JPS59128379A - Dibenzo(b,f)(1,5)oxazocine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R2 are H, halogen, lower alkyl, trihalomethyl, lower alkoxy or lower acyl; m and n are integer of 1-4). EXAMPLE:5H-Dibenzo[b,f][1,5]oxazocin-11(12H)one. USE:Intermediate of psychotropic agents especially antidepressant and analgesic. PROCESS:The compound of formula I can be prepared either by (i) subjecting the carboxylic acid of formula II (Q is NH2-protecting group) or its salt to the intramolecular condensation cyclization, or by (ii) subjecting the compound of formula III to Schimitt reaction, or by (iii) reacting the compound of formula IVwith hydroxyalamine, and subjecting the resultant ketoxime to Beckmann rearrangement reaction. The above drug for the central nervous system can be obtained by introducing various substituent groups to the 12-nitrogen site of the compound of formula I .

Description

[Detailed description of the invention] A novel dibenzo[1+, I'][1
, 5] relates to oxazosin derivatives and methods for producing the same.

Note that the symbols in the above general formula [1] and in the sections described below have the following meanings.

That is, 'B-1 and R2 are each a hydrogen atom, a halogen atom, a lower alkyl group, a trihalomethyl group, a lower alkoxy group, or a lower acyl group; R2 may be the same group or different groups. The halogen atom can be any of the four halogen atoms, but chlorine or bromine is preferable. Examples of lower alkyl groups include methyl, ethyl, propyl, and isopropyl.

Those having 1 to 6 carbon atoms such as butyl, isobutyl, 1-butyl, amyl, etc. are preferably used, and trihalomethyl groups include, for example, trifluoromethyl groups, and lower alkoxy groups include, for example, Those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups are preferably used, and lower acyl groups include, for example, acetyl, propionyl, butyl
Those having 1 to 4 carbon atoms such as lz group are preferably used.

Further, ■ and [l are each an integer from 1 to 4, and both may be the same number or different numbers.

According to the present invention, the compound [11] has the following general formula; Acyl groups and substituted acyl groups such as trifluoroacetyl group, propionyl group, butyryl group; substituted benzoyl groups such as benzoyl group; p-anisoyl group; It is synthesized by an intramolecular ring-closing reaction of a carboxylic acid represented by the following formula or a salt thereof, such as a substituted sulfenyl group.

As for the intramolecular ring-closing reaction, (a) the above compound [11
] A method in which a carboxylic acid or a salt thereof is used as a reactive derivative acid halide, and then treated with a base such as a trialkylamine to dehydrohalogenate and ring-close; In the case of a phenyl group, a redox condensing agent such as 2,2'-dibenzothiazolyl disulfite triphenylphosphine,
Alternatively, there is a method in which condensation and ring closure is performed using 2°2'-dipyridine disulfide-triphenylbosphine and triethylamine, and the objective compound [1] can be produced by these two methods.

To describe these methods more specifically, in the above method (a), first, 1 to 5 times the calculated amount (preferably 3 to 4 times the mole) of the raw material "11" is added at room temperature. Thionyl chloride is dissolved in dimethylformamide. The amount of dimethylformamide at this time is as follows:
1] in dimethylformamide is 0.01 to 0.
A concentration of 1 mol/e is preferable because the yield is improved, but the reaction proceeds regardless of the concentration. Next, when the raw material [11] is added while stirring under cooling or at room temperature,
A chloride of the raw material [1] is formed and dissolved. Furthermore, triethylamine as a trialkylamine is used at a ratio of 2 to 10 times the mole, preferably 4 to 6 times the mole, and it is used as it is or dimethylformamide is mixed with 2 to 3 times the mole.
When diluted to twice the molar amount and added under strong stirring under cooling or room temperature, the reaction proceeds immediately and triethylamine hydrochloride is precipitated. After stirring for 1 to 2 hours, the mixture is heated at 60 to 80°C for 3 to 5 hours, and then cooled to room temperature.

From the reaction mixture reacted in this way,
The compound of the above general formula [1m] can be separated and purified by means known per se, such as filtration, extraction, solvent distillation, recrystallization,
This can be carried out by any means such as chromatography.

Regarding the above method ([)), the method is a condensation reaction carried out without the aid of an acid or a base, for example, starting from the raw materials [11 and 2,2'-dibenzothiazolyldis? By suspending refuid in a Fi U mixed solvent such as dimethylformamide and dichloromethane, and adding a solution of triphenylphosphine in dichloromethane to this, the ring-closing reaction proceeds and the target product [1] is obtained in a good yield. This is what you get.

In addition, as condensing agents for ring closure, in addition to the above, 2,
The ring-closing reaction can be carried out in the same manner by using 2'-dipyridine disulfide-triphenylphosphine in combination. In addition, as reaction solvents, in addition to dimethylformamide and dichloromethane, acetonitrile, chloroform,
It is possible to use common organic solvents that do not participate in the reaction, such as tetrahydrofuran. Furthermore, the reaction temperature is preferably carried out under ice cooling or at room temperature, but if necessary, the reaction temperature is
There is no problem even if it is heated to 0 to 80°C.

By the way, the compound [ll] used as a raw material in the reaction described in - is a new compound, and can be produced, for example, by the following synthetic process.○
[] [■] [Vllll [11] (However, R3 is a lower alkyl group, X means a halogen atom, and Y represents a reactive residue of Q)" - explains the summary of the reaction The unsubstituted or R-substituted salicylic acid alkyl ester [111] is converted into an alkali metal salt with an alkali metal alcoholade or an alkali metal hydride, and then unsubstituted or JjQ
reacted with 0-nitrohensyl halide [IV],
A compound represented by formula [V] is formed. Next, this compound [V] is subjected to a reduction reaction (normal nitro group reduction reaction may be used, but in this case reduction with hydrogen chloride-stannic chloride in an acetate ester is more effective), and the formula [ ■
1] is prepared. A protecting group [as a protecting group, an acetyl group (when using pyridine-acetic anhydride or acetyl chloride-triethylamine) or a 0-nitrophenylsulfenyl group (0-nitrophenylsulfenyl chloride- in dichloromethane) is added to the amine group of compound "VI". In the case of reacting with triethylamine), a compound represented by the formula [■]] with an amine group blocked is obtained, and then in an organic solvent (for example, a lower alcohol, tetrahydrofuran, dioxane, etc.), The carboxylic acid represented by the formula [11] or its salt can be obtained by hydrolysis with a caustic alkali.In addition, the reaction can be accelerated by using 18-crown ether as a catalyst during the hydrolysis. It is possible to proceed smoothly.

In addition, in the present invention, as shown in formula [11], the reason why the amine 7 group is particularly protected is because when the amine 7 group is free, a decomposition reaction is easily induced as shown in the following formula. This is because the desired amino acid cannot be obtained.

(Vlll) to Xll] [IX] ↓ (However, M means lithium, sodium or potassium)
OH, NaOH or KOH, etc.) [W]
By saponification, an alkali metal salt [■11] is produced, but when this is neutralized in a dilute mineral acid to form compound [IX], the resulting compound [■1] is extremely unstable. This is because upon neutralization, the 10-CH2- bond (benzyl bond) breaks and decomposes, resulting in the decomposition of salicylic acid represented by formula [X] and 0-aminobenzyl alcohol represented by formula 1M]. However, the desired compound [IX] cannot be obtained.Also, by the method of hydrolyzing compound mV] with caustic alkali to form a carboxylic acid represented by the formula [Xll], and then reducing it in the presence of a Raney nickel catalyst, Via the compound [Vllll], the compound [1x
], but in this case too, for the same reason, and when R and R2 are halogens, dehalogenation also occurs, and the desired compound [IX] cannot be obtained. .

Therefore, in order to prevent such a hydrolysis reaction from occurring, it is essential to introduce a protecting group into the amine 77 group and stabilize it to form compound [11]. It is an effective method.

Compound [1] of the present invention can also be synthesized using Schmidt reaction or Beckmann rearrangement reaction. That is, dibenzo [b, c
Produced by (a) subjecting the oxepine derivative to the Schmidt reaction, or (b) reacting the above formula [XIII] with hydroxylamine to form the corresponding ketooxime form, and then subjecting the ketoxime form to the Beckmann rearrangement reaction. It is possible to do so.

When compound [1] of the present invention is synthesized by the Schmidt reaction method described in (a) above, compound [XI] is mixed with hydrazoic acid or This can be easily carried out by reacting with an alkali metal azide (eg, sodium azide, potassium azide).

Note that as the reaction solvent, the mineral acid present in the reaction system itself plays the role of a solvent, so it is not necessarily necessary to use other solvents, but if other solvents are used, For example, trichloroacetic acid and trifluoroacetic acid are suitable. Moreover, this reaction is preferably carried out at room temperature or under heating.

In addition, when synthesizing the compound [1'] according to the present invention by the method via the ketoxime form of -■2 (b), first react the above compound [X1ll] with hydroxylamine to form the corresponding ketoxime Body. This reaction is preferably carried out in a suitable solvent (eg, pyridine or a hydrous alkanol such as aqueous ethanol) under heating.

Next, the Cuman rearrangement reaction to be carried out can be suitably carried out by stirring the above-obtained ketoxime compound with phosphorus pentachloride in a polyphosphoric acid ester or ether under room temperature. Through this Beckmann rearrangement reaction, a reaction product (
A mixture) is obtained, which can be separated and purified by conventional means to extract the target compound [I].

Compounds [1] synthesized by various methods such as
1] is a new compound, and although it has some pharmacological effects such as analgesic effect on its own, by introducing various substituents to the 12-position nitrogen site of the compound, it has an excellent effect on the central nervous system. It has been recognized that it is useful as a synthetic intermediate for pharmaceutical compounds because it can synthesize pharmaceutical compounds that can be used as psychotropic drugs, especially antidepressants, and analgesics. There is.

Below, some reference examples and examples of the present invention will be shown to clarify the present invention more specifically, but it goes without saying that the present invention is not limited in any way by the description of these examples. be.

After 12.6 g of sodium metal was added and dissolved in 600 m/m of methanol, 83 g of methyl salicylate was added thereto and dissolved with stirring. Next, Konoly nl K ,
A solution prepared by dissolving 118 g of (1-nitrobenzylpromy) in 50 ml of methanol was added and humidified while stirring, and crystals precipitated after a while. This was boiled under reflux for 2 hours, and after cooling, crystals precipitated. The crystals were harvested, washed with methanol and water, and then dried to obtain 90 g of methyl 2-[(2-nitrobenzyl)oxy]benzoate as colorless needle-shaped crystals with a melting point of 126-128°C. Ta.

NMR (CDC53) δ: 8.95 (3I-I,
S).

5.56 (2H,S), 6.98-8.35 (8
H.

m) [Br　　　　、.

TRv cm, 1705.1240 (-COO
CH)); aX 1518 (NO2) Elemental analysis: C15H1305N Theoretical value C: 62.72. H: 4°56. N: 4.88
Actual value C: 62.96. H:4.49. N: 4.92
Stannous chloride (S n Cl
22H20) 288 g was added, and while stirring, 10-2
Dry hydrogen chloride gas was introduced at 0°C to saturate and dissolve the stannous chloride. Next, the content solution was heated to 40°C, and 90g of methyl 2-[(2-nitrobenzyl)oxy]benzoate obtained above was added, being careful not to allow the internal temperature to rise above 65°C. . Furthermore, this should be heated to an internal temperature of 50 to 6
After stirring at 0°C for 30 minutes, the mixture was cooled on ice and neutralized with concentrated aqueous ammonia while stirring.

The resulting yellow precipitate was removed by filtration, and the ethyl acetate layer of the P solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from this P solution, the residue was crystallized from n-hexane, and further recrystallized from ethanol'h,).
69 g of methyl 2-[(2-aminobenzyl)oxy]benzoate was obtained in the form of colorless needles with a melting point of 52-53°C.

NMR (CDC13) δ: 8.80 (8H,S)
, 4.54 (2H,S), 5.10 (2H2
S), 6.58-7.46 (7H9m), 7
゜78 (IH.

dd, J=8Hz,,y=3Hz)KBr.

TRv cm: 8425, 8840 (NH2)i
ax 1708, '1245 (-COOCH3) elemental analysis: C
15H1503N Theoretical value 0 near 0.02. Ding I: 5.87. N:
5.44 Actual value C near 0.08. I:I:5.82
．． N: 5.48 52 g of methyl 2-[(2-aminobenzyl)oxy]benzoate obtained above and triethylamine 22H were dissolved in 200 ml of dichloromethane,
To this solution, 36 g of 0-nitrophenylsulfenyl chloride was added to 20 g of dichloromethane at 5 to 10°C while cooling with water and stirring.
A solution of 0 ml was added dropwise.

Next, after stirring at room temperature for 15 hours, the mixture was concentrated under reduced pressure to distill off most of the solvent. Add 200 ml of methanol to the precipitated yellow crystal mass, thoroughly pulverize and suspend in methanol, filter, wash with methanol, and dry to obtain 2-[ (2-(
56 g of methyl 2-nitrophenylsulfenyl)aminobenzyl)oxy]benzoate was obtained.

NMR (CDO/!3) δ: 3.66 (3H,S
), 5.26 (2H,S), 6.72-7.1
0 (IOH, m).

7.33 (IH, d-(1, J = 8f(Z, J
=3Hz)8.20 (I H, dd, J
=8Hz, J =3Hz)KBr-1TRvcm:3310(-NH-);17
40°ax 1248 (-4300 (JI3).

1510 (NO2) Elemental analysis: C2+'HtsOs N28 theoretical value C
:, 61.45. H:4.42. N: 6.82 actual value
C':61.28. H:4.31. N: 6.75 15.4 g of potassium hydroxide was dissolved in 45 ml of water, 600 ml of ethanol was added thereto, and 2-[[
Add 56 g of methyl 2-(2-ditrophenylsulfenyl)aminobenzyl)oxy]benzoate and stir at room temperature.
Stirred for 6 hours. Next, the solvent was distilled off under reduced pressure at a temperature below 35°C. Water was added to the resulting residue to dissolve it, and the mixture was further extracted with benzene until the benzene layer was no longer orange colored. After removing the aqueous layer and distilling off the benzene in the aqueous layer under reduced pressure at a temperature below 35°C, it was neutralized with 2% hydrochloric acid, and the precipitated yellow crystals were washed several times with water and dried to form yellow powdery crystals. , melting point 140-141'Cno2-[(2-(2-
43 g of nitrophenylsulfenyl)aminobenzyl)oxy]benzoic acid were obtained.

NMR (CD0g3: DMSO-(16=4:1
) a: 5.38 (2H, S), 6.80-7.63
(10H, m), 7.88 (tH, S ), r, 92 (
tr(,+1-d, J=3Hz,,T=31-Tz)
.

8.3Q (IH, (1, J=8I(z)KBr
, ,.

IRν cm, 3340 (-N■■); 168
0In)1. X (-CO-) i 1500 (-NO2) elemental analysis:
C2oH1605N2S Theoretical value C: 60.60, H: 4.07. N
Near, 07 actual value C: 60.43. H:3.98. N
Near, 00 synthetic methanol 400 yttl and 10.2 g of metallic sodium
After adding and dissolving, 102 g of metal 5-bromosalicylate was further added and dissolved. Then add 0 to this
- 110 g of nitrobenzyl bromide and 10 g of methanol
A solution dissolved at 0 m/m was added and heated while stirring, and crystals precipitated after a while. Then, the mixture was boiled and refluxed for 2 hours, and then cooled to 30°C and filtered. Wash the thus obtained P solution with methanol until the color disappears,
By washing with water and drying, it becomes colorless needle crystals with a melting point of 15.
Methyl 2 = [(2-nitrobenzyl)oxyyo-5-bromobenzoate at 6-157 °C was obtained in a yield of 127 g.

NMJCDCd3:DMSO-d6=3:1)[
:3.82 (81(,S), 5.51'(2H
,S).

7, t 5~s, t 4 (7Fl,, n'+)
KBr.

■几ν　　. , 1718 (-43000H3).

ax 1510 ('N02) Elemental analysis: 01.5H1205NBr theoretical value C:
49.20. H:8.80. N: 8.88 actual value C
:49.42. H:3.12. Stannous chloride (SnC1!
2・217T20) Add 247 g and add H' while stirring.
After introducing Cl gas and dissolving it, 2-[(2-
2) When 100 g of methyl (lobenzyl)oxyo-5-bromobenzoate was added in 4 portions and dissolved, the content was 5.
The temperature ranged from 0 to 60°C. Thereafter, HCp gas was continued to be introduced to obtain a saturated solution, which was then cooled with ice and neutralized with concentrated aqueous ammonia while stirring. The precipitated yellow crystals of stannic chloride were separated and washed twice with 800 yyt of ethyl acetate.The mother liquor and washing liquid were combined, washed with water, and dried over anhydrous sulfuric acid. By distilling off the solvent and crystallizing the residue by adding n-hexane, the precipitated crystals are separated,
Further recrystallization from ethanol yielded 76 g of methyl 2-[(2-aminobenzyl)oxyyo-5-bromobenzoate in the form of colorless needles with a melting point of 78-79°C.

NMJCDCd3) δ: 8.82 (8H, S).

4.20 (2H,S)+5.09 (2H,S
).

6.62~7.89 (7H,In)T nvKBr
cm': 8480.8350 (NH2)ia
x 1715 (-COOCH3) Elemental analysis: C] 5I (+ 403 N B r theoretical value C: 5 B, 59, If: 4.20. N
:4.17 Actual value C:58.77, H:4.09. N
:4.052-[(2-aminobenzyl)oxyyo5
- 50ml of pyridine was added and dissolved in 10g of methyl bromobenzoate, and then 3.3g of acetic anhydride was added and stirred at room temperature for 2 hours. Next, this was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain colorless needle crystals of 2-[(2-7cetylaminobenzyl)oxy]-5 with a melting point of 115 to 136°C. -Methyl pro-7benzoate 1
0.6g was obtained.

NM'R (CDC#3)a: 2.22 (3H
, S ), 3.88 (8H, 8), 5.08 (2I (
, 8), 6.97-7.94 (7H,, rn), 9
．． 82(LH,S)Br IRvCm': 3350 (-CONH-)
+11aX 1720 (-COOCH3) 1685 (-coNH-) Elemental analysis: C17H1604NB "Theoretical value c: 53.99.H: 4.26.N: 3.7
0 Actual value C: 54.14. H:4.19. N: 3.7
Synthesis of 1 acid 1.8 g of potassium hydroxide was dissolved in 3 g of water, and 50 ynl of ethanol was added to the solution, and 9 methyl 2-[(2-acetylaminobenzyl)oxy]-5-prothianbenzoate was added.
．． 3 g was added and boiled for 1 hour. Next, the solvent was distilled off, and water was added to dissolve the residue, followed by extraction with chloroform, and the aqueous layer was taken and neutralized with 2% hydrochloric acid. The precipitated white crystals were collected, washed with water, and then re-M crystallized from methanol, resulting in colorless needle crystals with a melting point of 2.
7.1 g of 2-[(2-acetylaminobenzyl)oxy]-5-bromobenzoic acid having a temperature of 08-204°C was obtained.

NMR (CDC4: DMSO-(]6=lH3)δ-
2,10 (8H,s,), 5.19 (2H,S)
, 7.07-7.85 (7H, nl'), 9.
48 (IH,S)KBr −+ −TRν Cm, 8290(−CONi(−).

na X 1700 (-00-).

1618 (-CONH-) Elemental analysis: C, 6H, 404NBr theoretical value C: 5
105. H:3.82. N1.79 Actual value C: 53°11. H:8.82. N: Synthesis of 189 dimethylformamide 400 thionyl chloride 28.8
g and stirred at room temperature for 10 minutes, then 2-[+2-(
After adding 21 g of 2-nitrophenylsulfenyl)aminobenzyl)oxy]benzoic acid and stirring for an additional 10 minutes, a solution of 49 g of triethylamine dissolved in 80 ynt of dimethylformamide was added dropwise. After completion of this dropwise addition, the mixture was stirred at room temperature for 16 hours, and then the precipitated crystals of triethylamine hydrochloride were removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 200 Ie of chloroform, washed with water, and then dried over anhydrous sodium sulfate. Thereafter, this was concentrated under reduced pressure to form a concentrated solution to precipitate crystals. The precipitated crystals were collected and washed with chloroform to obtain pale yellow crystals. In addition, the Okifils mother liquor and the washing liquid were combined and concentrated for about 20 y.
This was subjected to silica gel column chromatography (developing solvent: chloroform), the fourth eluate was collected, and the solvent was distilled off to obtain pale yellow crystals. By combining this crystal with the crystal obtained earlier and recrystallizing it from ethanol, the melting point of colorless needle crystals is 250 to 251.
5 I-I”-dibenzocb, r+ct at °C.

5] O NMR obtained 6.1 g of oxazocin-11(12H)one (CDCβ3:DMSO-d6 =l:l)
δ: 5.22 (2i(,S), 6.76~
7.48 (8H,.

m>, 10.04 <IH,S) IRνKBrcm': 3175.8045(-CO
NH-); ax 1645 (-CONH-) Elemental analysis: C14H1102N Theoretical value C near 4.65. T(:4.92.N:6.2
2 Actual measurement value C: 74.85. H: 4.77. N
:620 In addition, various compounds having different substituents as shown in Table 1 were synthesized by carrying out the same reaction procedure as above.

Chapter 1 Table Example 29-bromo-5H-dibenzo[l).

Thionyl chloride 1.80 ynl dimethylformamide.
Add 8g at room temperature, stir for 30 minutes, and add 2=[
2.0 g of (2-acetylbenzyl)oxy]-5-prothianbenzoic acid was added and stirred for 30 minutes, then further stirred at 110°C for 1 hour, filtered while hot, and the furnace liquid was It was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water, aqueous sodium bicarbonate and water, and then dried over anhydrous sulfuric acid. Next, the solvent was distilled off, the residue was subjected to silica gel column chromatography using chloroform as a solvent, and the second eluate was collected,
Then, the solvent was distilled off, and the resulting residue was recrystallized from methanol, resulting in a melting point of 252-253°C.
0.2 g of colorless amorphous crystals were obtained.

Comparison of the melting point (blending test) and IR spectrum of the thus obtained crystals with the specimen obtained by the method of Example 1 revealed that 9-bromo-5■-dibenzo[+1. l'
][+,5]Oxazosin-11(12f()on) was confirmed.

Example 3 25 ml of dimethylformamide and 25 ml of dichloromethane
Add 10 g of 2-[(2-(2-nitrophenylsulfenyl)aminobenzyl)oxy]-5-bromobenzoic acid and 0.73 g of 2,2'-dibenzothiazolyl disulfide to the mixture of The obtained white cloudy liquid was cooled on ice, and 1.7% of triphenylphosphine was added to it at below 10°C.
A solution prepared by dissolving 10 g in 15 rlt of dichloromethane was added dropwise. The liquid, which was cloudy at first, dissolved as the latter was added dropwise and became a transparent yellow liquid. Next, the solvent was distilled off by stirring at room temperature for 16 hours, chloroform and water were added to the obtained residue to dissolve it, and the chloroform layer was collected, which was mixed with 2% hydrochloric acid, water, 2% % aqueous sodium hydroxide solution and water. Next, the chloroform layer was dried with anhydrous thorium sulfate, the chloroform was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent: chloroform), the fourth eluate was collected, and the solvent The chloroform was distilled off and the residue was recrystallized from methanol to obtain 0.28 g of colorless amorphous crystals with a melting point of 252-253°C. Samples obtained in Examples 1 and 2 and melting points (mixing melt test)
Identified from comparison of 9-bromo- and IR spectra,
5■-dibenzo[b,f'l[1,5]oxazosine-
It was confirmed that 11 (12H) was on.

Example 4 21゛ of dibenzo[b,(u]]oxepin-11one and 27g of concentrated sulfuric acid were added to 25g of trichloroacetic acid and 60
It is heated to ±2°C to dissolve it, and the temperature is the same as this)
1.0 g of IJumazide was added little by little over 3 hours. Further, the mixture was stirred at the same temperature for 5 hours, and the reaction was terminated when it was confirmed that almost no gas was generated. Next, the reaction contents were poured into cold water, neutralized with concentrated aqueous ammonia, extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off from this dry solution, the residue was subjected to silica gel column chromatography using chloroform as a solvent, the third eluate was collected, and the solvent was distilled off to precipitate white crystals, By recrystallizing this from ethanol, 50 mg of colorless needle crystals having a melting point of 251 to 252°C were obtained.

Comparison of the IR spectrum with the standard sample obtained in Example 1 and melting point (blending test) revealed that this product was 5 H-dibenzo[
b, confirmed to be fl[1,5]oxazosin-11(12T()one).

Example 5 Synthesis of xime 73 g of dibenzo[b,,e]oxepin-11one and pyridine 11 were mixed and stirred and refluxed on an oil bath for 48 hours. Pyridine was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed successively with water, 2% hydrochloric acid, water, 2% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous sulfuric acid. Ether was distilled off, and the precipitated crystals were recrystallized from ethanol. 45 g of colorless prismatic crystals, dibenzo[+](!)oxepin-11one oxime having a melting point of 198-204°C was obtained.

Elemental analysis: C14'T1102"=225.25 Theoretical value C: 74.65.H: 4.92.N: 6.22
Actual value 0 near 4.83. I(:4.85.N:6.1
30 g of 2dibenzo[1),e]oxepin-11one oxime was dissolved in 1.84 ml of ethyl ether, 5 g of pentachloride link was added thereto, and the mixture was stirred at room temperature for 24 hours. Next, 800 ml of ice water was carefully added little by little, and the ether layer was washed with an aqueous solution of 2% bicarbonate and then dried with anhydrous sulfuric acid. The ether was distilled off and the residue was crystallized with methanol to obtain 8.0 g of colorless amorphous crystals with a melting point of 206-235°C. This product is a mixture of two components, and is separated into each component by silica gel column chromatography (developing solvent: roloform:acetone = 95:5) or by fractional crystallization from ethanol. 210-21
2.5 g of colorless needles at 2°C and a melting point of 250-251
8.1 g of colorless needles were obtained.

Of these, the latter was identified based on the coincidence of the melting point (mixture test) and Illuminance spectrum with the sample obtained in Example 1.
-dibenzo[b, r][1,5] oxy"jpusin-
It was confirmed that 11 (12H) was on.

Note 5. The former is described in "Measurement of NMR Spectra, IR Spectra and Mass Spectra and 1 Journal on Heterocyclic Chemistry", 1972, No. 9.
6H-dibenzo[b.

r][L4]Oxazosine-11 (12FI).

In place of the raw material 2-[(2-(2-nitrophenylsulfenyl)aminobenzyl)oxy]benzoic acid of Example 1, 24.5 g of l-[(2-(2-nitrophenylsulfenyl)aminobenzyl) ) Oxy]-8,5-dichlorobenzoic acid, the same operation as in Example was carried out, and 7
,9-dichloro-5[■-dibenzo[b, ``l[+,
5]]Oxazocin-1112H)one was obtained.

Synthesis Example 1 Instead of the raw material 2-[(2-(2-nitrophenylphenyl)aminobenzyl)oxy]benzoic acid of Example 1, 27.8 g of 2-[j2- 2-Chloro-9-bromo-5H-dibenzo[1) by using sulfenyl)amino-4-chlorobenzyl)oxy]-5-bromobenzoic acid, "]lI
t, 5]]oxazocin-1112H)one was obtained.

Applicant: Arakawa Chodaibe LLC

Claims (7)

[Claims] (1) General formula; (However, R1 and R2 are each a hydrogen atom, a halogen atom, a lower alkyl group, a trihalomethyl group, a lower alkoxy group, or a lower acyl group; , each an integer from 1 to 4)
] One oxazocin derivative. (2) General formula: ((However, 'I (1 and R2 are each a hydrogen atom f1 halokene atom, a lower alkyl group, a trihalomethyl group, a lower alkoxy group, a lower acyl group), m
and n are integers of 1 to 4, respectively, and Q means a protecting group for amine 7 group) The following method is characterized by condensing and ring-closing a carboxylic acid or a salt thereof in the molecule. A method for producing a dibenzo[1), f ][1,5]oxazosine derivative represented by the general formula; (3) The method according to claim 2, wherein the Q is an acetyl group, and the intramolecular condensation ring-closing reaction is carried out in a dimethylbormamide solvent using thionyl chloride and trialkylamine as a condensing agent. Manufacturing method. (4) The above Q is a 0-nitrophenylsulfenyl group, and the intramolecular condensation ring-closing reaction is carried out in a dimethylformamide solvent using thionyl chloride and trialkylamine as a condensing agent. The manufacturing method described in Section 2. (5) The above Q is an O-nitrophenylsulfenyl group, and the intramolecular condensation ring-closing reaction is carried out using (a
) I-riphenylphosphine, 2゜2'-dibenzothiazolyl disulfide and trialkylamine, or (1+)) patent carried out using liphenylphosphine, 2,2'-dipyridine disulfide and trialkylamine The manufacturing method according to claim 2. (6) General formula: (However, R1 and R2 are each a hydrogen atom, a halogen atom, a lower alkyl group, a trihalomethyl group, a lower alkoxy group, or a lower acyl group, and m and 11 are The following general formula is characterized by subjecting dibenzo[1),, a]oxepine derivatives represented by (each being an integer of 1 to 4) to a Schmidt reaction; (However, "] + "2 + "+ 0 has the same meaning as above) dibenzo [11, i' ] [1,,5]
Method for producing oxazosin derivatives. (7) General formula; (However, R1 and R2 are each a hydrogen atom, a halogen atom, a lower alkyl group, a trino-lomethyl group, a lower alkoxy group, or a lower acyl group, and m and rl are , each an integer of 1 to 4) is reacted with hydroxylamine to form a corresponding ketoxime form, and the ketoxime form is further subjected to a Henkman rearrangement reaction. A method for producing a dibenzo[1+,l°][],5]oxazosine derivative represented by the following general formula: (wherein R, 1, R2, m, and n have the same meanings as above).