CN105837555B - T-3811 and its intermediate preparation - Google Patents
T-3811 and its intermediate preparation Download PDFInfo
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- CN105837555B CN105837555B CN201610195564.4A CN201610195564A CN105837555B CN 105837555 B CN105837555 B CN 105837555B CN 201610195564 A CN201610195564 A CN 201610195564A CN 105837555 B CN105837555 B CN 105837555B
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- 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 present invention is raw material with compound 5, it is reacted with connection boric acid pinacol ester or triisopropyl borate ester, compound 4 is obtained, the bromo- 1- cyclopropyl -8- difluoro-methoxy-Isosorbide-5-Nitrae-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester of 7-, palladium catalyst and inorganic alkali solution reaction is separately added into and generates compound 3；And compound 2 and T-3811 (compound 1) are obtained by hydrolysis, reduction reaction.Gained compound 3 has excellent stability, and prepares that raw material used in T-3811 are cheap and easy to get, operation is easy, high income, the three wastes are few, therefore has extraordinary industrial prospect.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of T-3811 and its intermediate preparation.
Background technique
Entitled 1-cyclopropyl-8- (difluoromethoxy) -7- [(the 1R) -2,3- of T-3811 chemistry
dihydro-1-methyl-1H-isoindol-5-yl]-1,4-dihydro-4-oxo-3-
quinolinecarboxylicacid monomethane sulfonate.T-3811 has a variety of grampostive bacterias
Activity, the range of MIC50s is 0.025-1.56mcg/mL, more stronger than Ciprofloxacin and levofloxacin star activity.For methoxy west
Woods and mediated quinolone resistance staphylococcus aureus, vancomycin-resistant enterococcus and penicillin resistance streptococcus pneumonia,
Its activity is suitable or stronger with trovafloxacin.To most of bacterial strains detected, the activity of garenoxacin all compares levofloxacin
Star strong (ICAAC, Abs F158, F159 suitable or stronger with trovafloxacin；In September, 1997).Garenoxacin is to a variety of lattice
Lan Shi negative bacterium is also effective, and zoopery shows that oral garenoxacin is golden yellow to mouse PRSP infection or mediated quinolone resistance
The effect of color staphylococcus general infection is better than Ciprofloxacin, lavo-ofloxacin and trovafloxacin, and hypodermic effect is wanted
It is better than Ciprofloxacin (ICAAC, Abs F 159).Pharmacokinetic properties of the Garenoxacin with mouse, rat and dog
Suitable with Ciprofloxacin, oral administration biaavailability is in the range of 43-96%.
Patent of invention CN1195752, which is disclosed, can be used as antibacterial agent and the 7- xylylenimine quinoline promise as shown in general formula (1)
The method of keto carboxylic acid derivatives and its intermediate；The salt and its water of 7- isoindoline-quinolonecarboxylic acid derivative shown in formula (1)
Close object.
Develop high yield, high-purity, excellent in stability the T-3811 intermediate for being suitable for industrialized production and its
Synthetic route is of great significance.
Summary of the invention
That the present invention provides a kind of raw material is cheap and easy to get, operation is easy, high income, the three wastes are few, is suitable for industry
The T-3811 and its intermediate preparation, technical solution that metaplasia produces are as follows:
A kind of preparation method of T-3811 midbody compound 3, reaction equation are as follows:
Including following reaction step:
(1) compound 5 is added in organic solvent, is separately added into connection boric acid pinacol ester, diethanol amine and anhydrous acetic acid
Any one in sodium, and in the presence of palladium catalyst, reaction generates compound 4；
(2) upper step institute produced compounds 4 are added in organic solvent, are separately added into the bromo- 1- cyclopropyl -8- difluoromethoxy of 7-
Base -1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester, palladium catalyst and inorganic alkali solution reaction generate compound 3.
Further, the organic solvent is any one in ethyl alcohol, dioxane or DMSO, the palladium chtalyst
Any one or a few in the bis- Diphenyl phosphino ferrocene palladium chlorides of 1,1'-, palladium acetate, palladium chloride or palladium carbon of agent
Combination, the inorganic alkali solution are selected from sodium carbonate or solution of potassium carbonate.
In a kind of scheme, step (1) adds to compound 5 in dimethyl sulfoxide, stirs evenly, and is separately added into connection boric acid
Pinacol ester, anhydrous sodium acetate, 1,1'- bis- Diphenyl phosphino ferrocene palladium chlorides are stirred at 70~95 DEG C under nitrogen protection
Reaction obtains compound 4.
In a kind of scheme, compound 4 is added in Isosorbide-5-Nitrae-dioxane step (2), stirs evenly, is separately added into 7-
Bromo- 1- cyclopropyl -8- difluoro-methoxy-Isosorbide-5-Nitrae-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester, 1,1'- bis- Diphenyl phosphino ferrocenes
Palladium chloride, 2N sodium carbonate liquor are warming up to 80~90 DEG C of reactions under nitrogen protection and obtain compound 3.
The object of the invention is also to provide a kind of preparation method of T-3811 (compound 1), reaction equation is as follows:
Including following reaction step:
(a) by compound 3, hydrolysis obtains compound 2 under the action of lithium hydroxide or sodium hydroxide；
(b) compound 2 is dissolved in tetrahydrofuran and is cooled to 10~15 DEG C, sodium borohydride, boron trifluoride ether is added
Solution is warming up to 50~75 DEG C of reactions, or in tetrahydrofuran 0~10 DEG C restore to obtain compound 1 by Lithium Aluminium Hydride.
Further, in step (a), the temperature of reaction is room temperature.
The object of the invention is also to provide a kind of T-3811 midbody compounds 3, and structural formula is as follows:
It is white or pale solid powder to compound 3, its stability is investigated, as a result, it has been found that, have excellent
Different stability, while purity is preferable, product quality is higher.
The present invention is raw material with compound 5, is reacted with connection boric acid pinacol ester, and compound 4 is obtained, and is separately added into the bromo- 1- of 7-
Cyclopropyl -8- difluoro-methoxy -1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester, palladium catalyst and inorganic alkali solution reaction life
At compound 3；And compound 2 and T-3811 (compound 1) are obtained by hydrolysis, reduction reaction.Gained compound 3 has excellent
Different stability, prepares that raw material used in T-3811 are cheap and easy to get, operation is easy, high income, the three wastes are few, therefore has
There is extraordinary industrial prospect.
Specific embodiment
For ease of understanding, the present invention will be described in detail by specific embodiment below.It needs to particularly point out
, specific example is merely to explanation, it is clear that those skilled in the art can be according to illustrating, of the invention herein
Amendment is made to the present invention in range.
Embodiment 1
(R) -2,3- dihydro -3- methyl -6- (penta ring -2- base of 4,4,5,5- tetramethyl -1,3,2- dioxy boron) the different Yin of -1H-
The synthesis of diindyl -1- ketone compound 4
Formula 5 (10.0g, 0.044mol) is added into dimethyl sulfoxide (100mL), is stirred evenly.It is separately added into
Connection boric acid pinacol ester (13.26g, 0.053mol), anhydrous sodium acetate (8.66g, 0.105mol), 1,1'- bis- diphenylphosphines two
Luxuriant iron palladium chloride (1.93g, 0.002mol) stirs 12h at 80~90 DEG C under nitrogen protection, and reaction solution is concentrated to dryness, and is obtained oily
Shape compounds formula 4.
Embodiment 2
1- cyclopropyl -8- (difluoro-methoxy) -7- [(3R) -2,3- dihydro -3- methyl-1 H- iso-indoles -1- ketone -6- base] -
The synthesis of 4- Oxoquinoline-3-carboxylic acid ethyl ester compound 3
Upper step institute produced compounds 4 (7.98g, 0.029mol) are added in Isosorbide-5-Nitrae-dioxane (80mL), are stirred evenly, point
Not Jia Ru the bromo- 1- cyclopropyl -8- difluoro-methoxy-Isosorbide-5-Nitrae-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester of 7- (11.67g,
0.029mol), the bis- Diphenyl phosphino ferrocene palladium chlorides (1.05g, 0.001mol) of 1,1'-, 2N sodium carbonate liquor (30ml), nitrogen
It is warming up to 85 DEG C of 2~3h of stirring under gas shielded, is cooled to room temperature, filters, filtrate adds in water (400ml), there is solid precipitation, takes out
Filter 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-1 H- iso-indoles -1- ketone -6- base] -
The synthesis of 4- Oxoquinoline-3-carboxylic acid compound 2
Compound 3 (12.33g, 0.026mol) is added into 6N lithium hydroxide solution (120mL), it is stirred at room temperature 10~
12h is added 2N hydrochloric acid to pH=6~7, has solid precipitation, suction 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- oxygen
For the synthesis of quinoline -3-carboxylic acid compound 1
Upper step institute produced compounds 2 (8.43g, 0.019mol) are added in tetrahydrofuran (270mL), are stirred evenly.It is cooling
It to 10~15 DEG C, is added sodium borohydride (7.98g, 0.216mol), is slowly added to boron trifluoride ether solution (6.33g), heat up
It to 60~65 DEG C of 3~5h of stirring, being cooled to room temperature, reaction solution is added in ice water, liquid separation takes organic layer, is then concentrated to dryness,
In tetrahydrofuran, acetone reflux stir elution it is pure, filtration drying obtains 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-1 H- iso-indoles -1- ketone -6- base] -4-
3 stability test of Oxoquinoline-3-carboxylic acid ethyl ester compound
5.1, referring to two annex XIXC of Chinese Pharmacopoeia version in 2010, carry out the compound 3 that the application is prepared
Stability test investigation, as a result as shown in the table.
Table 1
5.2 accelerated test
The polyethylene film plastic bag sealing of compound 3 is packed, be placed in 40 DEG C ± 2 DEG C, relative humidity be 75% ± 5%
Constant temperature and humidity incubator in, place 6 months, respectively at 1st month, 2 months, 3 months, 6 the end of month sample detections, and with 0
It result is compareed, and the results are shown in Table 2.
2 accelerated test of table (40 DEG C, relative humidity 75% ± 5%)
By test result it can be seen that cyclopropyl -8- (difluoro-methoxy) -7- [(3R) -2,3- dihydro -3- methyl-1 H- is different
Indoles -1- ketone -6- base] -4- Oxoquinoline-3-carboxylic acid ethyl ester compound 3 has excellent stability.Content of impurities and moisture
Without rising appreciably under illumination and super-humid conditions, do not increase under the high temperature conditions, under conditions of high humidity 30 days content of impurities
With 0 day ratio without significant changes.Accelerated test 6 months each check items and 0 day ratio are without significant changes.
Claims (3)
1. a kind of preparation method of T-3811 midbody compound 3, it is characterised in that reaction equation is as follows:
Including following reaction step:
(1) Formula 5 is added in dimethyl sulfoxide, is stirred evenly, be separately added into connection boric acid pinacol ester, anhydrous acetic acid
Sodium, 1,1'- bis- Diphenyl phosphino ferrocene palladium chlorides are stirred to react to obtain compound 4 at 70~95 DEG C under nitrogen protection；
(2) compound 4 is added in Isosorbide-5-Nitrae-dioxane, stirs evenly, is separately added into the bromo- 1- cyclopropyl -8- difluoromethoxy of 7-
Base-Isosorbide-5-Nitrae-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester, 1,1'- bis- Diphenyl phosphino ferrocene palladium chlorides, 2N sodium carbonate liquor,
It is warming up to 80~90 DEG C of reactions under nitrogen protection and obtains compound 3.
2. a kind of preparation method of T-3811, it is characterised in that reaction equation is as follows:
Including following reaction step:
(a) by compound 3, hydrolysis obtains compound 2 under the action of lithium hydroxide or sodium hydroxide；
(b) compound 2 is dissolved in tetrahydrofuran and is cooled to 10~15 DEG C, sodium borohydride, boron trifluoride ether solution is added
Be warming up to 50~75 DEG C of reactions, or in tetrahydrofuran 0~10 DEG C restore to obtain compound 1 by Lithium Aluminium Hydride.
3. preparation method as claimed in claim 2, it is characterised in that in step (a), the temperature of reaction is room temperature.
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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 |
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- 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 |
|---|
| METABOLISM AND DISPOSITION OF NOVEL DES-FLUORO QUINOLONE GARENOXACIN IN EXPERIMENTAL ANIMALS AND AN INTERSPECIES SCALING OF PHARMACOKINETIC PARAMETERS;HIROYOSHI HAYAKAWA, et al.;《DRUG METABOLISM AND DISPOSITION》;20031231;第31卷(第11期);第1409-1418页 |
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