CN105837555A - Preparation method for garenoxacin and intermediate thereof - Google Patents
Preparation method for garenoxacin and intermediate thereof Download PDFInfo
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- CN105837555A CN105837555A CN201610195564.4A CN201610195564A CN105837555A CN 105837555 A CN105837555 A CN 105837555A CN 201610195564 A CN201610195564 A CN 201610195564A CN 105837555 A CN105837555 A CN 105837555A
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- 0 C[C@](*1)c(ccc(Br)c2)c2C1=O Chemical compound C[C@](*1)c(ccc(Br)c2)c2C1=O 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a preparation method for garenoxacin and an intermediate thereof. The preparation method comprises the following steps: with a compound 5 as a raw material, reacting the compound 5 with bis(pinacolato)diboron or triisopropyl borate so as to obtain a compound 4; separately adding 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, a palladium catalyst and inorganic aqueous alkali and carrying out a reaction so as to obtain a compound 3; and subjecting the compound 3 to hydrolysis and a reduction reaction so as to obtain a compound 2 and garenoxacin (a compound 1). The compound 3 has excellent stability; raw materials for preparation of garenoxacin are cheap and easily available; reaction operation is simple; yield is high; litter waste gas, waste water and industrial residue are produced; and thus, the preparation method has good industrial prospects.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of T-3811 and intermediate preparation method thereof.
Background technology
T-3811 chemistry entitled 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-2,3-dihydro-1-
methyl-1H-isoindol-5-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid monomethane
sulfonate.T-3811 is the most active to multiple gram-positive bacteria, MIC50s in the range of
0.025-1.56mcg/mL, more higher than ciprofloxacin and levofloxacin star activity.For methicillin and quinolinones
Drug-resistant S. aureus, vancomycin-resistant enterococcus and penicillin resistance streptococcus pneumoniae, its
Activity and trovafloxacin are quite or higher.To the most of bacterial strains detected, the activity of garenoxacin all than
Levofloxacin is strong, and trovafloxacin is quite or higher (ICAAC, Abs F158, F159；In JIUYUE, 1997).
Garenoxacin is also effective to multiple gram-negative bacteria, and zoopery shows that oral garenoxacin is to little
Mus PRSP infects or the effect of mediated quinolone resistance staphylococcus aureus systemic infection be better than ciprofloxacin,
Levofloxacin and trovafloxacin, hypodermic effect is better than ciprofloxacin (ICAAC, Abs F 159).
Garenoxacin pharmacokinetic properties with mice, rat and Canis familiaris L. and ciprofloxacin are suitable, oral raw
Thing availability is in the range of 43-96%.
Patent of invention CN1195752 discloses and can be used as antibacterial and by the 7-xylylenimine shown in formula (1)
Carbostyril carboxylic acid derivatives and the method for intermediate thereof；7-isoindoline-quinolonecarboxylic acid shown in formula (1) derives
The salt of thing and hydrate thereof.
Develop high yield, high-purity, the T-3811 intermediate being suitable for industrialized production of excellent in stability and
Its synthetic route is significant.
Summary of the invention
Raw material is cheap and easy to get, operation is easy, yield is high, the three wastes are few to the invention provides one, is suitable for
In T-3811 and the intermediate preparation method thereof of industrialized production, technical scheme is as follows:
A kind of preparation method of T-3811 midbody compound 3, reaction equation is as follows:
Including following reactions steps:
(1) compound 5 is added in organic solvent, be separately added into connection boric acid pinacol ester or boric acid three isopropyl
Any one in ester, any one in diethanolamine and anhydrous sodium acetate, and at palladium chtalyst
In the presence of agent, reacting generating compound 4；
(2) upper step institute produced compounds 4 is added in organic solvent, be separately added into 7-bromo-1-cyclopropyl-8-difluoro first
Oxy-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, palladium catalyst and inorganic alkali solution reaction are raw
Become compound 3.
Further, described organic solvent is any one in ethanol, dioxane or DMSO, described
Palladium catalyst in the double Diphenyl phosphino ferrocene palladium chloride of 1,1'-, palladium, palladium chloride or palladium carbon
Any one or a few combination, described inorganic alkali solution be selected from sodium carbonate or solution of potassium carbonate.
In a kind of scheme, compound 5 is added to, in dimethyl sulfoxide, stir by step (1), respectively
Adding connection boric acid pinacol ester, anhydrous sodium acetate, 1,1'-double Diphenyl phosphino ferrocene palladium chlorides, nitrogen is protected
Under at 70～95 DEG C stir reaction obtain compound 4.
In a kind of scheme, compound 4 is added in Isosorbide-5-Nitrae-dioxane by step (2), stirs, respectively
Add 7-bromo-1-cyclopropyl-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, 1,1'-double hexichol
Base phosphine ferrocene palladium chloride, 2N sodium carbonate liquor, it is warming up to 80～90 DEG C of reactions under nitrogen protection
Compound 3.
The present invention also aims to provide the preparation method of a kind of T-3811 (compound 1), reactional equation
Formula is as follows:
Including following reactions steps:
A compound 3 hydrolysis under the effect of Lithium hydrate or sodium hydroxide is obtained compound 2 by ()；
B compound 2 is dissolved in oxolane and is cooled to 10～15 DEG C by (), add sodium borohydride, boron trifluoride
Diethyl ether solution is warming up to 50～75 DEG C of reactions, or 0～10 DEG C by Lithium Aluminium Hydride also in oxolane
Former obtain compound 1.
Further, in step (a), the temperature of reaction is room temperature.
The present invention also aims to provide a kind of T-3811 midbody compound 3, the following institute of its structural formula
Show:
It is white or pale solid powder to compound 3, its stability is investigated, it was found that
Having the stability of excellence, purity is preferable simultaneously, and product quality is higher.
The present invention, with compound 5 as raw material, reacts with connection boric acid pinacol ester or triisopropyl borate ester, obtaining
Compound 4, be separately added into 7-bromo-1-cyclopropyl-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester,
Palladium catalyst and inorganic alkali solution reacting generating compound 3；And obtain compound 2 by hydrolysis, reduction reaction
With T-3811 (compound 1).Gained compound 3 has the stability of excellence, prepares used by T-3811
Raw material cheap and easy to get, operation is easy, yield is high, the three wastes are few, before therefore having extraordinary industry
Scape.
Detailed description of the invention
For ease of understanding, below by specific embodiment, the present invention will be described in detail.Need especially
It is noted that instantiation is merely to explanation, it is clear that those of ordinary skill in the art can be according to saying herein
Bright, within the scope of the invention the present invention is made correction.
Embodiment 1
(R)-2,3-dihydro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base)-1H-iso-indoles-1-
The synthesis of ketonic compound 4
Formula 5 (10.0g, 0.044mol) is added to (100mL) in dimethyl sulfoxide, stirs.
It is separately added into and joins boric acid pinacol ester (13.26g, 0.053mol), anhydrous sodium acetate (8.66g, 0.105mol),
1,1'-double Diphenyl phosphino ferrocene palladium chlorides (1.93g, 0.002mol), stir at lower 80～90 DEG C of nitrogen protection
Mixing 12h, reactant liquor is concentrated to dryness, and obtains grease Formula 4.
Embodiment 2
1-cyclopropyl-8-(difluoro-methoxy)-7-[(3R)-2,3-dihydro-3-methyl isophthalic acid H-iso-indoles-1-ketone-6-base]-4-oxygen
Synthesis for quinoline-3-carboxylic acid ethyl ester compound 3
Upper step institute produced compounds 4 (7.98g, 0.029mol) is added in Isosorbide-5-Nitrae-dioxane (80mL), stirs
Mix uniformly, be separately added into 7-bromo-1-cyclopropyl-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
(11.67g, 0.029mol), 1,1'-double Diphenyl phosphino ferrocene palladium chlorides (1.05g, 0.001mol), 2N
Sodium carbonate liquor (30ml), is warming up to 85 DEG C of stirrings 2～3h under nitrogen protection, be cooled to room temperature, sucking filtration, filter
Liquid adds to, in water (400ml), have solid to separate out, and sucking filtration obtains 13g pale solid Formula 3.
1H-NMR(400MHz,DMSO-d6,δ):1.08(2H,d),1.18(2H,d),1.27(3H,t),1.42(3H,
d),3.96(1H,m),4.22(2H,q),4.70(1H,m),6.51-6.87(1H,t),7.60(1H,d),7.74(1H,d),
7.80(2H,q),8.20(1H,d),8.62(1H,s),8.81(1H,s)；
13C-NMR(400MHz,DMSO-d6,δ):9.9,14.7,20.6,52.1,60.4,111.1,117.7,120.3,
123.5,124.3,125.1,127.7,130.3,132.8,133.5,136.5,136.6,137.2,141.0,149.6,
152.4,164.4,168.9,172.4。
MS(+):469.4(MW:468.4)。
Embodiment 3
1-cyclopropyl-8-(difluoro-methoxy)-7-[(3R)-2,3-dihydro-3-methyl isophthalic acid H-iso-indoles-1-ketone-6-base]-4-oxygen
Synthesis for quinoline-3-carboxylic acid compound 2
Compound 3 (12.33g, 0.026mol) is added to (120mL), room temperature in 6N lithium hydroxide solution
Stirring 10～12h, addition 2N hydrochloric acid, to pH=6～7, has solid to separate out, and sucking filtration obtains 10.8g gray solid
Compound 2.
1H-NMR(400MHz,DMSO-d6,δ):1.18(4H,dd),1.43(3H,d),4.14(1H,m),4.73(1H,
m),6.54-6.91(1H,t),7.77-7.85(4H,m),8.36(1H,d),8.82(1H,s),8.91(1H,s),14.64(1H,
s)；13C-NMR(400MHz,DMSO-d6,δ):10.0,20.5,41.5,52.2,55.3,108.7,115.0,117.7,
120.3,123.7,124.4,124.8,127.6,129.2,132.9,133.6,136.2,137.1,137.5,142.5,
149.9,153.0,165.7,168.9,177.6。
MS(+):441.2(MW:440.4)。
Embodiment 4
1-cyclopropyl-8-(difluoro-methoxy)-7-[(1R)-1-methyl-2,3-dihydro-1H-iso-indoles-5-base]-4-oxo quinoline
The synthesis of quinoline-3-carboxylic acid compound 1
Upper step institute produced compounds 2 (8.43g, 0.019mol) is added in oxolane (270mL), stirs.
It is cooled to 10～15 DEG C, adds sodium borohydride (7.98g, 0.216mol), be slowly added to boron trifluoride diethyl etherate molten
Liquid (6.33g), is warming up to 60～65 DEG C of stirrings 3～5h, is cooled to room temperature, is added by reactant liquor in frozen water, point
Liquid, takes organic layer, is then concentrated to dryness, in oxolane, acetone backflow stir elution pure, filtration drying obtains
To 6.7g pale solid compound 1, HPLC purity 99.8%.
1H-NMR(400MHz,DMSO-d6,δ):1.19(4H,dd),1.49(3H,d),1.76(1H,s),4.15(1H,
m),4.29(2H,m),4.67(1H,m),6.52-6.89(1H,t),7.46-7.74(4H,m),8.35(1H,d),8.90(1H,
s)；13C-NMR(400MHz,DMSO-d6,δ):9.48,20.1,40.9,50.0,58.4,108.2,113.6,117.0,
120.5,122.1,123.6,124.1,126.9,128.5,128.9,135.0,136.6,136.9,140.0,142.4,
144.8,152.3,165.1,177.0。
MS(+):427.3(MW:426.4)。
Embodiment 5
Cyclopropyl-8-(difluoro-methoxy)-7-[(3R)-2,3-dihydro-3-methyl isophthalic acid H-iso-indoles-1-ketone-6-base]-4-oxo
Quinoline-3-carboxylic acid ethyl ester compound 3 stability test
5.1 with reference to Chinese Pharmacopoeia two annex XIXC of version in 2010, the compound 3 preparing the application
Having carried out stability test investigation, result is as shown in the table.
Table 1
5.2 accelerated test
Compound 3 polyethylene film plastic bag sealing is packed, be placed in 40 DEG C ± 2 DEG C, relative humidity be 75%
In the constant temperature and humidity incubator of ± 5%, place 6 months, respectively at 1st month, 2 months, 3 months, 6
The individual the end of month, sampling detected, and the result with 0 day compares, and the results are shown in Table 2.
Table 2 accelerated test (40 DEG C, relative humidity 75% ± 5%)
Cyclopropyl-8-(difluoro-methoxy)-7-[(3R)-2,3-dihydro-3-different Yin of methyl isophthalic acid H-is can be seen that by result of the test
Diindyl-1-ketone-6-base]-4-Oxoquinoline-3-carboxylic acid ethyl ester compound 3 have excellence stability.Content of impurities and
Moisture without rising appreciably, does not the most increase, under conditions of high humidity under illumination and super-humid conditions
30 days content of impurities and 0 day ratio do not have significant change.6 months each check items of accelerated test and 0 day ratio
Do not have significant change.
Claims (7)
1. the preparation method of a T-3811 midbody compound 3, it is characterised in that the following institute of reaction equation
Show:
Including following reactions steps:
(1) Formula 5 is added in organic solvent, be separately added into connection boric acid pinacol ester or boric acid three
Any one in isopropyl ester, any one in diethanolamine and anhydrous sodium acetate, and at palladium
In the presence of catalyst, reacting generating compound 4；
(2) compound 4 is added in organic solvent, be separately added into 7-bromo-1-cyclopropyl-8-difluoro-methoxy
-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, palladium catalyst and inorganic alkali solution reaction generationization
Compound 3.
2. preparation method as claimed in claim 1, it is characterised in that described organic solvent is ethanol, dioxy
Any one in six rings or DMSO, described palladium catalyst is selected from 1, the double Diphenyl phosphino ferrocene dichloro of 1'-
Change any one or a few combination in palladium, palladium, palladium chloride or palladium carbon, described inorganic alkali solution
Selected from sodium carbonate or solution of potassium carbonate.
3. preparation method as claimed in claim 1, it is characterised in that Formula 5 is added to by step (1)
In dimethyl sulfoxide, stir, be separately added into connection boric acid pinacol ester, anhydrous sodium acetate, 1,1'-double hexichol
Base phosphine ferrocene palladium chloride, stirs reaction at 70～95 DEG C and obtains compound 4 under nitrogen protection.
4. preparation method as claimed in claim 1, it is characterised in that step (2) compound 4 is added Isosorbide-5-Nitrae-
In dioxane, stir, be separately added into 7-bromo-1-cyclopropyl-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydro-4-oxo
Quinoline-3-carboxylic acid ethyl ester, 1,1'-double Diphenyl phosphino ferrocene palladium chlorides, 2N sodium carbonate liquor, nitrogen is protected
Under be warming up to 80～90 DEG C of reactions and obtain compound 3.
5. a T-3811 midbody compound 3, it is characterised in that structural formula is as follows:
6. the preparation method of a T-3811, it is characterised in that reaction equation is as follows:
Including following reactions steps:
A compound 3 hydrolysis under the effect of Lithium hydrate or sodium hydroxide is obtained by ()
Compound 2；
B compound 2 is dissolved in oxolane and is cooled to 10～15 DEG C by (), add hydroboration
Sodium, boron trifluoride ether solution are warming up to 50～75 DEG C of reactions, or in oxolane 0～10 DEG C lead to
Cross Lithium Aluminium Hydride reduction and obtain compound 1.
7. preparation method as claimed in claim 6, it is characterised in that in step (a), the temperature of reaction is
Room temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610195564.4A CN105837555B (en) | 2016-03-31 | 2016-03-31 | T-3811 and its intermediate preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610195564.4A CN105837555B (en) | 2016-03-31 | 2016-03-31 | T-3811 and its intermediate preparation |
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| Publication Number | Publication Date |
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| CN105837555A true CN105837555A (en) | 2016-08-10 |
| CN105837555B CN105837555B (en) | 2019-01-25 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210533A (en) * | 1996-02-09 | 1999-03-10 | 富山化学工业株式会社 | Quinolonecarboxylic acid derivatives or salts thereof |
| CN1278257A (en) * | 1997-10-27 | 2000-12-27 | 富山化学工业株式会社 | Processes for producing 7-isoindolinequinolonecarboxylic derivatives and intermediates therefor, solts of 7-isoindo-linequinolonecarboxylic acid, hydrates thereof, and composition contg. same |
-
2016
- 2016-03-31 CN CN201610195564.4A patent/CN105837555B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210533A (en) * | 1996-02-09 | 1999-03-10 | 富山化学工业株式会社 | Quinolonecarboxylic acid derivatives or salts thereof |
| CN1278257A (en) * | 1997-10-27 | 2000-12-27 | 富山化学工业株式会社 | Processes for producing 7-isoindolinequinolonecarboxylic derivatives and intermediates therefor, solts of 7-isoindo-linequinolonecarboxylic acid, hydrates thereof, and composition contg. same |
Non-Patent Citations (1)
| Title |
|---|
| HIROYOSHI HAYAKAWA, ET AL.: "METABOLISM AND DISPOSITION OF NOVEL DES-FLUORO QUINOLONE GARENOXACIN IN EXPERIMENTAL ANIMALS AND AN INTERSPECIES SCALING OF PHARMACOKINETIC PARAMETERS", 《DRUG METABOLISM AND DISPOSITION》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
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| CN105837555B (en) | 2019-01-25 |
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