CN85100796A - The preparation method of qualone derivative - Google Patents
The preparation method of qualone derivative Download PDFInfo
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- CN85100796A CN85100796A CN 85100796 CN85100796A CN85100796A CN 85100796 A CN85100796 A CN 85100796A CN 85100796 CN85100796 CN 85100796 CN 85100796 A CN85100796 A CN 85100796A CN 85100796 A CN85100796 A CN 85100796A
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- chemical formula
- quinolinone
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- SIQJISDIOKAGBS-UHFFFAOYSA-N COc1ccc(C=C(CC2)I)c2n1 Chemical compound COc1ccc(C=C(CC2)I)c2n1 SIQJISDIOKAGBS-UHFFFAOYSA-N 0.000 description 1
- DAPDFTQLJHLWBI-UHFFFAOYSA-N Cc(cc1)cc2c1nc(C=O)cc2 Chemical compound Cc(cc1)cc2c1nc(C=O)cc2 DAPDFTQLJHLWBI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The method for making of the medical salt that a kind of qualone derivative of manufacturing chemistry formula I or its can be accepted, wherein " Het ", R, R
1, R
2, Y as
Specification sheets, defined in the claim.
This derivative is used for treatment or the preventive treatment that the heart symptom has a weak heart.
Description
The present invention is the relevant quinolinone cardiostimulator that is substituted, and it can optionally increase myocardial contraction usually under the situation that does not increase heart speed, and these compounds can be used for treatment or the preventive treatment that heart trouble especially has a weak heart.
The present invention has the compound of chemical formula I
And the salt that pharmaceutically can be accepted, wherein " Het " is for being connected to the 5-of this quinolinone arbitrarily, 6-, 7-, or the 5-that is substituted of 8-position or 6-unit monocycle aromaticity heterocyclic radical with carbon atom; R is connected to 5-, 6-, and 7-or 8-position are oxygen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, C
1-C
4Alkyl sulfinyl, C
1-C
4Alkylsulfonyl, halogen, CF
3, hydroxyl, methylol, or cyano group; R
1Be hydrogen, cyano group, (C
1-C
4) alcoxyl, carbonyl, C
1-C
4Alkyl, nitro, halogen ,-NR
3R
4Or CONR
3R
4, R wherein
3And R
4Be respectively H or C
1-C
4Alkyl, or and nitrogen be connected together and form a saturated 5-or 6-unit heterocycle, it contains one and is selected from O, S and N-R
5(R
5Be hydrogen or C
1-C
4Alkyl) heteroatoms or base; R
2Be hydrogen, C
1-C
4Alkyl or 2-hydroxyethyl; Y is H or C
1-C
4Alkyl; The dotted line of 3-and 4-interdigit is represented can be or be non-is a key.
Especially R is a hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, C
1-C
4Alkyl sulfinyl, C
1-C
4The alkane alkylsulfonyl, halogen; CF
3Or hydroxyl; And Y is H.
Moreover the present invention also provides the intermediate with chemical formula II of the compound of chemical formula I:
Het wherein, R, R
1, the definition of Y and dotted line such as chemical formula I.
The present invention's particular orientation is that " Het " is for being connected to the 5-of this quinolinone arbitrarily, 6-, the 5-that is substituted of 7-or 8-position or 6-monocycle aromaticity nitrogen heterocyclic ring with carbon atom; R is connected to 5-6-, and 7-or 8-position are hydrogen, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; R
1Be hydrogen, cyano group, (C
1-C
4Alkyl) carbonyl, C
1-C
4Alkyl ,-NR
3R
4Or-CONR
3R
4, R wherein
3And R
4Be respectively H or C
1-C
4Alkyl, or and nitrogen be connected together and form a saturated 5-or a 6-unit heterocyclic radical, it optionally can contain one and be selected from O, S and N-R
5(R
5Be hydrogen or C
1-C
4Alkyl) heteroatoms or base; R
2Be hydrogen, C
1-C
4Alkyl or 2-hydroxyethyl; Y is H; And the dotted line of 3-and 4-interdigit to represent to become or be non-be a key.
The example that is somebody's turn to do " Het " base comprises: pyridyl, and pyrazinyl, pyrimidyl, imidazolyl, pyrazolyl,
The azoles base, different
The azoles base, thiazolyl, isothiazolyl, triazol radical, furyl, thienyl, ribavirin base, and when nitrogenous, its N-oxide compound, all wherein replace base system and are selected from arbitrarily by 1 or 2 substituents: C for example
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, cyano group, CF
3, halogen ,-NR
3R
4Or-CONR
3R
4, R wherein
3And R
4Definition such as chemical formula I, methylol and (C
1-C
4Alcoxyl) carbonyl.
Preferable N-oxide compound is pyridyl-N-oxide compound.
" halogen " means F, Cl, Br and I, C
3And C
4Alkyl and alkoxyl group can be straight or branched.
R
3And R
4Be connected together with nitrogen-atoms and when forming the saturated 5-of what is called or 6-unit heterocyclic radical, the example of this heterocyclic radical is the 1-pyridyl, piperidyl, morpholino base and 4-methylpiperazine base.
Though the compound of chemical formula I is designated as 2-(1H)-quinolinone, can recognize, work as R
2During for H, the different phenomenon of following change will take place:
Keto-acid is than stable change allosome, its last product is named and is joined and is quinolinone, all understand two kinds of tautomers and all exist and know this skill personage, even some specilization compound, preferable with existing of hydroxyl tautomer, but following announcement all merges the change abnormity formula of all to prove it.
Preferable compound, " Het " be with pyridyl, its N-oxide compound, pyrimidyl, pyrrole
Base, imidazolyl, triazol radical, the tetrazole base, phonetic azoles base, careless di azoly, thienyl or furyl, all are arbitrarily through being selected from C
1-C
4Alkyl, C
1-C
4Alkoxyl group, cyano group, 1 or 2 substituting group substituents of amido and amido formyl radical are preferable.
Better person: " Het " is selected from (a) by 1 or 2 methyl substituted, or quilt-single methoxyl group, cyano group, and the pyridyl of amino or the replacement of amido formyl radical, (b) pyridyl-N-oxide compound, (c) pyrimidine (d) is rattled away
Base, (e) pyrrole
Base, (f) triazol radical or N-methyl triazol radical, (g) tetrazole base or N-(just-butyl)-the tetrazole base, (h) N-methylimidazolyl, (i) oxygen ribavirin base, (j) thiazolyl, (k) thienyl, and (l) furyl.
Better person, " Het " they are pyridin-3-yl, pyridin-4-yl, and 2-, 6-lutidine-3-base, or the 1-methyl-(1H)-1,2,4-triazole-5-base.
" Het " being connected on 5-, 6-, the 7-position is preferable, with the 6-position for better.
R is with H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, C
1-C
4Alkyl sulfinyl, C
1-C
4The alkane alkylsulfonyl, halogen, hydroxyl, or methylol is preferable; With H, C
1-C
4Alkyl, methoxyl group, methylthio group, methylsulfinyl, methyl sulphonyl, bromo, hydroxyl and methylol are for more basic.
When R is substituting group, being preferable at 7-or 8-position, being preferable in the 8-position, with in the 8-position for better, the 8-methyl is especially better.
R
1With H, cyano group, C
1-C
4Carbalkoxy, nitro, halogen or amido are preferable, with H, cyano group, methoxycarbonyl, nitro, halogen or amido are preferable; With H is best.
R
2With H or CH
3For preferable, be best with H.
Y is with H or CH
3For preferable, be best with H.
The 3-of quinolinone and 4-interdigit are preferable with two keys.
Preferable compound is for having structure (I A) person:
Wherein Het and R definition is the same, and " Het " with 2,6-lutidine-3-base or 1-methyl-(1H)-1,2,4-triazole-5-base is preferable, and R is preferable with methyl.
The pharmaceutically acceptable salt of chemistry formula I compound is a nontoxicity, comprising: acid salt, and such as hydrocyanide, hydrobromide, hydriodide, vitriol or hydrosulfate, phosphoric acid salt or hydrophosphate, acetate, maleate, fumarate, lactic acid salt, tartrate, Citrate trianion, gluconate, mesylate, and right-toluene phosphoric acid salt, comprise metal-salt, especially acid metal salt and alkaline earth salt, particularly sodium salt or sylvite.
The heart of chemistry formula I compound is excited active, the validity of available following one or more test shows it: (a) record the increase of " Starling " dog heart one lung calligraphy or painting model convergent force via left cardic catheter, (b) record the increase of the cardiac contractility ability (the dp/dt max of left ventricle) through the dog of anesthesia via left cardic catheter.(c) implant left ventricle electric power forwarder (dp/dt max) or the dog of the carotid artery coil (systolic time interval) specialized, the increase of its cardiac contractility ability.
In the test (a), after pill was handled, the experiment with measuring compound was to the positive contractive effect of the heart one lung preparation of " Starling " dog, and the compound convergent force that can test increases the selectivity to frequency.
In the test (b), the experiment with measuring compound can get test compound to the size of this effect and firmly lasting to the positive contractive effect through the dog of anesthesia after intravascular injection, and the convergent force increase reaches end effect slightly to the selectivity of frequency, for example to the effect of blood vessel.
In the test (c), after intravascular injection, measure and implant left ventricle electric power forwarder (dp/dt max), or the positive contractive effect of the dog of the carotid artery coil of specializing (systolic time interval), can get the size of test compound contraction, convergent force increases the selectivity to frequency, and the lasting effect of contraction.
Chemistry formula I compound can use separately, but common and plan medication and the selected medical supporting agent mixed reagent of standard medicine practice for example in the oral medication of lozenge form, contain vehicle, as starch and lactose; Or in the capsule, can use separately, or and mixed with excipients; Or in elixir or suspension agent form, containing seasoning or colouration agent, it also can be injected outward in order to intestines, for example intravenous injection, intramuscular injection, or subcutaneous injection.In injection, preferably with the form of aseptic aqueous solution, it also can contain other solutes, and for example the salt of capacity or glucose make solution equivalent.
In heart trouble, during such as congested treatment that has a weak heart and preventive treatment, during to the human body medication, the oral dosage of The compounds of this invention is: to become for each person consumption (70kg) 10mg to 1g every day that is as the criterion, every day 2 to 4 times.Intravenous injection dosage is: in case of necessity, for example weak treatment of acute cardiac, every single dose is 1 to 100mg, typical case's adult patient, lozenge out of the ordinary or capsule contain 5 to 100mg active compound, are equipped with vehicle or supporting agent that medicine can be accepted.Can be changed consumption according to medical practice by the situation and the body weight of treatment body.
The present invention also provides a kind of medical component, comprises the compound of the above-mentioned chemical formula I that defines or the salt that its medicine can be accepted, and cooperates pharmaceutically acceptable thinner and supporting agent.
The present invention also provides a kind of stimulation animal, comprises the method for the mankind's heart.Comprise: to the compound or its salt class of animal with the capacity chemistry formula I that is enough to stimulate animal hearts, or the medical component of above-mentioned definition.
The present invention further provides a kind of compound of chemical formula I, or the salt that can accept of its medicine, to be used for medicine, be particularly useful for the heart of the congested heart that has a weak heart.
The present invention's compound can several methods be made it, comprises following method:
Method A
This law is in order to make R
2Compound (I) for H is described as follows:
R wherein, R
1Y, dotted line and " Het " definition as chemical formula I, demethylation is with in inorganic acid aqueous solution, with HCl or HBr is that the aqueous solution is preferable, and typically in the 48%HBr or the 5MHCl aqueous solution, heating methoxy yl-quinoline (II) is to refluxing concentration 0.5-4 hour, or in the ethanol of the 48%HBr solution that contains catalytic amount (being generally the volume of 5-15%), be heated to reflux temperature, be preferable with what carry out.Products therefrom can with traditional method single from and purifying it.
Use the type reaction of the 48%HBr aqueous solution to be described as follows:
The type reaction of ethanol that use contains the 48%HBr of catalytic amount is described as follows:
This method can replace 48%HBr with the 5MHCl aqueous solution, carries out it under the same terms, uses the type reaction of 5MHCl to be described as follows:
Under these situations, R
1For alkoxy carbonyl (for example-COOCH
3), go basicization can transform this base one-tenth-COOH, under these situations, but this carbonyl resterification traditionally for example uses methyl alcohol in sulfuric acid.
But the method for the raw material mat tradition of chemistry formula II is made it again, the typical manufacture method of these materials, and details are as follows:
Wherein Q is from base, such as C
1-C
4Alkoxyl group is preferable with methoxy or ethoxy.
This reaction relates to the cyclisation of acrylamide derivative, and typical case is a 3-ethoxy propylene acid amides, and it is to use dense (typical case is 98%) sulfuric acid.This reaction typically in stirring at room reactant 8-48 hour carrying out it, product can with traditional method separate and purifying it.
Type reaction is as follows:
Its raw material is known person, or available prior art method narrow the person.
Method C:
Present method is described as follows with general type:
Wherein Q is suitable to base, for example Cl, Br or I.It relates to the new cyclophane perfume base of chlorination zinc, accompanies by four (triphenyl phosphorus) palladium (O) catalysis, to replace from base.This reaction typically in organic solvent for example among the THF mat reacting by heating thing to reflux temperature to carry out it.
Typical case's reaction is as follows:
Also can use the new cyclophane perfume base of chlorination magnesium to replace zinc chloride, and use other suitable transition-metal catalysts (for example Ni-based).
Raw material or be known compound, or available traditional method winner, the new cyclic group zinc of chlorination lies among the THF, under-70 to-100 ℃, tributyl lithium reaction with suitable halogenation heterocycle and 2 equivalents gets the lithium derivative, and the solution of the sum that continues Zinc Chloride Anhydrous reacts in THF.This chlorination heterocycle zinc also can be reacted in THF by the solution of suitable Grignard reagent and zinc chloride and make.The end product of being desired typically can be heated to room temperature by its reaction mixture.Add suitable halogenated quinoline ketone and four (triphenyl phosphorus) palladium (O) again in THF, then reflux was generally 1 to 48 hour to reacting completely, but its product prior art method reclaims and purifying it.
The raw material of this method can be made by traditional method, and the typical method for making of these materials is as follows:
Method D:
This law is described as follows:
This reaction relates to the reduction of nitro, is preferable with the dihydrate with tin protochloride in ethanol, and this reacted typically the reacting by heating thing to reflux temperature 1-8 hour.
Type reaction is as follows:
Method E:
R
1Be Cl, Br, or the chemical formula I compound of I also can be with R
1For the compound of H with the traditional method halogenation to make, type reaction is as follows:
Method F:
" Het " is the chemical formula I compound of N-oxide compound, can make it by suitable former nitrogen heterocyclic ring oxidation, generally uses the peroxy acid oxygenant, such as a chlorine perbenzoic acid, or peroxy acid, and in the down manufacturing of general reaction conditions.Type reaction is as follows:
Method G:
R
2Be C
1-C
4The chemical formula I compound of alkyl or 2-hydroxyethyl also can be by with R
2For suitable compound N-alkanisation of H makes it, typical method is: quinolinone and sodium hydride or the reaction of other highly basic so that N-does not replace, form negatively charged ion, and the sum that continues is C for example
1-C
4Alkyl halide, two (C
1-C
4Alkyl) vitriol, or 2-hydroxyethyl nitride, reaction in a conventional manner, type reaction is as follows:
Method H:
This law general fashion is as follows:
This reaction is involved in suitable catalyzer, for example under the transition-metal catalyst, and with 3, the two ingot catalytic hydrogenations of 4-, this reaction is generally in ethanol, under the hydrogen of 25-100 ℃ and 15-5000psi.10% under the active alkali of palladiumization, raw material was heated 1-7 days.
Type reaction is as follows:
Method I:
Present method general type is as follows:
（X＝Cl，Br or I）
This reaction relates to raw material 3, the 8-position of 4-dihydro-quinolinone, and in dense (is preferable with 98%) sulfuric acid, the electrophilic halogenating reaction under Sulfuric acid disilver salt exists (X=Cl, Br, I).This reaction was carried out under 0-70 ° 1-16 hour usually, product can with the traditional method purifying it.
Type reaction is as follows:
Method J:
This law general type is as follows:
This reaction relates to the 3-position bromination with raw material, the bromination reaction of dehydrogenation again that continues, producing 3, the two keys of 4-, this reaction generally in acetic acid, with raw material 3,4-dihydro-quinolinone and bromine and sodium-acetate-through being heated to 25-120 ℃, 1-2 hour.
Product can with the prior art method purifying it.
Type reaction is as follows:
Method K:
Present method general type is as follows:
R wherein
6Be C
1-C
4Alkyl, and Q
1For from base.
This reaction relates to C
1-C
4Alkanethiol metal-salt (for example an alkali metal salt) is in the presence of copper (I) metal, to from basic Q
1(F for example, Cl, Br, nucleophilic substitution reaction I).Generally in high boiling organic solvent, in N-Methyl pyrrolidone, use sodium salt, be heated to reflux temperature (for example 160 ℃ (about 0.5-48 hour.Product can with traditional method single from and purifying.
Type reaction is as follows:
Method L:
Form is as follows as one of present method:
R wherein
6Be C
1-C
4Alkyl.
Reaction relates to the suitable oxidizing thing, such as organic peroxide acid or sodium metaperiodate, the sulfide partial oxygen is changed into suitable sulfoxide or sulfone class.Generally in organic solvent, in methylene dichloride, reaction is 1-24 hour between-70 ° to+30 °.
Type reaction is as follows:
Method M:
Present method general type is as follows:
R wherein
6Be C
1-C
4Alkyl.
Demethylation is preferable with in inorganic acid aqueous solution with 48%HBr, and with the heating of alkoxyl group quinoline, or with other piptonychia bases, such as boron tribromide or the processing of hydrogenchloride pyridine is preferable.
Type reaction is as follows:
Method N:
Present method general type is as follows:
This reaction relates to derive from C
1-C
4The lithium of lithium alkylide displacement halogen atom " X " (X=Cl, Br or I) continues it, with chloric acid formaldehyde (for example getting) by the paraformaldehyde distillation with the quenching of gained organo-metallic thing it.This reaction is in suitable organic solvent (for example tetrahydrofuran (THF)) generally, carries out it under-75 ° to 0 ℃.Work as R
2Be hydrogen, should use the C of 2 equivalents at least
1-C
4Lithium alkylide.Preferable lithium alkylide is being for just, butyllithium.
Typical case's reaction is as follows:
The salt of chemistry formula I compound can be made by complete traditional method, for example: with the suitable acid-respons in free alkali in the organic solvent and the organic acid, form acid salt, or with free alkali and suitable acid, the for example oxyhydroxide of basic metal or alkaline-earth metal (is preferable with aqueous sodium hydroxide solution) reaction forms pharmaceutically acceptable metal-salt.
The present invention's compound contains one or more asymmetric center, therefore the present invention includes enantiomer and diastereoisomer through separation, or its mixture, and its form through separation can obtain it by traditional method.
The following example is in order to the preparation of explanation compound (I).(concentration of all is 0 ℃):
Embodiment 1
The 6-(3-pyridyl)-2-(1H)-preparation of quinolinone
With 2-methoxyl group-6-(3-pyridyl) quinoline (1.83 gram) is dissolved in the HBr aqueous solution (6cm
3) stirred solution be heated to 100 °, about 1.5 hours, then in ice bath, cool off, being adjusted to pH with the NaOH solution of 5M is 8, with chloroform continuous extraction 6 hours, will be through (MgSO
4) the organic collection thing evaporation of drying, solid, with methyl alcohol-vinyl acetic monomer again through crystalline substance, the 6-(3-pyridyl)-2-(1H)-quinolinone, m.p.217-218 ° (0.62 gram).
Analyze (%):
Actual value: C, 75.9H4.8N12.2
By C
14H
12N
2The value of O calculating: C, 75.7H4.5N12.6
Embodiment 2-11:
Following compounds system by suitable 6-be substituted-2-methoxy quinoline and 48%HBr begin, with the similar method person of making of embodiment 1.
Embodiment 12 and 13
Following compounds can be by suitable 3, and 6-two is substituted-2 methoxy quinoline, with the method similar with embodiment 1, but replaces 48%HBr with the HCl of 5M, to make it.
Embodiment 14
3-methoxycarbonyl-6-(3-pyridyl)-2-(1H)-quinolinone hemihydrate
With 2-methoxyl group-3-methoxycarbonyl-6-(3-pyridyl)-quinoline (0.50 gram) is dissolved in 5MHCl(30cm
3) solution, in the heating down 20 minutes that refluxes, will be through the mixture filtration of cooling, with the methanol wash solid, thick intermediate 6-(3-pyridyl)-the hydrogen villaumite of 2-(1H)-quinolinone-3-carboxylic acid, m.p. is 350-352 °, (0.45 gram) inserts methyl alcohol (50cm with this material
3) in, in refluxing down and vinegar sulfuric acid (1cm
3) heated together 1 hour, with the mixture vacuum concentration, with remnant in chloroform (100cm
3) and sodium bicarbonate aqueous solution between distribute it, with chloroform (3 * 25cm
3) further aqueous phase extracted, organic extract is added together (the MgSO of drying
4), evaporate 3-methoxycarbonyl-6-(3-pyridyl)-2-(1H)-quinolinone semihydrate, m.p. is 223-225 °, (0.32 gram).
Analyze %:
Actual value: C, 66.9; H, 4.3; N, 9.4.
C
16H
12N
2O
3, 0.5H
2The calculated value of O.
C，66.5;H，4.5;N，9.7。
Embodiment 15
With 2-methoxyl group-3-methoxycarbonyl-6-(4-pyridyl) quinoline is raw material, the similar method of former embodiment makes 3-methoxycarbonyl-6-(4-pyridyl)-2-(1H)-quinolinone semihydrate, m.p.246-248 °.
Analyze %:
Actual value: C, 66.7; H, 4.2; N, 9.4.
C
16H
12N
2O
3, 1/2H
2The O calculated value:
C，66.4;H，4.5;N，9.7。
Embodiment 16:
8-methyl-6-(3-pyridyl)-2-(1H)-preparation of quinolinone
With 2-methyl-8-methyl-6-(3-pyridyl)-quinoline (1.07 gram) is dissolved in 5MHCl(10cm
3) stir solution liquid, in the heating down 2.5 hours that refluxes, and postcooling it, with the NaOH aqueous solution of 2M will alkalize through the solution of cooling to pH be 9, with chloroform: methyl alcohol is 9: 1(4 * 100cm
3) ratio extract it, will add together and dry (MgSO
4) the extraction liquid vacuum concentration of back, solid.With vinyl acetic monomer-methyl alcohol recrystallize it, 8-methyl-6-(3-pyridyl)-2-(1H)-quinolinone, m.p.235.5-236.5 °, (0.63 gram).
Analyze %:
Actual value: C, 76.0; H, 5.1; N, 11.6
C
15H
12N
2The calculated value of O:
C，76.2;H，5.1;N，11.9
Embodiment 17-56:
With the similar method of embodiment 16, be substituted 2 methoxy quinoline and in the 48%HBr aqueous solution (embodiment 37,42,46 and 51) in ethanol of physique 10% by suitable, or the HCl aqueous solution of 5M (other embodiment) preparation following compounds.
Among the embodiment 43, raw material is 2-methoxyl group-6-(1-tributyltin base tetrazole-5-yl) quinoline, this tributyltin base can be removed under the acid-reaction condition.
Among the embodiment 37, partly-CN is hydrolyzed into-CONH
2, the gained mixture can be used the stratography analysis on silica gel, and with chloroform: methyl alcohol: ammoniacal liquor (S.G.0.880) is that 94: 5: 1 volume ratio person dashes and carries to separate it.Amido methylthiolation compound is seen embodiment 51.
Embodiment 57
With the similar method of embodiment 16, with 6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-methoxyl group-4,8-dimethyl quinoline and 5MHCl are raw material, make 6-(1-methyl isophthalic acid, 2,4-triazole-5-yl), 4, and the 8-dimethyl-2-(1H)-quinolinone 0.75H
2O, m.p. are 327 °.
Analyze %:
Actual value: C, 62.8; H, 5.3; N, 20.6.
C
14H
14N
4O, 0.75H
2The O calculated value:
C，62.8;H，5.8;N，20.9。
Embodiment 58
8-methyl-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone, 3H
2The preparation of O sodium salt
With 8-methyl-6-(2,6-lutidine-3-yl)-2-(1H) quinolinone (94.7 gram) and 5MNaOH solution (379cm
3) sized mixing 4 hours, solid filtering is extremely washed (380cm
3), add Virahol (600cm
3), steam the material that falls to volatilize, solid, molten in the methyl alcohol (1620cm of boiling
3) in, hot solution is filtered vacuum concentration (270cm
3), be cooled to 0 °, with sedimentation and filtration,, get title compound, m.p.＞220 ° (decomposition) (60.4 gram) in 50 ° of vacuum-dryings.
Analyze %:
Actual value: C, 59.8; H, 5.5; N, 7.9.
C
17H
15N
2ONa, 3H
2The O calculated value:
C，60.0;H，6.2;N，8.2。
Embodiment 59
8-methylol-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone, 0.1H
2The preparation of O
In-70 °, with the solution (1.04cm of n-Butyl Lithium
3Be dissolved in the 1.6M solution of normal hexane), under nitrogen, add to 8-bromo-6-(2,6-dimethyl-pyridin-3-yl)-2-(1H)-quinolinone (0.25 gram) and be dissolved in 20cm
3In the stirred solution of THF.After 2 hours gaseous formaldehyde (rising accurate the generation by paraformaldehyde (0.3 gram)) is entered in the solution, further stirred 10 minutes, mixture heating up to room temperature, is added saturated NH
4Cl solution (10cm
3), then with chloroform (3 * 50cm
3) the extraction mixture, will add together and drying (MgSO
4) organic extract liquid evaporation, go up with methylene dichloride in silica gel (it " MK 60.9385 " trade(brand)name of Merck): methyl alcohol be dash at 19: 1 carry with chromatographic analysis it, suitably part adds together and evaporates it, get 3-methylol-6-(2,6-lutidine-3-yl)-2-(1H)-and quinolinone, 0.1H
2O, m.p. are 218.5-221 ℃ (0.094 gram).
Analyze %:
Actual value: C, 72.1; H, 5.8; N, 9.9.
C
17H
16N
2O
2, 0.1H
2The O calculated value:
C，72.4;H，5.7;N，9.9。
Embodiment 60
The 6-(3-pyridyl)-2-(1H)-preparation of quinolinone
In 98%H
2SO
4(4.0cm
3) in stir sulphur-3-(4-(3-ethoxy acryl) phenyl) pyridine (1.43 gram) 16 hours, mixture is added ice (50g), gained solution with 2.5M NaOH solution alkalize to pH be 8, with chloroform: methyl alcohol is 9: 1(10 * 100cm
3) person extracts mixture.To add together and drying (MgSO
4) the extract vacuum concentration, solid, with the Virahol recrystallize it, the 6-(3-pyridyl)-2-(1H)-quinolinone, m.p.228-230 ° (0.39 gram).
Analyze %:
Actual value: C, 75.3; H, 4.5; N, 12.5
C
14H
12N
2The O calculated value:
C，75.7;H，4.5;N，12.6
Embodiment 61
6-(2-pyridinyl methoxy-5-yl)-2-(1H)-preparation of quinolinone
5-bromo-2-pyridinyl methoxy (1.50 gram) is dissolved in tetrahydrofuran (THF) (THF) (10cm
3) solution, in-70 ° in nitrogen, in adding tributyl lithium (8.0cm
3The 2.0M solution that is dissolved in pentane) during stir it, add Zinc Chloride Anhydrous (1.09 gram) after 10 minutes and be dissolved in THF(10cm
3) solution, with the mixture temperature to room temperature 1 hour.Add 6-bromo-2-(1H)-quinolinone (0.813 gram) and four (triphen phosphorus) palladiums (O) (0.03 restrains) are in THF(10cm
3) suspension, reflux and heated 3 hours, with saturated NH
4Cl solution (1cm
3) add the mixture through cooling, the water-soluble solution of the adding ethylene Calcium Disodium Versenate salt that continues (6.0 restrain).Add chloroform (100cm
3) and methyl alcohol (30cm
3), mixture is heated to all solids material dissolution, be divided into two-phase, with 9: 1 chloroform: methyl alcohol (3 * 50cm
3) aqueous phase extracted.To add also dry together (MgSO
4) the extraction liquid vacuum concentration, solid, get 6-(2-pyridinyl methoxy-5-yl with the Virahol recrystallize)-2-(1H)-quinolinone, m.p.248-252 °, (0.56 gram).
Analyze %:
Actual value: C, 71.4; H, 4.9; N, 11.2
C
15H
12N
2O
2Calculated value:
C，71.4;H，4.8;N，11.1
Embodiment 62-72:
With the similar method of previous embodiment, by suitable 6-bromo-that is substituted or 6-bromo-2-(1H)-quinolinone and suitable chlorination heterocyclic aryl zinc, and be catalyzer with four (triphen phosphorus) palladiums (O), with the preparation following compounds.
Among the embodiment 69-72, chlorination 2,6-lutidine-3-base zinc thing is by suitable magnesium Grignard reagent (it is a known compound) but not made by the derivative of suitable lithium.
The method that embodiment 61 is similar, by 6-bromo-3, the 4-dihydro-2-(1H)-quinolinone, or 6-bromo-4-methyl-3, the 4-dihydro-2-(1H)-quinolinone, and suitable pyridinium chloride base zinc is raw material, with four (triphenyl phosphorus) palladium (O) is catalyzer, with the preparation following compounds.
Embodiment 76:
3-amido-6-(3-pyridyl)-2-(1H)-preparation of quinolinone 2/3 hydrate
Stannous chloride dihydrate (1.27 gram) is added on 3-nitro-6-(3-pyridyl)-2-(1H)-quinolinone (0.30 gram) is dissolved in ethanol (10cm
3) in the solution of stirring, with mixture reflux 1.5 hours, cool off it again.To distribute chloroform (100cm through the mixture of cooling
3) and Na
2CO
3The aqueous solution (50cm
3) between, filtering mixt, and separate each layer is with 9: 1 chloroform: methyl alcohol (2 * 50cm
3) further aqueous phase extracted.To add the also dry together (MgSO of mistake
4) the extraction liquid vacuum concentration.Get solid, make powdered, filter and drying, get 0.093 and restrain 3-amido-6-(3-pyridyl with hot Virahol)-2-(1H)-and quinolinone, 0.66H
2O, m.p. are 298-300 ° (decomposition).
Analyze %:
Actual value: C, 67.8; H, 4.7; N, 16.8.
C
14H
11N
3O, 0.66H
2The O calculated value:
C，67.5;H，4.9;N，16.9。
Embodiment 77
3-bromo-6-(3-pyridyl)-2-(1H)-preparation of quinolinone
With the 6-(3-pyridyl)-2-(1H)-and quinolinone list hydrochloride (0.50 gram), bromine (3.2 gram), acetic acid (10cm
3) and the mixture of three ethyleneamineses (0.195 gram), reflux 24 hours, and postcooling it.Add ether (20cm
3), with reaction mixture, the yellow solid of gained is filtered, with preparation with gluey chromatographic analysis purifying it.Chloroform with 15: 1: methyl alcohol (dash and carry 4 times) dashes carries it, gets 3-bromo-6-(3-pyridone)-2-(1H)-and quinolinone, m.p. is 297-300 °, (0.11 gram)
Analyze %:
Actual value: C, 55.7; H, 3.1; N, 9.2
C
14H
9N
2The OBr calculated value:
C，55.8;H，3.0;N，9.3
Embodiment 78:
6-(1-oxy picolinate-3-yl)-2-(1H)-quinolinone 1/4 hydrate
To be added on the 6-(3-pyridyl to a chlorine perbenzoic acid (3.74 gram))-2-(1H)-the molten chloroform (50cm of quinolinone (1.49 gram)
3) and methyl alcohol (50cm
3) stirred solution in, after 16 hours, add the NaOH(0.90 gram) water-soluble (5cm
3) solution, add silica gel (Merck produces, trade(brand)name " MK 60.9385 ", 30 grams) again, to doing, the gained powder places silica gel tubing string (Merck " Mk 60.9385 ") top with mixture vacuum-evaporation, with 9: 1 chloroform: methyl alcohol dashed and carries.To contain partly adding together and evaporation of product, get solid.With the Virahol recrystallize it, 6-(1-oxy picolinate-3-yl)-2-(1H)-quinolinone, 0.25H
2O, m.p.280 ° (decomposition), (0.44 gram).
Analyze %:
Actual value: C, 60.4; H, 4.4; N, 11.3
C
14H
10N
2O
2, 0.25H
2The O calculated value:
C，69.3;H，4.4;N，11.5
Embodiment 79:
With 8-methyl-6-(3-pyridyl)-2-(1H)-quinolinone is a raw material, utilizes the similar method of previous embodiment to prepare 8-methyl-6-(1-oxy picolinate-3-yl)-2-(1H)-and quinolinone, 0.35H
2O, m.p.290 ° (decomposition).
Analyze %:
Actual value: C, 69.3; H, 4.8; N, 10.6
C
15H
12N
2O, 0.35H
2The O calculated value:
C，69.7;H，4.9;N，10.8
Embodiment 80
1-methyl-6-(3-pyridyl)-2-(1H)-quinolinone 1/4 hydrate
50% oily dispersion liquid with the NaH(0.012 gram), at room temperature handle the 6-(3-pyridyl)-2-(1H)-quinolinone (0.05 gram) is dissolved in DMF(0.5cm
3) stirred solution 1 hour.With dimethyl sulfate (0.016 gram) in DMF(0.2cm
3) solution add.Stirred the mixture 1.5 hours.With the mixture vacuum concentration.Add water (5cm
3) with vinyl acetic monomer (3 * 10cm
3) the extraction mixture, add organic extract drying (MgSO together
4), vacuum concentration, in silica gel (Merck they " MK 60.9385 ") go up chromatographic analysis it, dash with chloroform and to carry it, solid, make powdered with ether, 1-methyl-6-(3-pyridyl)-2-(1H)-quinolinone 0.25H
2O, m.p. are 116-118 ° (0.02 gram).
Analyze %:
Actual value: C, 75.2; H, 5.3; N, 11.6
C
15H
12N
2O, 0.25H
2The O calculated value:
C，74.8;H，5.2;N，11.6
Embodiment 81:
8-methyl-6-(2,6-lutidine-3-yl)-3, the 4-dihydro-2-(1H)-quinolinone
In 60 ° and 60psi(4.13 * 10
5Crust) pressure, and in the activated carbon of 10% palladiumization (0.01 gram), with 8-methyl-6-(2,6-lutidine-3-yl)-2-(1H) the solution hydrogenation of quinoline (0.30 gram), then will be by " Solkafloc ") trade(brand)name of the filtration adjuvant of cellulose base), will filter through the solution of cooling.Vacuum-evaporation is to doing, remnant in silica gel (Merck they " MK 60.9385 ") go up chromatographic analysis it, with 49: 1 chloroform: methyl alcohol dashed and carries it.Suitably part add together to evaporation, solid, with vinyl acetic monomer/methyl alcohol recrystallize it, 8-methyl-6-(2,6-lutidine-3-yl)-3,4-dihydro-2-(1H)-quinolinone, m.p.255-258 °, (0.110 gram).
Analyze %:
Actual value: C, 76.2; H, 6.8; N, 10.4
C
17H
18N
2O calculated value: C, 76.7; H, 6.8; N, 10.5
Embodiment 82-88
With the similar method of previous embodiment, by suitable quinolinone and the H of being substituted
2/ Pd-C is a raw material, the preparation following compounds:
Embodiment 89
With the method similar with embodiment 81, with 4,8-dimethyl-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone and H
2/ Pd-C is a raw material, preparation 4, and 8-dimethyl-6-(2,6-lutidine-3-yl)-3, the 4-dihydro-2-(1H)-and quinolinone, 0.25H
2O, m.p. are 177-179 °.
Analyze %:
Actual value: C, 76.3; H, 7.3; N, 10.0
C
18H
20N
2O, 0.25H
2The O calculated value:
C，75.9;H，7.3;N，9.8
Embodiment 90
8-bromo-6-(2,6-lutidine-3-yl)-3, the 4-dihydro-2-(1H)-quinolinone
Under room temperature, with bromine (0.46cm
3) be added on 3,4-dihydro-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone (1.5 gram), and Sulfuric acid disilver salt (1.4 gram) is in 98%H
2SO
4(25cm
3) stirred solution in, heat to 50 ° after about 16 hours, will incline to (100 gram) in the ice through the mixture of cooling, being neutralized into pH with 5MNaOH solution is 7.Add chloroform (100cm
3), being divided into two-phase, water further extracts (2 * 100cm with chloroform again
3).To add the also extract vacuum-evaporation of drying together, and get 1.9 gram solids, this a small amount of material is with vinyl acetic monomer/methyl alcohol recrystallize, get 8-bromo-6 (2,6-lutidine-3-yl)-3, the 4-dihydro-2-(1H)-and quinolinone, m.p. is 194-195 °.
Analyze %:
Actual value: C, 57.7; H, 4.4; N, 8.7
C
16H
15N
2The OBr calculated value:
C，58.0;H，4.6;N，8.5。
Embodiment 91
With the similar method of previous embodiment, with 6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-3, the 4-dihydro-2-(1H)-and quinolinone, bromine and Sulfuric acid disilver salt are in H
2SO
4In be raw material, preparation 8-bromo-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-3,4-dihydro-2-(1H)-quinolinone, m.p.160-163 °.
Analyze %:
Enforcement value: C, 46.8; H, 3.6; N, 18.3.
C
12H
11BrN
4The O calculated value:
C，46.9;H，3.6;N，18.2。
Embodiment 92
8-bromo-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone
In room temperature with bromine (0.33cm
3) adding-bromo-6-(2,6-lutidine-3-yl)-3,4-dihydro-2-(1H)-quinolinone (1.9 gram) and sodium-acetate (1.06 restrain) are in acetic acid (50cm
3) stirred suspension in, be heated to 100 ° after about 18 hours, vacuum-evaporation is allocated in 10%Na through the solution of cooling with remnant
2CO
3Solution (50cm
3) and chloroform (100cm
3) between.Water is again with chloroform (3 * 100cm
3) extracting it, will add together and drying (MgSO
4) the extract vacuum concentration, get solid, it is gone up chromatographic analysis in silica gel (Merck they " MK 60.9385 "), towards carrying,, get 0.80 solid with chloroform with suitably partly adding together and evaporating, with vinyl acetic monomer/methyl alcohol recrystallize, get 8-bromo-6-(2,6-lutidine-3-yl)-2-(1H) quinolinone, m.p.212-215 ° (0.55 gram).
Analyze %:
Actual value: C, 58.2; H, 4.0; N, 8.5
C
16H
12BrN
2The O calculated value:
C，58.4;H，4.0;N，8.5
Embodiment 93
With the similar method of previous embodiment, with 8-bromo-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-3, the 4-dihydro-2-(1H)-and quinolinone, bromine and CH
3COONa, and CH
3COOH is a raw material, preparation 8-bromo-6 (1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-quinolinones, and m.p. is 257-259 °.
Analyze %:
Actual value: C, 47.0; H, 3.0; N, 18.2
C
12H
9BrN
4O calculated value: C, 47.2; H, 3.0; N, 18.4
Embodiment 94
6-(2,6-lutidine-3-yl)-8-thiomethyl-2-(1H)-quinolinone, 1/4 hydrate
In room temperature with CH
3SN
a(15cm
3The CH of 2.0M
3OH solution) solution adds to 8-bromo-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone (0.50 gram) and CuI(0.15 and restrains) N-methyl-2-pyrrolidone (12cm
3) in the solution, in being heated to 160 ° after about 48 hours, with CHCl
3(100cm
3) and water (50cm
3) will be through the mixture diluted of cooling.With CHCl
3(3 * 50cm
3) will extract again through the water of separation, will add together and drying (MgSO
4) CHCl
3Phase vacuum-evaporation gets oily matter, goes up chromatographic analysis in silica gel (Merck they " MK 60.9385 "), with CHCl
3Dash and carry.With suitably partly adding together and evaporation, get solid, with CH
3COOC
2H
5Recrystallize it, 6-(2,6-dimethyl-pyridin-3-yl)-8-thiomethyl-2-(1H)-quinolinone 0.25H
2O, m.p.146.5-148.5 °, (0.04 gram).
Analyze %:
Actual value: C, 67.9; H, 5.6; N, 9.4
C
18H
16N
2OS, 0.25H
2The O calculated value:
C，67.9;H，5.5;N，9.3
Embodiment 95
With the similar method of previous embodiment, with 8-bromo-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-quinolinone, CH
3SNa and CuI are raw material, make the 6-(1-methyl isophthalic acid, 2, and 4-triazole-5-yl)-the 8-thiomethyl-2-(1H)-quinolinone.
Analyze %
Actual value: C, 56.1; H, 4.5; N, 19.7
C
13H
2N
4OS, 0.25H
2The O calculated value:
C，56.1;H，4.5;N，20.1
Embodiment 96
8-methylsulfinyl-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-quinolinone
Under 0 °, m one chlorine peroxybenzoic acid (0.14 gram) is added the CH of 6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-8-thiomethyl-2-(1H)-quinolinone
2Cl
2(10cm
3) in the stirred solution.0.5 after hour, with solution for vacuum concentration, remnant is (Merck they " MK 60.9385 ") chromatographic analysis on silica gel, with 19: 1 CHCl
3: CH
3OH dashes and carries it, with suitably partly adding together and evaporation, gets solid, with CH
3COOC
2H
5Recrystallize, 8-methylsulfinyl-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(the 1H)-quinolinone of 0.86 gram, m.p.224-227 °.
Analyze %:
Actual value: C, 53.8; H, 4.3; N, 19.3
C
13H
12N
4O
2The S calculated value:
C，54.2;H，4.2;N，19.4
Embodiment 97
8-methyl sulphonyl-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-quinolinone
With 0.97 gram 8-methylsulfinyl-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-quinolinone, and between 0.088 gram-the chlorine peroxybenzoic acid is in 10cm
3CHCl
3Mixture, in stirring at room 18 hours, then with the mixture vacuum concentration, remnant was gone up chromatographic analysis in silica gel (Merck they " MK 60.9385 "), with 19: 1 CH
3COOC
2H
5/ CH
3OH dashes and carries it, and part is worked as in collection and evaporation part, gets solid, with CH
2Cl
2/ C
6H
14Recrystallize gets 8-methyl sulphonyl-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-quinolinone, and m.p. is 226-232 °, (0.051 gram).
Analyze %:
Actual value: C, 51.0; H, 4.2; N, 17.6
C
13H
12N
4O
3S calculated value: C, 51.3; H, 4.0; N, 18.4
Embodiment 98
8-hydroxyl-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone
With 0.15 gram 8-methoxyl group-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone and the 48%HBr aqueous solution (5cm
3) mixture, reflux 19 hours is with water (20cm
3) dilution, with 5MNaOH solution alkalize to PH be 7, with CHCl
3(3 * 50cm
3) extract it.Will be through concentrating and dry (MgSO
4) CHCl
3Extraction liquid vacuum-evaporation gets solid, with CH
3COOC
2H
5Recrystallize it, 0.132 the gram 8-hydroxyl-6-(2,6-lutidine-3-yl)-2-(1H)-quinolinone, m.p.276-277 °.
Analyze %:
Actual value: C, 71.8; H, 5.4; N, 10.3
C
16H
14N
2O
2Calculated value:
C，72.2;H，5.3;N，10.5
Embodiment 99
With the similar method of previous embodiment, with 8-methoxyl group-6-(2,6-lutidine-3-yl)-3, the 1-dihydro-2-(1H)-quinolinone, reaching 48%HBr is raw material, makes 8-hydroxyl-6-(2,6-lutidine-3-yl)-3, the 4-dihydro-2-(1H)-and quinolinone, m.p.178-185 °.
Analyze %:
Actual value: C, 69.8; H, 6.3; N, 9.4
C
16H
16N
2O
2, 0.5H
2The O calculated value:
C，71.6;H，6.0;N，10.4
Embodiment 100
With the similar method of embodiment 98, with 8-methoxyl group-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-and quinolinone, reaching 48%HBr is raw material, makes 3-hydroxyl-6-(1-methyl isophthalic acid, 2,4-triazole-5-yl)-2-(1H)-and quinolinone, m.p.312-313 °.
Analyze %:
Actual value: C, 59.2; H, 4.1; N, 23.4
C
12H
10N
4O
2Calculated value:
C，59.5;H，4.2;N，23.1
Under the preparation of taking second place, illustrate that new raw material is synthetic, all temperature are 0 ℃.
Preparation 1
2-methoxyl group-6-bromoquinoline
In 50cm
3CH
2Cl
2In, under nitrogen, stir 2.90 gram 6-bromo-2-(1H)-mixture of quinolinone and 2.10 gram trimethylammonium zinc tetrahydrochysene boric acid 48 hours.Add the 10%NaOH aqueous solution (20cm
3), with CH
2Cl
2(2 * 40cm
3) aqueous phase extracted, with drying (MgSO
4) extraction liquid evaporation, remnant is with sherwood oil
(b.p.60-80 °) crystallization it, 2.16 gram 2-methoxyl group-6-bromoquinolines, m.p.90-94 °.
Analyze %:
Actual value: C, 50.7; H, 3.5; N, 6.0
C
10H
8The NOBr calculated value:
C，50.4;H，3.4;N，5.9
Preparation 2
2-methoxyl group-6-bromoquinoline (method in addition of preparation 1)
With 4.0 gram 2-nitrogen-6-bromoquinoline-methyl alcohol (20cm
3) solution, and CH
3ONa(is by 0.5 gram sodium and 20cm
3Methyl alcohol makes) reflux 16 hours together.Vacuum is removed solvent, and remnant is allocated in water (20cm
3) and CHCl
3(2 * 3cm
3) aqueous phase extracted.With drying (MgSO
4) extraction liquid evaporation, solid, with petroleum gas ether (b.p.60-80 °) recrystallize it, 3.0 gram 2-methoxyl group-6-bromoquinolines, m.p.93-96 °.
Analyze %:
Actual value: C:50.4; H, 3.4; N, 6.0
C
10H
8The NOBr calculated value:
C，50.4;H，3.4;N，5.9
Preparation 3-9
To prepare 2 similar methods, with the suitable 2-chloroquinoline derivative that is substituted, and CH
3ONa is a raw material in the methyl alcohol first, the preparation following compounds:
Preparation 10
To prepare 2 similar methods, with 6-bromo-2-chloro-4,8-dimethyl quinoline and CH
3ONa is raw material in methyl alcohol, preparation 6-bromo-4,8-dimethyl-2 methoxy quinoline, 0.25H
2O, m.p.105 °.
Analyze %:
Actual value: C, 53.1; H, 4.4; N, 5.2
C
12H
12BrNO, 0.25H
2The O calculated value:
C，53.2;H，4.5;N，5.2
Preparation 11
2-methoxyl group-8-methyl-6-(3-pyridyl) quinoline
In-70 °, under nitrogen, with tributyl lithium (8.0cm
3In the 2.0M of pentane solution) add 2.0 gram 6-bromo-2-methoxyl group-8-toluquinolines gradually in 20cm
3In the stirred solution of THF, after 10 minutes, with anhydrous ZnCl
2(1.09 gram) is in THF(10cm
3) this mixture of solution-treated, gained solution is heated to 0 °.Adding contains 1.26 gram 3-bromopyridines and 0.05 and restrains palladium (triphen phosphorus) palladium (O) in THF(10cm
3) solution, with mixture reflux 2 hours, cool off this reaction mixture, vacuum concentration it, and with CHCl
3(100cm
3) and the water (100cm of Edamine four acetic acid disodium salts (6 gram)
3) solution-treated it.With CHCl
3(3 * 50 cm
3) aqueous phase extracted again, will concentrate and drying (MgSO
4) the extraction liquid vacuum concentration become oily matter.This oily matter is gone up chromatographic analysis in silica gel (Merck they " MK 60.9385 "), with CH
3COOC
2H
5Dash and carry it, concentrate and evaporate to contain the product part, get solid,, get 1.12 gram 2-methoxyl group-8-methyl-6-(3-pyridyl with the hexane recrystallize) quinoline, m.p.117-118.5 °.
Analyze %:
Actual value: C, 76.5; H, 5.7; N, 11.0
C
16H
14N
2The O calculated value:
C，76.8;H，5.6;N，11.2
Preparation 12-40
With the similar method of previous preparation method, with suitable be raw material through the heterocycle machine of bromine replacement and the suitable 2 methoxy quinoline that is substituted, the preparation following compounds:
The method in addition of preparation 41(preparation 20)
8-methyl-6-(2,6-lutidine-3-yl)-2-methoxy quinoline 0.33H
2O
With 0.935 gram 3-bromo-2, the 6-lutidine is in 5cm
3The solution of THF in refluxing down, dropwise adds to 0.133 gram magnesium and cuts wood and 0.05 and restrain iodine in 5cm
3In the stirred suspension of THF, after heating 1 hour, magnesium depletes fully.In adding anhydrous ZnCl
2(0.680 gram) is in 4cm
3During the solution of THF, be cooled to 0 °.After half an hour, 1.25 gram 6-bromo-8-methyl-2 methoxy quinolines and 0.05 gram, four-(triphenyl phosphorus) palladiums (O) are dissolved in 10cm
3The solution of THF added, with mixture reflux 4 hours.To be allocated in 100cm through the mixture of cooling
3CHCl
3Be dissolved in 80cm with 4 gram Edamines, four acetic acid disodium salts
3Between the solution of water, with CHCl
3(2 * 50cm
3) aqueous phase extracted, will concentrate and drying (MgSO
4) extraction vacuum-evaporation, oily matter, in silica gel (Merck they " MK 60.9385 ") chromatographic analysis, with chloroform CHCl
3Dash and carry.Concentrate and evaporate suitable part, 1.04 gram oily matter, make crystallization and powdered with hexane, 8-methyl-6-(2,6-lutidine-3-yl)-2-methoxy quinoline 0.33H
2O, m.p.74-76 °.
Analyze %:
Actual value: C, 76.5; H, 6.4; N, 9.7
C
18H
13N
2, 0.33H
2O calculated value: C, 76.0; H, 6.6; N, 9.8
The method in addition of preparation 42(preparation 12)
2-methoxyl group-6-(3-pyridyl)-quinoline
In-100 °, under the nitrogen, with tributyl lithium (7.7cm
3The 2.6M solution that is dissolved in pentane) in 5 minutes, dropwise add 1.44cm
3The 3-bromopyridine is dissolved in 2525cm
3In the stirred solution of THF.After stirring 10 minutes, with the anhydrous ZnCl of 2.05 grams
2Be dissolved in 20cm
3The solution of THF slowly adds, and mixture is heated to room temperature 1 hour.Add 2.38 gram 2-methoxyl group-6-bromoquinolines and 0.08 gram four (triphenyl phosphorus) palladium (O) and be dissolved in 10cm
3The solution of THF added, with mixture reflux 9 hours.Then add 20cm
3NH
4Cl solution is with the mixture vacuum concentration, with CHCl
3(3 * 50cm
3) aqueous phase extracted, with drying (MgSO
4) extract vacuum-evaporation, solid, (Merck they " MK 60.9385 ") chromatographic analysis on silica gel was with 1: 1 CH
3COOC
2H
5: C
6H
14Dash and to carry it, remnant, with sherwood oil (b.p.60-80 °) ether recrystallize it, 0.35 gram 2-methoxyl group-6-(3-pyridyl) quinoline.m.p.89-91°。
Analyze %:
Actual value: C, 76.4; H, 5.1; N, 11.6
C
15H
12N
2The O calculated value:
C，76.2;H，5.1;N，11.9
Preparation 43-46
With previous and so on like method for making, with suitable bromopyridine and 6-bromo-3-cyano group-2 methoxy quinoline (preparation 43 and 44), or 6-bromo-2-methoxycarbonyl quinoline (preparation 45 and 46) is raw material, the manufacturing following compounds.
*Preparation 43 and 45 make contain zinc chloride stablize the misfit thing, its structure is not clearly fixed, these materials are directly used in embodiment 12 and 14.
Preparation 47
2-methoxyl group-6-(4-pyrimidyl) quinoline
(2) pyrimidine
(3) KMnO
4/ acetone
With positive monobutyl lithium (2.7cm
3The 1.5M solution of molten hexane), under the nitrogen oxygen, dropwise be added on 0.95 gram 2-methyl-6-bromoquinoline and be dissolved in 5cm in-70 °
3In the stirred suspension of ether.When all solids all dissolves, 0.32 gram pyrimidine is dissolved in 1cm
3The solution of ether dropwise adds in the solution of gained, makes and heats to room temperature.Add 5cm
3Saturated NH
4Cl solution is with CHCl
3(3 * 10cm
3) aqueous phase extracted, vacuum concentration drying (MgSO
4) extraction liquid, oily matter.Remnant is inserted in the acetone, with 0.63 gram KMnO
4The solution that is dissolved in acetone dropwise adds handling it, till lasting purple occurring, filter with " Solkafloc " (trade(brand)name), and vacuum concentration it, oily matter, with silica gel (it " MK 60.9385 " chromatographic analysis of Merck it, with 1: 1 CH
3COOC
2H
5/ C
6H
14Dash and carry it, get solid, with CH
3COOC
2H
5Recrystallize, the 2-methoxyl group-6-(4-pyrimidyl of 0.54 gram) quinoline, m.p.164-165 °.
Analyze %:
Actual value: C, 70.5; H, 5.0; N, 17.9
C
14H
11N
3O calculated value: C, 70.9; H, 4.7; N, 17.7
Preparation 48 and 49
With the method for similar previous preparation, be raw material with 2-methoxyl group-6-lithium quinoline, the preparation following compounds.In in the case, form 2-methoxyl group-6-(4-pyrrole loudspeaker piperazine base) quinoline and 2-methoxyl group-6-(3-pyrrole loudspeaker
Base) mixture of quinoline, (it " MK 60.9385 " chromatographic analysis of Merck is with CH with silica gel
3COOC
2H
5Dash and carry it.
Preparation 50
2-methoxyl group-6-(pyrazine-2-yl) quinoline 1/4 hydrate
With tributyl lithium (4.6cm
3, be dissolved in the 2.6M solution of pentane) and in-70 °, under the nitrogen, dropwise add 1.43 gram 2-methoxyl group-6-bromoquinolines in 10cm
3In the stirred solution of THF, after 20 minutes, add pyrrole
(0.43 gram) is in 5cm
3The solution of THF stirred after 20 minutes, flow of dried air formed foam in-70 ° and fed in the solution 0.5 hour, and after heat was to room temperature 1 hour.Add 50cm
3CHCl
3, with 10cm
3Wash it, dry (MgSO
4) and vacuum concentration, get remnant, with silica gel (Merck " MK 60.9385 ") chromatographic analysis, with 1: 1 CH
3COOC
2H
5: C
6H
14Dash and carry it, get solid, with CH
3COOC
2H
5Recrystallize it, the 2-methoxyl group-6-(2-pyrrole of 0.22 gram
Base) quinoline, 1/4 H
2O, m.P.130-132 °.
Analyze %:
Actual value: C, 69.9; H, 4.6; N, 17.1
C
14H
11N
3O, 1/4 H
2The O calculated value:
C，69.6;H，4.8;N，17.4
Preparation 51
3-cyano group-6-bromo-2-(1H)-quinolinone
Under room temperature, with 4.1cm
3Be dissolved in CH
3COOH(10cm
3) solution, handle 13.3 gram 3-cyano group-2-(1H)-quinolinone in 130cm
3The suspension of acetic acid, reflux was cooled to room temperature with mixture after 4 hours, filtered, and washed solid with ethanol, 33-cyano group-6-bromo-2-(1H)-quinolinone (14.63 gram), with ethanol with its a small amount of recrystallize, m.p.308-311 °.
Analyze %:
Actual value: C, 48.6; H, 2.1; N, 11.4
C
10H
5The NOBr calculated value:
C，48.2;H，2.0;N，11.3
Preparation 52
6-bromo-3-cyano group-2 methoxy quinoline
Under nitrogen, with 1.46 gram 6-bromo-3-cyano group-2-(1H)-quinolinone in 150cm
3CH
2Cl
2Suspension and 10.55 gram trimethylammonium zinc Tetrafluoroboric acid trimethylammonium oxygen rise and stirred 2 days.Add 2MNaOH solution (100cm
3), with CH
2Cl
2(3 * 200cm
3) aqueous phase extracted, vacuum concentration drying (MgSO
4) extract, remnant is in silica gel (Merck " MK 60.9385 ") chromatographic analysis, with 4: 1 C
6H
14/ CH
3COOC
2H
5Dash and carry it, get solid, with CH
3COOC
2H
5Recrystallize gets 1.96 gram 6-bromo-3-cyano group-2 methoxy quinolines, m.p.169-172 °.
Analyze %:
Actual value: C, 50.4; H, 2.8; N, 10.8
C
11H
7N
2OBr
2Calculated value: C, 50.2; H, 2.7; N, 10.7
Preparation 53
2-chloro-6-bromo-3-cyano group-quinoline
In 500cm
3In the cyanogen phosphorus chloride, with 6-bromo-3-cyano group-2-(1H)-quinolinone (142 gram) reflux 1.5 hours, vacuum was removed evaporant, and residual solid is inserted CHCl
3(400cm
3) in, in gained slurry impouring ice, with NH
3The aqueous solution (S.G.0.880) neutralise mixt is with CHCl
3(2 * 150cm
3) aqueous phase extracted, vacuum concentration drying (MgSO
4) organic extract, remnant is (Merck " MK 60.9385 ") chromatographic analysis on silica gel, dash with toluene and carry, solid, with CH
3COOC
2H
5Recrystallize gets 80 gram 2-chloro-6-bromo-3-cyano group-quinoline, m.p.228-230 °.
Analyze %:
Actual value: C, 44.6; H, 1.5; N, 10.6
C
10H
5ClBrN
2Calculated value:
C，44.9;H，1.5;N，10.5
The method in addition of preparation 54(preparation 52)
6-bromo-3-cyano group-2 methoxy quinoline
Restrain 6-bromo-2-chloro-3-cyano group-quinoline in 30cm with 1.2
3The solution of methyl alcohol, and CH
3ONa(is by 0.116 gram sodium and 20cm
3Methyl alcohol makes) reflux 16 hours, mixture is cooled to 0 ℃.With solid filtering, get 0.60 gram 6-bromo-3-cyano group-2-methoxy quinoline, m.p.172-174 °.
Analyze %:
Actual value: C, 49.8; H, 2.8; N, 10.4
C
11H
7N
2The OBr calculated value:
C，50.2;H，2.7;N，10.7
Preparation 55
With similar previous method for making, prepare 6-bromo-2-methoxyl group-3-methoxycarbonyl-quinoline, m.p.144-145 ° with 6-bromo-2-chloro-3-methoxycarbonyl caye quinoline.
Analyze %:
Actual value: C, 49.0; H, 3.5; N, 5.1
C
12H
10BrNO
3Calculated value:
C，48.7;H，3.4;N，4.7
Preparation 56
6-bromo-2-(1H)-quinolinone-3-carboxylic acid
Under room temperature, restrain bromines in 20cm with 16
3CH
3The solution-treated 4.5 gram 3-ethoxycarbonyls of COOH-2-(1H)-quinolinone is in 50cm
3The stirred solution of acetic acid, its mixture reflux 24 hours, cooling is also filtered, 3.42 gram 6-bromo-2-(1H)-the thick solid of quinolinone-3-carboxylic acid, m.p.＞300 °.
Preparation 57
6-bromo-2-chloro-3-methoxycarbonyl quinoline
With phosphorus oxychloride (40cm
3) 6-bromo-2-(1H)-stirred suspension of quinolinone-3-carboxylic acid (3.4 gram), reflux 2 hours, with the mixture cooling, vacuum-evaporation is to doing.In 0 ° with methyl alcohol (50cm
3) handle this solid remnant, after 2 hours, filtering mixt is washed solid with methyl alcohol in stirring at room, gets 6-bromo-2-chloro-3-methoxycarbonyl quinoline, m.p.176-177 ° (1.82 gram).
Analyze %:
Actual value: C, 44.0; H, 2.3; N, 4.7
C
11H
7BrClNO
2Calculated value: C, 44.0; H, 2.3; N, 4.7
Preparation 58
6-iodo-2-(1H)-quinolinone
During adding iodine (3.5 gram), under room temperature, stir 2.0 gram 2-(1H)-quinolinone and 2.14 gram Ag
2SO
4In 15.0cm
3The solution of the vitriol oil.In being heated to 50 °, after 24 hours, pour mixture into ice, with Na
2CO
3Solid this solution that neutralizes is with solid filtering, with silica gel (Merck, MK 60.9385) chromatographic analysis, with CHCl
3Dash and to carry it, remnant, with the methyl alcohol recrystallize it, 6-iodo-2-(1H)-quinolinone, m.p.261 °, (0.8 gram).
Analyze %:
Actual value: C, 41.0; H, 2.4; N, 5.5
C
9H
6The INO calculated value:
C，39.9;H，2.2;N，5.2
Preparation 59
6-bromo-2-chloro-8-toluquinoline
With 12.0 gram 6-bromo-8-methyl-2-(1H)-quinolinone in POCl
3(100cm
3) mixture reflux 2 hours, vacuum is removed evaporant, remnant is dissolved in CHCl
3(200cm
3), gained solution is poured in the 200 gram ice, with NH
3The aqueous solution (S.G.0.88) alkalize to PH be 10, with CHCl
3(2 * 100cm
3) aqueous phase extracted, will concentrate and drying (MgSO
4) the extract vacuum concentration, 10.7 the gram solids, with the ethanol recrystallize it, 6-bromo-2-chloro-8-methyl-quinoline, m.p.114-116 °.
Analyze %:
Actual value: C, 47.2; H, 2.7; N, 5.8
C
10H
7The BrClN calculated value:
C，46.8;H，2.7;N，5.5
Preparation 60-65
With the similar method of previous preparation method, with the 5-bromo-2-(1H of 1.0:1.7)-quinolinone and 7-bromo-2-(1H)-quinolinone mixture (preparation 60 and 61); With the 6-bromo-5-methyl of 1.0:2.3-2-(1H)-quinolinone and 6-bromo-7-methyl-2-(1H)-quinolinone mixture (preparation 62), 6-iodo-8-ethyl-2-(1H)-quinolinone (preparation 63), 6-iodo-8-(third-2-yl)-2-(1H)-quinolinone (preparation 64), with 6-bromo-8-methoxyl group-2-(1H)-quinolinone (preparation 65), and POCl
3Be raw material, the preparation following compounds:
Preparation 66
To prepare 59 and so on like method, with 6-bromo-4, the 8-dimethyl-2-(1H)-quinolinone and POCI
3Be raw material, preparation 6-bromo-2-chloro-2,4-dimethyl quinoline, m.p.182 °.
Analyze %:
Actual value: C, 48.3; H, 3.3; N, 5.3
C
11H
9The BrClN calculated value:
C，48.3;H，3.3;N，5.2
Preparation 67
6-bromo-8-methyl-2-(1H)-quinolinone
Will anti--N-(4-bromo-2-aminomethyl phenyl in room temperature)-3-ethoxy-c enamine (2.0 gram) adds 98%H bit by bit
2SO
4(15cm
3) in, and stir it, be poured into (100cm in the ice in 16 hours
3) in, with the gained sedimentation and filtration, and dry (1.5 gram), with CH
3COOC
2H
5/ CH
3The OH recrystallize it, 6-bromo-8-methyl-2-(1H)-quinolinone, m.p.272-274 °.
Analyze %:
Actual value: C, 50.4; H, 3.4; N, 6.1
C
10H
8NOBr calculated value: C, 50.4; H, 3.4; N, 5.9
Preparation 68-75
With similar previous preparation method, with instead-the N-(3-bromophenyl)-3-ethoxy propylene acid amides (preparation 68 and 69), instead-N-(4-bromo-3-aminomethyl phenyl)-3-oxyethyl group-acrylamide (preparation 70 and 71), instead-the N-(4-iodophenyl)-3-ethoxy propylene acid amides-preparation 72), instead-N-iodo-2-ethylbenzene base)-3-ethoxy propylene acid amides (preparation 73), instead-N-(4-iodo-2-(third-2-yl)-phenyl)-3-ethoxy propylene acid amides (preparation 74), instead-N-(4-bromo-2-p-methoxy-phenyl)-3-ethoxy propylene acid amides (preparation 75), and 98%H
2SO
4Be raw material, be prepared as follows compound:
Preparation 76
6-bromo-4, the 8-dimethyl-2-(1H)-quinolinone
In 98%H
2SO
4In, heat and stir N-(4-bromo-2-aminomethyl phenyl)-ethanoyl ethanamide (18 gram) down at 100 ℃.To pour in the 200 gram ice through the mixture of cooling, cross filter solid, and, get 15.0 gram crude products, with CH in 100 ° of vacuum-dryings 2 hours
3COOC
2H
5/ CH
3This material of OH recrystallize a small amount of (1.5 gram), 1.1 gram 6-bromo-4,8-dimethyl-2-(1H)-quinolinone, m.p.＞300 °.
Analyze %:
Actual value: C, 52.0; H, 4.1; N, 5.5
C
11H
10The BrNO calculated value:
C，52.4;H，4.0;N，5.6
Preparation 77
N-(4-bromo-2-aminomethyl phenyl)-ethanoyl ethanamide
With 25 gram 4-bromo-2-aminotoluene and 11.8cm
3Dienone is in 100cm
3Mixture stir and reflux 5 hours, be cooled to room temperature, the solid of filtering-depositing is with C
6H
14/ CH
3COOC
2H
5Recrystallize it, N-(4-bromo-2-the aminomethyl phenyl)-ethanoyl ethanamide of 14.0 grams, m.p.109 °.
Analyze %:
Actual value: C, 48.5; H, 4.4; N, 5.4
C
11H
12BrNO
2Calculated value:
C，48.9;H，4.5;N，5.2
Preparation 78
Instead-N-(4-bromo-2-aminomethyl phenyl)-3-ethoxy propylene acid amides
In 0 °, anti--3-ethoxy propylene acyl chlorides (0.74 gram) is added to 0.93 gram 4-bromo-2-aminotoluene be dissolved in 10cm
3In the stirred solution of pyridine, add 40cm after 5 hours
3Water, with solid filtering, water (30cm
3) wash and drying, with CH
3COOC
2H
6Recrystallize gets instead-N-(4-bromo-2-methylbenzene)-3-ethoxy propylene acid amides 1.3 grams, m.p.163-164 °.
Analyze %:
Actual value: C, 50.7; H, 5.0; N, 5.1
C
12H
14NO
2The Br calculated value:
C，50.7;H，5.0;N，4.9
Preparation 79-85
With similar previous preparation method, be substituted with suitable that aniline and anti--3-ethoxy propylene acyl chlorides is a raw material, the preparation following compounds:
Preparation 86
4-iodo-2-(third-2-yl)-aniline
In room temperature with ICI(12.9cm
3) add to 27.0 the gram 2-(third-2-yl)-aniline and 16.4 the gram CH
3COONa is dissolved in 250cm
3CH
3In the stirred solution of COOH.After 1 hour, vacuum is removed volatile matter, and remnant is allocated in 200cm
3CH COOC
2H
5And 50cm
310%Na
2CO
3Between solution, drying (MgSO
4) organic extract liquid filter, and vacuum-evaporation it, oily matter, in silica gel (Merck " MK 60.9385 ") chromatographic analysis, dash with hexane and to carry it.Concentrate and evaporation contains the part of product, the oily crude product (38 gram) of furvous instability, it decides its structure fully, but is directly used in preparation 84.
Preparation 87
With similar previous preparation method, be raw material with the 2-ethylaniline, preparation 4-iodo-2-ethylaniline (thick oily matter), (4-bromo-2-methyl oxyaniline is a known compound).
Preparation 88
6-cyano group-2 methoxy quinoline
Restrain 6-bromo-2-methoxy quinoline in 135 ° with 0.476,0.26 gram KCN, 0.05mg KOH and 0.067 gram (CH
3COO)
2Pd is in 2.0cm
3The mixture heating up of DMF 3 hours will be allocated in 20cm through the solution of cooling
3Water and 50cm
3Between CHCl, with CHCl
3(2 * 25cm
3) aqueous phase extracted, will concentrate and drying (MgSO
4) extraction liquid vacuum-evaporation, in silica gel (Merck " MK 60.938 ") chromatographic analysis, dash with toluene and to carry it, collect and evaporate suitable part, 0.216 gram 6-cyano group-2 methoxy quinoline, m.p.163-165 °.
Analyze %:
Actual value: C, 71.7; H, 4.4; N, 14.8
C
11H
8N
2The O calculated value:
C，71.4;H，4.4;N，15.2
Preparation 89
2-methoxyl group-6-(1-tributyltin base-(1H)-tetrazole-5-yl) quinoline
In 110 ° 6-cyano group-2 methoxy quinoline (0.368 gram) and 0.73 gram, three positive fourth tinbase trinitride were heated 18 hours together, thick oily matter 2-methoxyl group-6-(1-tributyltin base-(1H)-tetrazole-5-yl) quinoline, it is not further purified promptly directly in order to preparation 6-(tetrazole-5-yl)-2-(1H)-quinolinone (seeing embodiment 43).
Preparation 90
2-methoxyl group-6-(1-butyl-(1H)-tetrazole-5-yl) quinoline and
2-methoxyl group-6-(2-butyl-(2H)-tetrazole-5-yl) quinoline
In 120 ° 0.368 gram 6-cyano group-2-methoxy quinoline and 0.73 gram azide, three positive fourth tin were heated 18 hours together, mixture is cooled to 100 °, add 0.42 gram n-butyl iodide, reaction mixture stirred 3 hours, and remnant is allocated in 20cm
3CH
3CN and 20cm
3C
6H
14Between, with CH
3CN layer vacuum concentration gets oily matter, and (Merck MK 60.9385) is with the oily matter chromatographic analysis, with CH on silica gel
2Cl
2At first must (CHCl towards what carry
3/ CH
3OH is 19: 1, R
F0.75; ) be 2-methoxyl group-6-(2-butyl-(2H)-tetrazole-5-yl of thick oily matter) quinoline (0.087 gram), the second (CHCl
3: CH
3OH is 19: 1, R
FBe 0.62) person is the 2-methoxyl group-6-(1-butyl of thick oily thing-(1H)-tetrazole-5-yl)-quinoline (0.30 gram), the not repurity of these compounds is directly used in embodiment 44 and 45.
Preparation 91
6-bromo-4-methyl-3, the 4-dihydro-2-(1H)-quinolinone
In room temperature with 0.08cm
3Bromine is in 1cm
3CH
3The solution of COOH adds 0.5 gram 4-methyl-3, and 4-dihydro-2-(1H)-quinolinone is in 4.0cm
3The stirred solution of acetic acid, final vacuum was removed volatile matter in 2 hours, then remnant was allocated in 50cm
3CHCl
3And 20cm
3Between the water, with CHCl
3(2 * 20cm
3) extracted organic phase, will concentrate and drying (MgSO
4) organic extract vacuum-evaporation, with CH
3COOC
2H
5With the remnant recrystallize, get 0.35 gram 6-bromo-4-methyl-3, the 4-dihydro-2-(1H)-and quinolinone, m.p.190 °.
Analyze %:
Actual value: C, 50.2; H, 4.2; N, 6.0
C
10H
10The BrNO calculated value:
C，50.0;H，4.2;N，5.8
6-bromo-3, the 4-dihydro-2-(1H)-quinolinone is known compound.
Preparation 92
6-iodo-3-nitro-2-(1H)-quinolinone
In o-Xylol, with 2.0 gram 2-amido-5-benzaldehyde iodines, 4.2 gram nitro vinyl acetic monomer, the reflux 1.5 hours of stirring the mixture with 0.7 gram piperidines, will be through the solution for vacuum concentration of cooling, with chloroform one Virahol with the residual solid recrystallize, 1.14 gram 6-iodo-3-nitros-2-(1H)-quinolinone, m.p.279-282 °.
Analyze %:
Actual value: C, 34.6; H, 1.7; N, 8.6
C
9H
5INO
3Calculated value:
C，34.2;H，1.6;N，8.9
Preparation 93
2-amido-5-benzaldehyde iodine semihydrate
With 0.044 gram MnO
2Add 0.125 gram 2-amido-5-bromobenzyl alcohol in 10cm
3CH
2CI
2Solution in.Stir the mixture compound 16 hours adds 0.44 gram MnO again
2Continue to stir 16 hours.Mixture is filtered, and vacuum concentrated filtrate, folding divided in silica gel (Merck " MK 60.9385 ") with the remnant chromatograph, with CH
3COOC
2H
5Dash and to carry, collect necessary part, the vacuum filter contract 0.1 gram 2-amido-5-benzaldehyde iodine 0.5H
2Body between the O, m, p, 105 °.
Analyze %:
Actual value: C, 33.0; H, 2.4; N, 6.1
C
7H
6INO
2, 0.5H
2The O calculated value:
C，32.8;H，2.5;N，5.5
Preparation 94
2-amido-5-silicon benzylalcohol
In-30 °, under the nitrogen with diisobutylaluminium hydride (210cm
3Be dissolved in the 1.5M solution of THF) add 28.0 gram-2 amidos-5-iodo-benzoic acid esters and be dissolved in 100cm
3The stirred solution of THF to room temperature, stirs mixture heating up 16 hours and with 35cm
3Methyl alcohol is handled it, adds 500cm
3CH
3COOC
2H
5, mixture filters to remove inorganics, and vacuum concentrated filtrate gets solid, divides folding in silica gel (Merck " MK60,9385 ") chromatograph, with 49: the CH CI 1(volume ratio)
3: CH
3OH dashes and to carry it, necessity is partly collected and vacuum-evaporation it, 19.0 gram-2 amidos-5 iodine benzylalcohols, m, p, 125 °.
Divide folding %:
Actual value: C, 34.4; H, 3.2; N, 6.0
C
17H
8NO calculated value: C, 33.8; H, 3.2; N, 5.6
The equipment value:
2 methoxy quinoline-6-carboxylic acid
Under-70 ° of hydrogen, with n-Butyl Lithium (63cm
3Be dissolved in the 1.6M solution of hexane) dropwise add 20 gram 6-bromo-2 methoxy quinolines and be dissolved in 250cm
3The stirred solution of THF is after 0.5 hour.Add 50 gram dry ice, solution is heated to room temperature, vacuum is removed volatile matter, and remnant is allocated in 100cm
3CHCI
3And 100cm
3Between water, with aqueous phase separation, and to be acidified to PH with 5MHCI be 3.5, with solid filtering and dry (14.2 gram) in shallow lake, Shen, will wherein a small amount of recrystallize with Virahol, 2 methoxy quinoline-6-carboxylic acid,
m，p，220-222°。
Divide folding %:
Actual value: C, 65.1; H, 4.5; N, 7.9
C
11H
9NO
3Calculated value: C, 65.0; 4.5; N, 6.9
Preparation 96-100
With equipment method before similar, by suitable 6-bromo-or 6-iodo-2 methoxy quinoline, n-BuLI and the CO of being substituted
2, with the preparation following compounds.
Preparation 101
2 methoxy quinoline-6-carboxylic acid amide
With oxalyl chloride (10.3cm
3), dropwise add 12.0 gram 2-methoxy QUINOLINE-6-CARBOXYLIC ACID in 0 ° and be dissolved in 100cm
3CH
2CI
2With the stirred solution of 0.1 gram DMF, to room temperature, 2 hours final vacuums are removed and are waved substrate, and remnant is inserted 100cm with mixture heating up
3CH
2CI
2In, be cooled to 0 °, with 30cm
3NH
3The aqueous solution (S.C.0.88) is handled it carefully, after 2 hours the filter of mixture vacuum is contracted.With solid-state residual thing recrystallize, get 7.9 gram 2 methoxy quinoline-6-carboxylic acid amides, m, p, 212-214 with Virahol.
Divide folding %:
Actual value: C, 65.0; 5.0; N, 13.8
C
11H
10N
2O
2Calculated value: C, 65.3; H, 5.0; N, 13.9
Preparation 102-106
With similar previous preparation method, by oxalyl chloride, suitable 2 methoxy quinoline-6-carboxylic acid and the nitrogen that is substituted, with the preparation following compounds:
Preparation 107
2 methoxy quinoline-6-(dimethyl amido methene) carboxylic acid amide
Restrain 2 methoxy quinoline-6-carboxylic acid amide and 6.0cm in 120 ° with 3.0
3The contract mixture of amine dimethylacetal of N, N-diformazan heated 1.5 hours.Leave standstill 16 with the crystallized product filtration in room temperature,, get 3.78 gram 2 methoxy quinoline-6-(N-(dimethyl-amido is pitched) carboxylic acids with hexane wash and dry
Amine, m, p, 192-195 °.
Divide folding %:
Actual value: c, 65.5; H, 5.9; N, 16.2
C
14H
15N
3O
2Calculated value: C, 65.4; H, 5.8; N, 16.3
Preparation 108-112
With similar previous preparation method, by suitable 2 methoxy quinoline-6 carboxylic acid amide and the N of being substituted ,-dimethyl formamide aldehyde, with the preparation following compounds:
Preparation 113
2-methoxyl group-6-((1H)-1,2,4-triazole-5-yl) quinoline
In Glacial acetic acid, under 90 °, restrain 2 methoxy quinoline-6-(N-(dimethyl amido methene) with 1.0) carboxylic acid amide and hydrazine hydrate (0.208cm
3) mixture stirred 1.5 hours, vacuum is removed volatile matter, on silica gel (Merck " MK 60.60.9385 "), with the remnant chromatographic analysis, with 49: the CH 1(volume ratio)
3COOC
2H
5: CH
3OH dashes and to carry it, concentrate and evaporate required part, 0.811 gram 2-methoxyl group-6-((1H)-1,2,4-triazole-5-yl) quinoline, m.p.198-200 °.
Analyze %:
Actual value: C, 63.8; H, 4.5; N, 24.8
C
12H
10N
4The O calculated value:
C，63.7;H，4.4;N，24.8
Preparation 114-122
With similar previous preparation method, by the suitable 2 methoxy quinoline-6-(N-(dimethyl amido methene) that is substituted) carboxylic acid amide, and hydrazine hydrate (preparation 114), or methyl hydrazine (preparation 115-122), with the preparation following compounds:
The mixture of the position isomer of preparation 116 and 117 gained is gone up chromatographic analysis in silica gel (Merck " MK 60.9385 "), dashes with ether and carries it, to separate it.Main isomer is at the R of ethyl acetate
FBe 0.8, quilt dashes and puts forward (preparation 116) earlier, and a small amount of product is at the R of ethyl acetate
FBe 0.28, then quilt dashes and puts forward (preparation 117).
The position isomer mixture of preparation 118 and 119 gained, (Merck " MK 60.9385 ") chromatographic analysis on silica gel, separating it, with 1: 1 hexane: ether dashes and carries it, main isomer (preparation 119), a small amount of product is by Guan Gui, with CH
3COOC
2H
5Dash carry it.
Preparation 123
2-methoxyl group-6-(1,2,4-grass ribavirin-5-yl) caye quinoline
With 5M NaOH solution (0.94cm
3) add 0.325 gram azanol base muriate in 3cm
3Water and 7cm
3CH
3In the solution of COOH.Add 1.0 gram 2 methoxy quinoline-6-N-((dimethyl amido methene)) carboxylic acid amide, mixture was stirred 10 minutes, add 10cm
3Water, solution keep 0 ° 1 hour, with sedimentation and filtration, insert dioxan (5cm
3) and acetic acid (5cm
3), in 90 ° of heating 1.5 hours, with 10cm
3Water treatment is through the solution of cooling, and with sedimentation and filtration, (Merck " MK 60.9385 ") chromatographic analysis on silica gel is with CH
2Cl
2Dash and carry, concentrated and vacuum-evaporation needs part, gets 0.537 gram solid.With CH
3COOC
2H
5The solid that recrystallize is a small amount of gets 2-methoxyl group-6-(1, and 2,4-grass ribavirin-5-yl) quinoline, m.p.150-152 °.
Analyze %:
Actual value: C, 63.3; H, 4.0; N, 18.6
C
12H
9N
3O
2Calculated value:
C，63.4;H，4.0;N，18.5
Preparation 124
6-(the 1-methyl-(1H)-imidazoles-2-yl)-2 methoxy quinoline
Under-45 ° of nitrogen, with n-Butyl Lithium (9cm
3Be dissolved in the 1.6M solution of hexane) be added on 1.03cm
31-methyl-(1H)-imidazoles is dissolved in 30cm
3In the stirred solution of THF, after 1.25 hours, with the anhydrous ZnCl of 1.95 grams
2Be dissolved in 30cm
3The solution of THF dropwise added in 5 minutes, got white precipitate.Mixture heating up is to room temperature, and adding 3 gram 6-bromo-2 methoxy quinolines and 0.2 gram four (triphenyl phosphorus) palladium (O) are dissolved in 20cm
3The solution of THF, and reflux 16 hours add 2cm
3Saturated NH
4Cl solution, with the reaction mixture vacuum concentration, remnant is allocated in 100cm
3CHCl
3Be dissolved in 100cm with 10 gram Edamines, four acetic acid disodium salts
3Between the solution of water, CHCl
3(2 * 50cm
3) aqueous phase extracted, will concentrate and drying (MgSO
4) extract vacuum-evaporation, solid, (Merck " MK 60.9385 ") chromatographic analysis on silica gel is with 19: the CHCl 1(volume ratio)
3: CH
3OH dashes and to carry it, in the segment set that will need and vacuum-evaporation it, foam, with CH
3COOC
2H
5/ C
6H
14Recrystallize it, 0.517 gram 6-(1-methyl-(1H)-imidazoles-2-yl)-2 methoxy quinoline, m.p.116.5-118.5 °.
Analyze %:
Actual value: C, 70.3; H, 5.5; N, 17.4
C
14H
13N
3The O calculated value:
C，70.3;H，5.5;N，17.5
Preparation 125
With similar previous preparation method, with 1-methyl-(1H)-imidazoles, four (triphenyl phosphorus) palladium (O) and 6-bromo-2-methoxyl group-8-toluquinoline are raw material, synthetic 6-(1-methyl-(1H)-imidazoles-2-yl)-2-methoxyl group-8-toluquinoline semihydrate, m.p.158-161 °.
Analyze %:
Actual value: C, 68.4; H, 5.8; N, 15.8
C
15H
15N
3O, 1/2 H
2The O calculated value:
C，68.7;H，6.1;N，16.0
Preparation 126
6-(the 1-methyl-(1H)-imidazoles-5-yl)-2-methoxyl group-3-toluquinoline
In-70 °, under the nitrogen, with tributyl lithium (11.9cm
3Be dissolved in the 2.0M solution of pentane) be added on 0.95cm
31-methyl-(1H)-imidazoles is dissolved in 3cm
3The stirred solution of THF.With mixture heating up to 0 °, continue to stir 1 hour after 10 minutes, then add the anhydrous ZnCl of 6.25 grams
2Be dissolved in 45cm
3The solution of THF adds, and restir 1 hour adds 1.0 gram 6-bromo-2-methoxyl group-8-toluquinolines, and 0.04 gram four (triphenyl phosphorus) palladium (O), with mixture reflux 18 hours, through cooling the mixture vacuum concentration and be allocated in 200cm
3CHCl
3Be dissolved in 250cm with 50 gram Edamines, four acetic acid disodium salts
3Between the solution of water, with CHCl
3(2 * 100cm
3) aqueous phase extracted, will concentrate and drying (MgSO
4) extract evaporation, solid, (Merck " MK 60.9385 ") chromatographic analysis on silica gel is with CHCl
3Dash and to carry, collect and evaporate suitable part, earlier (CHCl
3Middle R
fBe 0.32) 6-of 0.37 gram (the 1-methyl-(1H)-imidazoles-2-yl)-2-methoxyl group-8-toluquinoline, m.p.160-162 °.The product that adds preparation 125 is identical, the two (CHCl
3Middle R
fBe 0.26) be 6-(1-methyl-(1H)-imidazoles-5-yl)-2-methoxyl group-8-toluquinoline, m.p.174-175 °.
Analyze %:
Actual value: C, 71.2; H, 6.0; N, 16.2
C
15H
15N
3Calculated value: C, 71.1; H, 6.0; N, 16.6
Claims (17)
1, a kind of manufacturing chemistry formula I
Or the method for making of its salt that can be accepted, wherein " Het " is for being connected to the 5-of this quinolinone arbitrarily, 6-, the 5-that is substituted of 7-or 8-position or 6-unit monocycle aromaticity heterocyclic radical with carbon atom; R is connected to 5-, 6-, and 7-or 8-position are hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, halogen, CF
3, hydroxyl, methylol, or cyano group; R
1Be hydrogen, cyano group, (C
1-C
4Alcoxyl) carbonyl, C
1-C
4Alkyl, C
1-C
4Alkyl, nitro, halogen ,-NR
3R
4Or CONR
3R
4, R wherein
3And R
4Be respectively H or C
1-C
4Alkyl, or and nitrogen-atoms be connected together, form saturated 5-or 6-the unit heterocyclic radical, it can contain one and be selected from O, S and N-R
5(R
5Be hydrogen or C
1-C
4Alkyl) heteroatoms or base; R
2Be hydrogen, C
1-C
4Alkyl, or 2-hydroxyethyl; Y is H or C
1-C
4Alkyl; The dotted line of 3-and 4-interdigit is represented can be or be non-is a key.
Its characteristics exist: with the compound demethylation of chemical formula II,
R wherein, R
1, Het, Y and dotted line define as above, to form R
2Compound for the chemical formula I of H continues it, arbitrarily with one or more the following step:
(a) with the 3-position it-esterification of COOH base mat changes into-COO (C
1-C
4Alkyl);
(b) with R
1Represented nitro ester reduction changes into amido;
(c) with R
1Represented hydrogen atom, the mat halogenation changes into Cl, Br or I;
(d) use the peroxy acid oxygenant that " Het " represented nitrogen heterocyclic ring is oxidized to the N-oxide compound;
(e) with highly basic, respectively and C with it
1-C
4Alkyl halide or sulfuric acid two (C
1-C
4) alkyl, or the reaction of halogenation 2-hydroxyethyl, with R
2Represented hydrogen atom becomes C
1-C
4Alkyl, or 2-hydroxyethyl;
(f), will change into 3, the 4-dihydro derivative in the product that 3-and 4-interdigit have a chemical formula I of two keys with catalytic hydrogenation;
(g) at AG
2SO
4With dense H
2SO
4Exist down, respectively with chlorine, bromine or iodine reaction, will be 3, the represented hydrogen atom of R of the 8-position of the chemical formula I of 4-dihydro-quinolinone becomes Cl, Br or I;
(h) at CH
3Among the COOH, make 3 of chemical formula I, the reaction of 4-dihydro product and bromine and sodium sulfonate is to change into the compound that has the chemical formula I of two keys at 3-and 4-interdigit;
(i) in the presence of Cu (I) catalyzer, and C
1-C
4The salts reaction of alkylthio changes into C with the halogen atom of 8-position
1-C
4Alkylthio;
(j) with suitable organic fortune oxygen acid or sodium metaperiodate reaction, the C that R is represented
1-C
4Alkylthio changes into C
1-C
4Alkyl sulphinyl or C
1-C
4Alkyl sulphonyl;
(k) with the mineral acid C that R is represented
1-C
4The alkoxyl group demethylation changes into hydroxyl;
(l) elder generation and C
1-C
4Lithium alkylide is Cl with R then and formaldehyde reaction, Br or I, and at the compound of the 8-position of chemical formula I, changing into R is methylol;
(m) and suitably acid-respons changes into the acid salt that medicine can be accepted with the product of chemical formula I; And
(n) and suitably alkali reaction, the product with chemical formula I changes into metal-salt.
2, method according to claim 1, wherein characteristics exist: demethylation system uses mineral acid.
3, as the method as described in the claim 2, its characteristics exist: demethylation system uses the HBr aqueous solution, the HCl aqueous solution, or contain the ethanol of the HBr aqueous solution of 5-15% solidity ratio, to advance passerby.
4, as the method as described in the claim 1 to 3, its characteristics exist: it lies in room temperature and carry out reactor to the temperature of the reflux temperature of solution.
5, a kind of manufacturing has the method for the compound or the salt that its medicine can be accepted of the chemical formula I in the claim 1.Its characteristics exist: in chemical formula Pd(PPh
3)
4Catalyzer exist down, with the compound of chemical formula III:
RR wherein
1R
2The definition such as the claim 1 of Y and dotted line, and Q is assorted base;
With chemical formula be the compound of Het-Zn-Cl, the wherein definition such as the claim 1 of " Het "; This method can be arbitrarily with one or more step of step that claim 1 is defined (a) to (h).
6, as the method as described in the claim 5, its characteristics exist: it lies in the organic solvent, react to the temperature between the reflux temperature of material in room temperature, and Q is Cl, Br or I.
7, the method for the salt that can accept of the compound of the chemical according to claim 1 formula I of a kind of manufacturing or its medicine, its characteristics exist: with the compound cyclisation of chemical formula IV:
Wherein definition such as the claim 1 of " Het " and R, Q is assorted base, therefore forms the compound of chemical formula I, wherein R
1, R
2With Y be H, this method can be arbitrarily with it such as the claim part definition it (a) and (c) to one or more step of (n).
8, as the method as described in the claim 7, its characteristics are methoxy or ethoxy at Q, and passerby advances with the vitriol oil in cyclisation system.
9, as the method as described in the claim 1 to 6, its characteristics exist: R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, halogen, CF
3, hydroxyl or methylol.
10, as the method as described in the claim 9, its characteristics exist: R is connected to 7-or 8-position, and is H, C
1-C
4Alkyl, methoxyl group, methylthio group, methylsulfinyl, methyl sulphonyl, bromine, hydroxyl, or methylol; R
1Be H, cyano group, methoxycarbonyl, nitro, bromine or amido; R
2Be H or CH
3; " Het " is connected to 5-, and 6-or 7-position are pyridyl, its N-oxide compound, and pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, triazol radical, the tetrazole base, thiazolyl,
The azoles base, thienyl or furyl, all are to be selected from C by 1 or 2 arbitrarily
1-C
4Alkyl, C
1-C
4Alkoxyl group, cyano group, the substituent of substituting group institute of amido and amido formyl radical; 3-and 4-interdigit have two keys; And Y is H or CH
3
11, as the method as described in the claim 10, its characteristics exist: " Het " is selected from (a) arbitrarily by 1 or 2 methyl, or by single methoxyl group; cyano group, the pyridyl that amido or amido formyl radical are replaced, (b) pyridyl N-oxide compound; (c) pyrimidyl, (d) pyridazinyl, (e) pyrrole
Base, (f) triazol radical or N-methyl triazol radical, (g) tetrazole base or N-(normal-butyl)-the tetrazole base, (h) N-methylimidazolyl, (i)
The ribavirin base, (j) miaow thiophene base, (k) thienyl or (l) furyl.
12, as the method as described in the claim 11, its characteristics exist: it is in order to make the compound of tool chemical formula (I A):
The wherein definition of " Het " such as claim 11. and definition such as the claim 10 of R.
13, as the method as described in the claim 1 to 6, its characteristics exist: it is the compound in order to the manufacturing chemistry formula I, or the salt that can accept of its medicine, wherein " Het " is for being connected to the 5-of this quinolinone arbitrarily with carbon atom, 6-, the 5-that is substituted of 7-or 8-position or 6-unit monocycle aromaticity heterocyclic radical; R is connected to 5-, 6-, and 7-or 8-position are H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
1Be hydrogen, cyano group, (C
1-C
4Alcoxyl) carbon back, C
1-C
4Alkyl ,-NR
3R
4Or-CONR
3R
4, R wherein
3, R
4Be respectively H or C
1-C
4Alkyl, or and nitrogen-atoms be connected together, form 5-or 6-unit saturated heterocyclyl, it can contain one and be selected from O, S and N-R
5(R
5Be H or C
1-C
4Alkyl) heterocyclic atom or base;
R
2Be H, C
1-C
4Alkyl or 2-hydroxyethyl; Y is H or CH
3; And the dotted line of 3-position and 4-interdigit to can be or be non-be a key.
14, as the method as described in the claim 1 to 6, its characteristics exist: it is the compound in order to the manufacturing chemistry formula I, wherein R
1, R
2Be H with Y, R is the CH in the 3-position
3, at 3-and 4-interdigit two keys are arranged, and " Het " is connected to the 6-position, is 2,6-lutidine-3-base or 1-methyl-(1H)-1,2,4-triazole-5-base.
15, as the method as described in the claim 14, its characteristics exist: " Het " is 2,6-lutidine-3-base, and its product and NaOH reaction change into sodium salt.
16, a kind of method of making medical component, its characteristics exist: with the compound of the chemical formula I that defined in the claim, or thinner or supporting agent that the salt that can accept of its medicine and medicine can be accepted mix.
17, as the method as described in the claim 16, its characteristics exist: the compound or its salt class of this chemistry formula I is by the obtained person of the method for claim 1 to 15.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85100796 CN85100796A (en) | 1985-04-01 | 1985-04-01 | The preparation method of qualone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85100796 CN85100796A (en) | 1985-04-01 | 1985-04-01 | The preparation method of qualone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN85100796A true CN85100796A (en) | 1986-10-01 |
Family
ID=4791437
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7112653B2 (en) | 1996-12-09 | 2006-09-26 | Inclone Systems, Incorporated | Composition and method for preserving progenitor cells |
| CN103814021A (en) * | 2011-09-15 | 2014-05-21 | 霍夫曼-拉罗奇有限公司 | New dihydroquinoline-2-one derivatives |
| CN103992270A (en) * | 2014-05-13 | 2014-08-20 | 泸州医学院 | Preparation method for 2-chloro-5,6,7,8-tetrahydroquinoline |
| US20150291531A1 (en) * | 2012-11-09 | 2015-10-15 | Rutgers, The State University Of New Jersey | Therapeutic hydroxyquinolones |
| CN105102445A (en) * | 2013-03-08 | 2015-11-25 | 豪夫迈·罗氏有限公司 | New dihydroquinoline-2-one derivatives as aldosterone synthase (cyp1 1 b2 or cyp1 1 b1 ) inhibitors |
| CN105143204A (en) * | 2013-05-27 | 2015-12-09 | 豪夫迈·罗氏有限公司 | New 3,4-dihydro-2h-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds |
| CN105593212A (en) * | 2013-10-17 | 2016-05-18 | 豪夫迈·罗氏有限公司 | New phenyl-dihydropyridine derivatives as aldosterone synthase inhibitors |
-
1985
- 1985-04-01 CN CN 85100796 patent/CN85100796A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7112653B2 (en) | 1996-12-09 | 2006-09-26 | Inclone Systems, Incorporated | Composition and method for preserving progenitor cells |
| CN103814021B (en) * | 2011-09-15 | 2016-12-21 | 霍夫曼-拉罗奇有限公司 | Dihydroquinoline 2 ketone derivatives |
| CN103814021A (en) * | 2011-09-15 | 2014-05-21 | 霍夫曼-拉罗奇有限公司 | New dihydroquinoline-2-one derivatives |
| JP2014527077A (en) * | 2011-09-15 | 2014-10-09 | エフ．ホフマン−ラ ロシュ アーゲー | Novel dihydroquinolin-2-one derivatives |
| US9701638B2 (en) * | 2012-11-09 | 2017-07-11 | Rutgers, The State University Of New Jersey | Therapeutic hydroxyquinolones |
| US20150291531A1 (en) * | 2012-11-09 | 2015-10-15 | Rutgers, The State University Of New Jersey | Therapeutic hydroxyquinolones |
| CN105102445A (en) * | 2013-03-08 | 2015-11-25 | 豪夫迈·罗氏有限公司 | New dihydroquinoline-2-one derivatives as aldosterone synthase (cyp1 1 b2 or cyp1 1 b1 ) inhibitors |
| CN105102445B (en) * | 2013-03-08 | 2018-10-23 | 豪夫迈·罗氏有限公司 | New dihydroquinoline -2- ketone derivatives as aldosterone synthase (CYP11B2 or CYP11B1) inhibitor |
| CN105143204A (en) * | 2013-05-27 | 2015-12-09 | 豪夫迈·罗氏有限公司 | New 3,4-dihydro-2h-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds |
| CN105143204B (en) * | 2013-05-27 | 2018-02-02 | 豪夫迈·罗氏有限公司 | The ketone of 3,4 dihydro 2H isoquinolin 1 and the assimilation compound of 2,3 xylylenimine 1 |
| CN105593212A (en) * | 2013-10-17 | 2016-05-18 | 豪夫迈·罗氏有限公司 | New phenyl-dihydropyridine derivatives as aldosterone synthase inhibitors |
| CN105593212B (en) * | 2013-10-17 | 2019-06-04 | 豪夫迈·罗氏有限公司 | Phenyl-dihydrogen pyridine derivative as aldosterone synthase inhibitors |
| CN103992270A (en) * | 2014-05-13 | 2014-08-20 | 泸州医学院 | Preparation method for 2-chloro-5,6,7,8-tetrahydroquinoline |
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