CN107056810B - A kind of preparation method of Carbostyril carboxylic acid derivatives - Google Patents
A kind of preparation method of Carbostyril carboxylic acid derivatives Download PDFInfo
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- CN107056810B CN107056810B CN201710071381.6A CN201710071381A CN107056810B CN 107056810 B CN107056810 B CN 107056810B CN 201710071381 A CN201710071381 A CN 201710071381A CN 107056810 B CN107056810 B CN 107056810B
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The invention discloses the completely new preparation methods of one kind of formula (I) compound, the following steps are included: (1) 9- fluoro- 3,7- dihydro -3- methyl-1 0- (1- amino cyclopropyl) -7- oxo -2H- [1,4] oxazines simultaneously [2,3,4-ij] QUINOLINE-6-CARBOXYLIC ACID's ethyl ester carries out esterification in single methanol solvent in acid condition, (2) product application DMF-DMA reductive amination process and hydrolysis.Preparation method of the invention, have the advantages that higher safety, synthetic route compared with simple, reaction condition is mild, easily operated, yield is higher, suitable for industrialized production, be conducive to the popularization and application of formula (I) compound.
Description
Technical field
The present invention relates to the preparation methods of oxazines containing 1,4- and the quinolonecarboxylic acid compound of quinoline structure.
Background technique
The Chinese invention patent application of Publication No. CN1858052A discloses a kind of quinolonecarboxylic acid compound, its preparation
The structure of method and application thereof, such compound is shown below:
In above formula, work as R1For H, R2When for methyl, the compound is non-to the activity of gram-positive bacteria and Gram-negative bacteria
Often prominent, treatment disease as caused by both bacteriums has significant effect, therefore, and obtained in the application it is consistent good
It comments.The compound is generally all carried out using synthetic method disclosed in the Chinese invention patent application of Publication No. CN1858052A
Synthesis.But since the method use having the iodomethane of severe toxicity to be synthesized, synthesis process is abnormally dangerous, and the synthesis
Route needs five reaction steps, extremely complex, therefore, has seriously affected the compound and has promoted and applied on a large scale.
Summary of the invention
The object of the present invention is to provide the quinolonecarboxylic acid compounds of a kind of completely new oxazines containing 1,4- and quinoline structure
Preparation method, with improve the safety in its synthesis process, shorten the compound synthetic route, simplify its synthesis technology.
Shown in the structural formula such as formula (I) of 1,4- oxazines and quinoline structure compound of the invention:
According to an aspect of the present invention, the present invention provides the preparation method of above compound, detailed process is as follows:
(1) in acid condition, using compound shown in formula (II) as raw material, containing C1~C6Single methanol solvent in carry out ester
Change reaction, obtains compound shown in formula (III).After completion of the reaction, the post-processing approach generally used include evaporating solvent under reduced pressure,
Dissolution, extraction, dry and recrystallization.Wherein, acid condition can be by using sulfuric acid, hydrochloric acid, thionyl chloride, chloracetyl, right
Toluenesulfonic acid acid flux material or sodium bisulfate Acidic inorganic salts obtain, single methanol solvent it is preferable to use methanol, ethyl alcohol, propyl alcohol,
Butanol, the tert-butyl alcohol.
According to the concrete condition of particular compound, reaction temperature is generally 0 DEG C~100 DEG C, and reaction temperature is not to be exceeded
The boiling point of reaction dissolvent, reaction time are 0.2~48 hour.
Wherein, the R in formula (III)3For C1~C6Alkyl, preferably methyl, ethyl.
(2) DMF-DMA reductive amination process and hydrolysis are applied
(a) in neutral conditions, by compound shown in formula (III) and DMF-DMA, (n,N-Dimethylformamide dimethyl contracts
Aldehyde) in organic solvent carry out amino aldimine condensation reaction, obtain compound shown in formula (IV).
According to the response situation of particular compound, reaction temperature is 0 DEG C~100 DEG C, and the reaction time is 0.2~36 hour.
Solvent used in reaction include to any solvent for having no adverse effects of reaction, it is preferable to use DMF (dimethyl fumarate) or
CH3OH.The post-processing approach generally used after completion of the reaction includes washing, extraction, dry, column chromatography and recrystallization.
(b) compound shown in formula (IV) and Pt/C, Pt (OH)2/ C or Raney's nickel reducing agent are restored in organic solvent
Aminating reaction obtains compound shown in formula (V).
According to the response situation of particular compound, reaction temperature is 0~100 DEG C, and the reaction time is 0.2~48 hour.Instead
Organic solvent used in answering includes to any solvent for having no adverse effects of reaction, it is preferable to use methanol, ethyl alcohol, propyl alcohol, fourth
Alcohol or t-butanol solvent.The post-processing approach generally used after completion of the reaction includes washing, extraction, dry, column chromatography and ties again
It is brilliant.
(c) compound shown in formula (V), which is dissolved in organic solvent heating in acid condition, is hydrolyzed reaction, obtains formula
(I) compound shown in.
According to the response situation of particular compound, reaction temperature is 0~100 DEG C, and the reaction time is 3~12 hours.Reaction
In acid condition can by using the concentrated sulfuric acid, concentrated hydrochloric acid (such as: concentration be 6N HCl) or p-methyl benzenesulfonic acid obtain.It is used
Organic solvent includes any solvent having no adverse effects to reaction, wherein it is preferable to use methanol, ethyl alcohol, propyl alcohol, butanol or tertiary fourths
Alcohol makees solvent.The post-processing approach generally used after completion of the reaction includes washing, extraction, dry, column chromatography and recrystallization.
Wherein, the R in formula (III)~(V)3For C1~C6Alkyl, preferably methyl, ethyl.
Preparation method of the invention, has the advantages that
1, the chemical reagent (including catalyst, solvent, reactant) selected is the lower compound of toxicity, is disclosed relatively
The use of the Chinese invention patent application of number CN1858052A has the iodomethane of severe toxicity, present invention safety with higher.
2, synthetic route of the invention is four steps, for the Chinese invention patent application of opposite publication number CN1858052A,
Shorten a step.
3, reaction condition is mild in synthesis process of the invention, and easily operated, yield is higher, is suitable for industrialized production,
Be conducive to the popularization and application of formula (I) compound.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of formula (III -1) compound.
Fig. 2 is the mass spectrogram of formula (III -1) compound.
Fig. 3 is the mass spectrogram of formula (IV -1) compound.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of formula (I) compound.
Fig. 5 is the mass spectrogram of formula (I) compound.
Specific embodiment
Below by embodiment, the present invention is described in further detail.
Common agents used in following preparation examples, are commercial reagent, use instrument are as follows: 400 type of AvanceIII
Nuclear Magnetic Resonance (tetramethylsilane is internal standard, Bruker company, Switzerland), Orbitrap LC-MS instrument (LC-MS, the U.S.
Thermo company).If unspecified operating method in preparation example, the filtering refers to that Buchner funnel decompression filters, the drying
Finger is dried prepare compound with DHG-9070 type electric heating constant temperature blower vacuum drying box.
1, the fluoro- 3,7- dihydro -3- methyl-1 0- of (S) -9- (1- amino cyclopropyl) -7- oxo -2H- [1,4] oxazines simultaneously [2,
3,4-ij] QUINOLINE-6-CARBOXYLIC ACID's ethyl ester (for a kind of concrete form of compound shown in above-mentioned formula (III), change by hereinafter referred to as formula (III -1)
Close object) preparation
(S) the fluoro- 3,7- dihydro -3- methyl-1 0- of -9- (1- amino cyclopropyl) -7- oxo -2H- [1,4] oxazines simultaneously [2,3,
4-ij] QUINOLINE-6-CARBOXYLIC ACID (for compound shown in Chinese style of the present invention (II)) (10g, 31.42mmol), it is suspended in ethyl alcohol (150mL)
In, it is slowly added dropwise thionyl chloride (25mL, 314.2mmol), is dripped off in 35min, mixed solution flowed back under the condition of ice salt bath
Night.After the reaction was completed, evaporating solvent under reduced pressure is diluted with methylene chloride (200mL), with saturated sodium bicarbonate solution (300mL) point
Liquid, organic layer is washed twice with water (100mL), dry with anhydrous sodium sulfate.It removes methylene chloride under reduced pressure, obtains crude product 9.1g, quickly
Silicagel column is crossed, compound as white solid is obtained, is i.e. compound (9.0g, 82.05%) shown in formula (III -1).
Its1H-NMR spectrum as shown in Figure 1, mass spectrogram as shown in Fig. 2, hydrogen nuclear magnetic resonance modal data is as follows:
1H NMR(CDCl3) δ ppm:0.93 (2H), 1.16 (2H), 1.41 (3H, t, J=7.14Hz), 1.57 (3H, d, J=
6.86Hz), 4.35-4.40 (4H, m+q), 4.48 (2H, d, J=2.47Hz), 7.56 (1H, d, J=10.44Hz), 8.32 (1H,
s)。FTMS m/z:calcd for C18H19FN2O4[M+H]+347.14071,found 347.13983。
2, the fluoro- 3,7- dihydro -3- methyl-1 0- of (S) -9- (1- (((dimethylamino) methyl) amino) propyl) -7- oxygen
Generation -2H- [1,4] oxazines simultaneously [2,3,4-ij] QUINOLINE-6-CARBOXYLIC ACID ethyl ester (for a kind of specific shape of compound shown in above-mentioned formula (IV)
Formula, hereinafter referred to as formula (IV -1) compound) preparation
Compound (2g, 5.78mmol) shown in (III -1) is taken to be added to DMF-DMA (1.79g, 15.03mmol) and DMF
In the mixed liquor of (20mL), in N2Under protection, 110 degree heating reflux reaction 4 hours.After the reaction was completed, to reaction solution plus water
25mL is extracted with ethyl acetate (3 use acetic acid second L), merges organic phase, washed 1 time with saturated salt solution, then use anhydrous Na2SO4
Dry, evaporating solvent under reduced pressure obtains brown solid；Acetic acid second 15mL is finally used, is beaten, filtering obtains white solid, i.e. formula (IV -1)
Shown compound, (1.89g, 81.34%).Mass spectrogram is as shown in Figure 3:
FTMS m/z:calcd for C21H24FN3O4[M+H]+402.18291,found 402.18259。
3, the fluoro- 3,7- dihydro -3- methyl-1 0- of (S) -9- [1- methylamino cyclopropyl] -7- oxo -2H- [1,4] oxazines
And the preparation of [2,3,4-ij] QUINOLINE-6-CARBOXYLIC ACID hydrochloride (i.e. compound of formula I)
Methanol 15mL is added in modus ponens (IV -1) compound (900mg, 2.24mmol), is added Pd/C, Pd (OH)2/ C is each
40mg, in the double-deck H2Under ball sealing, heats 56 DEG C of degree and be stirred to react overnight.Reaction solution filtering, adds water 10mL, with DCM (dichloromethane
Alkane, 25mL) extraction, washing is primary, anhydrous Na2SO4Dry, evaporating solvent under reduced pressure obtains crude product 850mg compound IV, directly uses
Methanol (10mL) dilution is added the HCl (6mL) that concentration is 6N, flows back 10 hours, evaporating solvent under reduced pressure, crude product ethyl alcohol
(10mL) reflux, cooled and filtered obtain white solid, i.e. formula (I) compound (yield about 56.63%).
Its1H-NMR spectrum as shown in Figure 1, mass spectrogram as shown in Fig. 2, the hydrogen nuclear magnetic resonance modal data of product is as follows:
1H NMR(D2O) δ 8.87 (s, 1H), 7.62 (d, J=10.1Hz, 1H), 4.89 (m, 1H), 4.71 (dd, J=
11.9,2.4Hz, 1H), 4.59 (dd, J=11.9,2.6Hz, 1H), 2.75 (s, 3H), 1.65 (q, J=3.3,2.8Hz, 2H),
1.60 (d, J=6.8Hz, 3H), 1.51-1.40 (m, 2H)；
FTMS m/z:calcd for C17H17FN2O4[M+H]+333.12506,found 333.12506。
It can be seen that preparation method through the invention, has successfully been made formula (I) compound.
Above-described is only some embodiments of the present invention.For those of ordinary skill in the art, not
Under the premise of being detached from the invention design, various modifications and improvements can be made, these belong to protection model of the invention
It encloses.
Claims (7)
1. a kind of preparation method of Carbostyril carboxylic acid derivatives, characterized in that it comprises the following steps:
(1) in acid condition, using compound shown in formula (II) as raw material, containing C1~C6Single methanol solvent in be esterified it is anti-
It answers, obtains compound shown in formula (III)；
(2) DMF-DMA reductive amination process and hydrolysis are applied
(a) in neutral conditions, compound shown in formula (III) and DMF-DMA are carried out to the aldimine condensation of amino in organic solvent
Reaction, obtains compound shown in formula (IV)；
(b) compound shown in formula (IV) and Pt/C, Pt (OH)2/ C or Raney's nickel reducing agent carry out reduction amination in organic solvent
Reaction, obtains compound shown in formula (V)；
(c) compound shown in formula (V), which is dissolved in organic solvent heating in acid condition, is hydrolyzed reaction, obtains formula (I) institute
Show compound；
Wherein, the R in above-mentioned formula (III)~(V)3For C1~C6Alkyl；
Shown in the structural formula of the Carbostyril carboxylic acid derivatives such as formula (I):
2. the preparation method of Carbostyril carboxylic acid derivatives according to claim 1, which is characterized in that the formula (III)~
(V) R in3For methyl or ethyl.
3. the preparation method of Carbostyril carboxylic acid derivatives according to claim 1, which is characterized in that described in step (1)
Single methanol solvent be methanol, ethyl alcohol, propyl alcohol, butanol or the tert-butyl alcohol.
4. the preparation method of Carbostyril carboxylic acid derivatives according to claim 1, which is characterized in that described in step (1)
Acid condition by using sulfuric acid, hydrochloric acid, thionyl chloride, chloracetyl, p-methyl benzenesulfonic acid acid flux material or sodium bisulfate acid
Property inorganic salts obtain.
5. the preparation method of Carbostyril carboxylic acid derivatives according to claim 1, which is characterized in that (a) in step (2)
The organic solvent refers to DMF or CH3OH。
6. the preparation method of Carbostyril carboxylic acid derivatives according to claim 1, which is characterized in that (b) in step (2)
(c) organic solvent described in refers to methanol, ethyl alcohol, propyl alcohol, butanol or the tert-butyl alcohol.
7. the preparation method of Carbostyril carboxylic acid derivatives according to claim 1, which is characterized in that (c) in step (2)
The acid condition is obtained by using the concentrated sulfuric acid, concentrated hydrochloric acid or p-methyl benzenesulfonic acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1858052A (en) * | 2005-05-08 | 2006-11-08 | 中国科学院上海药物研究所 | Quinolone carboxylate compounds and their preparing method and use |
| CN104211682A (en) * | 2013-06-04 | 2014-12-17 | 沈阳药科大学 | pyridine compounds and applications thereof |
| US20160318913A1 (en) * | 2013-09-22 | 2016-11-03 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
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2017
- 2017-02-09 CN CN201710071381.6A patent/CN107056810B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1858052A (en) * | 2005-05-08 | 2006-11-08 | 中国科学院上海药物研究所 | Quinolone carboxylate compounds and their preparing method and use |
| CN104211682A (en) * | 2013-06-04 | 2014-12-17 | 沈阳药科大学 | pyridine compounds and applications thereof |
| US20160318913A1 (en) * | 2013-09-22 | 2016-11-03 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
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