JPH01294677A - Benzopyran derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The benzopyran derivative of formula I (R<1> and R<2> are lower alkyl or together form lower alkylene group; R<3> is H, hydroxy or acyloxy; R<4> is H or together with R<3> forms a bond). EXAMPLE:trans-3,4-Dihydro-3-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)sp iro[2H-1- benzopyran-2,1'-cyclopentane]-6-carbonitrile. USE:Useful as a vasodilator. It can be effectively applied for the remedy of diseases such as hypertension. PREPARATION:The compound of formula IV which is one of the compound of formula I can be produced, e.g., by reacting the compound of formula II with the compound of formula III. The dehydration of the compound of formula IV gives the compound of formula V which is another compound of formula I. The compound of formula VI is produced by reducing the compound of formula V.

Description

[Detailed description of the invention]

[Industrial Application Field] This invention relates to novel benzopyran derivatives. More specifically, the present invention relates to a novel benzopyran derivative having a vasodilatory effect, a method for producing the same, and a vasodilator containing the same as an active ingredient. [Object of the Invention] One object of this invention is to provide novel benzopyran derivatives useful as vasodilators. Another object of the present invention is to provide a method for producing the benzopyran derivative. Yet another object of the present invention is to provide a vasodilator containing the above benzopyran derivative as an active ingredient. The benzopyran derivatives of this invention are novel and have the formula (I)
It can be shown as (wherein R and R2 each mean a lower alkyl group, or R and R2 combine to form a lower alkylene group, R3 means hydrogen, a hydroxy group or an acyloxy group, R4 means hydrogen, or R and R4 together form a bond). Regarding the compounds (!) of this invention, one or more pairs of optical isomers may exist due to the presence of one or more asymmetric carbon atoms, and these isomers or mixtures thereof are also included in the invention. It is intended to be included within the scope of compound (I). According to this invention, the target compound (I) can be produced by the following production method.鳳JtLL or its salt (To1) 糺生盈1 (To1) (I-b) 1欁杞1 (1-b) (In the formula, R1 and R2 each have the same meaning as before). Some of the starting compounds (1) and (m) are new and can be produced by the operating methods described in Production Examples 1 to 11 below. Suitable salts of compound (II) are conventional non-toxic salts, such as salts with inorganic bases, such as alkali metal salts such as sodium salts, potassium salts, cesium salts, such as calcium salts, magnesium salts, etc. alkaline earth metal salts, ammonium salts; salts with organic bases, examples of which are:
For example, triethylamine salt, pyridine salt, pilin salt,
Organic amine salts such as ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.; for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc. : For example, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p
- Organic carboxylic acid addition salts or organic sulfonic acid addition salts such as toluene sulfonate: salts with bases or acid addition salts such as salts with basic amino acids or acidic amino acids such as arginine, aspartic acid, glutamic acid, etc. Can be mentioned. In the foregoing and following description of this specification, preferred examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below. By "lower" is meant, unless otherwise specified, 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Preferred 1-lower alkyl group for R1 and R2 is,
Mention may be made of straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. Suitable mono-lower alkylene groups formed by the bonding of R1 and R2 include methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, and the like. Preferred acyl groups in the acyloxy group include those commonly used in the pharmaceutical field, such as lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, and valeryl, such as methanesulfonyl, ethanesulfonyl, etc. Examples include organic acyl carboxylates and acyl organic sulfonates such as a lower alkanesulfonyl group.Processes 3 to 3 for producing the object compound (I) of the present invention will be described in detail below. -a) converts compound (II) into compound (I)
It can be produced by reacting with I[) or a salt thereof. This reaction is usually carried out in the presence of a base such as an alkyllithium such as n-butyllithium, an alkali metal hydride such as sodium hydride, potassium hydride, and the like. This reaction typically involves dioxane, dimethyl sulfoxide,
The reaction is carried out in a solvent such as dimethylformamide, diethylformamide, dimethylacetamide, benzene, or tetrahydrofuran, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction can usually be carried out under cooling, at room temperature, or under heating. The target compound (1-a) can be used as a raw material compound in Production Method 2 below, either isolated or without isolation. The main target compound (I-b) for W assembly can be produced by subjecting the compound (I-a) to a dehydration reaction. The dehydration reaction can usually be carried out using a base such as an alkali metal hydride such as sodium hydride or potassium hydride. This reaction can be carried out in a commonly used solvent that does not adversely affect the reaction, such as the solvents mentioned in the explanation of Production Method 1. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. In this reaction, an acylated compound (1-a') can also be used instead of the starting compound (I-a), and such an acylated compound can be used as a substitute for the compound (1-a).
It can be produced from a) by the following reaction. (T1) [In the formula, R1 and R2 each have the same meaning as before, and R3 means an acyloxy group). Compound (I-c) can be produced by subjecting compound (I-b) to a reduction reaction. This reaction is carried out according to conventional methods including chemical reduction and catalytic reduction. Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid. Suitable catalysts that can be used for catalytic reduction include platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, and platinum wire, such as palladium sponge, palladium black, palladium oxide, palladium-RX, colloidal palladium,
Palladium-barium sulfate, palladium-barium carbonate 41(7) Palladium catalysts, such as nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. , for example, commonly used copper catalysts such as reduced steel, Raney copper, Ullmann steel, etc. The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, or mixtures thereof. Furthermore, if the above-mentioned substances used for chemical reduction are liquids, they can also be used as solvents. Furthermore, suitable solvents used in the catalytic reduction include, in addition to the above-mentioned solvents, conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof. The reaction temperature for this reaction is not particularly limited, but the reaction is usually carried out under cooling or heating. The object compound (1) of this invention can be isolated and purified by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, chromatography, etc. The object compound (1) of this invention is novel, It exhibits a vasodilatory effect and is useful in treating diseases such as hypertension. In order to explain the usefulness of the target compound (1), the blood pressure lowering effect of representative compounds of this invention is shown below. [1] Part 1B

[1 product゛2,2-dimethyl-4-(1,1-dioxoisothiazolidin-2-yl)-2H-1-benzopyran-6-
Carbonitrile. [2] Male Wistar rats, 10-11 weeks old and weighing 250 g, were used after fasting overnight. Under ether anesthesia, a polyethylene cannula was inserted into the femoral artery to measure blood pressure, and another cannula was inserted into the femoral vein to inject the test compound. Approximately 2 hours after surgery, the test compound was administered intravenously. did. Blood pressure was measured in the femoral artery with a pressure transducer and recorded as the electrical integral of mean arterial pressure. [3] The average maximum rate of decrease in blood pressure (mmHg) is shown in the table. For therapeutic administration, the object compound of this invention (1
) is a conventional pharmaceutical product containing said compound as an active ingredient in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral and topical administration. Used in the form of preparations. Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, or liquid forms such as solutions, suspensions, syrups, emulsions, lemonades, and the like. If necessary, auxiliary agents, stabilizers, wetting agents, and other lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, cornstarch,
Commonly used additives such as talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, edelen glyfur, etc. may also be included. The dosage of compound (I) varies depending on the patient's age, condition, type of disease, type of compound (1) to be applied, etc. Generally, an amount between 1 mg and about 1000 a+g or more may be administered to a patient per day.
Smg, 10mg5255mg, 50mg, 10
0mg and 200mg may be used to treat diseases. The invention will now be explained in accordance with the Preparation Examples and Examples. Otori IJLL 3-acetyl-4-hydroxybenzonitrile (3g
), cyclopentanone (2,4IQ ”) and pyrrolidine (0,441111) in toluene (5,6111)
The warm mixture was stirred at room temperature overnight and then refluxed for 2 h with continuous water collection in a Dean-Stark apparatus. The reaction mixture was diluted with ethyl acetate and washed sequentially with 5% hydrochloric acid, water, and brine. , dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (200 g) with methylene chloride as eluent to give 3,4-dihydro-4
-oxospiro[2H-1-benzopyran-2,1'-
cyclopencune]-6-carponitrile (3.3 g) is obtained. mp: 76-79°C IR = 2220. 1690
cm-1NMR (CDCl2.8): 1.5-2
゜3 (8H, m), 2.87 <2H. s), 7.01 (IH, d, J=9Hz>, 7.
68 <IH, dd. J=2.9Hz>, 8.16 (IH, d, J=2H
z>11 1 Sodium borohydride (6.8 g) was converted into 3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,
A solution of 1゛-cyclopencune]-6-carbonitrile (42) in methanol (840111) was divided into small portions and added over 10 minutes at room temperature.The solvent of the reaction mixture was distilled off under reduced pressure, and water was added. The residue is extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified with silica gel (300 g) using chloroform and ethyl acetate as eluent.
) to give 3,4-dihydro-4-hydroxyspiro[2H-1
-Benzopyran-2,1'-cyclopentaco-6-carponitrile (30 g) is obtained. mp: 99-102°C IR (strewn carbonate): 3170. 2210
cra-”NMR (CDCl2.8)’ 1.5
7 (IH, br s), 1.4-2.4 (10H,
m), 4.7-5.1 (IH, m), 6.8 (
IH, d. J=9Hz), 7.42 (IH, dd, J=2.9
Hz), 7.78 (LH, br s) m 3.4-dihydro-4-hydroxyspiro[2H-1-
Benzopyran-2,1'-cyclobentanco-6-carponitrile (25 g) and p-toluenesulfonic acid.
A warm mixture of hydrate (2.1 g) of benzene (125011Q) is refluxed for 2 hours with azeotropic recovery of the water formed. The mixture is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (200 g) with methylene chloride as eluent to give spiro[2H-1-benzopyran-2,1'-cyclopentane]-6-carponitrile (19 g). obtain. tap: 47-50℃ IR (streak) 1 2220. 1640
am-'NMR (CDCl2.8): 1.4
-2.3 (811, 謹), 5.71 (IH
. d, J=lOHz), 6.30 (IH, d, J=1
0Hz), 6.74 (lH, d, J=8Hz), 7
．． 25 (IH, dd, J=2.8Hz). 7.39 (IH, d, J = 2 Hz) 11 value I N-bromosuccinimide (27 g) was added to spiro[2H-
1-benzopyran-2,1'-cyclopentane]-6-
Carponitrile (16g) dimethyl sulfoxide (2
12111) and water (2,71jl) all at once. After stirring vigorously for 20 minutes at room temperature, the mixture is poured into water and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give trans-3-bromo-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,11-cyclo Pentane]-6-carbonitrile (23 g) is obtained. mp: 133-136℃ IR (striped rail)' 3490. 2240
cm+-1HMR (CDCl2.8): 1.5
-2.3 (81 darkness, 3.58 (IH. d, J=411z), 3.91 (IH, d, J=4
Hz), 6.85 (111°d, J:8Hz),
7.51 (IH, dd, J=2.8Hz), 7.6
5 (IH, d, J = 2 Hz) 11 Fake 1 A solution of sodium hydroxide (3z) in water (100!11) was converted into trans-3-bromo-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran 1 of -2,1゛-cyclopentane]-6-carponitrile (21 g).
4-dioxane (300IQ") solution. After stirring for 0.5 h at room temperature, the mixture is poured into water and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and the solvent is removed under reduced pressure. 3.4-
Dihydro-3,4-epoxyspiro[2H-1-benzopyran-2,1'-cyclopencune]-6-carbonitrile (15 g) is obtained. mp: 73-78°C IR: 2220 cm''I
NMR (CDCl2.8) + 1.5-2.7 (8
H, m), 4.37 (IH. d, J=8Hz), 4.92 (IH, d, J=8H
z), 6.89 (11°d, J=9Hz), 7.
48 (IH, dd, J=3.9Hz), 7.79 (
IH, d, J = 3 Hz>11<1> 1jE The following compound is obtained in the same manner as in Example 2. (1) 3,4-dihydro-4-oxospiro[2H-1
-Benzopyran-2,1'-cyclobutane]-6-carbonitrile. Peng p, 112-114℃ IR (CCI): 2230.1700 crm-
'NMR (CDCl2.S): 1.6-2.5
(6H, m), 2.94 (21°s), 7.0
7 <IH, d, J=8Hz), 7.69 (LH,
dd. J=2. 8Hz), 8.15 (IH, d, J=
2Hz) (2) 3,4-dihydro-4-oxospiro C
2H-1-benzopyran-2,1'-cyclohexane]
-6-Carponitrile. mpj 91.5-92.5°C IR: 2215. 1685.
1600 am-1 HMR (CDCIs, 8): 1
, l-2,3 (IOH, m), 2°73 (2H. s), 7.03 (IH, d, J=8Hz>, 7.
66 (IH, dd, J=2°8Hz), 8.12
(IH, d, J=2Hz) (3) 2.2-diethyl-3
, 4-dihydro-4-dihydro-2H-1-benzopyran-6-carbonitrile. NMR (CDC1s, 8)' 1.20 <6H0
t, J=7Hz), 2.14 (2H, s), 2.42
(4H, q, J=7Hz), 6.68 (IH, d
. J=8)lz), 7.3-7.6 <lH, a+),
7.69 (IH,d. (1) 3,4-dihydro-4-hydroxyspiro [2]
! -1-benzopyran-2.1゛-cyclobutane]-6
-Carbonitrile. mp: 79-81”C IR (streak mark): 3330.2210
cm-”NMR (CDC13,8)’ 1.5-2
．． 5 (8B1m>, 2.5-3.0 (IH, m),
4.6-5.0 (18,m), 6.84 (11(
, d. J=8Hz), 7.45 (IH, dd, J=2.8
Hz), 7.73 (IH, br 5) (2) 3.4-dihydro-4-hydroxyspiro[2H
-1-benzopyran-2,1'-cyclohexane]-6
-Carponitrile. NMR (CDCIs, 8)” 1.1-2.5 (
12H1m), 4.61-5.12 (IH, a+),
6.87 (LH, d, J=8Hz), 7.46 (
11 (, dd. J=2.8tlz), 7.81 (IH, d, J=2
Hz) (3) 2,2-diethyl-3,4-dihydro 4
-Hydroxy-2H-1-benzopyran-6-carbonitrile. NMR (CDCIs, δ) 20. 92 (3H, t, J
=9Hz), 0.96(3H,t,J=9Hz),
1.4-2.0 (4H, m), 2.0-2.4 (2
B, theory), 2.6-3.0 (IH, +a), 4.
6-5.0 (IH, m). 6.82 (11(,d,J=9)1z), 7.39
(IH, dd, J=2°9Hz), 7.7-7.
9 (IH, ea) Damage 1 11 The following compound is obtained in the same manner as in Case 1. (1) Spiro[2H-1-benzopyran-2゜1'-
cyclobutane]-6-carponitrile. IR (Film)' 2220. 1640
cm-1 HMR (CDCIs, 8): 1.5-2.
7 (6H, 5Il), 6.02 (LHld, J=1
0Hz), 6.27 (IH, d, J=10Hz),
6.76 (LH, d, J=8Hz), 7.23 (
IH, dd, J=2.8Hz). 7.38 (IH, d, J = 2Hz) (2) Spiro[2H-1-benzopyran-2゜1' -
cyclohexane]-6-carponitrile. IIIp; 92-93℃ IR (X dil)' 2200 cm-'N
MR (CDCIs, S)' 1.1-2.3 (1
0H, m), s, 73 (IHld, J=10Hz
), 6.33 (IH, d, J: 10Hz), 6.
84 (IH, d, J=8Hz), 7.25 <LH,
d, J=2Hz), 7. tl(IH, dd, J=2.
8Hz) (3) 2.2-diethyl-2H-1-benzopyran-6
-Carbonitrile. IR (film): 2220. 1640
csa-1HMR (CDCIs, δ): 0.8-1
．． 0 (6H, m), 1.5-2.0 (4)1. s)
, 5.52 (IH, d, J=8Hz), 6.
38 (IH, d. J=8Hz), 6.75 (IH, d. J=8Hz
>, 7.18 (IH, d. J=2Hz>, 7.33 (IH, dd, J=2.
8Hz) Chestnut Plant ■The following compound was obtained in the same manner as in 1. (1) trans-3-promo 3,4-dihydro-4-
Hydroxyspiro[2H-1-benzopyran-2,1'
-Cycloptanko 6-carponitrile. mp: 115-116°C IR: 3440. 3400.
2230 cab-'NMR (CDCIs, 8)
' L, S-3,0 (6B9m), 4.39 (IH
ld, J=5Hz), 4.93 (IH, d, J=5
Hz), 6.95 (1B. d, J=9Hz), 7.47 (IH, dd, J
=2. 9Hz), 7.67 (IH, d, J 2H
z) (2) trans-3-promo 3,4-dihydro-4-
Hydroxyspiro[2H-1-benzopyra/-2,1'
-cyclohexane]-6-carbonitrile. atp' 149-152°C IR (line meeting): 3450. 2220
ePeng-1HMR (CDCIs, l; )' 1.0
-2.3 (IOH-m), 3.0-3°3 (IH
, m), 4.10 (IH, d, J=9Hz), 4
．． 8-5.1 (IH. m), 6.93 (IH, d, J=9Hz>, 7.
43 (IH, dd, J=2°9Hz), 7.80
(IH, d, J=2Hz>(3) trans-3-bromo-2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile. Peng p + 116- 119℃ IR (Stripe 1-L) @ 347G, 222 (
1CSI-1HMR (CDCIs, 8)”
0.91 (3H, t, J=7Hz), 0.98
(3H, t, J=7Hz), 1.6-2.2 (4H
, m), 3.0-3.1 (IH, m), 4.27
(IH, d, J=9Hz), 4.8-5.1 (IH, Cabinet), 6.88 (IH, d, J-9Hz),
7.47 (IH, dd. J=2.9Hz), 7.7-7.9 (lH, m) Otori J 11 The following compound is obtained in the same manner as in Production Example 5. (1) 3,4-dihydro-3,4-epoxyspiro[2
H-1-benzopyran-2,1'-cyclobutane]-6
-Carbonitrile. mp 7139-141℃ IR (line) '2220 crm-'
NMR<CDCl3. δ)! 1.6-2.4 (4
)1. a+), 2.4-2.8 (2H, a), 3.
94 (2H, s), 6.87 (lH, d, J=8
Hz). 7.48 (IH, dd, J=2.8Hz), 7.6
1 (IH, d. J-2Hz) (2) 3,4-dihydro-3,4-epoxyspiro[2
8-1-benzopyran-2,1'-cyclohexane]-
6-Carbonitrile. IR (Film): 222G am-'NM
R(CDCIg, 8)' 1.0-2-2 (10
H, m), 3.52 (IH9d, J=4Hz>,
3.86 (lH, d, J=4Hz), 6.89 (
IH. d, J=8Hz>, 7.51 (lH, dd, J=2
．． 8Hz>, 7.63 (lH, d, Jg2Hz) (3) 2.2-diethyl-3,4-dihydro-3°4-
Epoxy-2H-1-benzopyran-6-carbonitrile. IR(74&&)? 2210 am-1HM
R(CDCIs, 8): 0.89 (3H,t,J
=7Hz), 1.09(3H,t,J=7Hz),
1.5-2.1 (4H, m), 3.59 (IH. d, J=4Hz), 3.87 <IH, d, J=4H
z), 6.86 (18°d, J=9Hz), 7.
51 (IH, dd, J-2, 9Hz), 7.63 (
lH, d, J = 2 Hz) I production: A 28% (v/v) solution of sodium methoxide in methanol (90.7 g) was added to isothiazolidine 1,1-dioxide (59.1 gg) in ethanol (118,3111
) The reaction mixture is stirred at room temperature for 30 minutes and the solvent is distilled off under reduced pressure. The residue was dissolved in toluene (1
001111), and the precipitate was mixed with toluene (30111).
) to obtain a white powder. 7. Powder at 50℃ under reduced pressure
After drying for hours, the sodium salt of isothiazolidine 1,1-dioxide (62,41 g) is obtained as a white powder. IIp + >300°C IR (Streak Sole): 1380. 1120
am-1HMR (5 o-d, 8) + 1.
70-2.23 (211, ■), 2.33-2.7
0 (2H, m), 3.10 (2H, t, J
-6 Hz > 11 uisothiazolidine 1,1-dioxide (14 g > N,
To the N-dimethylformamide (7,211) solution is added 1.6 M n-butyllithium (7,2111) in hexane dropwise and the mixture is stirred at room temperature for 0.5 h. 3 to this
．． 4-dihydro-3,4-epoxyspiro[2H-1-
N,N-dimethylformamide of benzopyran-2,1'-cyclopentane]-6-carbonitrile (21) (
7,21d) Add solution dropwise. After stirring overnight at room temperature, the mixture is poured into water and extracted with chloroform. The extract is washed with brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (Zoom) using chloroform and then a mixture of chloroform and ethyl acetate (10:1).
) and purified to obtain trans-3゜4-dihydro-3
-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)spiro[2H-1-benzopyran-2,
1'-cyclopentafco-6-carponitrile (2,4
g) is obtained. mp: 257-259°C IR: 3500. 2230
cm''''INMR (CDCIs, 8)' 1.4
-2.1 (8H-m), 2.1-2.7 (2H, m)
, 2.9-3.7 (4H, ■), 3.98 (I
H,d. J = lGHz), 4.70 (IH, d, J 10H
z>, 8.87 (18°d, J=9Hz), 7
．． 46 (lH, dd, JM2.9Hz), 7.6
0 (IH, br s) 叉1''. To a solution of isothiazolidine 1,1-dioxide (4,8 g) in dimethyl sulfoxide (81111) is added 60% sodium hydride (1,6 g) portionwise in portions and the mixture is stirred at room temperature for 0.5 h. To this was added 3°4-dihydro-3,4-epoxyspiro[2H-1-benzopyran-2,1'-cyclopentane]-6-carponitrile (6 g). After stirring overnight at room temperature, the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (lOOg), eluting with a mixture of n-hexane and ethyl acetate (2:4) to give 4-(1,1-dioxoisothiazolidine-2). -yl) spiro[2H-1-
Benzopyran-2,1'-cyclopencune]-6-carbonitrile (1,4 g) is obtained. sep: 192-195°C IR: 2220. 1640
cken-1HMR (CDCIs, 8)! 1.5
-2.3 (8H, Peng), 2.3-2.7 (2H
,s), 3.27-3.45 (2H,ll), 3.
55 (2H, t. J=7Hz), 6.05 (IH, s), 6.82
(IH, d, J=8Hz). 7.42 (IH, dd, J-2, 8Hz), 7.5
4 (IH, d. J = 2 Hz) Back 111 To a solution of isothiazolidine 1,1-dioxide (0,45 g) in tetrahydrofuran (0,5 m ) was added dropwise 1.6 M n-butyllithium (2,311) in hexane. ,
The mixture is stirred at 0° C. for 0.5 h. To this, 3゜4-dihydro-2,2-dimethyl-3,4-epoxy-2H-
A solution of 1-benzopyran-6-carbonitrile (0.5 g) in N,N-dimethylformamide (7 mQ) is added. After stirring overnight at room temperature, the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residual solid was recrystallized from diethyl ether to give trans-3,4-dihydro-2,2-dimethyl-4-(1,1-dioxoisothiazolidin-2-yl)-3-hydroxy-2H-1 -Benzopyran-6-carbonitrile (0,415 g) is obtained. up 7196-200℃ IR! 3520. 2210
am-1HMR (CDCIs, 8) ”t,so
(3H,s), 1.59 (3H1s). 2.3-2.7 (2H, m), 2.9-3.6 <
4H, a+), 3.76 (IH, d, J=10Hz)
, 4.68 (IH, d, J=10Hz),
6.90 (IH, d, J=9Hz), 7.49 (l
H, dd, J = 3.9Hz). 7.65 (IH, br s) Add at 0°C and stir the mixture at room temperature for 0.5 h. 3.
4-dihyro2,2-dimethyl-3,4-epoxy-
2H-1-benzopyran-6-carbonitrile (5z)
A solution of in dimethyl sulfoxide (10 mQ) is added at 0°C. After stirring overnight at room temperature, the mixture is poured into water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in tetrahydrofuran (1201d) and 60% sodium hydride (1.48 g) is added thereto. The f1 compound is refluxed for 14 hours, then poured into water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residual solid was recrystallized from diethyl ether to give 2,2-dimethyl-4-(1,1-dioxoisothiazolidin-2-yl)-2H-1-benzopyran-6-carbonitrile (2.24 g). get. apr 146-150”C IR (Stripe 1-R)! 2210. 1630
cm”INMR (CDCIs, ε): 1.49
(6H, s), 2.3-2.7 (2H. s), 3.28-3.45 (2H, m), 3.5
5 (2H, t. J=7Hz>, 6.85 (IH, d, J=8Hz)
, 7.44 (IH, dd. J=2.8Hz), 7.62 (IH, d, J=2H
z) Ship UU The following compound is obtained in the same manner as in Example 1. (1) trans-3,4-dihydro-3-hydroxy-
4-(1,1-dioxoisothiazolidin-2-yl)
Spiro[2H-1-benzopyran-2,1'-cyclobutane]-6-carponitrile. mp: 196-199℃ IR (sujiru) + 3520. 2210
c@-1BMR(Dl!5O-ds, 8)' 1
．． 5-2.7 (6H1s)-2,7-3-0(2H,
s), 3.0-3.5 (4H, m), 3.77
(lH, dd. J=5.9Hz), 4.48 (IH, d, J=9
11z), 5.81 (II. d, J=5Hz>, 7.00 (IH, d, Jg9
Hz), 7.5-7.7(2H, at) (2) trans-3,4-dihydro-3-hydroxy-
4-(1,1-dioxoisodeacyridin-2-yl)
Spiro[2H-1-benzopyran-2,1'-cyclohexane]-6-carponitrile. mp: 243-244℃ IR (streak (to) - breath): 349G, 22
20 cs*-1BMR (DMSO-da, 8)
' O-7-2-0 (10H, sa>, 2.0-2-
4 (2B, +a), 2.6-3°O (2H, m),
3.0-3.4 <2H, a+). 3.4-3.7 (IH, m), 4.48 (IH
,d,,Cl0Hz＞,5.4-5.7 (IH,m)
, 7.00 (IH, dd, J-1, 8Hz),
7.5-7.7 (IH, s+), 7.68 (
lH, br 5) (3) trans-2,2-diethyl-
3,4-dihydro-3-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)-2H-1-benzopyran-6-carbonitrile. rap 155-156℃ IR (Nugir): 3400. 2220
cra-'NMR (DMSO-da, δ): 0.
7-1.2 (6H, m), 1.4-2.0 (4H,
m), 2.1-2.5 (2H, m), 2.7-3.
0 (2M, m). 3.1-3.6 (2H, m), 3.7-4.0
(1M, ■), 4.56 (lH, d, J=10Hz
), 5.54 (IH, d, J=5Hz), 6
．． 97 (IH, d, Jg8Hz), 7.5-7.7
(2H, m) Inu Todo Fake 1 The following compound was obtained in the same manner as in Example 2. (1) 4-(1,1-dioxoisothiazolidine-2-
yl) spiro[2H-1-benzopyran-2,1' -
cyclobutane]-6-carponitrile. mp 155-158℃ IR (sujiru): 2200. 16th Oc
m-1NWR (CDCIs, 8); 1.6-2.1
(2H1), 2-1-2.8 (6H, s), 3.
2-3.7 (4H, m), 6.31 <IH, s
). 6.86 (IH, d, J=9Hz), 7.42
(lH, dd, J=2°9Hz), 7.55 (I
H, d, J=2Hz) (2) 4-(1,1-dioxoisothiazolidin-2-yl)spiro[2H-1-benzopyran-2,1'-cyclohexane]-6-carponitrile. rap: 167-168℃ IR (line meeting): 22G0. 1640
am-1BMR (CDC13, & ): 1
．． 1-2.2 (10M, pcs->, 2.3-2
．． 7 (2H1■>, 3.2-3゜4 (2H, a+
), 3.54 (2H, t. J=7Hz), 6.02 (IH, s), 6.
89 (IH, d, J=8Hz>. 7.44 (IH, dd, J=2.8Hz), 7
．． 56 (IH, d. J=2H2) (3) 2.2-diethyl-4-(1,1-dioxoisothiazolidin-2-yl)-2H-1-benzopyran-
6-Carbonitrile. tap: 123-1256C IR (line meeting) + 2220. 1630
am-1BMR<CDCl3. δ)XO19-1,1
(6H, a+), 1.6-2.0 (4H, im),
2.4-2.7 (2H, m), 3.3-3.5 (
2H, m). 3.5-3.7 (28, ■>, 5.87 (IH,
s), 6.82 (1B. d, J=8Hz), 7.41 (18,dd, J=2
．． 8Hz), 7.55 (IH, d, J = 2Hz)
A suspension of the sodium salt of isothiazolidine 1,1-dioxide (36,7 g) in dry dimethyl sulfoxide (500 m+1) was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and diluted with 500 IQ of ethyl acetate. Extract twice at 250m+1. The ethyl acetate extract is washed with a saturated aqueous sodium chloride solution (500%), dried over magnesium sulfate and treated with activated carbon. The solvent is removed under reduced pressure. The residue (tz, tg) was transferred to silica gel (2
40g) and subjected to column chromatography using
Elute with dichloromethane and a mixture of dichloromethane and methanol (30:1). Both fractions containing the target compound were combined and concentrated under reduced pressure to obtain trans-3#4-dihydro-
2,2-dimethyl-4-(1,1-dioxoisothiazolidin-2-yl)-3-hydroxy-2H-1-benzopyran-6-carbonitrile (9.3 g) is obtained as white crystals. IR (streak soda): 3520. 2210
am-1Xl■1 trans-3,4-dihydro-2,2-dimethyl-4-
(1,1-dioxoisothiazolidin-2-yl)-3
-Hydroxy-2H-1-benzopyran-6-carbonitrile (12.5 g) in a solution of acetic anhydride (5 g) in pyridine.
, 7111) was added dropwise under water cooling. The reaction mixture was stirred at room temperature overnight and diluted with ethyl acetate (zsom). Sequentially add 10% salt to this mixture (200mffi, twice)
, water (200 ml), saturated aqueous sodium bicarbonate solution (200 fiLil) and saturated aqueous sodium chloride solution (200111') and dried over magnesium sulfate. The solvent is removed under reduced pressure. This residue, trans-3-acetoxy-3,4-dihydro-2,2-dimethyl-4-(1,1-dioxoisothiazolidin-2-yl)-2H-1-benzopyran-6-carbonitrile (
133g) was dissolved in toluene, and 1,5-diazabicyclo[5°4.0]undes-5-ene (7,25
! Add 1 liter). The reaction mixture is heated to 100'C for 2.5 hours, cooled and diluted with ethyl acetate (2601d). The ethyl acetate layer is washed successively with water (1701111) and saturated aqueous sodium chloride solution (170II11) and dried over magnesium sulfate. The solvent is removed under reduced pressure. J! The J residue was subjected to column chromatography using silica gel (240 g), and a mixture of ethyl acetate and n-hexane (1:4 → l
:2→1:1). Both fractions containing the target compound are combined and concentrated under reduced pressure. The residue was dissolved in ethanol (60ffll
2,2-dimethyl-4-(1,
1-Dioxoisothiazolidin-2-yl)-2H-1
-Benzopyran-6-carbonitol (8,07g
) is obtained as white crystals. IR (Stripe 1-L): 2210. 1630
2.2-dimethyl-4- in ethyl acetate (151111)
(1,1-dioxoisothiazolidin-2-yl)-2
H-1-benzopyran-6-carbonitrile (304t
ag ) and 10% palladium-carbon (60 mg) are shaken under a pressure of 40 psi in a hydrogen atmosphere for 8.5 hours. The catalyst is filtered off, washed with ethyl acetate, and the filtrate and washings are combined and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (
IIIQ') and water (0,1811111), and N-bromosuccinimide (0,23
Add g). The reaction mixture is stirred at room temperature for 40 minutes, poured into water (3:M!) and extracted with ethyl acetate (30ml). The ethyl acetate layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is removed under reduced pressure. Apply the residue to silica gel (202)
The mixture was subjected to column chromatography using a mixture of ethyl acetate and n-hexane (1:4-+1:2) as elution. Both parts containing the desired compound are combined and concentrated under reduced pressure. The residue was mixed with ethanol (1 relative) and n-hexane (1 m
Recrystallized from a mixture with 1) to give 3,4-dihydro-2
, 2-dimethyl-4-(1,1-dioxoisothiazolidin-2-yl)-28-1-benzopyran-6-carbonitrile (58seg) is obtained as white crystals. rap: 151-153@C IR (x Zeal) 2 2220. 1296.
1140 am-'NMR (CDCl2.8):
1.33 (3H,s), 1.48 (3H,s)
. 1.90-2.70 (4H, a+), 2.90-3
．． 53 (4H, a+). 4.80-5.23 (IH, m), 6.87 (I
H, d, J = 8Hz). 7.63 (IH, dd, J=2.8Hz), 7.7
2 (IH, d. J=2Hz> MASS + 306. 186 Elemental analysis Calculated value as C15H18N203S:
C5g, 80. H5, 92, N 9.14 actual measurement value:
C5g, 85. H5,95,N 9.12 Todoroki Gotan The following compound was obtained in the same manner as in Example 8. (1) 4-(1,1-dioxoisothiazolidine-2-
yl) spiro[2H-1-benzopyran-2,1'-cyclobutane]-6-carponitrile. Temperature: 155-158℃ IR (Suji Book)” 2200. 1640
cm-'NMR (CDCl2.δ): 1.6-2
．． 1 (2H, m), 2.1-2.8 (6H, m),
3.2-3.7 (4H, +m), 6.31
(IH, s). 6.86 (IH, d, J=9Hz), 7.42
(IH, dd, J=2°9Hz>, 7.55 (LH
, d, J=2Hz) (2) 4-(1,1-dioxoisothiazolidin-2-yl)spiro[2H-1-benzopyran-2,1'-cyclohexane]-6-carbonitrile. mp: 167-168°C IR: 2220. 1640
am-1HMR(CDC1s,S)' 1.1-
2.2 (IOHom), 2.3-2゜7 (2H, m)
, 3.2-3.4 (2H, m), 3.54
(2H, t. J near) 1z), 6.02 (LH, s), 6
．． 89 (IH, d, J=8Hz). 7.44 (IH, dd, J=2.8Hz), 7
．． 56 (IH, d. J=2Hz) (3) 2.2-diethyl-4-(1,1-dioxothiazolidin-2-yl)-2H-1-benzopyran-
6-Carbonitrile. mp: 123-125℃ IR (line threat): 2220. 1630
c+a-'NMR (CDCl2.8) + 0.9-
1.1 (6H, m), 1.6-2.0 (4H, m)
, 2.4-2.7 <2H, ea), 3.3-3.
5 (2H, m). 3.5-3.7 (2H, m), 5.87 (IH,
s), 6.82 (IH. d, J:8)1z), 7.41 (1t1.dd, J
:2.8Hz>, 7.55 (IH, d, J=2Hz)

Claims (1)

[Claims] 1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each mean a lower alkyl group, or R^1 and R^2 combined to form a lower alkylene group, R^3 is hydrogen, hydroxy group or acyloxy group, R^4 is hydrogen, or R^3 and R^4 together form a bond) The compound shown in 2) Formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each mean a lower alkyl group, or R^1 and R^2 are combined Forming a lower alkylene group) is reacted with a compound represented by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ or a salt thereof to form the formula: ▲Mathematical formula, chemical formula, table, etc.▼ In the formula, R^1 and R^2 each have the same meaning as before)
Or obtain a compound represented by formula (2): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each have the same meaning as before)
When the compound represented by is subjected to a dehydration reaction, the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 each have the same meaning as before)
Or obtain a compound represented by formula (3): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each have the same meaning as before)
When the compound represented by is subjected to a reduction reaction, the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 each have the same meaning as before)
There are formulas, ▲mathematical formulas, chemical formulas, tables, etc., which are characterized by obtaining a compound represented by A process for producing a compound represented by a hydroxy group, R^4 means hydrogen or R^3 and R^4 together form a bond. 3) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each mean a lower alkyl group, or R^1 and R^2 combine to form a lower alkylene group. and R^3 means hydrogen, hydroxy group or acyloxy group, R^4 means hydrogen, or R^3 and R^4 together form a bond). Vasodilator as an ingredient.