JPH03141286A - Optically active pyranobenzooxadiazole derivative - Google Patents

Abstract

PURPOSE:To carry out optical resolution of the subject compounds useful as an intermediate for synthesis of remedies of hypertension, asthma, etc., by reacting a pyranobenzooxazole compound with an optically active carboxylic acid and subsequently isolating the resultant diastereomer salt. CONSTITUTION:A pyranobenzooxadiazole compound represented by formula I is reacted with an optically active carboxylic acid expressed by formula II and the resultant diastereomer salt is isolated to carry out optical resolution of the compound of formula I. In addition, the compound of formula I is obtained by treating a compound of formula III with sodium hypochlorite, reducing N-oxide group of the resultant compound of formula IV using a reducing agent such as triethyl phosphite and then reacting the obtained compound of formula V with ammonia in an inert solvent.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to optically active pyranobenzoxadiazole derivatives, which are important synthetic intermediates for optically active pyranobenzoxadiazole derivatives useful for the treatment of hypertension, asthma, etc. This invention relates to an optical resolution method for a benzoxadiazole compound and a racemic pyranobenzoxadiazole compound.

(Hereinafter in the margin) [3 types of problems to be solved by conventional technology and invention (
I[) [wherein A is a hydroxyl group or QC(0)CH,,X, (
X means a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group, and n means an integer of 0 to 3. ), when R1 is a hydrogen atom, R2 is a hydrogen atom, C(Z)CH3
-, X, (Z means an oxygen atom or a sulfur atom.

n is the same as above. ) or C(Z)NHCH,,X, (Z and n are the same as above), and when R1 is not a hydrogen atom, R1 and R2 together (
CH2) ffi-+C(Z) (m means 4 or 5. Z is the same as above.) , (CH2), , NHC
(Z) or (CH2), -20C(Z) (Z and m
is the same as above. ) is shown. ] A pyranobenzoxadiazole derivative represented by (hereinafter referred to as compound CI). ) is published in Japanese Unexamined Patent Publication No. 2-497.
It is a racemic compound described in Publication No. 88 and U.S. Patent No. 4,900,752, and has strong vasodilatory and blood pressure lowering effects, and is useful for the treatment of hypertension, angina, arrhythmia, cerebral circulation disorders, asthma, etc. It is expected to be used as a medicine in the future.

Compound (III) can be synthesized as described in JP-A-2-49788 as follows.

Reaction formula 1 Reaction formula 2 Compound [(±) I) (catalyst) Reaction formula 4 % formula % ()) () Reaction formula 3 Compound [(±) I] Reaction formula 5 % formula % ()) In the above reaction formula , Y means a leaving group such as halogen atom (chlorine atom, bromine atom or iodine atom), acetoxy or trifluoroacetoxy, Y1 is chlorine atom, bromine atom, iodine atom, 〇- or p-1-luenesulfonate or methanesulfonate, mSn and X are the same as above.

Compound CI) in which R1 is a hydrogen atom (A
) is a racemic pyranobenzoxadiazole compound (hereinafter abbreviated as compound [(±)I). ) in the presence or absence of a deoxidizer, the acylating agent YC(0)CHa
-, X, (X, Y, n are the same as above) can be synthesized by reacting (see reaction formula 1).

Compound CB in which R1 is a hydrogen atom in compound CI)
) is the isocyanate C(0)N to the compound [(±)I)
CH3, X, or isothiocyanate X, CH3-,N
It can be synthesized by reacting C(S) (X, Z, n are the same as above) (reaction formula 2
reference).

In compound CI), R1 and R2 together form (CH
2), -1c(0) Compound [C] is compound [(
±) In the presence or absence of a deoxidizing agent in I), the acylating agent YC
(OXCH2) , , -IY' (Y , Y',
m is the same as above. ), and then cyclized in the presence or absence of an acid absorbing agent (see Reaction Scheme 3).

In compound (III), R1 and R2 are combined,
(CH2), NHC (ZXZ and m are the same as above.)
Compound CD) is a compound [(±)Ill with isocyanate (0)CN(CH2), , Y' or isothiocyanate (S)CN(CH2),2Y'(Y' and m are the same as above.) It can be synthesized by reacting and then cyclizing in the presence or absence of a deoxidizing agent (see Reaction Scheme 4).

In compound (III) (cH2), -2oc(o)
(m is the same as above.) Compound (E) is prepared by adding compound [(±)I) to halogenocarbonate YC(0)O(CH2), , -2Y' (Y , Y
', m are the same as above. ), and then cyclized in the presence or absence of an acid absorbing agent (see Reaction Scheme 5).

In the above reaction formula, a compound in which Z in compound (III) is a sulfur atom can be synthesized by sulfurizing a compound in which Z is an oxygen atom using Lawesson's reagent.

Further, the compound [(±)I) can be synthesized as described in JP-A-2-49788 as follows.

CF) [G] (H) H2 Compound [(±)I) is a known compound CF) treated with sodium hypochlorite, and the N-oxide group of the generated compound (G) is reduced with triethyl phosphite etc. After reducing with agent,
It is obtained by reacting the generated compound (H) with ammonia in an inert solvent.

However, there is no description of the optical resolution method for the racemic compound [(±)■].

Furthermore, since the racemic compound CI [) mentioned above has asymmetric carbon atoms at the 3- and 4-positions of the biran ring, it has two optical isomers ([compound [■°]] and compound CI''). ), but the above-mentioned JP-A-2-49788 does not specifically describe these optically active pyranobenzoxadiazole derivatives and their production methods.

In the case of pharmaceuticals, there are many examples of differences in pharmacological activity and safety between optical isomers, and in order to develop better pharmaceuticals,
It is desired to optically separate them.

[Means for solving problems]

Among the pyranobenzoxadiazole derivatives of the racemic compound CI), the present inventors discovered an optically active pyranobenzoxadiazole compound (described later) that exhibits dextrorotation when the optical rotation is measured in ethanol. Compound ((+)I)
The optically active pyranobenzoxadiazole derivative (corresponding to compound [■1]) synthesized via the enantiomer (corresponding to compound It has significantly superior activity as a pharmaceutical compared to the optically active pyranobenzoxadiazole derivative (corresponding to compound CI'') synthesized via the compound (corresponding to (-)I)). The present invention was completed based on this discovery.

That is, the present invention provides a racemic pyranobenzoxadiazole compound represented by the formula [(±)■] (the above-mentioned compound [(±)■]), which has an optical activity represented by the formula (II) Carboxylic acid (hereinafter, compound (II)
It is abbreviated as. ) Compound [(±)I) characterized in that the resulting diastereomeric salt is separated after reaction with [(±)I)
Among the optical resolution methods and the two optical isomers obtained as a result, an optically active pyranobenzoxadiazole compound (the above-mentioned compound (
(+)I)).

Compound [■] which is an optical resolving agent (This includes a compound (
(+) II) and the compound (there are two types of optical isomers (-> II)) can be synthesized according to the description in JP-A-61-83144.

Below, the compound [(±)■] is optically resolved, and the compound ((+
)I) and the enantiomer of compound ((+)I) (the above-mentioned compound ((-)I)) will be described.

[Reaction formula l]

Step A [(±)I) In Step A, compound [(±)I) is reacted with compound ((-) II) as an optical resolving agent and crystallized to form a diastereomeric salt ((+) )I・(-') II
) can be easily obtained as crystals.

However, depending on the solvent used, crystals may be obtained in the form of solvates (see Examples).

Similarly, when compound ((+) II) is used as an optical resolving agent, diastereomeric salt ((-)I・(+)II
) can be obtained.

Therefore, by selecting the optical resolving agent, the compound [(±
) The desired optical isomer of I) can be easily obtained.

There are no particular restrictions on the solvent used in step A, but ketone solvents such as acetone and methyl isobutyl ketone are preferred, in which case the diastereomeric salt crystallizes in the form of a solvate.

The reaction temperature is usually in the range of -20°C to 100°C, preferably in the range of 10°C to 30°C.

The crystallization temperature is usually in the range of -20°C to 50°C, preferably in the range of -10°C to 20°C.

If necessary, the crystallized diastereomeric salt can be recrystallized from acetone or the like to obtain a highly pure crystalline diastereomeric salt.

In step B, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, A target compound ((+)I) that exhibits dextrorotatory optical rotation in ethanol by reacting with a base selected from sodium hydroxide, potassium hydroxide, etc.
can be easily obtained.

Similarly, the compound [(-)■] can be easily obtained from the diastereomeric salt ((-)I.(+)■) or its solvate.

The optical purity of the compound ((+)I) was determined using an optically active liquid chromatography column (Daicel Corporation, Chiralcel OC) after reacting it with methyl isocyanate to derive the urea compound of formula ((+)IV). It can be measured by analysis.

Similarly, the optical purity of compound ((-)I) can also be measured.

Compound ((+)I) according to the synthesis method of racemic compound CI[I] described in JP-A-2-49788 mentioned above.
The compound [■゛] synthesized from this compound has extremely higher activity than the enantiomer compound (III'') synthesized from the compound ((-)I), as shown in the blood pressure lowering test results described below.

Therefore, it is clear that the use of compound [■0] is more useful for the treatment of hypertension, etc., than the use of compound (I[) in its racemic form.

Furthermore, racemization during the synthesis of compound [■°] from compound C(+)I) or during the synthesis of compound (III") from compound (-)I) can be achieved using an optically active liquid chromatography column (Daicel Corporation). As a result of analysis using Chiralcel QC), it was found that this did not occur at all.

[Test examples, working examples and reference examples]

(1) Test example (hypertensive effect) Compound [■9] and compound [■-] were suspended or dissolved in a 0.5% methylcellulose aqueous solution, and a gastrosonde was used to test the results for male spontaneous hypertension (11 weeks). (age) 3 animals were forcibly administered orally.

After heating the rats in a greenhouse at 50°C for 3 to 5 molecules,
The animal was transferred to a restraint cage at 7°C, and systolic blood pressure was measured at the caudal artery using a non-invasive blood pressure measuring device (Natsume KN-210-1 model). Blood pressure reduction rate (%) 1 hour after oral administration
are shown in Table 1. The value is the average value of 3 animals.

Further, chemical analysis values of compound [■°] and compound (III'') are shown in Table 2.

(Hereinafter, blank space) (2) Examples Example 1 (a) Step A: Diastereomeric salt ((+)I・(-)
■・acetone solvate] and diastereomeric salt ((-)I・(+) ■・acetone solvate) separation (±)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8- Amino-6H-pyrano[2,3f]benzo-2,1,3-oxadiazole (compound [(±)I
)') 117.6g (0,500 mol) and (-)-
92.9 g (0.510 mol) of 2-(4-hydroxyphenoxy)propionic acid (compound (-) II) was dissolved in 1000 g of acetone and stirred for 3 hours under water cooling.

Suction filter the crystallized crystals and add 500ml of ice-cooled acetone.
After washing with 1 and drying under reduced pressure, 64.6 g (yield 27.2%, optical Purity 9
5.7%e,e,) was obtained.

This diastereomeric salt ((+)I・(−)It・
Acetone solvate] was heated and refluxed in 270 g of acetone, 77 g of acetone was distilled off, and crystallized for 2 hours under cooling with water to obtain the diastereomeric salt ((+)I/(-)
■・Acetone solvate] optical purity is 100%e, e
(recovery rate of 80%).

When the melting point of this product was measured, gradual decomposition was observed from around 102°C, and the results of non-aqueous titration with perchloric acid in an acetic acid solvent confirmed that one molecule of acetone was solvated.

On the other hand, after combining the filtrates and distilling off the acetone, 1500 mt' of ethyl acetate, 1000 mt of water, 3 mt of sodium hydrogen carbonate,
2.8 g (0.39 mol) and 200 g of sodium chloride were added and shaken.

After allowing this solution to stand, separate the layers to separate the ethyl acetate layer, and add 200 mj7 of water, 6.56 g of sodium hydrogen carbonate (0,
078 mol) and 40 g of sodium chloride were added thereto, and the mixture was shaken again and allowed to stand for liquid separation.

Anhydrous sodium sulfate was added to the obtained ethyl acetate layer to dry it, and after filtering, ethyl acetate was distilled off to obtain 94.7 g of a brown solid.

This brown solid and (+)-2-(4-hydroxyphenoxy)propionic acid (compound [(+)II)) 7
3.4 g (0,403 mol) was dissolved in 7°Og of acetone and stirred for 3 hours under water cooling.

Suction filter the crystallized crystals and add 280ml of ice-cooled acetone.
After washing and drying under reduced pressure, 75.79 g (yield 31.9%, optical purity 100%) of the diastereomeric salt ((-)I・(+)■・acetone solvate) of pale yellow crystals was obtained.
, e, ) were obtained.

When the melting point of this product was measured, gradual decomposition was observed from around 102°C, and the results of non-aqueous titration with perchloric acid in an acetic acid solvent confirmed that one molecule of acetone was solvated.

(b) Step B: Compound ((+)I) and compound ((-)
Separation of I) ((+)I・(−)■・acetone solvate) 66.7
g (0,140 mol), ethyl acetate 10100O, water 700771i7, sodium carbonate 17.0g (0,1
After adding 140 g of sodium chloride and shaking,
It was left to stand and the liquid was separated.

Separate the ethyl acetate layer, add 200 mff of water, 2.1 g (0,020 mol) of sodium carbonate, and 40 g of sodium chloride.
After washing by adding sodium chloride aqueous solution (40
g/200 ml of water). Anhydrous sodium sulfate was added to the ethyl acetate layer for drying, filtration, and then ethyl acetate was distilled off to obtain 31.85 g (yield 96%) of compound ((+)I).

Compound C(-)I) could also be obtained by treating the diastereomeric salt ((-)I.(+).-acetone solvate) in the same manner as above.

[Analysis value]

Melting point: 145~ for both compound ((+)I) and compound ((-)I)
146°C Optical rotation: Compound ((+)I) (α) o +189° (c=0.50.EtOH)
Compound ((-)I) (α), -189° (c = 0.50, EtOH
) Optical purity analysis: (Analysis conditions are the same as Table 2) After reacting with methyl isocyanate and deriving into a urea compound,
Analysis was performed using an optically active liquid chromatography column (Chiralcel QC, Daicel Corporation).

The optical purity of both the compound ((+)IL compound ((-)I) was 100% e, e.

Nuclear magnetic resonance spectra of the compound [(+)■] and compound ((-)I) both matched the spectra of the racemic compound [(±)I).

NMR (CDfJ!, +DMSO-d') (p1
]ITl): 1, 26 (3H), 1.49 (3H)
, 2.80-3.30 (5H).

3, 33 (IH), 3.78 (IH), 6.82 (
IH), 7.98 (IH) Example 2 (a) Step A: Diastereomeric salt ((+)I・(-)
Resolution of I [・Methyl isobutyl ketone solvate] and diastereomeric salt ((-)I・(+)■・Methyl isobutyl ketone solvate) (±)-7,8-dihydro-6,6-dimethyl- 7-hydroxy-8-amino-6H-pyrano[2,3-f)benzo-2,1,3-oxadiazole (compound [(±)
I)) 4.70 g (20 mmol) and (-)-2-
(4-hydroxyphenoxy)propionic acid (compound (
(-) II) ) 3.70g (20°3 mmol) was added to 27.8g of methyl isobutyl ketone, and 21'
Stir for 15 minutes at C.

10 μ of seed crystals ((+)I/(-)II/methyl isobutyl ketone solvate) were added to the obtained solution, and after crystallization was continued for 2 hours, stirring was stopped and the mixture was left in the refrigerator overnight. .

The crystallized crystals were filtered with suction, washed with 7.1 g of cold methyl isobutyl ketone, and dried under reduced pressure to give a diastereomeric salt ((+)I・(−)n・methylisobutylketone solvent) as pale yellow crystals. ] 4゜59g (yield 44.4
%)was gotten.

When the melting point of this product was measured, gradual decomposition was observed from around 95°C, and the results of non-aqueous titration with perchloric acid in an acetic acid solvent confirmed that one molecule of methyl isobutyl ketone was solvated.

Meanwhile, the filtrate was combined with 20% sodium chloride aqueous solution 28.
2g and 1.22g (11.5 mmol) of sodium carbonate
was added and shaken. After standing still, separate the layers to remove the methyl isobutyl ketone layer, and add 20% sodium chloride aqueous solution 9.
．． 4 g was added, distributed again, and allowed to stand to separate the liquids.

(+)-2-(4
-hydroxyphenoxy)propionic acid (compound ((+
) II) ) 2.07 g (11.4 mmol) was added and dissolved by stirring at room temperature, and the seed crystals [(=)■・ (+
) 10 mg of methyl isobutyl ketone solvate was added to cause crystallization. After leaving it in the refrigerator overnight, the crystals were collected by suction filtration, washed with 7.1 g of cold methyl isobutyl ketone, and dried under reduced pressure. (2) 4.25 g (yield: 41.1%) of methyl isobutyl ketone solvate was obtained.

When the melting point of this product was measured, gradual decomposition was observed from around 95°C, and the results of non-aqueous titration with perchloric acid in an acetic acid solvent confirmed that one molecule of methyl isobutyl ketone was solvated.

(b) Step B: Compound ((+)I) and compound ((-)
The crystalline diastereomeric salt ((+) obtained in separation step A of I)
I. (-)■.Isobutylketone solvate) 4.2
6 g (8.23 mmol) of ethyl acetate 53.4
g, water 42.7 g, sodium carbonate 0.873 g (8
, 23 mmol) and 10.7 g of sodium chloride were added and shaken, then allowed to stand and the liquids were separated.

The ethyl acetate layer was separated and washed with 14.2 g of water and 3.6 g of sodium chloride.

Anhydrous sodium sulfate was added to the ethyl acetate layer, and after drying and filtration, 48.6 g of ethyl acetate was distilled off, and 7.3 g of hexane was added.
When the precipitated crystals were collected by filtration, 84 g (yield 95%) of compound [(+)I)l was obtained.

Further, the compound ((-) I) could be obtained by treating the diastereomeric salt ((-) I. (+) ■. isobutyl ketone solvate) in the same manner as above.

The optical purity of the obtained compound ((+)I) and compound [(-)■] was 100% e, e.

(3) Reference Example Reference Example 1 (a) (→-)7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(n-(1-oxo-5-chloro)pentyl)amino-6H-pyraf [2,3f] Synthesis of benzo-2,1,3-oxadiazole [Synthesis of intermediate] (Hereafter, blank space) C(0)CH2CH2CH2CH2Cff/ (+)7.8-dihydro-6,6-dimethyl-7 Hydroxy-8-amino-6H-pyrano(2,3-f]benzo-2,1,3-oxadiazole [Compound (+) I) 7
15■ (3.04 mmol), triethylamine 470
μA (3.34 mmol), methylene chloride Toml was stirred at room temperature, and this solution was added with 5-chlorovaleryl chloride 4.
30 μA (3.34 mmol) was added. After reacting for 2 hours, the mixture was washed three times with water, the methylene chloride layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain the title compound. This compound was not purified further (it was used in the following reaction).

(b) (+) 7.8-dihydro-6,6-dimethyl-7hydroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano (2,3-f)benzo-2°1.
Synthesis of 3-oxadiazole (corresponding to compound [■8]) ) pentyl)amino-6H-pyrano (2,3-f)benzo-
2,1,3-year-old xadiazole 1.08g, potassium carbonate 8.40g (60.8 mmol), potassium iodide t
, o1g (6.08 mmol) was suspended in 200 mj of acetone and refluxed under nitrogen atmosphere for 9 hours.

After cooling, insoluble materials were removed by filtration, and the filtrate was diluted with ethyl acetate. After washing twice with water and once with saturated saline, it was dried over anhydrous sodium sulfate.

After evaporation of the solvent, the residue was subjected to preparative silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound 40.
(yield: 4%). A portion of this was recrystallized from ethyl acetate to obtain pale yellow crystals.

[Analysis value]

Melting point 180-182°C Optical purity 100% e, e, (See Table 2) Reference example 2 (a) (-) 7.8-dihydro-6,6-dimethyl-7-hydroxy-8-(n-(1- Synthesis of oxo-5-wolfberry pentyl)amino-6H-pyrano[2,3f]benzo-2,1,3-oxadiazole [Synthesis of intermediate] C(0)CH2CH2CH2CH2CA/ (-)7.8 -dihydro-6,6-simethyl-7hydroxy-8-amino-6H-pyrano(2,3-f]benzo-2,1,3-oxadiazole [compound (-) I
) 769 mg (3,27 mmol), triethylamine 500 μ! ! (3.60 mmol) and methylene chloride 7077+1 were stirred at room temperature, and to this solution was added 5-chlorovaleryl chloride (465 μm, 3.60 mmol). After reacting for 2 hours, the mixture was washed three times with water, and the methylene chloride layer was dried over anhydrous sodium sulfate, followed by filtration and evaporation of the solvent to obtain the title compound. This compound was used in the following reaction without further purification.

(b) (-) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano(2,3-f)benzo-2,1,3
-Synthesis of oxadiazole (corresponding to compound CI"°) (-)7,8-dihydro-6,6-dimethyl-7hydroxy-8-(n-(1-oxo-5-chloro)pentyl)amino-6H -pyrano (2,3-f)benzo-2
, 1,3-oxadiazole 1.16 g, potassium carbonate 9.04 g (65.4 mmol), potassium iodide 1
．． 09g (6.54 mmol) in acetone 200mj7
The mixture was suspended in water and refluxed for 9 hours under a nitrogen atmosphere.

After cooling, insoluble materials were removed by filtration, and the filtrate was diluted with ethyl acetate. After washing twice with water and once with saturated saline, it was dried over anhydrous sodium sulfate.

After evaporation of the solvent, the residue was subjected to preparative silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound 47.
(yield: 5%). A portion of this was recrystallized from ethyl acetate to obtain pale yellow crystals.

[Analysis value]

Melting point 179-180°C Optical purity 100% e, e, (See Table 2) Reference example 3 (+)7.8-dihydro-6,6-dimethyl-7-hydroxy-8-propionylamino-6H-pyrano(2,
3-f) Synthesis of benzo-2,1,3-oxadiazole (corresponding to compound [■8]) (10) 7.8-dihydro-6,6-dimethyl-7=hydroxy-8-amino-6H -pyrano C2,3-f]benzo-2,1,3
-Oxadiazole [Compound (+) I) 1.2
9 g (5.48 mmol), triethylamine 69
0■ (6.8 mmol), propionyl chloride 610 mg (6
, 6 mmol) and stirred at room temperature for 4 hours. This reaction solution was extracted by adding 60 ml of ethyl acetate (hy+j' and 300 ml of water), and the organic layer was taken and dried over anhydrous sodium sulfate.
Crystallized in a mixed solvent of 0g and 5g of hexane, overnight.
After leaving it in the refrigerator, it was filtered with suction. The crystals were washed with 3 mj'x of ethyl acetate-hexane (2:1) twice and dried under reduced pressure to obtain the colorless title compound.

[Analysis value]

Melting point 179-180°C Optical purity 100% e, e, (See Table 2) Reference example 4 (-)7.8-dihydro-6,6-cymethyl-7-hydroxy-8-propionylamino-6H-pyrano(2,
3-f) Synthesis of benzo-2,1,3-oxadiazole (corresponding to compound (III”°)) (-) 7.8
-dihydro-6,6-dimethyl-7-hydroxy-8-
(n-(1-oxo-5-chloro)pentyl)amino-
6H-pyrano[2,3f]benzo-2,1,3-oxadiazole [compound (-) I) 52μ (0.22 mmol), triethylamine 34μ17 (0.24 mmol), and methylene chloride 5ml at room temperature. While stirring, 21 μA (0.24 mmol) of propionyl chloride was added and stirred for 6 hours.

After the reaction, the mixture was washed three times with water and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol to obtain pure title compound 15 (yield: 23%).

[Analysis value]

Melting point 179-180°C Optical purity 100% e, e, (See Table 2) Reference example 5 (+) 7.8-dihydro-6,6-dimethyl-7-hydroxy-8-methylureido-6H-pyrano(2, 3-
f) Synthesis of benzo-2,1,3-oxadiazolezole (corresponding to compound (+) ■) (+) I) 300
(1.28 mmol) and dichloromethane (15 mmol) were stirred at room temperature, and 120 mmol of methyl isocyanate was added to this solution.
(2.10 mmol) was added and stirred at room temperature (20°C) for 5 hours.

After crystallization in a refrigerated bed, the precipitated crystals were filtered to obtain colorless crystals of the title compound 214 (yield 58%).

[Analysis value]

Melting point 165-167°C Optical purity 100% e, e, (See Table 2) Reference example 6 (-)7.8-dihydro-6,6-cymethyl-7-hydroxy-8-methylureido-6H-pyrano(2, 3-
f) Synthesis of benzo-2,1,3-oxadiazolezole (corresponding to compound (-)■) (+)7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [ 2,3f] Hency 2.1.3-oxadiazole [compound (-)7.8-dihydro-6,
6-dimethyl-7-hydroxy-8-amino-6H-pyrano(2,3-f)benzo-2,1,3-oxadiazole [Compound (-) I) 300 mg (1,28 mmol) and 20 ml of dichloromethane were heated at room temperature. 120 μm (2.10 mmol) of methyl isocyanate was added to this solution, and the mixture was stirred at room temperature (20° C.) for 5 hours.

The product was analyzed in the refrigerator, and the precipitated crystals were filtered to obtain 195+++ g (yield: 52%) of the title compound as colorless crystals.

[Analysis value]

Melting point 165-167°C Optical purity 100% e, e, (see Table 2) Reference example 7 7.8-dihydro-6,6-dimethyl-7.8-epoxy-6H-pyrano (2,3-f)benzo -2,1,3
-Synthesis of oxadiazole 3-oxide (compound [G]
) 6-Amino-3,4-dihydro-2,2-dimethyl-3
, 4-epoxy-7-nitro 2H-benzo(b) bilane (compound CF)) 4.41 g (18.9 mmol), sodium hydroxide 1.29 g (32 mmol),
While stirring 400 ml of ethanol and 40 ml of water at room temperature, add 32.2 g (26 ml) of 6% aqueous sodium hypochlorite solution.
(mmol) was slowly added dropwise, and the mixture was stirred for 1 hour.

After the reaction was completed, brine 11' was added and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate.

After evaporating the solvent, the residue was subjected to silica gel column chromatography [developing solvent, ethyl acetate:hexane = 1:2 (
v/v) ) to give 4.00 g of the title compound (yield 9
2%) of yellow crystals were obtained.

[Analysis value]

Melting point 144-145°C Reference example 8 7.8-dihydro-6,6-dimethyl-7.8-epoxy-6H-pyrano(2,3-f)benzo-2,1,3
Synthesis of oxadiazole (compound [H]) 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano (2,3-f)benzo-2,1,3oxadiazole 3- Oxide (compound [G]) 1.00g (4,2
7 mmol) and 6 ml of benzene were stirred at 60°C, while 0.80 mfl' (4.70 mmol) of triethyl phosphite was added dropwise over 15 minutes, followed by stirring for 3 hours.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel chromatography [developing solvent, ethyl acetate:hexane-1:1
(v/v) ) to obtain 0.82 g (yield: 88%) of the title compound.

A portion of this was recrystallized from hexane to obtain yellow crystals.

[Analysis value]

Melting point 97-99°C Reference Example 9 7.8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano(2,3-f)benzo-
Synthesis of 2,1,3-oxadiazole (compound (±)■
) 7.8-dihydro-6,6-dimethyl-7.8-epoxy-6H-pyrano (2,3-f)benzo-2,1,3
-Oxadiazole (compound (H)) 0.82g
(3°8 mmol) was dissolved in 25 ml of 16.7% ammonia-ethanol and heated at 60° in a pressure glass tube.
The reaction was carried out at C for 48 hours.

The reaction solution was distilled off, and the residue was subjected to silica gel column chromatography [developing solvent, ethyl acetate:methanol=5:
1 (v/v)) to give 0.77 g of the title compound (
Yield: 87%) was obtained as a brown solid.

A portion of this was recrystallized from ethanol to obtain a pure surface layer compound as colorless crystals.

[Analysis value]

Melting point 159-162℃ NMR (CD (J', + DMSO-d') δ (pp
m): 1, 26 (3H), 1.49 (3H), 2
．． 80-3.30 (5H).

3.33 (IH), 3.78 (IH), 6.82 (
IH), 7.98 (IH) mass spectrometry value

Claims (2)

[Claims] (1) Formula [(±) I] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [(±) I ] The pyranobenzoxadiazole compound represented by the formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. There is a formula [II] characterized by separating the generated diastereomer salt after reacting with the optically active carboxylic acid represented by [II]
Optical resolution method of pyranobenzoxadiazole compound represented by (±)I]. (2) An optically active pyranobenzoxadiazole compound whose optical rotation in ethanol is dextrorotatory and is represented by the formula [(+) I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[(+) I] .