JP2876712B2 - Optically active pyranobenzoxadiazole derivative - Google Patents

Description

The present invention relates to an optically active pyrano which is an important synthetic intermediate of an optically active pyranobenzoxadiazole derivative useful for treating hypertension, asthma and the like. The present invention relates to a method for resolving a benzoxadiazole compound and a racemic pyranobenzoxadiazole compound.

[Problems to be solved by conventional technology and invention]

Formula (III) Wherein, A represents a hydroxyl group or a _{OC (O) CH 3-n} X n (X denotes a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group, n represents an integer of 0 to 3. ) indicates, when R ¹ is a hydrogen atom and R ² represents a hydrogen _{atom, C (Z) CH 3-} n X n
(Z represents an oxygen atom or a sulfur atom; n is the same as described above) or C (Z) NHCH _{3-n Xn} (Z and n are the same as described above), and when R ¹ is not a hydrogen atom R ¹ and R ² together (C
H ₂ ) _m-1 C (Z) (m means 4 or 5. Z is the same as above.), (CH ₂ ) _m-2 NHC (Z) or (CH ₂ ) _m-2 OC
(Z) (Z and m are the same as described above). The pyranobenzoxadiazole derivative represented by the following formula (hereinafter abbreviated as compound [III]) is disclosed in JP-A-2-49788.
And racemic compounds described in US Patent No. 4900752, which have strong vasodilatory and hypotensive effects, hypertension, angina, arrhythmia, cerebral circulation disorder,
It is expected as a medicine in the treatment of asthma and the like.

Compound [III] can be synthesized as follows as described in JP-A-2-49788.

In the above reaction, Y represents a leaving group, for example, a halogen atom (a chlorine atom, a bromine atom or an iodine atom), acetoxy or trifluoroacetoxy, and Y ¹ represents a chlorine atom, a bromine atom, an iodine atom, o- or p-. It means toluenesulfonate or methanesulfonate, and m, n, and X are the same as described above.

Compound [A] in which R ¹ is a hydrogen atom in compound [III] is a racemic pyranobenzoxadiazole compound (hereinafter abbreviated as compound [(±) I]) in the presence of a deoxidizing agent. Under the presence or absence of the acylating agent YC (O) CH
_{3-n X n (X,} Y, n are as. Above) can be synthesized by reacting (see Scheme 1).

Compound [B] in which R ¹ is a hydrogen atom in compound [III] is obtained by adding isocyanate C to compound [(±) I].
(O) NCH _3-n X _n or isothiocyanate X _n CH _3-n NC
It can be synthesized by reacting (S) (X, Z and n are the same as described above) (see Reaction Scheme 2).

In compound [III], R ¹ and R ² together form (CH ₂ )
_The compound [C] which is _m-1 C (O) is a compound [(±) I]
In the presence or absence of a deoxidizing agent, the acylating agent YC (O) (CH
₂ ) It can be synthesized by reacting _m-1 Y ¹ (Y, Y ¹ and m are the same as described above), followed by cyclization in the presence or absence of a deoxidizing agent (reaction formula 3). reference).

In compound [III], R ¹ and R ² together form (C
Compound [D], which is H ₂ ) _m-2 NHC (Z) (Z and m are the same as above), isocyanate (O) CN (CH ₂ ) _m-2 Y ¹ Or isothiocyanate (S) CN
(CH ₂ ) _m-2 Y ¹ (Y ¹ and m are the same as described above), and then cyclized in the presence or absence of a deoxidizing agent (reaction formula 4). reference).

In the compound [III], the compound [E] which is (CH ₂ ) _m-2 OC (O) (m is the same as described above) is a compound [(±)
I] in the presence of a deoxidizing agent, halogenocarbonate YC (O)
O (CH ₂ ) _m-2 Y ¹ (Y, Y ′, and m are the same as described above), and then cyclized in the presence or absence of a deoxidizing agent. See Reaction Scheme 5).

The compound of formula [III] wherein Z is a sulfur atom in the above reaction formula can be synthesized by sulfurizing a compound wherein Z is an oxygen atom with a Lawesson's reagent.

The compound [(±) I] can be synthesized as described below in JP-A-2-49788.

The compound [(±) I] was produced by treating a known compound [F] with sodium hypochlorite, reducing the N-oxide group of the produced compound [G] with a reducing agent such as triethyl phosphite. It is obtained by reacting compound [H] with ammonia in an inert solvent.

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

Furthermore, since the above-mentioned racemic compound [III] has an asymmetric carbon at the 3- and 4-positions of the pyran ring, it has two kinds of optical isomers ([compound [III ^* ] and compound [III ^** ] ], But there is no specific description of these optically active pyranobenzoxadiazole derivatives and their production methods in JP-A-2-49788.

In the case of pharmaceuticals, there are many examples in which pharmacological activity and safety are different between optical isomers, and in order to develop better pharmaceuticals, it is desired to optically resolve them.

[Means for solving the problem]

The present inventors have found that among the pyranobenzoxadiazole derivatives of the racemic compound [III], an optically active pyranobenzoxadiazole compound exhibiting dextrorotation when measured in optical rotation in ethanol (see below). Compound [(+)
Optically active pyranobenzoxadiazole derivative (equivalent to compound [III ^* ])
Is an optically active pyranobenzoxadiazole derivative (compound) which is synthesized via an enantiomer (corresponding to a compound [(-) I] described later) which is another optically active pyranobenzoxadiazole compound. (Corresponding to [III ^** ]) and found to have remarkably superior activity as a pharmaceutical product, and completed the present invention.

That is, the present invention relates to a racemic compound of the formula [(±) I] With a pyranobenzoxadiazole compound represented by the formula (II) After reacting with an optically active carboxylic acid represented by the following formula (hereinafter abbreviated as compound [II]), and separating the resulting diastereomer salt: The method and two optical isomers obtained as a result thereof relate to an optical property pyranobenzoxadiazole compound (the above-mentioned compound [(+) I]) having an optical rotation of dextrorotatory rotation in ethanol. is there.

Compound [II] (which has two optical isomers of compound [(+) II] and compound [(-) II]) as an optical resolving agent is disclosed in JP-A-61-83144. Can be synthesized according to the description.

Hereinafter, a method for optically resolving the compound [(±) I] to obtain an enantiomer of the compound [(+) I] and the compound [(+) I] (the above-mentioned compound [(−) I]) will be described. .

In the step A, the compound [(±) I] is reacted with the compound [(−) II] as an optical resolving agent, and crystallization is performed to obtain a diastereomer salt [(+) I · (−) II]. Can be easily obtained as crystals.

However, depending on the solvent used, crystals can be obtained in the form of a solvate (see Examples).

Similarly, when the compound [(+) II] is used as an optical resolving agent, a diastereomer salt [(−) I. (+) II] can be obtained.

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

The solvent used in step A is not particularly limited, but is preferably a ketone solvent such as acetone or methyl isobutyl ketone, in which case the diastereomer salt crystallizes in the form of a solvate.

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

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

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

In Step B, the crystalline diastereomer salt [(+) I. (−) II] obtained in Step A or a solvate thereof is added to sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, By reacting a base selected from sodium hydroxide, potassium hydroxide and the like, the desired compound [(+) I] whose rotatory power in ethanol is dextrorotatory can be easily obtained.

Similarly, diastereomer salts [(-) I. (+) II]
Alternatively, the compound [(-) I] can be easily obtained from the solvate thereof.

The optical purity of the compound [(+) I] is calculated by reacting the compound [(+) I] with methyl isocyanate. After derivation to a urea compound of the formula (I), it can be measured by analysis using an optically active liquid chromatography column (Daicel, Chiralcel OC).

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

The compound [III ^* ] synthesized from the compound [(+) I] according to the method for synthesizing the racemic compound [III] described in the above-mentioned JP-A-2-49788 has the following blood pressure lowering effect test results. As shown, it is much more active than the enantiomer (compound [III ^** ]) synthesized from compound [(-) I].

Therefore, it is clear that the use of the compound [III ^* ] is more useful for the treatment of hypertension and the like than when the compound [III] is used as it is in a racemic form.

In the synthesis of compound [III ^* ] from compound [(+) I] or in the synthesis of compound [III ^** ] from compound [(-) I], the optical activity is determined by the liquid chromatography column (Daicel As a result of analysis using Chiral Cell OC), it was found that it did not occur at all.

(Test Examples, Examples and Reference Examples)

(1) Test example (blood pressure lowering effect) Compound [III ^* ] and compound [III ^** ] are suspended or dissolved in a 0.5% aqueous solution of methylcellulose, and male spontaneously hypertensive rats (11-week-old) 3 are prepared using a gastric tube. Animals were forcibly administered orally.

After preheating the rats in a greenhouse at 50 ° C for 3-5 minutes,
And the systolic blood pressure was measured using a non-invasive blood pressure measurement device (Natsume KN-210-1) in the tail artery. Table 1 shows the blood pressure reduction rate (%) one hour after oral administration. Values are the average of three animals.

Further, the chemical analysis values of the compound [III ^*] and compound [III ^**] were shown in Table 2.

(2) Examples Example 1 (a) Step A: diastereomer salt [(+) I. (-) II
Acetone solvate] and diastereomer salt [(-)
I. (+) II.acetone solvate] (±) -7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo- 2,
117.6 g of 1,3-oxadiazole (compound [(±) I])
(0.500 mol) and 92.9 g of (-)-2- (4-hydroxyphenoxy) propionic acid (compound [(-) II])
(0.510 mol) was dissolved in 1000 g of acetone, and the mixture was stirred for 3 hours under ice cooling.

The crystallized crystals are filtered by suction, and ice-cooled acetone 500 ml
After drying under reduced pressure, 64.6 g (yield 27.2%, optical purity 95.7% ee) of diastereomer salt [(+) I. (-) II.acetone solvate] as pale yellow crystals were obtained. )
was gotten.

This diastereomer salt [(+) I. (-) II.acetone solvate] was heated and refluxed in 270 g of acetone, after which 77 g of acetone was distilled off and crystallized under ice cooling for 2 hours. The optical purity of the diastereomer salt [(+) I. (−) II.acetone solvate] was improved to 100% ee (recovery 8
0%).

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

On the other hand, after the acetone was distilled off together with the filtrate, 1500 ml of ethyl acetate, 1000 ml of water, 32.8 g of sodium hydrogen carbonate (0.39 g)
Mol) and 200 g of sodium chloride.

After allowing this solution to stand, liquid separation was performed to separate the ethyl acetate layer.
200 ml of water, 6.56 g (0.078 mol) of sodium hydrogen carbonate and 40 g of sodium chloride were added, and the mixture was shaken again, allowed to stand still, and separated.

Anhydrous sodium acetate was added to the obtained ethyl acetate layer, followed by drying and filtration. Ethyl acetate was distilled off to obtain 94.7 g of a brown solid.

73.4 g of this brown solid and (+)-2- (4-hydroxyphenoxy) propionic acid (compound [(+) II])
(0.403 mol) was dissolved in 700 g of acetone, and the mixture was stirred under ice cooling for 3 hours.

The crystallized crystals are filtered by suction and 280 ml of ice-cooled acetone
And dried under reduced pressure to give diastereomeric salts of pale yellow crystals [(-) I. (+) II.acetone solvate] 7
5.79 g (yield 31.9%, optical purity 100% ee) was obtained.

When the melting point was measured, decomposition was gradually observed at around 102 ° C., and 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 [(+) I-(-) II-acetone solvate] 66.7 g (0.1
(40 mol), 1000 ml of methyl acetate, 700 ml of water, 17.0 g (0.160 mol) of sodium carbonate, and 140 g of sodium chloride were added, shaken, allowed to stand, and separated.

Separate the ethyl acetate layer, water 200 ml, sodium carbonate 2.1
g (0.020 mol) and 40 g of sodium chloride, followed by washing, followed by washing with an aqueous sodium chloride solution (40 g / 200 ml of water). Anhydrous sodium sulfate was added to the ethyl acetate layer, followed by drying and filtration. Ethyl acetate was distilled off to obtain 31.85 g of the compound [(+) I] (96% yield).

The compound [(-) I] was obtained by treating the diastereomer salt [(+) I. (-) II.acetone solvate] in the same manner as described above.

(Analysis value)

Melting point: 145-1 for both compound [(+) I] and compound [(-) I]
46 ° C. Optical rotation: compound [(+) I] ▲ [α] ²⁵ _D ▼ + 189 ゜ (c = 0.50, EtOH) Compound [(−) I] ▲ [α] ²⁵ _D ▲ -189 ゜ (c = 0.50, EtOH) Optical purity analysis: (Analysis conditions are the same as in Table 2.) After reacting with methyl isocyanate to derive a urea compound, analysis was performed using an optically active liquid chromatography column (Daicel, Chiralcel OC).

The optical purity of both the compound [(+) I] and the compound [(-) I] was 100% ee.

Nuclear Magnetic Resonance Spectra Both the compound [(+) I] and the compound [(-) I] matched the spectra of the racemic compound [(+) I].

_{NMR (CDCl 3 + DMSO-d} 6) (ppm): 1.26 (3H), 1.49 (3H), 2.80~3.30 (5H), 3.33 (1H), 3.78 (1H), 6.82 (1H), 7.98 (1H) carried Example 2 (a) Step A: diastereomer salt [(+) I. (-) II
-Resolution of methyl isobutyl ketone solvate] and diastereomer salt [(-) I • (+) II • methyl isobutyl ketone solvate] (±) -7,8-dihydro-6,6-dimethyl-7 -Hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,
4.70 g of 1,3-oxadiazole (compound [(±) I])
(20 mmol) and 3.70 g of (-)-2- (4-hydroxyphenoxy) propionic acid (compound [(-) II])
0.3 mmol) to 27.8 g of methyl isobutyl ketone,
Stirred at 21 ° C. for 15 minutes.

10 mg of a seed crystal [(+) I. (-) II.methylisobutylketone solvate] was added to the obtained solution, and the mixture was allowed to crystallize for 2 hours. Then, stirring was stopped and the mixture was allowed to stand overnight in a refrigerator.

The crystallized crystals are filtered by suction, washed with 7.1 g of cold methyl isobutyl ketone, and then dried under reduced pressure. The diastereomer salt which is a pale yellow crystal [(+) I. (−) II. The product] 4.59 g (44.4% yield) was obtained.

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

On the other hand, the combined filtrate was 28.2 g of a 20% aqueous sodium chloride solution.
And 1.22 g (11.5 mmol) of sodium carbonate were added and shaken. After standing, liquid separation was performed to remove a methyl isobutyl ketone layer, 9.4 g of a 20% aqueous sodium chloride solution was added, the mixture was shaken again, and left to stand to separate.

(+)-2- was added to the obtained methyl isobutyl ketone layer.
2.07 g (11.4 mmol) of (4-hydroxyphenoxy) propionic acid (compound [(+) II]) was added and dissolved by stirring at room temperature to give a seed crystal [(-) I. (+) II.methylisobutylketone]. [Solvate] 10 mg was added for crystallization. After standing in a refrigerator overnight, the crystals were collected by suction filtration, washed with 7.1 g of cold methyl isobutyl ketone, and dried under reduced pressure to give diastereomeric salts of pale yellow crystals [(+) I.
(−) II. Methyl isobutyl ketone solvate] 4.25 g
(41.1% yield) was obtained.

When the melting point was measured, decomposition was gradually observed at around 95 ° C., and 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 [(−)
Separation of I] The crystalline diastereomer salt obtained in step A [(+) I. (−) II.isobutylketone solvate] 4.
26 g (8.23 mmol) of ethyl acetate 53.4 g, water 42.7 g, sodium carbonate 0.873 g (8.23 mmol), sodium chloride
After adding 10.7 g and shaking, it was left still and separated.

Separate the ethyl acetate layer, water 14.2 g, sodium chloride 3.6
g was added and washed.

Anhydrous sodium sulfate was added to the ethyl acetate layer, followed by drying and filtration. 48.6 g of ethyl acetate was distilled off, 7.3 g of hexane was added, and the mixture was crystallized for 3 hours under ice-cooling. [(+) I] 1.84 g (95% yield) was obtained.

The compound [(-) I] was obtained by treating the diastereomer salt [(-) I. (+) II.isobutylketone solvate] in the same manner as described above.

The obtained compound [(+) I] and compound [(-) I]
Was 100% ee.

(3) Reference Example Reference Example 1 (a) (+) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (n- (1-oxo-5-chloro) pentyl) amino-6H- Synthesis of pyrano [2,3-f] benzo-2,1,3-oxadiazole [Synthesis of Intermediate] (+) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3
-Oxadiazole [compound (+) I] 715 mg (3.04 mmol), triethylamine 470 µ (3.34 mmol) and methylene chloride 70 ml were stirred at room temperature, and 5
430 μ (3.34 mmol) of chlorovaleryl chloride was added. After reacting for 2 hours, the mixture is 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 used for the following reaction without further purification.

(B) (+) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxo-1-piperidinyl) -6H-
Synthesis of pyrano [2,3-f] 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 [2,3-f] benzo- 1.08 g of 2,1,3-oxadiazole, 8.40 g (60.8 mmol) of potassium carbonate, and 1.01 g (6.08 mmol) of potassium iodide were suspended in 200 ml of acetone and refluxed for 9 hours under a nitrogen atmosphere.

After cooling, insolubles were removed by filtration, and the filtrate was diluted with ethyl acetate. The extract was washed twice with water and once with a saturated saline solution, and then dried over anhydrous sodium sulfate.

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

(Analysis value)

Melting point 180-182 ° C Optical purity 100% ee (see Table 2) Reference Example 2 (a) (−) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (n- (1-oxo- Synthesis of 5-chloro) pentyl) amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole [Synthesis of Intermediate] (−) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3
769 mg (3.27 mmol) of -oxadiazole [compound (-) I], 500 µ (3.60 mmol) of triethylamine and 70 ml of methylene chloride were stirred at room temperature.
465 μl (3.60 mmol) of chlorovaleryl chloride 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, and then filtered and the solvent was distilled off to obtain the title compound. This compound was used for the following reaction without further purification.

(B) (-) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxo-1-piperidinyl) -6H-
Synthesis of pyrano [2,3-f] 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-virano [2,3-f] benzo-2 , 1,3-oxadiazole 1.16 g, potassium carbonate 9.04 g (65.4 mmol),
1.09 g (6.54 mmol) of potassium iodide in 200 ml of acetone
And refluxed under a nitrogen atmosphere for 9 hours.

After cooling, insolubles were removed by filtration, and the filtrate was diluted with ethyl acetate. The extract was washed twice with water and once with a saturated saline solution, and then dried over anhydrous sodium sulfate.

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

(Analysis value)

Melting point 180-182 ° C Optical purity 100% ee (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 (compound [III
^* ]) (+) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3
While stirring 1.29 g (5.48 mmol) of -oxadiazole [compound (+) I], 690 mg (6.8 mmol) of triethylamine and 40 ml of methylene chloride at room temperature, 610 mg (6.6 mmol) of propionyl chloride were added, and the mixture was stirred at room temperature for 4 hours. 600 ml of ethyl acetate and 30 ml of water were added to the reaction solution for extraction, and the organic layer was taken and dried over anhydrous sodium sulfate. The filtrate and the residue obtained by evaporating the solvent were diluted with 10 g of ethyl acetate.
Crystallized in a mixed solvent of hexane and 5 g of hexane, left in a refrigerator overnight, and suction-filtered. The crystals were washed twice with 3 ml of ethyl acetate-hexane (2: 1) x 2 and dried under reduced pressure to obtain the colorless title compound.

(Analysis value)

Melting point 179-180 ° C Optical purity 100% ee (see Table 2) Reference Example 4 (−) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-propionylamino-6H-pyrano [2,3- f]
Synthesis of benzo-2,1,3-oxadiazole (compound [III
^** ]) (-) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (n- (1-oxo-5-chloro) pentyl) amino-6H-pyrano [2,3-f] benzo-2 52 mg (0.22 mmol) of 1,1,3-oxadiazole [compound (-) I], 34 μ (0.24 mmol) of triethylamine, methylene chloride
While stirring 5 ml at room temperature, propionyl chloride 21μ
(0.24 mmol) and stirred for 6 hours.

After the reaction, the resultant was washed three times with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethanol to obtain 15 mg of pure title compound (yield 23%).

(Analysis value)

Melting point 179-180 ° C Optical purity 100% ee (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 (+) IV) (+) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3
300 mg (1.28 mmol) of -oxadiazole [compound (+) I] and 15 ml of dichloromethane were stirred at room temperature, 120 mg (2.10 mmol) of methyl isocyanate was added to this solution, and the mixture was stirred at room temperature (20 ° C) for 5 hours. .

After crystallization in a refrigerator, the precipitated crystals were filtered to give the title compound (214 mg, yield 58%) as colorless crystals.

[Analytical value] Melting point 165-167 ° C Optical purity 100% ee (see Table 2) Reference Example 6 (−) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methylureido-6H-pyrano [ Synthesis of 2,3-f] benzo-2,1,3-oxadiazolezole (corresponding to compound (-) IV) (−) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3
300 mg (1.28 mmol) of -oxadiazole [compound (-) I] and 20 ml of dichloromethane were stirred at room temperature, 120 mg (2.10 mmol) of methyl isocyanate was added to this solution, and the mixture was stirred at room temperature (20 ° C) for 5 hours. .

Crystallization was performed in a refrigerator, and the precipitated crystals were filtered to obtain 195 mg (yield: 52%) of the title compound as colorless crystals.

(Analysis value)

Melting point 165-167 ° C Optical purity 100% ee (see Table 2) Reference Example 7 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H
-Synthesis of pyrano [2,3-f] benzo-2,1,3-oxadiazole 3-oxide (compound [G]) 6-amino-3,4-dihydro-2,2-dimethyl-3,4-
Epoxy-7-nitro-2H-benzo [b] pyran (compound [F]) 4.41 g (18.9 mmol), sodium hydroxide
1.29 g (32 mmol), 400 ml of ethanol and 40 ml of water were stirred at room temperature, and a 6% aqueous solution of sodium hypochlorite 32.2 was added.
g (26 mmol) was slowly added dropwise, followed by stirring for 1 hour.

After completion of the reaction, brine 1 was added, and the mixture was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated saline, and 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 (yield 92%) of the title compound as yellow crystals.

(Analysis value)

Melting point 144-145 ° C Reference Example 8 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H
Synthesis of -pyrano [2,3-f] benzo-2,1,3-oxadiazole (compound [H]) 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H
While stirring 1.00 g (4.27 mmol) of pyrano [2,3-f] benzo-2,1,3-oxadiazole 3-oxide (compound [G]) and 6 ml of benzene at 60 ° C., triethyl phosphite was added. After dropping 0.80 ml (4.70 mmol) in 15 minutes,
Stir for 3 hours.

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

This part 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
Synthesis of -amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (compound (±) I) 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H
-0.82 g (3.8 mmol) of pyrano [2,3-f] benzo-2,1,3-oxadiazole (compound [H]) is dissolved in 25 ml of 16.7% ammonia-ethanol, and the solution is heated to 60 ° C in a pressure-resistant glass tube. 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 (yield: 87%) of the title compound as a brown solid.

Part of this was recrystallized from ethanol to give the pure title compound as colorless crystals.

(Analysis value)

Melting point 159-162 ° C NMR (CDCl ₃ + DMSO-d ₆ ) δ (ppm): 1.26 (3H), 1.49 (3H), 2.80-3.30 (5H), 3.33 (1H), 3.78 (1H), 6.82 (1H) , 7.98 (1H) Mass spec. 133 (50%), 163 (100%), 235 (M ⁺ , 3%)

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 498/04 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The formula [(±) I] A pyranobenzoxadiazole compound represented by the formula (II) A pyranobenzoxadiazole compound represented by the formula [(±) I], after reacting with an optically active carboxylic acid represented by the formula: . 2. The formula [(±) I] An optically active pyranobenzoxadiazole compound showing a right-handed rotation in ethanol represented by the formula: