JP2857760B2 - Production method of propoxynitrobenzenes - Google Patents

Description

The present invention relates to a propoxynitrobenzene compound useful as an intermediate for producing a synthetic antibacterial drug, and a compound represented by the formula (III) having an epoxy structure: The present invention relates to a method for producing a compound represented by the formula:

(Prior Art) Ofloxacin (OFLX) is a synthetic antibacterial agent having excellent antibacterial activity, pharmacokinetics and high safety, and is widely used. In addition, subsequent studies have shown that
-3355 has higher antibacterial activity and safety than racemic ofloxacin, and was found to be a more useful compound as an antibacterial agent (JP-A-57-46986 and JP-A-62-8686). 252790).

The present inventors have conducted research on advantageous methods for synthesizing these compounds and completed the present invention.

(Constitution of the Invention) The present invention provides a reaction of a 3,4-dihalogenonitrobenzene derivative I with an allyl compound A to give 2-allyloxy-3,
A method for producing a 4-dihalogenonitrobenzene derivative II, a method for producing a 2-oxiranylmethyloxy-3,4-dihalogenonitrobenzene III by reacting an oxirane derivative B with a 3,4-dihalogenonitrobenzene derivative I, The propylene oxide C is reacted with the 3,4-dihalogenonitrobenzene derivative I to give 2,3-dihalogeno-6
Method for producing -nitro-[(2-hydroxypropyl) oxy] benzene IV, oxidation of 2-allyloxy-3,4-dihalogenonitrobenzene derivative II to give 2-oxiranylmethyloxy-3,4-dihalogeno Nitrobenzene I
II, and reduction of 2-oxiranylmethyloxy-3,4-dihalogenonitrobenzene III to 2,2
The present invention relates to a method for producing 3-dihalogeno-6-nitro-[(2-hydroxypropyl) oxy] benzene IV.

 Hereinafter, the reaction formula is shown and described in detail in the present invention.

(Wherein R represents a lower alkyl group having about 1 to 10 carbon atoms. For example, a methyl group, an ethyl group, an n-propyl group, an iso group
-Propyl group, n-butyl group and the like. X ¹ and X ² are the same or different and represent fluorine or another halogen atom. Z represents a halogen atom such as chlorine, bromine or iodine, or a substituted sulfonyloxy group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a paratoluenesulfonyloxy group, or a hydroxyl group. The same applies hereinafter. Next, each step of the present invention will be specifically described.

By condensing the halogenonitrobenzene derivative represented by the formula I and the oxirane derivative represented by the formula B, 2-oxiranylmethyloxy-3,4-dihalogenonitrobenzene III can be obtained.

For example, in the halogenonitrobenzene derivative I, Y
Is a hydroxyl group, and in the oxirane derivative B, when Z is a halogen atom or a substituted sulfonyloxy group, condensation can be carried out by a nucleophilic substitution reaction of a phenolic hydroxyl group under basic conditions.

When Y is a halogen atom in the halogenonitrobenzene derivative I and Z is a hydroxyl group in the oxirane derivative B, the condensation can be performed by a nucleophilic substitution reaction of an alcoholic hydroxyl group with an aromatic nucleus under basic conditions.

In these cases, the base used for the reaction includes sodium hydride, lithium hydride, sodium amide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and other inorganic bases, triethylamine, diisopropylethylamine, 1 Organic bases such as, 8-diazabicyclo [5,4,0] -7-undecene (DBU) and triton B, metal alkoxides such as potassium tert-butoxide, sodium exoxide and sodium methoxide, butyllithium and phenyllithium A lithium reagent can be mentioned, and it is preferable to use about 1 to 10 equivalents.

Examples of the solvent used in the reaction include hydrocarbon solvents such as benzene, toluene, xylene, and n-hexane; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, and n-butanol; diethyl ether; tetrahydrofuran; , 4-dioxane, 1,2-
Examples thereof include ether solvents such as dimethoxyethane, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as dimethylacetamide and dimethylformamide, chlorine solvents such as dichloromethane, dichloroethane and chloroform, and dimethyl sulfoxide and sulfolane. .

These condensation reactions are preferably carried out in a temperature range from -78 ° C to the boiling point of the solvent, and the reaction time is from about 10 minutes to several days, and sometimes it may be desirable to carry out the reaction under anhydrous conditions. Also, potassium iodide, sodium iodide,
Addition of about 1/100 to equivalent of a crown ether or the like may accelerate these reactions.

When both Y and Z in the halogenonitrobenzene derivative I and the oxirane derivative B are hydroxyl groups, the condensation can be performed using 1 to 1.5 equivalents of a Mitsunobu reagent.

In this case, the Mitsunobu reagent is a complex of azodicarboxylic acid diester (dimethyl ester, diethyl ester, diisopropyl ester, dibenzyl ester, etc.) and triphenylphosphine or trialkylphosphine, and diethyl ether, tetrahydrofuran, 1,4-dioxane It is preferable to prepare a reagent in an ether-based solvent such as under anhydrous conditions at the time of use, and react at 0 ° C to 50 ° C (O. Mitsunobu, Synthesis 1-28 1981).
Jan.).

The halogenonitrobenzene derivative I and the allyl compound represented by the formula A can be condensed in the same manner as described above to obtain 2-allyloxy-3,4-dihalogenonitrobenzene represented by the formula II.

Oxidation of 2-allyloxy-3,4-dihalogenonitrobenzene II gives 2-oxiranylmethyloxy-3,4-
Dihalogenonitrobenzene III can be obtained.

Examples of the oxidizing agent for forming the oxirane ring include peroxides of lower fatty acids such as formic acid and acetic acid and higher fatty acids having about 20 carbon atoms, and peroxides of aromatic carboxylic acids such as benzoic acid and m-chlorobenzoic acid. And trifluoroacetic acid peroxide, hydrogen peroxide, tert-butanol peroxide and the like. As a solvent to be used, a chlorine-based solvent such as chloroform, dichloromethane, dichloroethane, a hydrocarbon-based solvent such as benzene and toluene, an alcohol-based solvent such as methanol and ethanol, other ethyl acetate, formic acid,
Acetic acid, trifluoroacetic acid, water and the like can be mentioned, and the reaction may be performed in a mixed solvent in which these are combined.

This oxidation reaction is preferably carried out in a temperature range from -78 ° C to the boiling point of the solvent, and the reaction time is about 10 minutes to several days, and sometimes the presence of a base such as sodium acetate, potassium acetate, sodium hydroxide, and sodium carbonate. It may be desirable to do the following:

Or by reductively cleaving the oxirane ring of 2-oxiranylmethyloxy-3,4-dihalogenonitrobenzene III obtained in the above to form a 2-hydroxypropyl group, and 2,3-dihalogeno-6-nitro- [(2-Hydroxypropyl) oxy] benzene IV and, simultaneously or subsequently, also reduce the nitro group as an amino group,
2,3-dihalogeno-6-amino-[(2-hydroxypropyl) oxy] benzene V.

In the present production method, as a reduction reaction used for forming a 2-hydroxypropyl group by cleavage of an oxirane ring and converting a nitro group to an amino group, catalytic reduction using a catalyst such as palladium-carbon, Raney nickel, an oxide alloy, etc. It is desirable to carry out under a pressure of about 50 kg / cm ² from the pressure), reduction with lithium aluminum hydride (LiAlH ₄ ), reduction with sodium borohydride (NaBH ₄ ), reduction with hydrosulfite, diborane (B
Reduction by ₂ H ₆ ). in this case,
Solvents used in the reaction include benzene, toluene, n
Hydrocarbon solvents such as hexane; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and n-butanol; ether solvents such as diethyl ether tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. Solvents, chlorinated solvents such as dichloromethane, dichloroethane, chloroform, other formic acid, acetic acid,
There may be mentioned trifluoroacetic acid, water and the like, and the reaction may be carried out in a mixed solvent in which these are combined.

These reduction reactions are preferably carried out in a temperature range from -78 ° C to about the boiling point of the solvent, and the reaction time is from about 10 minutes to several days, and sometimes boron trifluoride ether complex (BF ₃ · OEt ₂ ) Aluminum chloride (AlC
l ₃ ), titanium tetrachloride (TiCl ₄ ), magnesium chloride (MgC
The reaction may be accelerated by adding a Lewis acid such as l ₂ ).

2,3-Dihalogeno-6-amino-[(2-hydroxypropyl) oxy] benzene V is used as a crude product, or after isolation and purification, the amino group is methylenemalonated to give 2,3-dihalogeno-6. -(2,2-dialkoxycarbonylethenyl) amino-[(2-hydroxypropyl)
[Oxy] benzene VI.

This methylene malonation is carried out according to the formula VII W—CH ＝ C [COOR] ₂ VII (where W is a lower alkoxy group such as methoxy group and ethoxy group, a halogen atom such as chlorine, bromine and iodine, a dimethylamino group and a diethylamino group) Wherein R is a lower alkyl group such as methyl, ethyl, etc.), and heated to reflux in an alcoholic solvent such as methanol, ethanol or other suitable solvent using at least an equimolar amount of the compound represented by It can be carried out by heating and stirring both at about 80 to 180 ° C. without solvent.

When Y is a hydroxyl group (when it is dihalogenonitrophenol) in the halogenonitrobenzene derivative represented by the formula I, the propylene oxide represented by the formula C is sometimes condensed with a condensing agent such as an acid or a base. , 2,3-Dihalogeno-6-nitro-[(2-
[Hydroxypropyl) oxy] benzene IV can be obtained.

Examples of the condensing agent used in this reaction include acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, organic acids and inorganic acids such as concentrated sulfuric acid, boron trifluoride ether complex, Aluminum chloride, titanium tetrachloride, Lewis acid such as magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, Grignard reagent such as phenyl magnesium chloride, sodium hydride,
Lithium hydride, sodium amide, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate,
Inorganic bases such as sodium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,
0] -7-undecene (DBU), triton B, pyridine,
Organic bases such as quinoline and isoquinoline, potassium tert-butoxide, sodium ethoxide, metal alkoxides such as sodium methoxide, and other butyllithium, phenyllithium, and the like can be used. Is preferred. It is also possible to carry out condensation without using these condensing agents.

Solvents used in the reaction include benzene, toluene, xylene, hydrocarbon solvents such as n-hexane, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-
Ether solvents such as dimethoxyethane, ketone solvents such as acetone and methyl ethyl ketone, amide solvents such as dimethylacetamide and dimethylformamide, chlorine solvents such as dichloromethane, dichloroethane and chloroform, other dimethyl sulfoxide, sulfolane, 2-propanol, tert -Butanol, ethyl acetate and the like can be mentioned, but the reaction can be carried out without a solvent.

This condensation reaction is preferably carried out in a temperature range of about -78 ° C to about 300 ° C, and the reaction time is about 10 minutes to several days, and sometimes it is desirable to carry out the reaction under anhydrous conditions.

In this case, the obtained 2,3-dihalogeno-6-nitro-[(2-hydroxypropyl) oxy] benzene IV
Is treated as a crude product or after isolation and purification according to the method for reducing the nitro group and the method for converting the amino group to methylene malonate as described above to give 2,3-dihalogeno-6- Amino-[(2-hydroxypropyl) oxy]
Benzene V can be obtained and converted to 2,3-dihalogeno-6- (2,2-dialkoxycarbonylethenyl) amino-[(2-hydroxypropyl) oxy] benzene VI.

In the above-mentioned production method, optically active isomers of the oxirane derivative represented by the formula B and the propylene oxide represented by the formula C can be easily obtained [Ref. J. Org. Chem. 43 , 4876 (1978)] , 52, 3710
(1986), Angew. Chem. Int. Ed. Engl. 17 , 937 (1978), S
synthesis 316 (1982), J. Org. Chem. 46 , 3348 (1981),
Can. J. Chem. 57, 233 (1979)]. By using those optically active substances, optically active substances of the compounds represented by the formulas III, IV, V and VI can be obtained.

Reference Example 1 2,3-difluoro-6-nitro- (2,3-epoxypropyloxy) benzene (III: X ¹ = X ² = F) 2,3-difluoro-6-nitrophenol (I: Y = OH ,
X ¹ = X ² = F) 35.02 g of anhydrous dimethylformamide (DM
F) Dissolve in 350 ml, add 27.64 g of K ₂ CO _{3 and} stir at 85-90 ° C. for 20 minutes, then add ₃ g of KI and 18.50 g of epichlorohydrin and stir at the same temperature for 3 hours. K ₂ CO ₃ was added 4.61g and 3 times epichlorohydrin 6.17g every 1-2 hours, stirred overnight further at the same temperature.

After the reaction, DMF was distilled off, and the residue was dissolved in ethyl acetate.
aHCO ₃ Washed with water and water in that order, dried (MgSO ₄ ), and evaporated, and the residue obtained was subjected to silica gel column chromatography to obtain 22.92 g of the title oxiranylmethyl compound as an oil.
9.6% was obtained. NMR (CDCl ₃ ) δ: 2.68 to 2.95 (2H, m, methylene of oxirane ring) 3.33 to 3.52 (1H, m, methine of oxirane ring) 4.12 to 4.62 (2H, m , -O-C H 2 _- oxirane ring) 7.09 (1H, d, d , d, J = 7.2,9and 9Hz nitro group meta position of the nuclear protons) 7.76 (1H, d, d , d, J = 2.4,5.4 and 7.2 Hz nitro group ortho-position proton) Reference Example 2 2,3-difluoro-6-nitro-[(R) -2,3-epoxypropyloxy] benzene (III: X ¹ = X ² = F) 2, 3-difluoro-6-nitrophenol (I: Y = OH X
¹ = X ² = F) After dissolving 700.4 mg in 4 ml of anhydrous DMF, 304.1 mg of K ₂ CO ₃
Add mg and stir at 70 ° C for 30 minutes. A catalytic amount of 18-crown-6-ether, 242.4 mg of KI and 1 g of (R) -glycidyl tosylate are added, and the mixture is heated and stirred at the same temperature for 6 hours.

After the reaction, ethyl acetate was added, and the organic layer was washed with water and dried (MgSO 4).
₄ ) Thereafter, the residue obtained by evaporation was subjected to silica gel column chromatography to obtain 507 mg of the title condensate as an oil from the benzene stream, and a yield of 55%.

NMR (CDCl ₃ ) δ: 2.72 (1H, d, d, J = 2.7 and 4.8 Hz, 3rd proton of epoxypropyl group) 2.89 (1H, d, d, J = 4.8 and 4.8 Hz, epoxypropyl group 3 3.42 (1H, multiple line of 18Hz width, methylene proton at 2nd position of epoxypropyl group) 4.21 (1H, d, d, d, J = 1.2,6.0and 7.2Hz, proton at 1st position of epoxypropyl group) 4.53 (1H, d, d, d, J = 1.2, 3.6 and 4.8 Hz, 1st proton of epoxypropyl group) 7.07 (1H, d, d, d, J = 7.2, 9.0 and 9.6 Hz, 4th nuclear proton) 7.74 (1H, d, d, d, J = 2.4,5.4 and 7.2 Hz, 5-position proton) Reference Example 3 2,3-difluoro-6-nitro-[(R) -2,3-epoxypropyloxy Benzene (III: X ¹ = X ² = F) According to the method of obtaining a racemate, 2,3-difluoro-6-
17.98 g of nitrophenol, 14.19 g of K ₂ CO ₃ , 3.32 g of KI and 10 g of (R) -epichlorohydrin were reacted at 85-90 ° C. in anhydrous DMF to yield the title (R) -2,3-epoxypropyl derivative 8.06 g 34% was obtained. Oil NMR was consistent with that obtained in Reference Example 2.

Reference Example 4 2,3-Difluoro-6-nitro- [2,3-epoxypropyloxy] benzene (III: X ¹ = X ² = F) 1.00 g of sodium hydride (60%) and 20 ml of anhydrous toluene
And glycidol (1.85 g) was added dropwise while stirring under ice-cooling, followed by washing with 16 ml of anhydrous toluene (almost no mixing). After the dropping, the sodium salt is blocked, and the mixture is vigorously stirred and pulverized at room temperature (25 minutes). After cooling again with ice, 3.54 g of 2,3,4-trifluoronitrobenzene was dissolved in 20 ml of anhydrous toluene, added dropwise, and stirred overnight in an ice room. After the reaction, ice water is added, and the organic layer is washed with aqueous sodium bicarbonate and water. After drying (MgSO ₄ ), the residue obtained by evaporation was subjected to silica gel column chromatography to obtain 793 mg of the desired compound. Match with NMR standard.

Reference Example 5 2,3-Difluoro-6-nitro- [2,3-epoxypropyloxy] benzene (III: X ¹ = X ² = F) 3.93 g of triphenylphosphine and 2.61 g of diethyl azodicarboxylate were added to anhydrous tetrahydrofuran. (THF)
Stir in 30 ml under ice-cooling for 20 minutes (preparation of Mitsunobu reagent). A solution of 1.75 g of 2,3-difluoro-6-nitrophenol and 815 mg of glycidol in 20 ml of anhydrous THF is added, and the mixture is stirred at room temperature overnight.

After the reaction, THF was distilled off, benzene was added to the residue, and NaHCO
₃ Wash with aqueous solution and water. The residue obtained by evaporating the organic layer after dehydration (Na ₂ SO ₄ ) was subjected to silica gel column chromatography to obtain 590 mg of the title compound. Match with NMR standard.

Example 1 2,3-Difluoro-6-nitro - (2-propenyloxy) benzene ^{(II: X 1 = X 2} = F) and 2,3-difluoro-6-nitro - (2,3-epoxypropyloxy ) Benzene (III: X ¹ = X ² = F) 1.00 g of sodium hydride (60%) in 20 ml of anhydrous toluene
While stirring under ice cooling, a solution of 1.54 g of allyl alcohol dissolved in 16 ml of anhydrous toluene is added dropwise, and the mixture is stirred at the same temperature for 15 minutes and at room temperature for 20 minutes. The resulting solution was combined with 2,3,4-
3.54 g of trifluoronitrobenzene in 20 ml of anhydrous toluene
The solution is added dropwise to the solution dissolved in ice-cooled solution, and stirred at the same temperature overnight. After the reaction, ice water was added, and the organic layer was washed with water, dried (MgSO ₄ ) and evaporated to obtain a crude product of 2,3-difluoro-6-nitro- (2-propenyloxy) benzene.

This was dissolved in 100 ml of dichloromethane, and 4.75 g of m-chloroperbenzoic acid (80%) was added, followed by stirring at room temperature overnight.
The reaction solution was washed with a 3% aqueous solution of Na ₂ CO ₃ and water, and dried (MgSO 4).
₄ ) The residue obtained by subsequent distillation is subjected to silica gel column chromatography to give 2,3-difluoro-6-nitro- (2,3-
3.36 g of epoxypropyloxy) benzene (73% yield)
I got Reference Example 6 2,3-difluoro-6- (2,2-diethoxycarbonylethenyl) amino-[(2-hydroxypropyl) oxy] benzene (VI: X ¹ = X ² = F; R = Et) 1.16 g of the oxiranylmethyl compound obtained in Example 1 is dissolved in 35 ml of methanol, and 1.0 g of 5% Pd-C is added as a catalyst, followed by catalytic hydrogenation at room temperature and normal pressure (total 5 hours). After the reaction, the catalyst was removed by filtration, the solvent was distilled off, and 2,3-difluoro-6-amino-
A crude product of (2,3-epoxypropyloxy) benzene was obtained, and without isolation and purification, 1.19 g of diethyl ethoxymethylene malonate (EMME) was added thereto.
30 minutes while removing ethanol under reduced pressure for 30 minutes, then at normal pressure
The mixture is heated and stirred for 30 minutes (by TLC at the end of the reaction, the formation of a primary alcohol by-produced when contact hydrogenation under pressure is not observed). After the reaction, the mixture was subjected to silica gel column chromatography to obtain 1.32 g (yield 71%) of the target compound VI. N of this one
MR spectra were consistent with those obtained by another method.

Reference Example 7 2,3-difluoro- (2,2-diethoxycarbonylethenyl) amino-[(R) -2-hydroxypropyloxy] benzene (VI: X ¹ = X ² = F, R = Et) Dissolve 505 mg of the compound obtained in Example 2 in 17 ml of methanol, add 300 mg of 5% Pd-C, and hydrogenate at normal temperature and normal pressure (about 3.5 hours). After the reaction, the catalyst is filtered off, and the solvent is distilled off.
A crude product of 2,3-difluoro-6-amino-[(R) -2-hydroxypropyloxy] benzene is obtained. This and EM
Heat ME518mg without solvent at 120 ° C, at normal pressure for 20 minutes,
Stir again for 20 minutes at normal pressure for 20 minutes. After cooling, the mixture was subjected to silica gel column chromatography, and benzene / ethyl acetate was added.
From the 5: 1 stream, methylene malonate VI514mg (yield 63
%). In agreement with the sample, triphenylphosphine and diethyl azodicarboxylate were stirred in anhydrous THF under ice cooling for 20 minutes (preparation of Mitsunobu reagent). The above methylene malonate VI was added to anhydrous TH.
A solution dissolved in F was added and the mixture was stirred at room temperature overnight. The residue obtained by distilling off THF was subjected to silica gel column chromatography and subjected to (S) -dimethyl. (7,8-difluoro-3-methyl-
3,4-Dihydro-2H- [1,4] benzoxazin-4-yl) methylene malonate was obtained. The optical purity of this is
It was 92% ee.

Reference Example 8 2,3-difluoro- (2,2-diethoxycarbonylethenyl) amino- (2-hydroxypropyloxy) benzene (VI: X ¹ = X ² = F, R = Et) 2,3-difluoro 2.5 g of -6-nitrophenol, 2.3 ml of propylene oxide and 0.11 ml of pyridine are dissolved in 5 ml of anhydrous toluene, and the mixture is heated and stirred in a sealed tube at 50 ° C for 72 hours.
The reaction solution was dissolved in ethyl acetate, washed with an aqueous solution of NaHCO ₃ and water, dried (MgSO ₄ ), and distilled off to give 2,3-difluoro-6.
2.17 g of crude nitro- (2-hydroxypropyloxy) benzene are obtained. This is dissolved in 25 ml of ethanol, and 5
% Pd-C 450 mg is added as a catalyst and subjected to catalytic reduction at normal pressure. After the reaction, the catalyst was removed by filtration, and the solvent was distilled off to obtain a crude product of 2,3-difluoro-6-amino- (2-hydroxypropyloxy) benzene. Add 2.42 g of EMME to this and add
The mixture is heated and stirred at 120 ° C. for 30 minutes while removing ethanol generated under reduced pressure for 0 minute and at normal pressure for 30 minutes. , The reaction mixture was subjected to silica gel column chromatography,
2.19 g of the title compound were obtained. Match with standard

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Claims (3)

(57) [Claims] (1) Formula (I) (Wherein, X ¹ and X ² each independently represent a halogen atom, and Y represents a hydroxyl group or a halogen atom). (Wherein, Z represents a halogen atom, a substituted sulfonyloxy group or a hydroxyl group). When Y is a compound having a halogen atom, Z is a compound having a hydroxyl group in the presence of a base. When Y is a compound having a hydroxyl group, Z is a compound having a substituted sulfonyloxy group or a halogen atom, in the presence of a base, or a compound wherein Y is a hydroxyl group and Z is also a hydroxyl group. Is reacted in the presence of a Mitsunobu reagent to obtain a compound of the formula (II) (Wherein, X ¹ and X ² each independently represent a halogen atom), and oxidizing the compound; (Wherein X ¹ and X ² each independently represent a halogen atom). 2. The method according to claim 1, wherein Y is a halogen atom and Z is a hydroxyl group. 3. The method according to claim 1, wherein X ¹ and X ² are each a fluorine atom.