CN1038840C - para-dinitrogen naphthalene derivative, its preparation method and its medical use - Google Patents

para-dinitrogen naphthalene derivative, its preparation method and its medical use Download PDF

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CN1038840C
CN1038840C CN92113338A CN92113338A CN1038840C CN 1038840 C CN1038840 C CN 1038840C CN 92113338 A CN92113338 A CN 92113338A CN 92113338 A CN92113338 A CN 92113338A CN 1038840 C CN1038840 C CN 1038840C
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amino
alkyl
phenopiazine
dioxo
tetrahydrochysene
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CN1072929A (en
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A·胡斯
R·施米切尼
I·比茨
I·舒曼
L·塔斯基
P·A·洛斯克曼
D·N·斯蒂芬
D·塞德曼
M·克鲁格
D·拉兹
P·霍尔切尔
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Bayer Pharma AG
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Abstract

Para-dinitronaphthalene derivatives of formula I, processes for their preparation and their pharmaceutical use are described:

Description

To phenodiazine bitter edible plant derivative, its method for making and medicinal use thereof
The present invention relates to phenopiazine diketone-carboxylic acid and-phosphonate derivative, its method for making and medicinal use thereof.
Known phenopiazine derivative has affinity to the quisqualat acceptor, and owing to this affinity is suitable for as the medicine for the treatment of central nervous system disease.
Have now found that compound of the present invention is because good to the binding ability of quisqualat acceptor, thereby be better than EP-A-315959 and the disclosed phenopiazine of WO91-13878.
The structural formula of The compounds of this invention is a following formula I:
Figure C9211333800051
In the formula:
R 1For by R 2The C that replaces 1-12-alkyl, by R 2The C that replaces 2-12-alkenyl, by R 2The C that replaces 2-12-alkynyl, by R 2The C that replaces 3-7Cycloalkyl ,-(CH 2) n-C 5-10-aryl, on aryl or alkyl by R 2Replace, or be on heteroaryl or alkyl by R 2Replaced-(CH 2) n-heteroaryl,
R 4For hydrogen, by R 2The C that replaces 1-12-alkyl is by R 2The C that replaces 2-12-alkenyl, by R 2The C that replaces 2-12-alkynyl, become on the alkyl by R at aryl 2(the CH that is replaced 2) n-C 6-12-aryl or be on heteroaryl or alkyl by R 2Replaced-(CH 2) n-heteroaryl,
R 5, R 6, R 7And R 8Can be identical or different, represent hydrogen, halogen, nitro, NR 9R 10, NHCOR 11, SO 2R 12, C 3-7-cycloalkyloxy group, COR 13, cyano group, CF 3, C 1-6-alkyl, C 1-4Alkoxyl group or in case of necessity by cyano group, C 1-4-alkyl or-COO-C 15The imidazoles that-alkyl replaces, perhaps
R 5And R 6Or R 7And R 6Represent a condensed phenyl ring, wherein:
R 2For-CO-R 3Or-PO-XY and R 2Can one or twice identical or different,
N is 0,1,2,3,4 or 5,
R 3Be hydroxyl, C 1-5-alkoxyl group or NR 9R 10,
X and Y are identical or different, expression hydroxyl, C 1-5Alkoxyl group, C 1-4-alkyl or NR 9R 10,
R 9And R 10Identical or different, expression hydrogen, C 1-4-alkyl or form 5 or 6 yuan of saturated heterocycles with nitrogen-atoms is common, this ring also can contain oxygen, sulphur or a nitrogen-atoms,
R 11Be C 1-5Alkyl or phenyl,
R 12Be hydrogen, C 1-4Alkyl, NH 2, N (C 1-4-alkyl) 2With
R 13Be hydroxyl, C 1-5-alkoxyl group, C 1-6-alkyl or NR 9R 10And isomer or salt, wherein,
If R 4, R 5, R 6, R 7And R 5Be hydrogen, R 1Can not for carbamyl ylmethyl, 1-carboxyl-1-phenmethyl or on 1 by-COOH or-COO-C 1-5The straight chain C that-alkyl replaces 1-6-alkyl and
If R 1For on 1 by-COOH or-COO-C 1-5The straight chain C that-alkyl replaces 1-5-alkyl, R 6And/or R 7And R 6And R 8Can not be fluorine, chlorine or bromine and R 4-R 8Be always hydrogen and
If R 1For-CH 2-COOH,
A) R 6And R 7Can not be simultaneously methyl or
B) R 6Or R 7Can not be NO 2And R 4-R 8Be always hydrogen.
Compound of Formula I also comprises possible tautomer formula and comprises E-or the Z-isomer, a chiral centre perhaps occurs, then comprises raceme or enantiomorph.
Substituting group is preferably on 6 and/or 7.
Substituent R 2Can one be positioned on any position of alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl or aryl to secondary identical or differently.
Alkyl refers to a straight or branched alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, heptyl, octyl group, nonyl, decyl, wherein preferred C 1-5-alkyl.
Alkenyl is particularly including the C that can be straight or branched 2-6-thiazolinyl, for example 2-propenyl, crotyl, 3-methyl-2-propenyl, 1-propenyl, 1-butylene base, vinyl.
As alkynyl, specially suitable is ethynyl, 1-proyl, 2-propynyl, the ethyl acetylene base that 2-4 carbon atom arranged.
C 3-7-cycloalkyl finger ring propyl group, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, especially C 3-5-cycloalkyl.
Aryl for example can be phenyl, naphthyl, xenyl and indenyl, especially (CH 2) n-phenyl, n are 0,1 or 2.
As heteroaryl suitable be 5 or 6 yuan of assorted aromatoising substances of 1-3 nitrogen-atoms, for example pyrazoles, imidazoles, pyrrole crop, pyridine, pyrimidine, pyridazine, triazine.
Halogen refers to fluorine, chlorine, bromine and iodine.
Work as R 9And R 10When forming a saturated heterocyclic, for example be meant piperidines, tetramethyleneimine, morpholine, thiomorpholine or piperazine with nitrogen-atoms is common.
If R 1Be C 1-12-alkyl and R 2Be COR 3, R then 5-R 8Be special substituting group such as NO 2, NR 9R 10, NHCOR 11, SO 2R 12, C 3-7-cycloalkyloxy group, COR 12, cyano group, CF 3, C 1-4-alkoxyl group, the imidazoles of Qu Daiing or a condensed phenyl ring in case of necessity.R among the formula I 2The outstanding compound of=-PO-XY has well water-soluble.
Physiology can hold salt and refer to organic and salt mineral alkali, for example easily molten basic metal and alkaline earth salt and N-methylglucosamine, dimethyl glycosamine, ethyl glycosamine, Methionin, 1,6-hexanediamine, thanomin, glycosamine, sarkosine, serinol, three-hydroxyl-methyl-aminomethane, amino-propanediol, Sovak alkali, 1-amino-2,3, the 4-trihydroxybutane.
Formula 1 compound and physiology thereof can hold salt because it is to the affinity of quisqualat acceptor and useful as drug.According to its sphere of action, The compounds of this invention is applicable to treatment because excitability amino acid such as glutaminate or the caused disease of aspartate superfunction.Because these new compounds play the effect of excitability amino acid antagonistic, and ampa receptor there is high specific affinity, they replace specific stimulant (RS)-alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole propionic salt (AMPA) of ampa receptor radioscanning, thereby be specially adapted to treat the especially disease of ampa receptor influence of acidic amino acid acceptor that is stimulated, for example damage after Parkinson's disease, degenerative brain disorder, Huntington Chorea, insane carbuncle, hypoglycemia, psychosis, muscle rigidity, vomiting, pain, anoxia and the local asphyxia.
In test tube with classical in conjunction with the affinity of experimental examination The compounds of this invention to the center ampa receptor.They are combined in usefulness with high-affinity 3On the binding site that H-AMPA demarcates.
In order to check interaction property and efficient in vivo, the situation after checking these compounds to the mouse intravenous administration.After the The compounds of this invention pre-treatment, the spasm that causes owing to intracerebral injection AMPA is according to the different inhibition that obtain in various degree of dosage.
These check results show, these compounds are AMPA antagonistics of strong central role.Therefore, they are applicable to treatment because the disease that the glutaminate metabolism disorder causes.They are specially adapted to treat cerebral ischemia, Parkinson's disease and other disease of mentioning at last joint that various situations take place.
In order to make medicine with The compounds of this invention, be made into a kind of pharmaceutical preparation of form, this medicament is except that activeconstituents, also contain and be suitable for medicine, organic or inorganic inert carrier, for example water, gelatin, Sudan Gum-arabic, lactose, starch, Magnesium Stearate, talcum powder, vegetables oil, polyglycol or the like that intestines are interior or parenteral is used.Pharmaceutical preparation can be solid form, for example as tablet, drageeing, suppository, capsule, also can be liquid form, for example as solution, suspension or emulsion.In case of necessity, they also contain auxiliary agent such as sanitas, stablizer, lubricant or emulsifying agent, are used to change the salt or the buffer substance of osmotic pressure.
Use for parenteral, specially suitable is the aqueous solution that injection solution or suspension, especially active compound form in poly-hydroxy ethoxyquin Viscotrol C.
As carrier system, also can utilize interfacial activity to help to wash salt or animal or plant phosphatide as cholic acid, but also available its mixture and liposome or its component.
For using in the intestines, specially suitablely be tablet, drageeing or contain talcum and/or the capsule of hydrocarbon carrier or tackiness agent that for example lactose, corn or potato starch can be made above-mentioned carrier or tackiness agent.Also can applied in liquid form, for example as juice, also can add sweetener in case of necessity.
The dosage of active substance can change according to the kind of age of the mode of taking, patient and body weight, disease to be treated and severity and other similar factor.Day dosing is 0.5～1000mg, preferred 50-200mg, and wherein this dosage can be used as disposable take individually dosed or was divided into 2 or the dosage repeatedly taken in one day.
Compound of the present invention can known method preparation own.For example obtain the compound of formula I with following method:
A) make the compound of formula II R in the formula 1, R 5, R 6, R 7And R 8Implication is the same, by the cyclisation of active oxalic acid derivative, and when needed with R 4'-X reaction, wherein X is halogen, tosylate, mesylate or fluoroform sulphonate, R 4Outside the dehydrogenation of ' implication with R 4Identical, perhaps
B) make the compound of formula III
Figure C9211333800111
R in the formula 4, R 5, R 6, R 7And R 8Implication is the same, with R 1-X reaction production I compound; and make its ester group saponification where necessary or make the acidic group esterification or amidation or make nitroreduction become amino or make amino alkanisation or acidylate or make amino and halogen or cyano group exchange, perhaps make amino 2-aza-butadiene reaction generate imdazole derivatives with formula IV. U and V are leavings groups in the formula, R 11Be hydrogen, hydrogen base or COOC 1-5-alkyl, R 12Be hydrogen C 1-5-alkyl, perhaps separating isomerism body or formation salt.
With active oxalic acid derivative make the cyclisation of formula II compound can one step or also can finish in two steps.The preferred two-step approach that adopts wherein makes diamines and a kind of oxalic acid derivative such as barkite half muriate for example for example react in the presence of triethylamine, pyridine, Honig alkali or the diethylin pyridine in a kind of alkali such as organic amine in tetrahydrofuran (THF), diethyl ether or the methylene dichloride in polar solvent such as dimethyl formamide or ring or acyclic ethers or halohydrocarbon.Cyclisation subsequently can wherein add alcohol in alkalescence or also can be in acidity but carry out in the preferred acidic medium in solvent.
Substituent R 1And R 4Importing undertaken by common alkylation, wherein make phenopiazine diketone and R 1-or R 4-X reacts in aprotic solvent under room temperature or high temperature in the presence of alkali, and X is tosylate, mesylate or particularly Triflat or halogen in the formula.Adding P 1-or R 4Before-the X, also can produce negatively charged ion.As alkali suitable be for example as salt of wormwood sodium hydroxide, the basic cpd that the alkali alcoholate is such and particularly metal hydride as the sodium hydride.Basic cpd is reacted under condition of phase transition.If obtain being with substituent R 1And R 4, the mixture of compound, available common method is separated.
The solvent that is applicable to this reaction is aprotic polar solvent such as dimethyl formamide, N-Methyl pyrrolidone, but also available cyclic ethers such as diox or tetrahydrofuran (THF).
If at process program b) in use 2Mol R 1-X reacts under other similar reaction conditions, then introduces substituent R simultaneously 1And R 4
The saponification of the ester group that carries out subsequently in case of necessity can or preferably be carried out under acidic conditions in alkalescence, wherein until under the high temperature of reaction mixture boiling point in the presence of acid as the high dense moisture salt in for example hydrolysis in trifluoracetic acid or the alcohol of solvent.Phosphonic acid ester is preferably by in for example heating or by handling hydrolysis with the processing of trimethyl silyl bromine and with the aftertreatment water in the concentrated hydrochloric acid of the dense aqueous acids of height.
Carboxylic acid or phosphonic esterification are finished in a manner known way with corresponding alcohol in acid or in the presence of active acid derivant.For example can consider chloride of acid, acylimidazole thing or acid anhydrides as active acid derivant.Phosphonic acids can react with the ortho ester of correspondent alcohol.But react also XianCheng's ester with the adduct and the correspondent alcohol of dicyclohexyl carbodiimide.Can produce methyl esters with diazomethane reaction.
For example chloride of acid, mixed anhydride, imidazoles thing or trinitride and corresponding amine at room temperature react and carry out by making free acid or its reactive derivative in amidation.
Nitro become amino be reflected in the polar solvent under room temperature or the high temperature under hydrogen-pressure catalysis carry out.Catalyzer available metal such as Raney nickel or noble metal catalyst such as palladium or platinum are in case of necessity on carrier.Also available ammonium formiate replaces hydrogen with known manner.Reductive agent can use as the metal hydride of complexing equally as zinc chloride-II or titanium chloride-III, in case of necessity in the presence of heavy metallic salt.It may be favourable introducing ester group before reduction.
If need make aminoalkyl groupization, can for example use the alkyl halide alkylation in the usual way.Also can carry out reduction amination with aldehyde and reductive agent such as sodium cyanoborohydride.Acylations is carried out with currently known methods.For example in water-bearing media, in the presence of alkali, react with corresponding acid anhydrides or acyl halide.
The introducing of cyano group can be finished by means of the Sandmeyer reaction; For example can make by the diazonium salt of aminocompound and nitrite intermediate formation and prussiate in the presence of cupric cyanide-I or and K 2Ni (CN) 4Reaction.
Introducing halogens chlorine, bromine or iodine through amino can be anhydrous or have in the presence of the water and carry out; For example use aqueous Sandmeyer method, make with nitrite in the middle of the diazonium salt that generates in the presence of corresponding hydrochlorate or bromine hydracid, reacting or reacting with cupric chloride (I) or cupric bromide with potassiumiodide.Non-water law is reacted hydrogenchloride in a known way in the presence of aprotic solvent such as dimethyl formamide with i-nitrous acid penta vinegar and for example methylene iodide or bromofom.The introducing of fluorine is for example finished by the balz-sehiemann reaction of diazonium tetrafluoroborate.
Amino 2-aza-butadiene with formula IV generates the acid existence that is reflected at of imdazole derivatives to carry out under 0 to 150 ℃ of temperature down.Volatile groups U and V can be identical or different; Specially suitable is C 1-3-dialkylamine such as dimethyl-, diethyl-and the cyclammonium such as the tetramethyleneimine of dipropylamine.
This reaction is for example carried out like this: sulfonamide derivatives and aza-diene are at room temperature stirred earlier in organic acid such as formic acid, acetic acid, propionic acid or trifluoracetic acid, be heated to the boiling point (until about 120 ℃) of reaction mixture then.
Acid can be simultaneously as reaction reagent and solvent.But also can add solvent for example alcohol, ether, ketone, ester such as vinyl acetic monomer, hydrocarbon such as toluene or halon such as tetracol phenixin.
The amount of acid can coup on a large scale in, but answers excessive application.The excessive 3-10 of preferred acid is a benchmark with amine and aza-diene doubly.
Isomer mixture can be with common methods for example crystallization, chromatographic separation or change into diastereomer and for example form salt and separate and to reflect body or E/Z isomer in pairs.
Prepare salt in common mode, the solution that wherein makes formula I compound and equivalent or excessive basic metal or alkaline earth metal compound (in case of necessity in solution) mix, and separate throw out to occur or handle this solution in common mode.
Because do not describe the preparation of starting compound, they are known or are similar to known compound or the preparation of available method described here.
For example, the compound of formula II can prepare like this: with the method preparation 2 of Sanger, 4-dinitrobenzene arylamines, make the preferred neighbour of neighbour-halogen-nitryl aromatic thing-fluoro-nitryl aromatic thing for example dinitrofluorobenzene in the aqueous solution, in the presence of alkali such as yellow soda ash or sodium bicarbonate, to reflux temperature, react in 0 ℃ with amino acid derivative, subsequently the reduction.This reaction also can be migrated on the 2-nitro halogenide of other replacement.Ullman reaction by dinitrochlorobenzene and aromatic amine also can obtain the diarylamine based compound.To this reaction, can adopt high boiling solvent such as dimethyl formamide or collidine and solid carbonic acid potassium and comminuted steel shot as alkali.Also can or carry out standard reductive alkylation and prepare corresponding o-Nitraniline by alkylation with the aldehyde that replaces.The reduction of adjacent nitro is subsequently optionally finished under room temperature or high temperature in polar solvent in the presence of ammonia and the ammonium chloride by S-WAT in the presence of a plurality of nitros.Under several situations, earlier with the ester reaction, in the end to make its hydrolysis be favourable a step.
Chiral Separation in the end step or the intermediate stage by the photoactivation auxiliary alkali for example brucine or 1-phenylethylamine finish, perhaps also can carry out chromatographic separation through the photoactivation carrier substance.But enantiomorph also can prepare by making corresponding photoactivation amino acid synthesize also and then handle amino nitryl aromatic material as mentioned above by the Sanger method with corresponding fluorine nitryl aromatic material.
Should be noted that to need not to do further to explain that those skilled in the art just can be with reference to above-mentioned explanation and full and effective implementation the present invention.Therefore, preferred specific embodiments only is illustrative, and limits open or enforcement of the present invention never in any form.
Above-mentioned all patent applications, whole disclosures of patent and publication and corresponding German patent application P4d135871.6 and P4224200.2 are all as this paper reference.
With embodiment in detail method of the present invention is described in detail below:
Example 1
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-methyl benzoate and
3-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-methyl benzoate
With 1.03g (nM) 6-nitro-2,3-dioxo-l, 2,3,4-tetrahydrochysene phenopiazine is at N 2Flow down and get rid of and at room temperature put into the 50ml dimethyl formamide under the moisture condition.330mg (11mM) sodium hydride (80%) is divided into three parts of addings.At room temperature stirred then 1 hour.Splashing into the 3-bromomethyl-benzoic acid methyl ester that 1.26g (5.5mM) is dissolved in the 5ml dimethyl formamide stirs
Figure C9211333800151
Hour.Concentrate the back and in acetic acid water/vinegar ester ethyl ester, distribute residue.Separate organic phase drying, filtration and concentrated.Use methylene dichloride: the silica gel of ethanol=95: 5 carries out chromatographic separation to residue.3-(the 6-nitro-2 that does not further purify except 211mg, 3-dioxo-l, 2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-methyl benzoate outside, also obtain the molten point of 222mg and be 265～267 ℃ 3-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-methyl benzoate.
Prepared in a similar manner:
4-(6-nitro-2,3-dioxo-1,2,3 ,-tetrahydrochysene phenopiazine-1-ylmethyl)-methyl benzoate, molten point: 308-314 ℃;
4-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-methyl benzoate, molten point:＞300 ℃;
2-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-ethyl benzoate, molten point: 279 °/283-284 ℃;
2-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-ethyl benzoate (do not purify promptly and then handle);
1-(3-methoxycarbonyl-2-propenyl)-6-nitro phenopiazine-2, and 3-(1H, 4H)-diketone, molten point: 258-265 ℃ and decomposition.
1-(3-oxyethyl group carbonyl propyl group)-6-nitro phenopiazine-2, and 3-(1H, 4H)-diketone, molten point: 215-217 ℃;
1-(3-oxyethyl group carbonyl propyl group)-7-nitro phenopiazine-2, and 3-(1H, 4H)-diketone, molten point: 215-217 ℃;
4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenyl-phosphonic acid diethyl ester, molten point: 114 ℃/129-131 ℃;
4-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenyl-phosphonic acid diethyl ester (do not purify promptly and handle);
3-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-third-1-alkene-1-diethyl phosphonate;
3-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-third-1-alkynes-1-diethyl phosphonate;
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-propane-1-diethyl phosphonate;
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane carboxylic acid tert-butyl ester.
Example 2
Add twice methyl-3-bromo methyl acid ester, other reaction process is identical with example 1, separablely in addition goes out 503mg 3-[4-(3-methoxycarbonyl benzyl)-6-nitro-2,3-dioxy-1,2,3,4-tetrahydrochysene phenopiazine-1-yl]-phenylformic acid, fusing point: 238-240 ℃.
Similar making:
4-[4-(4-methoxycarbonyl benzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl]-methyl benzoate, fusing point: 225-227 ℃;
2-[4-(2-ethoxy carbonyl benzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl]-ethyl benzoate, fusing point: 230-234 ℃;
1,4-pair-(3-methoxycarbonyl-2-propenyl)-6-nitro phenopiazine-2,3-(1H, 4H)-diketone, fusing point: 181-183 ℃.
Example 3
A) 4-(2, the 4-dinitrophenyl)-Methyl anthranilate
With 1.01g (5mM) 1-chloro-2,4-dinitrobenzene, 1.01g (6mM) 4-subcutin, 13mg (0.2mM) copper powder and 961mg (7mM) salt of wormwood stirred 25 minutes with getting rid of under the moisture condition at argon gas under 180 ℃ of hot temperature of bath in the absolute dimethyl formamide of 5ml.
Put into water after concentrating,, shake extraction, with organic phase drying, filtration and concentrated with vinyl acetic monomer with ammonia furnishing alkalescence.Use hexanaphthene: the silica gel of vinyl acetic monomer=8: 2 carries out chromatographic separation.Obtain 768mg 4-(2, the 4-dinitrophenyl)-subcutin, fusing point is 99-102 ℃.
Make in a similar manner:
3-(2, the 4-dinitrophenyl)-subcutin, fusing point: 108-110C;
3-(2, the 4-dinitrophenyl)-aminophenyl phosphinic acid ethyl ester does not purify promptly and then handles;
2-(2, the 4-dinitrophenyl)-subcutin does not purify promptly and then handles.
B) 4-(2-amino-4-nitrophenyl amino)-ethyl benzoate
566mg (1.7mM) 4-(2,4-dinitrophenyl amino)-ethyl benzoate, 761mg (12.2mM) ammonium chloride, 0.68ml strong aqua, 15ml ethanol and 6ml distilled water (are bathed 90 ℃ of temperature) under 78 ℃ interior temperature put together.Three parts of addings of branch 1.27g (5.68mM) S-WATs (35%), restir 1 hour.At room temperature extract throw out out, then water washs with ether again.Obtain 535mg 4-(2-amino-4-nitrophenyl amino)-ethyl benzoate crude product (do not purify promptly and then handle).
Make in a similar manner:
3-(2-amino-4-nitrophenyl amino)-ethyl benzoate, fusing point: 145-150 ℃;
3-(2-amino-4-nitrophenyl amino)-phenyl-phosphonic acid ethyl ester, fusing point: 160-163 ℃.
C) 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl benzoate
582mg (2.3mM) 4-(2-amino-4-nitrophenyl amino)-ethyl benzoate and 488mg (4.8mM) triethylamine are put into+4 ℃ of 27ml anhydrous tetrahydro furans of bathing under the temperature under argon gas and eliminating moisture condition.Drip a kind of solution that is made into by 659mg (4.8mM) ethyl oxalate muriate and 8ml anhydrous tetrahydro furan, and at room temperature stirred 2 hours.Add 0.2ml triethylamine and 0.1ml ethyl oxalate muriate then, at room temperature stirred again 1 hour.Leach throw out, concentrated filtrate.In water/vinyl acetic monomer, distribute.Concentrate organic phase.Bathing under temperature and the reflux conditions resistates boiling 2 hours in 25ml 1-N hydrochloric acid and 25ml ethanol.Extract sedimentary product out, wash with water and drying.Obtain: 220mg 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl benzoate (do not purify and promptly continue to use).
Make in a similar manner:
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl benzoate, fusing point: 258-263 ℃;
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-phenyl-phosphonic acid ethyl ester.
Example 4
A) 2-(2, the 4-dinitrophenyl)-benzaminic acid
1.37g (10mM) 2-benzaminic acid and 2g (18.7mM) yellow soda ash are bathed under the temperature under vigorous stirring and 1.86g (10mM) 2 in 40 ℃ in 40ml water, and the 4-dinitrofluorobenzene mixes, and stirs 2 hours.Dilute throw out with about 400ml water, and make it precipitation with 4-N HCl.Extract product out, washing is also dry.Obtain 2.8g 2-(2,4-dinitrophenyl amino) phenylformic acid, fusing point: 266-270 ℃.
Make in a similar manner:
3-(2,4-dinitrophenyl amino)-propionic acid, fusing point: 134-137 ℃;
4-(2,4-dinitrophenyl amino)-phenyl-phosphonic acid, decomposes simultaneously by fusing point: 271-272 ℃;
2-(2,4-dinitrophenyl amino)-phenyl-phosphonic acid does not purify and promptly continues processing;
(2,4-dinitrophenyl amino)-methane phosphonic acid, fusing point: 225-227 ℃;
2-(2,4-dinitrophenyl amino)-ethyl phosphonic acid does not purify and promptly continues processing;
3-(2,4-dinitrophenyl amino)-phenyl-phosphonic acid;
(2-nitro-1-naphthyl amino)-methane phosphonic acid;
(1-nitro-2-naphthyl amino)-methane phosphonic acid;
1-(2-nitro-1-naphthyl amino)-ethane-1-phosphonic acids;
1-(1-nitro-2-naphthyl amino)-ethane-1-phosphonic acids;
(2-nitro-4-trifluoromethyl-phenyl amino)-methane phosphonic acid;
1-(2-nitro-4-trifluoromethyl-phenyl amino)-ethane-1-phosphonic acids;
1-(2,4-dinitrophenyl amino)-ethane-1-phosphonic acids;
3-(2,4-dinitrophenyl amino)-propane-1-phosphonic acids;
4-(2,4-dinitrophenyl amino)-butane-1-phosphonic acids;
(2-nitro-4-fluorophenyl amino)-methane phosphonic acid;
(2-nitro-4-chloro-phenyl-amino)-methane phosphonic acid;
(2-nitro-4-bromophenyl amino)-methane phosphonic acid;
(2-nitro-4-methyl phenyl amino)-methane phosphonic acid;
1-(2-nitro-4-fluorophenyl amino)-ethane-1-phosphonic acids;
1-(2-nitro-4-chloro-phenyl-amino)-ethane-1-phosphonic acids;
1-(2-nitro-4-bromophenyl amino)-ethane-1-phosphonic acids;
1-(2-nitro 4-aminomethyl phenyl amino)-ethane-1-phosphonic acids;
1-phenyl-1-(2-nitro-4-trifluoromethyl-phenyl amino)-methane phosphonic acid;
1-methyl 1-(2-nitro-4-trifluoromethyl-phenyl amino)-ethane-1-phosphonic acids;
1-(2-nitro-4-trifluoromethyl-phenyl amino)-hexane-1-phosphonic acids;
1-methyl-2-(2-nitro-4-trifluoromethyl-phenyl amino)-ethane-1-phosphonic acids;
2-(2-nitro-4-trifluoromethyl-phenyl amino)-propane-1-phosphonic acids;
1-methyl-2-(2-nitro-4-trifluoromethyl-phenyl amino)-propane-1-phosphonic acids;
1-(2-nitro-4-trifluoromethyl-phenyl amino)-cyclopropane-1-phosphonic acids;
(+)-1-(2-nitro-4-trifluoromethyl-phenyl amino)-ethane-1-phosphonic acids;
(-)-1-(2-nitro-4-trifluoromethyl-phenyl amino)-ethane-1-phosphonic acids;
P, P-dimethyl-(2,4-dinitrophenyl amino)-methane phosphine oxygen;
P-methyl-(2,4-dinitrophenyl amino)-methane phosphonic acid;
1-[5-(imidazoles-1-yl)-2,4-dinitrophenyl amino]-methyl-phosphorous acid;
1-[5-(imidazoles-1-yl)-2-nitro-4-trifluoromethyl amino]-methyl-phosphorous acid;
B) 1-[5-(imidazoles-1-yl)-2,4-dinitrophenyl amino]-ethane-1-phosphonic acids
With 600mg 5-fluoro-2, the 2-dinitrofluorobenzene is put into 30ml water and 10ml ethanol under 40 ℃, and splashes into a kind of solution that is formed with 600mg yellow soda ash in 10ml water by 376mg racemic amino ethylphosphonic acid.Under temperature, stirred 1.5 hours.Extract with acetic acid after steaming ethanol.To water admixture 200mg imidazoles, be heated to 110 ℃ 2 hours, after this add the 200mg imidazoles again, and be heated to 110 ℃ 2 hours.Use the 4N hcl acidifying, suction strainer goes out insolubles, uses the vinyl acetic monomer washing filtrate.Concentrated aqueous phase, well-done with ethanol.Concentrate ethanolic extract, and use methyl alcohol: butanols: water: ammonia=75: 25: 17: 3 silica gel carries out chromatographic separation.Obtain 300mg 5-(imidazoles-1-yl)-2,4-dinitrophenyl-(1-ciliatine).
C) 2-(2-amino-4-nitrophenyl amino)-phenylformic acid
1.80g (6mM) 2-(2,4-dinitrophenyl amino)-phenylformic acid, 2.66g (42.6mM) ammonium chloride, 2.4ml strong aqua, 52ml ethanol and 21ml distilled water (are bathed temperature for 90 ℃) under the temperature in 78 ℃ put together.3 parts of addings of branch 4.44g (20mM) S-WATs (35%) and stirred 1 hour.At room temperature extract throw out out, water and ether washing successively.Filtrate being condensed into contained water, with the extraction of vinegar ester ethyl ester shake.To organic phase dehydration, filtration and concentrated.Contain water and with its extraction with the 1N hcl acidifying.Obtain 1.1g 2-(2-amino-4-nitrophenyl amino)-phenylformic acid (do not purify and promptly further use).
The preparation in a similar manner and the i.e. continuation processing of purifying:
3-(2-amino-4-nitrophenyl amino)-propionic acid;
4-(2-amino-4-nitrophenyl amino)-phenyl-phosphonic acid;
2-(2-amino-4-nitrophenyl amino)-phenyl-phosphonic acid;
(2-amino-4-nitrophenyl amino)-methyl-phosphorous acid;
(2-amino-4-nitrophenyl amino)-ethylphosphonic acid;
1-(2-amino-4-nitrophenyl amino)-ethane-1-phosphonic acids;
3-(2-amino-4-nitrophenyl amino)-propane-1-phosphonic acids;
4-(2-amino-4-nitrophenyl amino)-butane-1-phosphonic acids;
1-(2-amino-4-trifluoromethyl amino)-cyclopropane-1-phosphonic acids;
P, P-dimethyl-(2-amino-4-nitrophenyl amino)-first phosphine oxygen;
P-methyl-(2-amino-4-nitrophenyl amino)-methane phosphonic acid;
1-[5-(imidazoles-1-yl)-2-amino-4-nitrophenyl amino]-methyl-phosphorous acid.
D) (2-amino-4-trifluoromethyl amino)-methane phosphonic acid
With 894mg (2-NO 2-4-trifluoromethyl amino)-methane phosphonic acid and 3g Raney nickel mix in 180ml ethanol mutually, and hydrogenation 3 hours under room temperature and hydrogen normal pressure.By suction strainer throw out in the catalyzer, and concentrated filtrate.Purify and be about to its adding step D.
Make in substantially similar mode:
1-(2-amino-1-naphthyl amino)-ethane-1-phosphonic acids;
1-(1-amino-2-naphthyl amino)-ethane-1-phosphonic acids;
1-(2-amino-1-naphthyl amino)-methane phosphonic acid;
1-(1-amino-2-naphthyl amino)-methane phosphonic acid;
1-(the amino 4-trifluoromethyl of 2-amino)-ethane-1-phosphonic acids;
1-(2-amino-4-trifluoromethyl amino)-methane-1-phosphonic acids;
(2-amino-4-aminomethyl phenyl amino)-methane phosphonic acid;
1-(2-amino-4-aminomethyl phenyl amino)-ethane-1-phosphonic acids;
1-phenyl-1-(2-amino-4-trifluoromethyl amino)-methane phosphonic acid;
1-methyl isophthalic acid-(2-amino-4-trifluoromethyl amino)-ethane-1-phosphonic acids;
1-(2-amino-4-trifluoromethyl amino)-hexane-1-phosphonic acids;
1-methyl-2-(2-amino-4-trifluoromethyl amino)-ethane-1-phosphonic acids;
2-(2-amino-4-trifluoromethyl amino)-propane-1-phosphonic acids;
1-methyl-2-(2-amino-4-trifluoromethyl amino)-propane-1-phosphonic acids;
(+)-1-(2-amino-4-trifluoromethyl amino)-ethane-1-phosphonic acids;
(-)-1-(2-amino-4-trifluoromethyl amino)-ethane-1-phosphonic acids;
(4-chloro-2-aminophenyl amino)-methane phosphonic acid;
1-(4-chloro-2-aminophenyl amino)-ethane-1-phosphonic acids;
(4-fluoro-2-aminophenyl amino)-methane phosphonic acid;
[5-(imidazoles-1-yl)-4-trifluoromethyl-2-aminophenyl amino]-methyl-phosphorous acid;
1-(4-fluoro-2-aminophenyl amino)-ethane-1-phosphonic acids;
D) 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-propionic acid
211mg (0.9mM) 3-(2-amino-4-nitrophenyl amino)-propionic acid is put into the anhydrous tetrahydrofuran (THF) of 20ml with 200mg (2mM) triethylamine under+4 ℃ of bath temperature and argon gas and eliminating moisture condition.Drip a kind of solution that is made into by 270mg (2mM) ethyl oxalate muriate and 5ml anhydrous tetrahydro furan, and at room temperature stirred 2 hours.Adding 0.05ml triethylamine and 0.05 ethyl oxalate muriate more also at room temperature stirred 1 hour.Leach throw out, concentrated filtrate.In water and vinegar ester ethyl ester, distribute.Concentrate organic phase.Residue is put into 15ml ethanol and 15ml 1N hydrochloric acid, and the backflow boiling is 2 hours under 110 ℃ of bath temperature.The concentrating and precipitating thing adds a little water and suction strainer.Obtain 120mg 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-propionic acid, fusing point: 148-156 ℃ and decomposition.
Make in a similar manner:
2-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-phenylformic acid, fusing point:＞255 ℃;
4-(6-nitro-2,3 dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-phenyl-phosphonic acid, fusing point:＞252 ℃;
2-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-phenyl-phosphonic acid, fusing point:＞310 ℃;
(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid, decomposes simultaneously by fusing point: 180-200 ℃
2-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl phosphonic acid, decomposes simultaneously by fusing point: 304-308 ℃
2,3-dioxo-1,2,3,4-tetrahydro benzo (f)-phenopiazine-4-base methane phosphonic acid;
2,3-dioxo-1,2,3,4-tetrahydro benzo (f)-phenopiazine-4-base ethane-1-phosphonic acids;
2,3-dioxo-1,2,3,4-tetrahydro benzo (f)-phenopiazine-1-base methane phosphonic acid;
2,3-dioxo-1,2,3,4-tetrahydro benzo (f)-phenopiazine-1-base ethane-1-phosphonic acids;
(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid, fusing point: 202 ℃
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethyl phosphonic acid, fusing point: 274 ℃
1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids, fusing point: 297-300 ℃, and decompose;
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-propane-1-phosphonic acids, fusing point: 200 ℃, and bubble
4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-butane-1-phosphonic acids, fusing point: 285-287 ℃
(6-fluoro-2,3-dioxo 1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid;
(6-chloro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid;
(6-bromo-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid;
(6-methyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid;
1-(6-fluoro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids; Fusing point: 259 ℃
1-(6-chloro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids
1-(6-bromo-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids
1-(6-methyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-1-phenyl-methane-1-phosphonic acids, fusing point: 245 ℃
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-1-methyl-ethane-1-phosphonic acids,
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-hexane-1-phosphonic acids,
1-methyl-2-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids;
2-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-propane-1-phosphonic acids,
1-methyl-2-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-propane-1-phosphonic acids;
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-cyclopropane-1-phosphonic acids,
(+)-1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids, [α 546 207.4 ° of (C=0.505 of]=+; H 2O);
(-)-1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids, [α 546 205.9 ° of (C=0.510 of]=-; H 2O);
P-(methyl-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid, fusing point: 320-325 ℃, and decompose;
P, P-dimethyl-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl) first phosphine oxygen, fusing point: 325-330 ℃, and decompose;
6-(nitro-7-(imidazoles-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methyl-phosphorous acid,
6-(trifluoromethyl-7-(imidazoles-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methyl-phosphorous acid;
Example 5
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid
211mg (0.6mM) 3-(6-nitro-2,3-dioxo-1,2,3,4 one tetrahydrochysene phenopiazine-1-ylmethyls)-methyl benzoate is put into 4ml4N hydrochloric acid, mix the 4ml trifluoracetic acid and bathe under the temperature and stir at 110 ℃ Hour.Dilute with water and suction strainer behind the throw out cool to room temperature.Water and ethanol filter wash are also dry.Obtain 179mg 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-phenylformic acid, fusing point:＞330 ℃.
Make in a similar manner:
3-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, fusing point:＞330 ℃;
3-[4-(3-carboxyl benzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl]-phenylformic acid, fusing point: 298-300 ℃;
2-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, decomposes simultaneously by fusing point: 329-334 ℃
2-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, fusing point: 328-330 ℃,
2-[4-(2-carboxyl benzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl]-phenylformic acid, fusing point:＞300 ℃;
4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, fusing point:＞310 ℃;
4-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, fusing point: 320-324 ℃, and decompose
4-[4-(4-carboxymethyl benzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl]-phenylformic acid, fusing point:＞310 ℃;
4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, fusing point:＞345 ℃;
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenylformic acid, fusing point:＞250 ℃;
1-(3-carboxyl-2-propenyl)-6-nitro phenopiazine-2, and 3-(1H, 4H)-diketone, fusing point: 242-243 ℃
1,4-pair-(3-carboxyl-2-propenyl)-6-nitro phenopiazine-2,3-(1H, 4H)-diketone, fusing point: 241-247 ℃, and decompose
1-(3-carboxylic propyl group)-6-nitro phenopiazine-2, and 3-(1H, 4H)-diketone, fusing point: 230-232 ℃
1-(3-carboxylic propyl group)-7-nitro phenopiazine-2,3-(1H, 4H)-diketone, fusing point: 325-327 ℃, and decompose
1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-acetic acid, fusing point: 320 ℃
Example 6
4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenyl-phosphonic acid
With the backflow boiling 2 hours in the 6ml concentrated hydrochloric acid of 582mg (1.4mM) 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-methyl)-phenyl-phosphonic acid ethyl ester.Cooling back dilute with water throw out and suction strainer.Dry cake.Obtain 253mg 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenyl-phosphonic acid, fusing point is 253-265 ℃, and decomposes.
Make in a similar manner:
4-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-ylmethyl)-phenyl-phosphonic acid, fusing point:＞250 ℃
3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-phenyl-phosphonic acid, fusing point: 304-307 ℃, and decompose
3-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-third-1-alkynes-1-phosphonic acids
3-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-third-1-alkene-1-phosphonic acids
Example 7
(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid-second and diethyl ester
Splash into 0.29ml (476mg) thionyl hydrogen at the 300mg in dissolving in the absolute dimethyl formamide of 5ml under-15 ℃ (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid.After adding end, under+4 ℃ of bath temperature, stirred throw out 20 minutes.Then add 0.35ml (276mg) ethanol, and at room temperature stirred 1.5 hours to throw out.
Behind the vacuum concentration, use toluene: vinyl acetic monomer: the silica gel of water=10: 10: 1 carries out chromatographic separation.Obtain 100mg (6-nitro-2,3-dioxo-1,2,3 earlier, 4-tetrahydrochysene-phenopiazine-1-yl)-and the methane phosphonic acid diethyl ester, fusing point is 220-260 ℃, obtains 36mg (6-nitro-2,3-dioxo-1 subsequently, 2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid-ethyl ester, fusing point is 197 ℃.
Make in a similar manner:
(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid-list-N, N-dimethylformamide and two-N, N-dimethylformamide.
Example 8
1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid
300mg 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid is dissolved in the 60mg methyl alcohol, under nitrogen atmosphere, successively mixes 50mg Pd/c (10%), 300mg ammonium formate and 18ml water and heated 1 hour to 80 ℃.The cooling back is by leaching evaporated filtrate and lyophilize residue in the catalyzer.Obtain 200mg1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid, it is shaped as white solid.
Preparation in a similar manner:
1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl phosphonic acid.
Example 9
1-[6-(4-ethoxycarbonyl-imidazoles-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl]-methane phosphonic acid
Make 200mg 1,4-Bis-dimethylamino-3-ethanoyl-2-aza-butadiene-1,4 mixes under slight cooling with the 3ml Glacial acetic acid, and at room temperature stirs 10 minutes.Then add 180mg and be dissolved in 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-the yl)-methane phosphonic acid of 3ml Glacial acetic acid, at room temperature stir a night.Heat 4 hours to 100 ℃ bath temperature then.Obtain 50mg buttery 1-[6-(4-ethoxycarbonyl-imidazoles-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl after concentrating]-methane phosphonic acid.
Make in a similar manner:
1-[6-(4-cyano group-5-methyl-imidazoles-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid.
Example 10
1-(6-iodo-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid
180mg 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid is splashed in the sulfuric acid of 10ml 25%.Stir the suspension that forms a kind of salt after 5 minutes, it is cooled to 0 ℃.Splash into a kind of solution that in 2ml water, forms by the 60mg Sodium Nitrite to it.Stirring 15 minutes afterreaction mixtures at 0 ℃ almost dissolves.Splash into a kind of solution that in 2ml water, forms by the 180mg potassiumiodide to it.Remove ice bath and be heated to 100 ℃.With in the concentrated ammonia solution and refrigerative reaction mixture and be evaporated to dried.With ethanol and the well-done residue of less water, filter and concentrated filtrate.Water: after the silanized silica gel of methyl alcohol=4: 1 carries out chromatographic separation, obtain 40mg 6-iodo-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-base-methane phosphonic acid, fusing point: 295-297 ℃.
Obtain with similar and the known similar fashion of document:
1-(6-iodo-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids;
1-(6-bromo-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid;
1-(6-bromo-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-ethane-1-phosphonic acids;
1-(6-cyano group-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-yl)-methane phosphonic acid;
Example 11
6-iodo-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-base-methane phosphonic acid
Make 100mg6-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-base-methane phosphonic acid is dissolved in the concentrated hydrochloric acid and is concentrated into dried.
The hydrogenchloride of well dehydration is put into the dimethyl formamide of 10ml, successively mix 4ml methylene iodide and 0.6ml Isopentyl nitrite.Bathe all dissolvings after 2 hours under the temperature at 80 ℃.Vacuum concentration in bulb, water: methyl alcohol=make eluent at the silica gel 60 (anti-phase) of silanization residue carried out chromatographic separation at 4: 1.Obtain 20mg 6-iodo-2,3-dioxo-1,2,3,4-tetrahydrochysene-phenopiazine-1-base-methane phosphonic acid, fusing point: 295-297 ℃.
Make in a similar manner:
6-bromo-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-base-methane phosphonic acid;
1-(6-iodo-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl phosphonic acid;
1-(6-bromo-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-ethyl phosphonic acid;
Example 12
100mg 1-(δ-amino-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid is dissolved in the 20ml water, the pH value is adjusted to 9.5, add the 0.2ml acetic anhydride with saturated sodium carbonate solution.Stir after 1 hour and to concentrate, in the least possible water, dissolve, send into (IR120, strongly-acid) in the ion-exchanger water wash-out: collect corresponding fraction, concentrate and dry.Obtain 110mg 1-(6-acetamido-2,3-dioxo-1,2,3,4-tetrahydrochysene phenopiazine-1-yl)-methane phosphonic acid, fusing point: 120 ℃.
Repeat the foregoing description and obtained success with used reactant and condition in generality or the reactant of the present invention that specifies and/or operational condition replacement the foregoing description.
According to the above description, those skilled in the art can be easy to determine essential characteristic of the present invention, and in its design and scope, also can make various changes and modifications to adapt to different purposes and condition to the present invention.

Claims (1)

1. the preparation method of formula I compound and salt thereof or isomer
Figure C9211333800021
In the formula:
R 1For by R 2The C that replaces 1-12-alkyl, by R 2The C that replaces 2-12-alkenyl, by R 2The C that replaces 2-12-alkynyl, by R 2The C that replaces 3-7Cycloalkyl, on phenyl or alkyl by R 2Replace-(CH 2) n-phenyl,
R 4For hydrogen, by R 2The C that replaces 1-12-alkyl, by R 2The C that replaces 2-12-alkenyl, by R 2The C that replaces 2-12-alkynyl, on phenyl or alkyl by R 2(the CH that replaces 2) n-phenyl,
R 5, R 6, R 7And R 8Identical or different, represent hydrogen, halogen, nitro, NR 9R 10, NHCOR 11, cyano group, CF 3, C 1-6-alkyl or in case of necessity by cyano group, C 1-4Alkyl or-COOC 1-6Imidazoles or R that-alkyl replaces 5And R 6Or R 7And R 8Form a condensed phenyl ring, wherein
R 2For-CO-R 3Or-POXY and R 2Can one or twice identical or different,
N is 0,1,2,3,4 or 5,
R 3Be hydroxyl, C 1-6-alkoxyl group,
X and Y are identical or different, are hydroxyl, C 1-6-alkoxyl group, C 1-4-alkyl or NR 9R 10,
R 9And R 10Identical or different, be hydrogen, C 1-4-alkyl or form an imidazole ring with nitrogen-atoms,
R 11Be C 1-6-alkyl,
And wherein, if R 4Be hydrogen and R 1Be R 2=-COR 3The C that replaces 1-12Alkyl or by R 2=-COR 3Replace-(CH 2) n-phenyl, then R 5, R 6, R 7And R 8Be not hydrogen, NO 2, halogen or alkyl,
It is characterized in that, a) make formula II compound
R in the formula 1, R 5, R 6, R 7And R 8Implication is the same, with the cyclisation of active oxalic acid derivative, and where necessary with R 4,-X reaction, wherein X is halogen, tosylate, mesylate or fluoroform sulphonate, R 4' implication and R 4Identical, but except the hydrogen, perhaps
B) make the compound of formula III R in the formula 4, R 5, R 6, R 7And R 8Implication is the same, with R 1The compound of-X reaction production I, and saponification ester group or esterification or amidation acidic group or make nitroreduction become amino or make aminoalkyl groupization or acidylate or make amino with halogen or cyano group exchange or make 2-aza-butadiene amino and formula IV where necessary
U and V represent leavings group in the formula, R 11Be hydrogen, cyano group or COOC 1-6-alkyl, R 12Be hydrogen or C 1-6-alkyl, reaction generate imdazole derivatives or separating isomerism body or form salt.
CN92113338A 1991-10-26 1992-10-26 para-dinitrogen naphthalene derivative, its preparation method and its medical use Expired - Fee Related CN1038840C (en)

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