CN1037607C - 3'-alkyl or aryl silicaneoxybenzoxazinorifamycin - Google Patents

3'-alkyl or aryl silicaneoxybenzoxazinorifamycin Download PDF

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CN1037607C
CN1037607C CN91105825A CN91105825A CN1037607C CN 1037607 C CN1037607 C CN 1037607C CN 91105825 A CN91105825 A CN 91105825A CN 91105825 A CN91105825 A CN 91105825A CN 1037607 C CN1037607 C CN 1037607C
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alkyl
reaction
benzoxazine
rifomycin
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CN1059145A (en
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山下胜治
山根毅彦
古贺照义
桥爪卓士
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Zhongyuan Chemical Industry Co ltd
Kanegafuchi Chemical Industry Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

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Abstract

The invention relates to 3'-alkyl/arylsilyloxybenzoxazinorifamycin derivatives which is intermediates for synthesizing antibacterial agent 3'-hydroxy-5'-substituted aminobenzoxazinorifamycin derivatives, and the synthesis method thereof. Further, the invention relates to 3'-hydroxy-5'-substituted aminobenzoxazinorifamycin derivatives using 3'-alkyl/arylsilyloxybenzoxazinorifamycin derivatives as the synthesis intermediate and the synthesis method thereof.

Description

3 '-preparation method of alkyl or aryl siloxy-benzoxazine and Ryfamycin derivative
The present invention relates to the synthetic intermediate, 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin and synthesis method thereof used of 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and Ryfamycin derivative antibiotic.And, the present invention relates to 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin and make 3 ＇-hydroxyl-5 ＇ of intermediate-substituted-amino benzoxazine and Ryfamycin derivative and synthesis method thereof.
3 ＇-hydroxyl-5 ＇-replacement benzoxazine and Ryfamycin derivative can be made antibiotic and use as can be known to open flat 1-239676 and 1-239677 from the spy.But no matter the spy opens the much amounts of the described auxiliary material 2-of clear 63-183587 aminoresorcinol, therefore its synthetic intermediate 3 ＇-Qiang base benzoxazine and rifomycin have the low problem of synthesis yield with rifamycin-S synthetic yield less than 10%.
The present invention develops new synthesis method, solved the problems referred to above, wherein 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin are synthetic replaces 3 ＇-Qiang base benzoxazine and rifomycin with intermediate with 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin.
The present invention 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin react with rifamycin-S and formula (I) 3-alkyl or aryl siloxy--2-amino phenol and synthesize.
Figure C9110582500061
(R1, R2 and R3 represent alkyl, phenyl, toluyl, phenmethyl or the styroyl of identical or different carbon number 1-6 in the formula)
R 1, R 2And R 3Shown in 1-6 carbon alkyl can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, tert-pentyl, hexyl etc., aryl can be enumerated phenyl, tolyl etc., and aralkyl can be enumerated phenmethyl, styroyl etc.
3-alkyl or aryl siloxy-benzoxazine of the present invention and rifomycin are synthetic can be synthetic with following way with formula (I) 3-alkyl or aryl siloxy--2-amino phenol.
(1) is being with or without in the presence of the alkali 2-aminoresorcinol and formula R 2-
Figure C9110582500062
(R in the formula 1, R 2And R 3The same, X is a fluorine, chlorine, bromine, iodine, OClO 3And OSO 2CF 3) reaction.
Available bases can be enumerated imidazoles, pyridine.Picoline, xylidine, triethylamine, _ piperazine, morpholine, 2 grades or 3 grades organic basess such as tetramethyleneimine.
Same available mineral alkali, as sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, calcium hydroxide, alkaline earth metal hydroxidess such as hydrated barta, sodium hydride, potassium hydride KH, basic metal or alkaline earth metal hydrides such as hydrolith, sodium bicarbonate, alkaline metal bicarbonates such as saleratus, yellow soda ash, alkaline carbonates such as salt of wormwood.
Also available sodium acetate, organic acid alkali metal salt such as potassium acetate are preferably used _ piperazine as alkali, organic basess such as triethylamine, and its effect is good especially.
Reaction solvent can be used ester classes such as ethyl acetate, butylacetate, N, dinethylformamide, N, N-diethylformamide, N,N-dimethylacetamide, 1,1,3, the 3-tetramethyl-urea, aprotic polar solvents such as methyl-sulphoxide, Methylal(dimethoxymethane), ether and acetonitriles such as diethoxyethane are preferably used N, dinethylformamide, aprotic polar solvents such as N,N-dimethylacetamide, its effect are good especially.
Temperature of reaction is chosen as the solvent zero pour to boiling point, generally uses low temperature, and preferred below-10 ℃, its effect is good especially.The optimum reaction times is depended on reaction reagent, solvent etc., and available high-speed liquid chromatography, thin-layer chromatographys etc. are followed the tracks of reaction and are determined.As for reaction reagent, remove above-mentioned formula (R in the formula 1, R 2, R 3The same with X) shown in outside the compound, also available formula , H 3CCONHSiR 1R 2R 3, R 1R 2R 3SiNHCOOSiR 1R 2R 3, R 1R 2R 3SiN (C 2H 5) 2,
R 1R 2R 3SiNHSO 3SiR 1R 2R 3, (R 1R 2R 3SiNH) 2(the R in the formula of compound shown in the CO 1, R 2And R 3The same, R 1R 2R 3Si represents (2) with 2-nitro-resorcinol and formula
Figure C9110582500081
(R in the formula 1, R 2R 3The same with X) shown in compound reaction and synthetic 3-alkyl or aryl siloxy--2-oil of mirbane, with the palladium carbon contact nitroreduction is become amino again.2-nitro-resorcinol and formula
Figure C9110582500082
(R in the formula 1, R 2, R 3The same with X) shown in compound under above-mentioned (1) same condition, react and same available formula Reaction reagent in addition.
Available energy is reduced into amino the whole bag of tricks with aromatic nitro during nitroreduction in carrying out 3-alkyl or aryl siloxy--2-oil of mirbane, as draw reduction such as Buddhist nun's nickel and metallic zinc good especially, also available palladium carbon, platinum oxide, catalyzer such as Strontium carbonate powder-palladium contact reduction.
Formula (I) 3-alkyl or aryl siloxy--2-amino phenol can be enumerated
Formula (I) 3-alkyl or aryl siloxy-of the present invention-2-amino phenol separation and purification from resultant of reaction is easy to, and removes solvent under reduced pressure from resultant of reaction, makes thick resultant partial crystallization, again with chromatography etc. refining and the purpose compound.
3-alkyl or aryl siloxy--2-amino phenol and rifamycin-S shown in the formula (I) react and synthesis type (II) 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin
Figure C9110582500101
(R1, R2 and R3 are same as described above in the formula)
Formula (II) 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin can be used as above-mentioned 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and the synthetic intermediate of using of rifomycin antibiotic.
The synthetic way of formula (II) 3 ＇ alkyl or aryl siloxy-benzoxazines and rifomycin is as follows.
Be about to rifamycin-S and formula (I) 3-alkyl or aryl siloxy--2-amino phenol and be dissolved in benzene, in the toluene equal solvent, room temperature stirring reaction to the solvent boiling point.Reaction solvent can be used esters such as aromatic hydrocarbons such as benzene, toluene, ethyl acetate, butylacetate, acetate, and acetonitriles etc. are preferably used aromatic hydrocarbons such as benzene, toluene, and its effect is good especially.
Temperature of reaction is generally elected room temperature as to solvent boiling point, considers the thermostability of raw material and resultant, and it is good especially that temperature of reaction is elected 60 ℃ of left and right sides effects as.
The optimum reaction times is depended on reaction reagent, and solvent etc. can be by high-speed liquid chromatography, and tracking such as tlc are reacted and determined.
Formula (II) 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin are synthetic under these conditions, wherein the subsidiary Rifamycin Sodium that is reduced into of rifamycin-S.Add the oxidable one-tenth rifamycin-Ss of this Rifamycin Sodium of oxygenant such as Manganse Dioxide in the reaction system.This rifamycin-S need not separate, and gets final product adding type (I) 3-alkyl or aryl siloxy--2-amino phenol and reacts, and gets extra high 3 ＇ of yield-alkyl or aryl siloxy-benzoxazine and rifomycin purpose product.The Rifamycin Sodium oxidation can be enumerated air with oxygenant, oxygen, and persulphate, the Tripotassium iron hexacyanide, Manganse Dioxide, plumbic oxide, silver suboxide, cupric oxide, alkyl nitrite, hydrogen peroxide etc. are preferably used Manganse Dioxide, plumbic oxide, silver suboxide etc., its effect is good especially.Formula (II) the present invention 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin separate from resultant of reaction and are easy to, from resultant of reaction, remove by filter solids such as oxygenant, remove reaction solvent then under reduced pressure, allow thick resultant partial crystallization, methods such as chromatogram refining the purpose compound.
Formula (II) 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin convert 3 ＇-Qiang base benzoxazine and rifomycin that 3 ＇-position alkyl or aryl siloxy-converts hydroxyl to processing such as tetrabutylammonium fluoride.Reaction solvent can be used alcohol such as methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile etc.
Siloxy-cracking reagent, except that above-mentioned tetrabutylammonium fluoride, also available Potassium monofluoride and TBAC tetrabutylammonium chloride coexistence system, acetate, hydrofluoric acid etc., the available siloxy-rimose the whole bag of tricks that makes.
Gained 3 ＇-Qiang base benzoxazine and rifomycin are synthetic known with the intermediate application as 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin antibiotic.
(A is in the formula with formula (II) the present invention 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin and formula AH
Figure C9110582500111
Base and formula shown in (n is the integer of 3-7) (R in the formula 4And R 5Identical or different, be hydrogen or 1-3 carbon alkyl, R 6Be 1-6 carbon alkyl) shown in base) shown in amine react 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin shown in the formula (III)
Figure C9110582500121
(A is the same in the formula).Be that formula (II) 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin can be used as 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and the synthetic intermediate of using of rifomycin.
The reaction of formula (II) 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin and formula AH amine is dissolved in it under existence such as the oxygenant that is with or without Manganse Dioxide in the solvent to be carried out.Solvent can be enumerated for example methylene dichloride, halohydrocarbon such as chloroform, methyl alcohol, alcohol such as ethanol, pyridine, pyridines such as picoline, acetonitrile, benzene, aromatic hydrocarbons such as toluene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N, N, N ＇, N ＇-tetramethyl-urea, aprotic polar solvents such as methyl-sulphoxide, reaction reagent AH amine itself is also available.The preferred solvent dimethyl formamide, N,N-DIMETHYLACETAMIDE, aprotic polar solvents such as methyl-sulphoxide, its effect is good especially.
Temperature of reaction is elected solvent boiling point as to the ice temperature, considers formula (III) 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine of speed of response and generation and the stability of rifomycin, is preferably about room temperature.
Formula
Figure C9110582500122
The basic concrete example of (n is the integer of 3-7) is
Figure C9110582500131
Deng.Formula
Figure C9110582500132
(R 4, R 5And R 6The same) basic concrete example be
Figure C9110582500133
Figure C9110582500134
Deng.
When using oxygenant, available for example air in the reaction, oxygen, Manganse Dioxide, plumbic oxide, silver suboxide, cupric oxide, alkyl nitrites etc. are preferably used Manganse Dioxide, plumbic oxide, silver suboxide etc., it is respond well.
Most preferably the reaction times is depended on used AH amine of reaction and consumption thereof, has or not oxygenant, solvent species, and temperature of reaction etc. can be by high-speed liquid chromatography, and thin-layer chromatographys etc. are followed the tracks of reaction and are determined.
3 ＇ that above-mentioned formula (II) is new-alkyl or aryl siloxy-benzoxazine and rifomycin can be used as the synthetic intermediate of 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin, 3 ＇ wherein-alkyl or aryl siloxy-is convertible into hydroxyl, imports substituted-amino simultaneously in 5 ＇ positions.
(embodiment)
Following examples are described in more detail the present invention, and these embodiment only for for example, can not be interpreted as it is limitation of the present invention.
Embodiment 1
(synthesizing of 2-amino-3-t-butyldimethylsilyloxy base phenol).
2-aminoresorcinol hydrochloride 161.6g is dissolved in the N,N-DIMETHYLACETAMIDE (calling DMA in the following text) 11, replaces into argon gas in the reactive tank.Add anhydrous _ piperazine 94.8g then, stir, mixture is chilled to-15 ℃.Fully under the agitation condition, drip dissolved tert-butyldimethylsilyl chloride among the DMAll in about 1 hour.℃ stirring is 3 hours then-15, adds water 3.6ml, about 1 hour of restir.Reaction mixture high-speed liquid chromatography (post: Na カ ラ イ テ ス Network Cosnnosil 5C18,4.6 * 250mm, mobile phase: methanol-water (95: 5), flow velocity: 1.5ml/ branch, detect: 254nm) analyze, results verification has the purpose compound to generate (reaction yield: 88%).
Leach the post precipitation filtrate decompression in the reaction mixture and concentrate, add toluene 0.7l in the enriched material, leach the heavy pyridine of generation.Filtrate is washed 4 times with the 1N sodium carbonate buffer 0.5l of pH9.1 earlier, and water 1l washing is 2 times then.Toluene layer is evaporated to dried, adds hexane 0.5l in the residue, 60 ℃ of following heating for dissolving.Solution cools off, and leaches the needle-like crystal of generation, and vacuum-drying gets purpose compound 134.1g.Filtrate is dissolved among the toluene 0.13l after being concentrated into and doing again, washs 2 times with water 0.5l after the aforementioned sodium carbonate buffer 0.1l washing 2 times.Toluene layer separates, and removes toluene under reduced pressure, adds hexane 0.12l in the residue, 60 ℃ of following heating for dissolving.The needle-like crystal that the cooling back generates leaches, and vacuum-drying gets purpose compound 33.1g.
1H-NMR〔CDCl 3，δ(ppm)〕
0.23(Si-CH 3，3H，S)，1.02(C(CH 3) 3，9H，S)，
4.34 (NH 2, 2H, wide, OH, 1H, wide), 6.30-6.62 (aromatics proton, 1H, multimodal)
Ultimate analysis value (C 12H 21NO 2Si)
Equivalent 60.21 8.84 5.85 measured values 60.11 8.90 5.88 of C (%) H (%) N (%) meter
Embodiment 2
(synthesizing of 2-amino-3-t-butyldimethylsilyloxy base phenol)
Replace embodiment 1 used _ piperazine with triethylamine 0.35l, and under the condition that is same as embodiment 1, react.The high-speed liquid phase chromatogram analysis result is really there to be the purpose compound to generate (reaction yield: 90%).Be same as embodiment 1 handle 172.3g purpose compound.
Embodiment 3
(synthesizing of 2-amino-3-t-butyldimethylsilyloxy base phenol)
Replace embodiment 2 used reaction solvent DMA with dimethyl formamide, and under the condition that is same as embodiment 2, react.The high-speed liquid phase chromatogram analysis results verification has the purpose compound to generate (reaction yield: 78%).Be same as embodiment 1 handle 138.8g purpose compound.
Embodiment 4
(synthesizing of 2-amino-3-t-butyldimethylsilyloxy base phenol)
Replace embodiment 1 used _ piperazine with imidazoles 163.4g, and under the condition that is same as embodiment 1, react.The high-speed liquid phase chromatogram analysis results verification has the purpose compound to generate (reaction yield: 75%).Be same as that embodiment 1 handles and 131.7g purpose compound.
Embodiment 5
(synthesizing of 3 ＇-t-butyldimethylsilyloxy base benzoxazine and rifomycin)
Rifamycin-S 69.58g is dissolved among the toluene 508ml, is heated to 50 ℃, adds the toluene 192ml solution of 2-amino-3-t-butyldimethylsilyloxy base phenol 19.15g in 30 minutes.Dripped the back 50 ℃ of stirring reactions of material 6 hours.About 50ml toluene is removed in underpressure distillation, adds Manganse Dioxide 10.43g then, and 40 ℃ were stirred 40 minutes.The filtering insolubles, toluene is cleaned residue.Filtrate and washing lotion merge the back concentrating under reduced pressure must about 700ml.Be heated to the toluene 72ml solution that added 2-amino-3-t-butyldimethylsilyloxy base phenol 7.18g after 50 ℃ in about 10 minutes.Drip and expected back 50 ℃ of stirring reactions 14 hours.Leach insolubles, residue is cleaned with toluene.Filtrate and washing lotion merge back high-speed liquid chromatography (post: Japanese beam split FinepakSIL C18-10 4.6 * 250mm, mobile phase: acetonitrile-water (3: 1), flow velocity: the 2.0ml/ branch detects: 265nm) analytical results confirms to have the purpose compound to generate (reaction yield: 90%).
This solution decompression is concentrated into 300ml, adds hexane 300ml, and room temperature is placed and made its partial crystallization.Generate the dry purpose compound 62.9g of getting of crystallization leaching final vacuum.
1H-NMR〔CDCl 3，δ(ppm)〕
0.25 (Si-CH 3, 3H, S), 1.03 (C (CH 3) 3, 9H, S), 0.61,0.84,1.00 (CHCH 3, 3H, d), 1.78,2.03,2.11,2.30 (CH 3, 3H, s), 3.05 (OCH 3, 3H, s), 6.85-7.43 (aromatics proton, 1H, multimodal), 7.51 (NH, 1H, wide), (4.18 (phenol character, 1H, wide)
Ultimate analysis value (C 49H 62O 13N 2Si)
C (%) H (%) N (%) calculated value 64.31 6.83 3.06 measured values 64.13 6.81 3.06
Embodiment 6
(3) hydroxyl-5 ＇-tetramethyleneimine and benzoxazine and rifomycin is synthetic)
Introduce DMA4.5ml in the 100ml eggplant type flask, the vacuum pump degassing replaces argon gas.Add 3 ＇-t-butyldimethylsilyloxy base benzoxazine and rifomycin 1.83g again, make its dissolving.Add tetramethyleneimine 0.284g and Manganse Dioxide 0.522g then, stirring at room reaction 24 hours.Filtering is used methanol cleaning as the Manganse Dioxide of filtration adjuvant.Filtrate and washing lotion merge back high-speed liquid chromatography (post: Na カ ラ イ テ ス Network Cosnnosil 5CS, 4.6 * 150mm, mobile phase: methanol-water-trifluoroacetic acid (75: 25: 0.1), flow velocity: the 1.0ml/ branch detects: 290nm) analytical results confirms to have the purpose compound to generate (reaction yield: 90%).
Solution concentration adds ethyl acetate 30ml dissolving to doing.Wash then 3 times, saturated common salt is washed once, and anhydrous sodium sulfate drying spends the night.After the filtering anhydrous sodium sulphate, filtrate is concentrated into dried, and (carrier: ワ コ-ゲ Le C-200, launch solvent: chloroform-methanol (99: 1-98: 2)) is refining with silica gel chromatography for residue.Be concentrated into driedly after in the diversity of food purpose compound, add ethanol 36ml in the residue, 55 ℃ of dissolvings, room temperature is placed and partial crystallization.Generate the crystallization filtering, vacuum-drying gets purpose compound 1.11g again.This purpose compound 1The H-nuclear magnetic resonance spectrum is consistent with known compound, thereby has confirmed its structure.
Embodiment 7-25
(synthesizing of 3-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin)
Use at 2 of rifamycin-S and work as amine replacement embodiment 6 used tetramethyleneimine shown in flow control 1 table, and under the condition that is same as embodiment 6, react, handle, the results are shown in the 1st table.Each compound 1The H-nuclear magnetic resonance spectrum is with known consistent, thereby confirmed its structure.
The 1st table embodiment amine reaction yield, (%) separation yield, (%) 7 _ pyridine, 90 60 8 N-methyl _ piperazines, 91 57 9 N-ethyl _ piperazines, 90 6310 N-propyl group _ piperazines, 91 6511 N-isopropyl _ piperazines, 93 6212 N-butyl _ piperazines, 92 6413 N-isobutyl group _ piperazines, 93 5814 N-sec-butyl _ piperazines, the 90 6315 N-tert-butyl group _ piperazines, 91 6516 N-cyclopropyl _ piperazines, 92 6217 N-cyclobutyl _ piperazines, 90 5818 N-cyclopropyl methyl _ piperazines, 90 6119 N-cyclopenta _ piperazines 91 6,320 1; 2-dimethyl _ piperazine 92 6221 1-Ethyl-2-Methyl _ piperazines 90 6422 1-isopropyl-2-methyl _ piperazine 93 6,023 1; 2; 6-trimethyl _ piperazine 92 6, and 124 2; 6-dimethyl-1-ethyl _ piperazine 90 5,925 2,6-dimethyl-1-propyl group _ piperazine 91 60
Annotate: *Be high-speed liquid phase chromatogram analysis value (analysis condition is with embodiment 6).
Embodiment 26
(3 ＇-hydroxyl-5-(2,4,5-trimethylammonium _ piperazine base) benzoxazine and rifomycin synthetic)
Import DMA4.5ml in the 100ml eggplant type flask, replace argon gas after the vacuum pump degassing, dissolve in 3 '-tertiary butyl dimethyl three siloxy-benzoxazines and rifomycin 1.373g, add 1 again, 2,5-trimethylammonium _ piperazine 0.763g and Manganse Dioxide 0.39g, stirring at room reaction 96 hours.Filtering filtration adjuvant Manganse Dioxide is also used methanol cleaning, and filtrate and washing lotion merge back high-speed liquid chromatography (with embodiment 6 analysis conditions) analytical results and confirm to have the purpose compound to generate (reaction yield: 90%).
Be same as embodiment 6 and carry out aftertreatment, refining.Contain and be concentrated into driedly after the purpose compound component is concentrated, add ethyl acetate 8ml in the residue, 55 ℃ of dissolvings, add the 12ml hexane after room temperature place partial crystallization.The crystallization leaching that generates is come out, and vacuum-drying gets purpose compound 0.73g.Gained purpose compound 1The H-nuclear magnetic resonance spectrum is with known consistent, thereby confirmed its structure.
Embodiment 27-29
(synthesizing of 3 ＇-hydroxyl-5-substituted-amino benzoxazine and rifomycin)
Replace embodiment 26 used 1,2 at amine shown in 4 normal the 2nd tables of rifamycin-S, 5-trimethylammonium _ piperazine, and react in the condition that is same as embodiment 26, to handle, gained the results are shown in the 2nd table.Each compound 1The H-nuclear magnetic resonance spectrum is with known consistent, thereby confirmed its structure.
The 2nd table embodiment amine * reaction yield (%) separation yield (%) 27 2,5-dimethyl-1-ethyl _ piperazine 90 6,028 2,5-dimethyl-1-propyl group _ piperazine 89 5,529 2,5-dimethyl-1-sec.-propyl _ piperazine 91 53
Annotate: *Annotate with the 1st table.
The present invention develops 3 ＇-alkyl or aryl siloxy-benzoxazine and rifomycin, can be used as and have excellent antibiotic result of treatment, and the synthetic intermediate of using of the efficient high yield that is difficult to synthetic 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin at present, so, 3 ＇-hydroxyl-5 ＇-substituted-amino benzoxazine and rifomycin just can be easy to make.

Claims (3)

  1. One kind by 3 shown in the formula III '-hydroxyl-5 '-preparation method of substituted-amino benzoxazine and rifomycin, (in the formula, the A expression
    Figure C9110582500022
    The group (wherein n is 3～7 integer) and the formula of expression
    Figure C9110582500023
    The group of expression, R in the formula 4And R 5Be identical or different hydrogen atom or C 1-3Alkyl, R 6Be C 1-6Alkyl)
    It is characterized in that, the amine reaction that shown in the following formula II 3 '-alkyl or aryl siloxy-benzoxazine and rifomycin and following formula AH are represented, reaction is to carry out under the condition that the compound of selecting from Manganse Dioxide, plumbic oxide and silver suboxide more than a kind exists
    Figure C9110582500031
    (in the formula, R 1, R 2And R 3Represent identical or different C 1-6Alkyl, phenyl, toluyl, phenmethyl or styroyl), AH (in the formula, A is identical with implication in the above-mentioned formula III).
  2. 2. method as claimed in claim 1, it is characterized in that, use therein formula II represent 3 '-alkyl or aryl siloxy-benzoxazine and rifomycin are to be made by 3-alkyl or aryl siloxy--2-amino phenol and rifamycin-S reaction that following formula I represents
    Figure C9110582500032
    (in the formula, R 1, R 2And R 3Represent identical or different C 1-6Alkyl, phenyl, methyl acyl group, phenmethyl or styroyl).
  3. 3. method as claimed in claim 2 is characterized in that, 3-alkyl or aryl siloxy--2-amino phenol that use therein formula I represents is to be made by the compound reaction that 2-aminoresorcinol and following formula are represented,
    Figure C9110582500041
    (in the formula, R 1, R 2And R 3Represent identical or different C 1-6Alkyl, phenyl, toluyl, phenmethyl or styroyl, X is fluorine atom, chlorine atom, bromine atoms, iodine atom or by OClO 3, OSO 2CF 3The group of expression).
CN91105825A 1990-08-20 1991-08-19 3'-alkyl or aryl silicaneoxybenzoxazinorifamycin Expired - Lifetime CN1037607C (en)

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JPS6377884A (en) * 1986-09-20 1988-04-08 Kanegafuchi Chem Ind Co Ltd Benzoxazino or benzothiazinorifamycin having introduced aromatic amine
JPS63183587A (en) * 1985-02-05 1988-07-28 Kanegafuchi Chem Ind Co Ltd Benzoxazino-rifamycin derivative
JPH03101681A (en) * 1989-09-14 1991-04-26 Kanegafuchi Chem Ind Co Ltd 5'-(4-propyl-or 4-isopropylpiperazinyl) benzoxazinorifamycin derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63183587A (en) * 1985-02-05 1988-07-28 Kanegafuchi Chem Ind Co Ltd Benzoxazino-rifamycin derivative
JPS6377884A (en) * 1986-09-20 1988-04-08 Kanegafuchi Chem Ind Co Ltd Benzoxazino or benzothiazinorifamycin having introduced aromatic amine
JPH03101681A (en) * 1989-09-14 1991-04-26 Kanegafuchi Chem Ind Co Ltd 5'-(4-propyl-or 4-isopropylpiperazinyl) benzoxazinorifamycin derivative

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KR100203729B1 (en) 1999-06-15
JPH04103589A (en) 1992-04-06
JP2620399B2 (en) 1997-06-11
CN1059145A (en) 1992-03-04
KR920004403A (en) 1992-03-27
KR100203615B1 (en) 1999-06-15

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