stirring at 50-60 ° C. for 1 hour. 40 ml of concentrated hydrochloric acid is added to the reaction mixture to make it acidic, and the precipitated crystals are filtered to recover unreacted 3-methylsalicylic acid. The filtrate was extracted with ethyl acetate, washed with water and dried to remove the solvent under reduced pressure, and the residue was dried over 50 hours at 50 ° C. with phosphorus pentoxide, and then recrystallized from ethyl acetate-hexane to give α-[(2-carboxy-6 12 g of colorless acicular crystals of -methylphenyl) oxy] -r-butyrolactone are obtained. Melting Point is 129-131 ℃

Elemental Analysis Value, as C ₁₂ H ₁₂ O ₅

Calculated: C, 61.01; H, 5.12

Found: C, 61.00; H, 5.12

Reference Example 4

22 g of 3,5-diclosalicylic acid methyl ester was reacted as in Reference Example 3 to obtain 14 g of colorless crystals of α-[(2-carboxy-4,6-dichlorophenyl) oxy] -r-butyrolactone. Melting Point is 129-131 ℃

Elemental Analysis Value, as C ₁₁₈ HCl ₂ O ₅

Calculated: C, 45.38; H, 2.77

Found: C, 45.43; H, 2.66

Reference Example 5

To a mixture of 32 g of 5-benzoxysalicylate methyl ester, 17 g of anhydrous potassium carbonate, and 500 ml of acetone was added 30.7 g of α-bromo-r-butyrolactone under ice cooling and heated to reflux for 15 hours. After cooling, acetone is distilled off and hydrolyzed by adding 10% methanolic sodium hydroxide to the residue. The reaction mixture is made acidic with hydrochloric acid and extracted as ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is taken up in dioxane (300 mL) -benzene (200 mL) and the solution is heated to reflux with distillation of the resulting water in the presence of P-toluenesulfonic acid (30 g). The solvent is distilled off and the residue is diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent, and the residue was recrystallized from ethyl acetate to give 21.5 g of colorless acicular crystal of α-[(2-carboxy-4-benzyloxyphenyl) oxy] -r-butyrolactone. Get Melting Point is 120-122 ℃

Elemental Analysis Value, as C ₁₈ H ₁₆ O ₆

Calculated: C, 65.85; H, 4.91

Found: C, 65.86; H, 4.96

Reference Example 6-12

The compound obtained by the method similar to the reference example 5 is shown below.

Reference Example 13

51 g of 4-acetylamino-5-chloro-2-hydroxybenzoic acid methyl ester and 36.8 g of anhydrous potassium carbonate were suspended in 350 ml of N, N-dimethylformamide and added to 55 g of α-bromo-r-butyrolactone and 60 Stir at 12 ° C. for 12 hours and mix. The solvent is evaporated under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to remove the solvent. The residue is taken up in chloroform and attached to silica gel column chromatography. Elution as chloroform gives 32 g of α-[(5-acetylamido-4-chloro-2-methoxycarbonylphenyl) oxy] -r-butyrolactone of the pale yellow prism crystal recrystallized from methanol. Melting Point is 118-119 ℃

Elemental Analysis, C ₁₄ H ₁₄ O ₆ NCl

Calculated: C, 51.31; H, 4.31; N, 4.27

Found: C, 51.24; H, 4. 26; N, 4.16

Reference Example 14

63 g of 4-acetylamino-2-hydroxybenzoic acid methyl ester are reacted in the same manner as in Reference Example 13, and the product is attached to silica gel column chromatography to differentiate into two fractions. The crystals obtained in pollen 1 are recrystallized from methanol to obtain 1.4 g of 6-acetylamino-4 ', 5'-dihydrospiro [benzo [b] -furan] -2', and 3-dione as colorless plate crystals. Melting Point is 220-234 ℃

Elemental Analysis Value, as C ₁₃ H ₁₁ O ₅ N

Calculated: C, 59.77; H, 4. 24; N, 5.36

Found: C, 59.71; H, 4. 21; N, 5.28

From pollen 2, 35 g of pale yellow oily α-[(5-acetylamino-2-methoxy carbonylphenyl) oxy] -r-butyrolactone is obtained. This oil can be added to the next step without refining.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.10 (3H, s, NCOCH ₃ ), 2.65 (2H, m, CH ₂ ), 3.83 (3H, s, COOCH ₃ ), 4.45 (2H, m, OCH ₂ ), 4.98 (1H, t, OCHCO), 7.09 (1H, d, aromatic ring H), 7.66 (1H, s, aromatic ring H), 7.73 (1H, d aromatic ring H).

Reference Example 15

24.4 g of α-[(2-carboxy-6-methylphenyl) oxy] -r-butyrolactone are added to 120 ml of fuming nitric acid at 40 캜 or lower. The reaction solution was poured into iced water, and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized with methanol to give α-[(2-carboxy-6-methyl-4-nitrophenyl) oxy] -r-butyro as a pale yellow prism crystal. Obtain 20.3 g of lactone. Melting point 210 deg.

Elemental Analysis Value, as C ₁₂ H ₁₁ O ₇ N

Calculated: C, 51.25; H, 3.94; N, 4.98

Found: C, 51.16; H, 3.93; N, 4.82

Reference Example 16

Reaction of methyl salicylic acid methyl ester (3.04) with α-bromo-r-butyrolactone in the same manner as in the corresponding step of Reference Example 1 was recrystallized from methanol to give α-[(2-methoxycarbonylphenyl) as a colorless needle. 3.3 g of oxy] -r-butyrolactone are obtained. Melting point is 62-87 ℃

Elemental Analysis Value, as C ₁₂ H ₁₂ O ₅

Calculated: C, 61.01; H, 5.12

Found: C, 60.98; H, 4.99

Reference Example 17

A mixture of 1.38 g of α-[(2-carboxyphenyl) oxy] -r-butyrolactone, 15 ml of acetic anhydride and 3 ml of triethylamine was stirred for 3.5 hours at 140 ° C. in a nitrogen stream, and the solvent was distilled off under reduced pressure. . The residue was added to tube chromatography using 32.5 g of silica gel and carbon tetrachloride-acetone (10: 1), and the desired pollen was collected, concentrated under reduced pressure, and recrystallized from n-hexane-ethyl acetate (3: 1). 633 mg of colorless needles of 5'-dihydrospiro [benzo [b] -furan-2 (3H) and 3 '(2'H) -furan] -2', 3-dione were obtained. Melting Point is 111-111.5 ℃

Elemental Analysis Value, as C ₁₁ H ₈ O ₄

Calculated: C, 64.70; H, 3.95

Found: C, 64.74; H, 3.70

Reference Example 18-29

The compound obtained by the method similar to the reference example 17 is shown below.

(Ph in the table represents a phenyl group).

Reference Example 30

A mixture of 23 g of α-[(5-acetylamino-4-chloro-2-methoxycarbonylphenyl) oxy] -r-butyrolactone, 46 ml of triethylamine and 230 ml of acetic anhydride was added at 120 ° C. for 5 hours. Heat. The solvent was evaporated under reduced pressure, and the residue was poured into iced water, and the precipitated crystals were collected by filtration, washed with water and dried and then recrystallized from til to give 6-diacetylamino-5-chloro- as a colorless columnar crystal. 6.8 g of 4 ', 5'-dihydrospiro [benzo [b] furan-2 (3H), 3' (2'H) -furan] -2 ', 3-dione is obtained. Melting Point is 181-185 ℃

Elemental Analysis Value, as C ₁₅ H ₁₂ O ₆ NCl

Calculated: C, 53.34; H, 3.58; N, 4.15

Found: C, 53.08; H, 3. 49; N, 4.12

Reference Example 31

39 g of α-[(5-acetylamino-2-methoxycarbonylphenyl) oxy] -r-butyrolactone was reacted in the same manner as in Reference Example 30 to give 6-acetylamino-4 ', 5'-dihydro 1.8 g of pyro [benzo [b] furan-2 (3H), 3 '(2'H) -furan] -2', 3-dione (melting point: 220-234 ° C) and 6-diacetylamino-4 ', 2.7 g of 5'-dihydrospiro [benzo [b] furan-2 (3H), 3 '(2'H) -furan] -2', 3-dione (melting point: 178 ° C) is obtained.

Elemental analysis value as C ₁₅ H ₁₃ O ₆ N

Calculated: C, 59.40; H, 4. 32; N, 4.62

Found: C, 59.49; H, 4. 21; N, 4.34

Reference Example 32

1.1 g of α-[(2-methoxycarbonylphenyl) oxy] -r-butyrolactone was treated in the same manner as in Reference Example 17, and the product was recrystallized from ethyl acetate-hexane to give 4 ', 5'-dihydrospiro 330 mg of colorless needles of [benzo [b] furan-2 (3H), 3 '(2'H) -furan] -2', 3-dione are obtained. Melting Point is 111-111.5 ℃

Reference Example 33

0.48 g of 4 ', 5'-dihydrospiro [benzo [b] furan-2 (3H), 3' (2'H) -furan] -2 ', 3-dione nitric acid (d) = 1.42) A mixture of 0.35 ml and 0.36 ml of concentrated sulfuric acid is added dropwise under ice cooling and stirred for 2 hours. The reaction mixture was poured into iced water, and the precipitated crystals were filtered off, washed with water and dried, and then recrystallized with ethyl acetate. 4 ', 5'-dihydro-5-nitrospiro [benzo [b] furan-2 (3H), 3' A colorless acicular crystal of (2'H) -furan] -2 ', 3-dione is obtained. Melting Point is 199-200 ℃

Elemental Analysis Value, as C ₁₁ H ₇ NO ₆

Calculated: C, 53.02; H, 2.83; N, 5.62

Found: C, 52.89; H, 2. 65; N, 5.55

Reference Example 34

A mixture of 4 ', 5'-dihydrospiro [benzo [b] furan-2 (3H), 3' (2'H) -furan] -2 ', 3-dione (3 g) with chlorosulfonic acid and Then stir at 40 ° C. for 1.5 hours. The reaction mixture was poured into iced water to obtain white crystals. The crystals were dissolved in tetrahydrofuran solution, ammonia water (2.2 mL) was added, and the mixture was stirred for 5 minutes under ice cooling. The precipitated powder was filtered off and the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol-water to give 5-sulfamoyl-4 ', 5'-dihydrospiro [benzo [b] furan-2 (3H), 3. 2.8 g of colorless needles of '(2'H) -furan] -2', 3-dione are obtained. Melting Point is 202-215 ℃

Elemental Analysis Value, as C ₁₁ H ₉ O ₆ N _S

Calculated: C, 46.64; H, 3. 20; N, 4.95

Found: C, 46.39; H, 3.14; N, 4.87

Example 1

4 ', 5'-dihydrospiro [benzo [b] furan-2 (3H), 3' (2'H) -furan] -2 ', 3-dione1.75 g, sodium chloride 552 mg and dimethyl sulfoxide 9 ml The mixture was stirred at 155 ° C. for 2 hours in a stream of nitrogen. The reaction mixture was poured into iced water (about 150 mL), and the precipitate formed was collected by filtration, washed with water, recrystallized from ethanol-water (3: 2), and spiro [benzo [b] furan-2 (3H), 1'-cyclopropane]. Obtain 1.21 g of colorless acicular crystals of 3-one. Melting Point is 89-90.5 ℃

Elemental analysis value, as C ₁₀ H ₈ O ₂

Calculated: C, 74.99; H, 5.03

Found: C, 74.71; H, 4.96

Example 2-15

The mixture prepared in the same manner as in Example 1 is shown below.

(Ph in the table represents a phenyl group, Ac represents an acetyl group)

Example 16

Example 4 ', 5'-dihydrospiro [napro [2,3-b] furan-2 (3H), 3' (2'H) -furan] -2 ', 3-dione (1.2 g) When the reaction mixture was recrystallized from methanol in the same manner as in 1, 0.75 g of colorless needles of spi [[naph [2,3-b] furan-2 (3H), 1'-cyclopropane] -3-one were obtained. Get

Melting Point is 127-129 ℃

Elemental Analysis Value, as C ₁₄ H ₁₀ O ₂

Calculated: C, 79.98; H, 4.79

Found: C, 79.89; H, 4.65

Example 17

Carboxy leaving 5-hexyl-4 ', 5'-dihydrospiro [benzo [b] furan-2 (3H), 3' (2'H) -furan] -2 ', 3-dione as in Example 1 The reaction is carried out to obtain pale yellow oily 5-hexylspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one.

; 1700(CO)

; 1700 (CO)

NMR (CDCl ₃ ) δ; 087 (3H, t, CH ₃ ), 1.36 (8H, b, CH ₂ ) 1.59 (4H, m, cychloropropane), 2.63 (2H, t, nuclear CH ₂ ) 7.02 (1H, d, nuclear H), 7.40 (1H, d, nuclear H), 4.48 (1H, s, nuclear H)

Elemental Analysis Value, as C ₁₆ H ₂₀ O ₂

Calculated: C, 78.65; H, 8.25

Found: C, 78.37; H, 8.36

Example 18

Spiro [benzo [b] furan-2 (3H) and 1'-cyclopropane] -3-one-0.94 g were dissolved in 30 ml of anhydrous acetic acid, and 5.6 g of copper nitrate was added at 60-70 ° C. to keep the solution overnight. Stir. The reaction mixture is added to ice water and extracted with ethyl acetate. The extract was washed with water, dried, the solvent was distilled off and the residue was separated on two gels, followed by silica gel column chromatography.

(1) The first pot is recrystallized with ethyl acetate-n-hexane to give 5-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one as colorless columnar crystals. Melting point is 107-110 ℃

Elemental Analysis Value, as C ₁₀ H ₇ NO ₄

Calculated: C, 58.54; H, 3. 44; N, 6.83

Found: C, 58.85; H, 3.50; N, 6.68

(2) The second pot is recrystallized from ethyl acetate to obtain colorless needles of 7-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -one. Melting point is 131-134 ℃

Elemental Analysis Value, as C ₁₀ H ₇ NO ₄

Calculated: C, 58.54; H, 3. 44; N, 6.83

Found: C, 58.42; H, 3. 37; N, 6.65

Example 19

Spiro [benzo [b] furan-2 (3H) and 1'-cyclopropane] -3-one (7.0 g) are added in small portions to fumed nitric acid (70 ml) previously cooled down to -50 ° C to 60 ° C. do. After stirring for 20 minutes, the reaction solution was poured into iced water, the precipitated crystals were filtered off, washed with water and recrystallized from ethanol to give 5-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] as colorless columnar crystals. 7.3 g of 3-one is obtained. The melting point is 107-110 ° C. The product is consistent with the crystals obtained in Example 18. The recrystallized mother liquor is subjected to silica gel column chromatography to separate and recrystallized from methanol to obtain 5,7-dinitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one as pale yellow needle crystals. . Melting Point is 158-161 ℃

Elemental analysis value, as C ₁₀ H ₆ O ₆ N ₂

Calculated: C, 48.01; H, 2. 42; N, 11.20

Found: C, 48.03; H, 2. 33; N, 11.01

Example 20

5.4 g of 6-methoxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one was dissolved in a mixed solution of 25 ml of anhydrous acetic acid and 7 ml of glacial acetic acid, and the reaction temperature was 10-15 ° C. 3 ml of fuming nitric acid (d = 1.52) was added dropwise while maintaining the solution temperature. Stir for 30 minutes, pour into iced water, filter out the resulting precipitate, wash the water and recrystallize from ethanol. 6-methoxy-5-nitrospiro [benzo [b] furan-2 (3H), 1 ' 4.5 g of cyclopropane] -3-one are obtained. Melting Point is 160-163 ℃

Elemental Analysis Value, as C ₁₁ H ₉ NO ₅

Calculated: C, 56.17; H, 3.86; N, 5.96

Found: C, 56.44; H, 3.76; N, 5.80

Example 21

190 mg of 6-methoxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one is added while stirring 2 ml of fuming nitric acid (d = 1.52) at -50 ° C. After 10 minutes, the reaction solution was poured into iced water and extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution, followed by saturated brine and dried over anhydrous sodium sulfate. The crystals obtained by evaporation of the solvent were recrystallized from methanol to give 6-methoxy-5,7-dinitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3- as a pale yellow plate crystal. Get mg. Melting point is 121-124 ℃

Elemental Analysis Value, as C ₁₈ H ₈ O ₇ N ₂

Calculated: C, 47.15; H, 2.88; N, 10.00

Found: C, 46.86; H, 2.79; N, 9.83

Example 22

An ethanol solution of 5-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (7.2 g) is stirred in a hydrogen stream in the presence of platinum dioxide. After hydrogen absorption, the catalyst was filtered off, the filtrate was distilled under reduced pressure, and a small amount of hydrochloric acid-diethyl ester was added to the residue to recrystallize from ethanol to give 5-aminospiro [benzo [b] furan, a light brown needle. -2 (3H), 1'-cyclopropane] -3-one.

Melting Point is 139-142 ℃

Elemental Analysis, C ₁₀ H ₁₉ O ₂ NHCl

Calculated: C, 56.75; H, 4.76; N, 6.62

Found: C, 56.67; H, 4.83; N, 6.67

Example 23

7-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one was reacted in the same manner as in Example 22 and recrystallized from ethanol to give 7-aminospiro [benzo [ b] furan-2 (3H), 1'-cyclopropane] -3-one. Melting point is 135.8 ℃

Elemental Analysis Value, As C ₁₀ H ₁₉ O ₂ N

Calculated: C, 68.56; H, 5. 18; N, 8.00

Found: C, 68.42; H, 5.49; N, 7.74

Example 24

1.0 g of 6-methoxy-5-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one was reacted in the same manner as in Example 22, and the reaction product was recrystallized from ethanol. 415 mg of 5-amino-6-methoxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one as light brown crystals was obtained. Melting Point is 175-177 ℃

Elemental Analysis Value, as C ₁₁ H ₁₁ NO ₃

Calculated: C, 64.38; H, 5.40; N, 6.83

Found: C, 64.39; H, 5.49; N, 6.71

Example 25

219 mg of 7-methyl-5-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one was catalytically reduced in the same manner as in Example 22 and recrystallized from ethanol-water to give a yellow needle. 74 mg of 5-amino-7-methylspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one as a crystal was obtained. Melting Point is 138-141 ℃

Elemental Analysis Value, as C ₁₁ H ₁₁ O ₂ N

Calculated: C, 69.82; H, 5.86; N, 7.40

Found: C, 69.66; H, 5.71; N, 7.43

Example 26

5-7-nitrospiro [benzo [b] furan-2 (3H), 250 mg of 1'-cyclopropane] -3-one, 50 mg of platinum oxide and 20 ml of ethanol were stirred under hydrogen atmosphere at atmospheric pressure for 1.25 hours do. Oxalic acid is added to the reaction solution and the catalyst is filtered off. The filtrate is concentrated under reduced pressure to about 3 ml. Only ether was added and precipitated was filtered off. The powder was dissolved in ethanol, decolorized with activated charcoal, ether was added, and the precipitated powder was collected by filtration to obtain 5,7-diaminospiro [benzo [b] furan- (2 (3H), 1'-cyclopropane] -3-. One-half oxalate to yield a tan powder of monohydrate.

Elemental _{analysis, C 10 H 10 O 2 N} 2 1/2 (COOH) 2 · H ₂ O as

Calculated: C, 52.17; H, 5. 17; N, 11.06

Found: C, 52.12; H, 4.69; N, 10.87

Using hydrochloric acid instead of oxalic acid gives 5,7-diaminospiro [benzo [b] furan- (2 (3H), 1'-cyclopropane] -3-one hydrochloride monohydrate, with a melting point of 300 Above ℃

Elemental Analysis Value, as C ₁₀ H ₁₀ O ₂ N ₂ HClH ₂ O

Calculated: C, 49.08; H, 5. 35; N, 11.45

Found: C, 48.80; H, 5.13; N, 11.64

Example 27

Carbobenzyloxychloride (30% toluene) under ice cold in a pyridine (13.5 ml) solution of 5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.35 g) 7 g) is added and the mixture is stirred for 1 hour. The reaction mixture was poured into ice-hydrochloric acid (14 ml), extracted with ethyl acetate, the extract was washed with water and concentrated to dryness to remove the solvent. The residue is recrystallized from ethanol to obtain 1.57 g of pale yellow acicular crystal 5-benzyl oxycarbonylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one. Melting Point is 118-119 ℃

Potassium hydroxide powder (0.57 g) and iomethyl (1 ml) are added to the acetone (30 ml) solution of this product, stirred for 30 minutes under ice cooling, and further stirred at room temperature for 4 hours. Dilute hydrochloric acid is added to the reaction mixture, which is extracted with ethyl acetate. The extract is washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel column chromatography and the chloroform eluted fraction was recrystallized from ethanol to give 5- (N-benzyloxycarbonyl-N-methylamino) spiro [benzo [b] furan-2 (3H), 1 as a colorless needle. 1.44 g of '-cyclopropane] -3-one are obtained. Melting Point is 79-81 ℃

This product is dissolved in methanol (129 mL) and stirred for 30 minutes in a hydrogen stream in the presence of 5% palladium-carbon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol and hydrochloric acid-diethyl ether was added to give the yellow acicular crystal 5-methylaminospiro [benzo [b] furan-2 (3H), 1 '-Cyclopropane] -3-one hydrochloride is obtained. Melting Point is 141-144 ℃

Elemental Analysis Value, as C ₁₁ H ₁₁ O ₂ NHCl1 / 2H ₂ O

Calculated: C, 56.29; H, 5.58; N, 5.97

Found: C, 56.38; H, 5. 15; N, 6.07

Example 28

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.75 g) and 37% formalin (14 mL) were dissolved in acetonitrile and boron hydride under ice cooling Lithium (1.52 g) is added in small portions. Stir the mixture at room temperature for 40 minutes, add acetic acid to neutral, and stir another 2.5 hours. The solvent is distilled off under reduced pressure, and an aqueous sodium hydroxide solution is added to the residue, followed by extraction with chloroform. The extract was washed with water, dried and concentrated to remove the solvent, and the residue was added to silica gel chromatography. The residue was eluted with chloroform and hydrochloric acid-diethyl ether was added and recrystallized from ethanol to give 5-dimethylaminospiro [benzo]. 0.546 g of [b] furan-2 (3H), 1'-cyclopropane] -3-one hydrochloride is obtained. Melting Point is 136-140 ℃

NMR (D ₂ O) δ: 1.67 (2H, m, CH ₂ ), 1.93 (2H, m, CH ₂ ), 3.37 (6H, s, CH ₃ ), 7.43 (1H, d, aromatic ring H), 7.93 (2H, m, aromatic ring H).

Elemental Analysis Value, as C ₁₂ H ₁₃ O ₂ N · HCl

Calculated: C, 60.13; H, 5.89; N, 5.85

Found: C, 60.19; H, 5.72; N, 6.00

Example 29

A mixture of 35 g of 5-nitrospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one, 60 ml of 37% formalin, 30 ml of acetic acid, 3 g of platinum oxide and 500 ml of ethanol was subjected to hydrogen pressure. Reduce at room temperature with 20 kg / cm ² . After hydrogen absorption ceases, the catalyst is filtered off and the filtrate is eluted under reduced pressure. The concentrate is dissolved in chloroform, washed with 2N sodium hydroxide followed by water and dried. Chloroform was removed by evaporation under reduced pressure, and the oily substance was recrystallized from ethanol to give yellow cube crystal 5-dimethyldaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one. Get Melting Point is 96.5-97.5 ℃

Elemental Analysis Value, as C ₁₂ H ₁₃ O ₂ N

Calculated: C, 70.91; H, 6. 45; N, 6.89

Found: C, 71.06; H, 6.39; N, 6.71

Example 30

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.75 g) and acetaldehyde (3 mL) were dissolved in methanol (105 mL) and the methanolic solution Is stirred for 22 hours in the presence of platinum oxide in a hydrogen stream. The catalyst is filtered off, the solvent is evaporated off and the residue is subjected to silica gel column chromatography to elute as carbon tetrachloride-ethyl acetate (10: 1).

Hydrochloride was prepared as ether saturated with hydrogen chloride and the first pot was recrystallized from ethanol ether to give 5-dimethylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3- as a pale yellow needle. You get 0.86g. Melting Point is 172-176 ℃

Elemental Analysis Value, as C ₁₄ H ₁₇ O ₂ N · HCl

Calculated: C, 62.80; H, 6. 78; N, 5.23

Found: C, 62.78; H, 6. 85; N, 5.10

The second pot is made of hydrochloride as ether saturated with hydrogen chloride and recrystallized from ethanol-ether to give 5-ethylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3- as a pale yellow needle. On. Hydrochloride. You get 0.129 g of 1/4 hydrate. Melting Point is 155-160 ℃

Elemental Analysis Value, as C ₁₂ H ₁₃ O ₂ NHCl, 1/4 H ₂ O

Calculated: C, 59.02; H, 5.98; N, 5.73

Found: C, 58.94; H, 5.86; N, 5.73

Example 31

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (3.0 g), 1,4-diboromobutane (3.7 g), sodium hydrogencarbonate (2.89 g) And a mixture of N, N-dimethyl formamide (150 mL) was heated to reflux for 1 hour. The reaction solution is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to remove the solvent and the residue is subjected to silica gel chromatography. The first elution with chloroform is distilled off under reduced pressure to give yellow crystals (1.74 g). Recrystallization from ethanol by addition of hydrochloric acid-diethyl ether gave yellow needle crystal 5- (1-pyrrolidinyl) spiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one hydrochloride. do. Melting Point is 136 ℃

Elemental Analysis Value, as C ₁₄ H ₁₅ O ₂ N · HCl

Calculated: C, 63.27; H, 6.07; N, 5.27

Found: C, 63.26; H, 6. 10; N, 5.26

Example 32

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (2.62 g), bis (2-iodoethyl) ether (5.4 g), sodium hydrogencarbonate (3.75 g A suspension of N, N-dimethyl formamide (150 mL) is stirred at 120-140 ° C. for 2.5 hours. The reaction solution is poured into water and extracted with ethyl acetate. The extract is washed with water and dried to remove the solvent by evaporation. The residue was attached to silica gel column chromatography, and the flowerpot eluted with chloroform-ethanol (99: 1) was evaporated and concentrated to give a yellow crystal (1.12 g) under reduced pressure. When hydrochloric acid-ether is added thereto and recrystallized from ethanol-ether, 0.927 g of 5-morpholinospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one hydrochloride is obtained as a light brown needle. . Melting point is 128-131 ℃

Elemental Analysis Value, as C ₁₄ H ₁₅ O ₃ N · HCl

Calculated: C, 59.68; H, 5.73; N, 4.97

Found: C, 59.59; H, 5. 60; N, 4.95

Example 33

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.75 g) was converted to N-benzyl-β, β'-diiodine diethylamine (6.8 g), The reaction was carried out in the same manner as in Example 32 with sodium hydrogen carbonate (4 g) to give 5- (4-benzyl-1-piperazinyl) spiro [benzo [b] furan-2 (3H), 1′-cyclone as a yellow needle crystal. 0.831 g of propane] -3-one is obtained.

Melting Point is 125-125.5 ℃

Elemental Analysis Value, as C ₂₁ H ₂₂ O ₂ N ₂

Calculated: C, 75.42; H, 6.63; N, 8.38

Found: C, 75.26; H, 6. 78; N, 8.41

Example 34

5-Aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.74 g) was converted to N-ethyl-β, β'-diiodo diethylamine (5.84 g). , Reacted with sodium hydrogen carbonate (4 g) in the same manner as in Example 32 to give 5- (4-ethyl-1-piperazinyl) spiro [benzo [b] furan-2 (3H), 1'- as a yellow needle. Cyclopropane] -3-one. Oxalate. Get 1/2 hydrate. Melting Point is 175-179 ℃

Elemental analysis value, C ₁₆ H ₂₀ O ₂ N ₂ · C ₂ H ₂ O ₄ · 1 / 2H ₂ O

Calculated: C, 58.20; H, 6. 24; N, 7.54

Found: C, 58.00; H, 6.56; N, 7.24

Example 35

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (0.875 g) was acetylated as acetic anhydride (7 mL), acetic acid (7 mL) and its acetylation Recrystallization of the product from ethanol yielded 0.426 g of 5-acetylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one. Melting Point is 211-212 ℃

Elemental Analysis Value, as C ₁₂ H ₁₁ O ₃ N

Calculated: C, 66.35; H, 5. 10; N, 6.45

Found: C, 66.37; H, 5. 12; N, 6.38

Example 36

Methanesulfonyl chloride (0.28) under ice cooling in a solution of 5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (0.519 g) dissolved in pyridine (5 mL). ㎖) is added and stirred. The reaction solution was poured into cold dilute hydrochloric acid, extracted with ethyl acetate, the extract was washed with water, dried and concentrated to remove the solvent. Recrystallization of the residue from ethanol yielded 0.38 g of colorless needle crystal 5-methylsulfonylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one. Melting Point is 152-154 ℃

Elemental Analysis Value, C ₁₁ H ₁₁ O ₄ NS

Calculated: C, 52.16; H, 4.38; N, 5.53; S, 12.66

Found: C, 52.20; H, 4. 37; N, 5. 32; S, 12.56

Example 37

10% aqueous sodium hydroxide solution is added to 4-acetoxyspiro [benzo [b] furan-2 (3H) and 1'-cyclopropane] -3-one and stirred at room temperature.

The reaction solution is acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and distilled to remove the solvent, and the residue was recrystallized from petroleum ether to give yellow needles of 4-hydroxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one. You get Melting Point is 100-109 ℃

Elemental Analysis Value, as C ₁₀ H ₈ O ₃

Calculated: C, 68.18; H, 4.58;

Found: C, 68.38; H, 4.42

Example 38

To a solution of 1.09 g of 6-acetylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one in 50 ml of methanol, 0.8 g of potassium hydroxide was added to reflux for 0.5 hour. Let's do it. The solvent was evaporated under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration, washed with water and dried. The crystals were recrystallized from methanol to give aminospiro [benzo [b] furan-2 (3H) as colorless prism crystals. 1'-cyclopropane] -3-one is obtained. Melting Point is 188-189 ℃

Elemental analysis value, as C ₁₀ H ₉ O ₂ H

Calculated: C, 68.56; H, 5. 18; N, 8.00

Found: C, 68.34; H, 5.05; N, 7.88

Example 39

6-acetylamino-5-chlorospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.8 g) was reacted in the same manner as in Example 38 and the product was reacted with methanol. Recrystallization gave 1.5 g of 6-amino-5-chlorospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one as a yellow plate crystal. Melting Point is 201 ℃

Elemental Analysis Value, C ₁₀ H ₈ O ₂ NCl

Calculated: C, 57.29; H, 3.85; N, 6.68

Found: C, 57.24; H, 3. 74; N, 6.67

Example 40

5-Benzyloxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (3.3 g) was benzyl derivatized by catalytic catalytic reduction in methanol to give a pale yellow acicular crystal. 1.8 g of hydroxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one are obtained. Melting Point is 180-185 ℃

Elemental Analysis Value, as C ₁₀ H ₈ O ₃

Calculated: C, 68.18; H, 4.58

Found: C, 68.12; H, 4.44

Example 41

4-hydroxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (0.176 g), potassium carbonate (0.276 g), β-diethylaminoethyl chloride (0.215 g) And a mixture of N, N-dimethylformamide (5 ml) at room temperature for 3 hours. The reaction mixture is diluted with water and extracted as ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent and the residue is subjected to silica gel column chromatography to elute as chloroform. The product was reacted with hydrochloric acid-saturated diethyl ether to recrystallize the resulting hydrochloride from ethanol-diethyl ether to give 4- (2-diethylaminoethyloxy) spiro [benzo [b] furan-2 (3H) as a colorless needle. , 1'-cyclopropane] -3-one. You get 0.221 g of hydrochloride. Melting Point is 160-168 ℃

Elemental analysis value, C ₁₆ H ₂₁ O ₃ N · HCl

Calculated: C, 61.63; H, 7. 11; N, 4.49

Found: C, 61.38; H, 7. 23; N, 4.38

Example 42

5-hydroxyspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (1.06 g) was reacted in the same manner as in Example 41 to give a colorless oily 5- (2-di Ethylaminoethyloxy) spiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one is obtained.

Nuclear magnetic resonance spectrum (δ value in heavy chloroform): 1.07 (6H, t, CH ₃ ) 1.63 (4H, m, 2 ', 3'-CH ₂ ), 2.64 (4H, q, NCH ₂ CH ₃ ), 2.88 ( 2H, t, NCH ₂ CH ₂ O), 4.04 (2H, t, CH ₂ O), 6.95-7.40 (3H, m, aromatic ring H)

Example 43

5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (0.747 g), calcium carbonate (0.47 g), carbon tetrachloride (20 mL) and methylene chloride (5 mL) Suspended in a mixture of. The suspension is cooled to -17 ° C, bromine (0.22 ml) is added dropwise, and the mixture is stirred for 45 minutes. The reaction mixture is poured into iced water, extracted with ethyl acetate, the extract is washed with water and dried to evaporate the solvent. The residue is recrystallized from ethanol-water to give 0.6 g of yellow needle crystal 5-amino-4-bromospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one.

Melting Point is 167-170 ℃

Elemental analysis value, as C ₁₀ H ₈ O ₂ NBr

Calculated: C, 47.27; H, 3. 19; N, 5.51

Found: C, 47.48; H, 3. 12; N, 5.64

Example 44

A suspension of carbon tetrachloride (10 ml) of 5-dimethylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (0.455 g) and calcium carbonate (0.246 g) was prepared in Example 43. The reaction was carried out in the same manner to obtain 0.213 g of 4-bromo-5-dimethylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one as a dark needle. Melting Point is 79-81 ℃

Elemental Analysis Value, as C ₁₂ H ₁₂ O ₂ NBr

Calculated: C, 51.08; H, 4. 29; N, 4.97

Found: C, 50.87; H, 4.13; N, 5.03

Example 45

A tetrahydrofuran (5 mL) solution of 5-aminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one (0.181 g) and pyridine (0.083 mL) to -17 ° C. After cooling, a tetrahydrofuran (1.15 mL) solution of iodinebenzene dichloride (0.282 g) prepared by a conventional method is added dropwise for 50 minutes or more, and stirred for 1 hour as it is. The reaction mixture is poured into iced water, extracted with ethyl acetate, the extract is washed with water and dried to evaporate the solvent, and the residue is subjected to column chromatography. The first elution eluted from chloroform was concentrated under reduced pressure to remove the solvent. Yellow amino acid 5-amino-4-chlorospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one 0.038 get g

Mass spectrum: C ₁₂ H ₁₂ O ₂ NCl, molecular ion peak (209)

[Preparation Example]

For example, when the compound (1) of the present invention is used as an anti-ulcer agent, for example, it can be used by the following prescription.

1. Tablet

(1) 50 g of 5-acetylspiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one

(2) 50 g lactose (lactose)

(3) 29 g of corn starch

(4) 130 g of magnesium stearate 100 tablets

(1), (2) and 17 g of corn starch are mixed and granulated together with the paste made from 7 g of corn starch, and 5 g of corn starch and (4) are added to the granules, and the mixture is compressed with a compressed tablet and purified. 1000 tablets of 7 mm in diameter containing 50 mg of sugar (1) were prepared.

2. Capshuulje

(1) 5-dimethylaminospiro [benzo [b] furan-2 (3H), 1'-cyclopropane] -3-one

50 g

(2) 50 g of lactose

(3) 29 g of cellulose fine powder

(4) Magnesium Stearate 1000capsule 200g

All ingredients are mixed to fill 1,000 gelatin caps with No. 3 (Eighth Amendment of Japan Pharmacopoeia), to prepare a capsule containing 50 mg (1) per capswool.

Claims (1)

As described above in the text, the method for producing a spiro benzofuran compound of the general formula (I), which is obtained by decarboxylating a compound of the general formula (II) below.

In the above formula, Ring A represents a benzene ring or naphthalene ring, and the benzene ring or naphthalene ring is substituted with at least one of lower alkyl group, nitro group, halogen atom, optionally substituted amino group, optionally substituted hydroxyl group, acyl group and sulfamoyl group. You may be.