CN1720236A

CN1720236A - 4-substituted benzimidazoles and their use as inhibitors of gastric secretion

Info

Publication number: CN1720236A
Application number: CN 200380105120
Authority: CN
Inventors: 维多利亚·切萨; 安德烈亚斯·帕尔默; 克里斯托弗·布雷姆; 格哈德·格林德勒; 约尔格·森－比尔芬格; 沃尔夫冈－亚历山大·西蒙; 斯特凡·波斯蒂尔斯; 沃尔夫冈·克勒默; 维尔姆·波尔; 彼得·简·齐默尔曼
Original assignee: Altana Pharma AG
Current assignee: Takeda GmbH
Priority date: 2002-12-13
Filing date: 2003-12-11
Publication date: 2006-01-11
Also published as: UA79843C2; ZA200503910B

Abstract

The invention relates to 6-substituted benzimidazoles of formula 1, in which X is O (oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, or Y denotes the group gp, formula (gp) wherein Z has the meaning -CHR8- or -CHR8-CHR9-. The compounds have gastric secretion inhibiting and excellent gastric and intestinal protective action properties.

Description

4-is substituted benzoglyoxaline and its purposes as gastric secretion inhibitor

Technical field

The present invention relates to can be used in the medicine industry as the compounds that is used for the active compound that medicine makes.

Background technology

(corresponding to United States Patent (USP) 5,106,862) have been disclosed and have been had a variety of substituent benzimidizole derivatives in European patent application 266326, describe them in this case and have activity as anti ulcer agent.International application WO 97/47603 (corresponding to United States Patent (USP) 6,465,505) discloses through 2, the benzimidizole derivatives that 6-dialkyl phenyl organic half family replaces, and it can be effectively as H ⁺, K ⁺The inhibitor of-ATP enzyme.

Summary of the invention

The present invention relates to formula 1 compound

Wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-carbalkoxy, 2-4C-thiazolinyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxyl-1-4C-alkyl, list-or two-1-4C-alkyl amine group or 1-4C-alkyl carbonyl oxy-1-4C-alkyl

R2 is a hydrogen, the 1-4C-alkyl, aryl, the 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, the 1-4C-carbalkoxy, single-or two-1-4C-alkyl amine group-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxyl group-1-4C-alkyl, hydroxyl or 1-4C-alkoxyl group, R3 are hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, cyano group,-CO-NR31R32 group, SO ₂-NR31R32 group or Het group,

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or 3-7C-cycloalkyl, amido, and

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Or wherein

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl, '-aziridino or azetidine base together with the nitrogen-atoms of their common bonds, and Het is the heterocycle residue through R33, R34 and R35 replacement, it is to be selected from the group that is made up of oxadiazole base, dihydro-oxazole base, glyoxalidine Ji, oxazolyl, imidazolyl, isoxazolyl, dihydro-isoxazole base, pyrazolyl and tetrazyl

Wherein

R33 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; the 1-4C-alkyl-carbonyl; carboxyl; the 1-4C-carbalkoxy; carboxyl-1-4C-alkyl; 1-4C-carbalkoxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryloxy; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amido; single-or two-1-4C-alkyl amine group; 1-4C-alkyl-carbonyl amido; 1-4C-carbalkoxy amido; 1-4C-alkoxyl group-1-4C-carbalkoxy amido or alkylsulfonyl

R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-carbalkoxy, halogen, trifluoromethyl or hydroxyl,

R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-carbalkoxy, halogen, trifluoromethyl or hydroxyl,

X is O (oxygen) or NH, and

Y has implication-CH ₂-Ar

Wherein

Ar is list or the bicyclic aromatic residue that replaces through R4, R5, R6 and R7, it is to be selected from by phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2, the group that 3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl are formed, perhaps Y represents the gp group

Wherein

Z have implication-CHR8-or-CHR8-CHR9-

Wherein, in Ar and/or gp group

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; the 1-4C-alkyl-carbonyl; carboxyl; the 1-4C-carbalkoxy; carboxyl-1-4C-alkyl; 1-4C-carbalkoxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryloxy; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amido; single-or two-1-4C-alkyl amine group; 1-4C-alkyl-carbonyl amido; 1-4C-carbalkoxy amido; 1-4C-alkoxyl group-1-4C-carbalkoxy amido or alkylsulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-carbalkoxy, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

R8 is a hydrogen, the 1-7C-alkyl, the 2-7C-thiazolinyl, hydroxyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group through the oxygen replacement, the 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-4C-alkoxyl group, hydroxyl-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkoxyl group, 3-7C-cycloalkyloxy-1-4C-alkoxyl group, 3-7C-cycloalkyl-1-4C-alkoxyl group-1-4C-alkoxyl group, the 1-4C-alkyl carbonyl oxy, halo-1-4C-alkoxyl group, amido, single-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, single-or two-1-4C-alkyl amine group-1-4C-alkyl carbonyl oxy, 1-4C-alkoxyl group-1-4C-carbalkoxy amido or 1-4C-alkoxyl group-1-4C-alkyl carbonyl oxy

R9 is a hydrogen, the 1-7C-alkyl, the 2-7C-thiazolinyl, hydroxyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group through the oxygen replacement, the 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-4C-alkoxyl group, hydroxyl-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkoxyl group, 3-7C-cycloalkyloxy-1-4C-alkoxyl group, 3-7C-cycloalkyl-1-4C-alkoxyl group-1-4C-alkoxyl group, the 1-4C-alkyl carbonyl oxy, halo-1-4C-alkoxyl group, amido, single-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, single-or two-1-4C-alkyl amine group-1-4C-alkyl carbonyl oxy, 1-4C-alkoxyl group-1-4C-carbalkoxy amido or 1-4C-alkoxyl group-1-4C-alkyl carbonyl oxy

And wherein

Aryl is phenyl or the phenyl that replaces through one, two or three identical or different substituting group, described substituting group is to be selected from the group that is made up of 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-carbalkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group, and its restricted condition is to represent-CH as Y ₂When-Ar and R2 represented hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, R3 did not have the implication of hydrogen or halogen and the salt of these compounds.

The 1-4C-alkyl represent has the straight or branched alkyl of 1 to 4 carbon atom.The example that can mention is butyl, isobutyl-, second butyl, tributyl, propyl group, sec.-propyl, ethyl and methyl.The 3-7C-cycloalkyl is represented cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, wherein preferably cyclopropyl, cyclobutyl and cyclopentyl.

3-7C-cycloalkyl-1-4C-alkyl represent is through an above-mentioned 1-4C-alkyl of an above-mentioned 3-7C-cycloalkyl substituted.The example that can mention is cyclopropyl methyl, cyclohexyl methyl and cyclohexyl ethyl.

The representative of 1-4C-alkoxyl group also contains the group of the straight or branched alkyl of 1 to 4 carbon atom except that Sauerstoffatom.The example that can mention is butoxy, isobutoxy, second butoxy, the 3rd butoxy, propoxy-, isopropoxy and preferably oxyethyl group and methoxyl group.

The above-mentioned 1-4C-alkyl that 1-4C-alkoxyl group-1-4C-alkyl represent replaces through an above-mentioned 1-4C-alkoxyl group.The example that can mention is methoxyl methyl, methoxyethyl and fourth oxygen ethyl.

On behalf of bond on it, 1-4C-carbalkoxy (CO-1-4C-alkoxyl group) carbonyl of an above-mentioned 1-4C-alkoxyl group is arranged.The example that can mention is methoxycarbonyl (CH ₃O-C (O)-) and ethoxycarbonyl (CH ₃CH ₂O-C (O)-).

The representative of 2-4C-thiazolinyl has the straight or branched thiazolinyl of 2 to 4 carbon atoms.The example that can mention is crotyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl group).

The representative of 2-4C-alkynyl has the straight or branched alkynyl of 2 to 4 carbon atoms.The example that can mention is 2-butyne base, 3-butynyl, and 2-propynyl (propargyl) preferably.

The above-mentioned 1-4C-alkyl that fluoro-1-4C-alkyl represent replaces through one or more fluorine atom.The example that can mention is a trifluoromethyl.

The above-mentioned 1-4C-alkyl that hydroxyl-1-4C-alkyl represent replaces through hydroxyl.The example that can mention is methylol, 2-hydroxyethyl and 3-hydroxypropyl.

The representative of 1-4C-alkyl-carbonyl also contains the group of an above-mentioned 1-4C-alkyl except that carbonyl.The example that can mention is an ethanoyl.

Single-or the amido that replaces through one or two identical or different group that is selected from above-mentioned 1-4C-alkyl of two-1-4C-alkyl amine group representative.The example that can mention is dimethyl amido, diethyl amido and diisopropyl amido.

Single-or two-1-4C-alkyl amine group-1-4C-alkyl-carbonyl representative through single-or 1-4C-alkyl-carbonyl of replacing of two-1-4C-alkyl amine group.The example that can mention is dimethyl amido-methyl carbonyl and dimethyl amido-ethyl carbonyl.

The 2-4C-alkyl that fluoro-2-4C-alkyl represent replaces through one or more fluorine atom.The example that can mention is 2,2, the 2-trifluoroethyl.

Aryl-1-4C-alkoxyl group is represented the 1-4C-alkoxyl group through the aryl replacement.The example that can mention is a benzyloxy.

Aryl-1-4C-alkoxyl group-1-4C-alkyl is represented an above-mentioned 1-4C-alkyl through an above-mentioned aryl-1-4C-alkoxyl group replacement.The example that can mention is a benzyloxymethyl.

Halogen in the implication of the present invention is bromine, chlorine and fluorine.

The above-mentioned 1-4C-alkoxyl group that the 1-4C-alkoxyl group-representative of 1-4C-alkoxyl group replaces through another 1-4C-alkoxyl group.The example that can mention is 2-(methoxyl group) oxyethyl group (CH ₃-O-CH ₂-CH ₂-O-) and 2-(oxyethyl group) oxyethyl group (CH ₃-CH ₂-O-CH ₂-CH ₂-O-) group.

The above-mentioned 1-4C-alkoxyl group-1-4C-alkyl that 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl represent replaces through an above-mentioned 1-4C-alkoxyl group.The example that can mention is 2-(methoxyl group) ethoxymethyl (CH ₃-O-CH ₂-CH ₂-O-CH ₂-) group.

The above-mentioned 1-4C-alkyl that fluoro-1-4C-alkoxyl group-1-4C-alkyl represent replaces through fluoro-1-4C-alkoxyl group.Fluoro-1-4C-alkoxyl group is represented fully or an above-mentioned 1-4C-alkoxyl group that mainly replaces through fluorine in the case.The example of the 1-4C-alkoxyl group that fully or mainly replaces through fluorine that can mention is 1,1,1,3,3,3-hexafluoro--2-propoxy-, 2-trifluoromethyl-2-propoxy-, 1,1,1-three fluoro-2-propoxy-, perfluor-Di three butoxy, 2,2,3,3,4,4,4-seven fluoro-1-butoxy, 4,4,4-three fluoro-1-butoxy, 2,2,3,3,3-five fluorine propoxy-, perfluor oxyethyl group, 1,2, the 2-trifluoro ethoxy, especially 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy, trifluoromethoxy and difluoro-methoxy preferably.

The 1-7C-alkyl represent has the straight or branched alkyl of 1 to 7 carbon atom.The example that can mention is heptyl, different heptyl (5-methyl hexyl), hexyl, isohexyl (4-methyl amyl), new hexyl (3, the 3-dimethylbutyl), amyl group, isopentyl (3-methyl butyl), neo-pentyl (2, the 2-dimethyl propyl), butyl, isobutyl-, second butyl, tributyl, propyl group, sec.-propyl, ethyl and methyl.

The representative of 2-4C-alkene oxygen base also contains the group of an above-mentioned 2-4C-thiazolinyl except that Sauerstoffatom.The example that can mention is 2-butylene oxygen base, 3-butenyloxy, 1-propenyloxy group and 2-propenyloxy group (allyloxy).

Carboxyl-1-4C-alkyl represent is through the 1-4C-of carboxyl substituted alkyl.The example that can mention is carboxymethyl and 2-propyloic.

The 1-4C-alkyl that 1-4C-carbalkoxy-1-4C-alkyl represent replaces through an above-mentioned 1-4C-carbalkoxy.The example that can mention is methoxycarbonyl methyl and ethoxycarbonylmethyl group.

Aryl-1-4C-alkyl is represented the 1-4C-alkyl through the aryl replacement.The example that can mention is a benzyl.

On behalf of bond on it, 1-4C-alkyl-carbonyl amido the amido of 1-4C-alkyl-carbonyl is arranged.The example that can mention is propionamido-(C ₃H ₇NH-) and acetamido (acetamido) (CH (O) ₃C (O) NH-).

The amido that the representative of 1-4C-carbalkoxy amido replaces through an above-mentioned 1-4C-carbalkoxy.The example that can mention is ethoxycarbonyl amido and methoxycarbonyl amido.

On behalf of bond on it, 1-4C-alkoxyl group-1-4C-carbalkoxy the carbonyl of an above-mentioned 1-4C-alkoxyl group-1-4C-alkoxyl group is arranged.The example that can mention is 2-(methoxyl group)-ethoxycarbonyl (CH ₃-O-CH ₂CH ₂-O-CO-) and 2-(oxyethyl group) ethoxycarbonyl (CH ₃CH ₂-O-CH ₂CH ₂-O-CO-).

The amido that the 1-4C-alkoxyl group-representative of 1-4C-carbalkoxy amido replaces through an above-mentioned 1-4C-alkoxyl group-1-4C-carbalkoxy.The example that can mention is 2-(methoxyl group) ethoxycarbonyl amido and 2-(oxyethyl group) ethoxycarbonyl amido.

The representative of 2-7C-thiazolinyl has the straight or branched thiazolinyl of 2 to 7 carbon atoms.The example that can mention is crotyl, 3-butenyl, 1-propenyl, 2-propenyl (allyl group) and vinyl.Preferably above-mentioned 2-4C-thiazolinyl.

The 1-4C-alkoxyl group representative that replaces through oxygen contains carbonyl but not the 1-4C-alkoxyl group of methylene radical.The example that can mention is the 2-oxopropoxy.

3-7C-cycloalkyloxy representative ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy and ring oxygen base in heptan wherein preferably encircle propoxy-, cyclobutoxy group and cyclopentyloxy.

3-7C-cycloalkyl-1-4C-alkoxyl group representative is through an above-mentioned 1-4C-alkoxyl group of an above-mentioned 3-7C-cycloalkyl substituted.The example that can mention is cyclo propyl methoxy, cyclobutyl methoxy base and cyclohexyl oxyethyl group.

The above-mentioned 1-4C-alkoxyl group that hydroxyl-representative of 1-4C-alkoxyl group replaces through hydroxyl.The preferred embodiment that can mention is the 2-hydroxyl-oxethyl.

The above-mentioned 1-4C-alkoxyl group that 1-4C-alkoxyl group-1-4C-alkoxyl group-representative of 1-4C-alkoxyl group replaces through an above-mentioned 1-4C-alkoxyl group-1-4C-alkoxyl group.The preferred embodiment that can mention is the methoxy (ethoxy) oxyethyl group.

The above-mentioned 1-4C-alkoxyl group that the 3-7C-cycloalkyloxy-representative of 1-4C-alkoxyl group replaces through an above-mentioned 3-7C-cycloalkyloxy.The example that can mention is ring propoxy-methoxyl group, cyclobutoxy group methoxyl group and cyclohexyloxy oxyethyl group.

The above-mentioned 1-4C-alkoxyl group that 3-7C-cycloalkyl-1-4C-alkoxyl group-representative of 1-4C-alkoxyl group replaces through an above-mentioned 3-7C-cycloalkyl-1-4C-alkoxyl group.The example that can mention is cyclopropyl methoxyethoxy, cyclobutyl methoxy oxyethyl group and cyclohexyl ethoxy oxyethyl group.

On behalf of bond on it, the 1-4C-alkyl carbonyl oxy 1-4C-alkyl-carbonyl of one Sauerstoffatom is arranged.The example that can mention is acetoxyl group (CH ₃CO-O-).

1-4C-alkyl carbonyl oxy-1-4C-alkyl represent is through an above-mentioned 1-4C-alkyl that replaces through above-mentioned 1-4C-alkyl carbonyl oxy.The example that can mention is acetyl-o-methyl (CH ₃CO-O-CH ₂).

Halo-1-4C-alkoxyl group representative 1-4C-alkoxyl group complete or that mainly replace through halogen." mainly " is meant herein has the hydrogen atom above half to be replaced by halogen atom in the 1-4C-alkoxyl group.Halo-1-4C-alkoxyl group is mainly through chlorine and/or the 1-4C-alkoxyl group that especially replaces through fluorine.The example of the 1-4C-alkoxyl group that replaces through halogen that can mention is 2,2,2-three chloroethoxies, the chlordene isopropoxy, the pentachloro-isopropoxy, 1,1,1-three chloro-3,3,3-three fluoro-2-propoxy-, 1,1,1-three chloro-2-methyl-2-propoxy-, 1,1,1-three chloro-2-propoxy-, 3-bromo-1,1,1-three fluoro-2-propoxy-, 3-bromo-1,1,1-three fluoro-2-butoxy, 4-bromo-3,3,4,4-tetrafluoro-1-butoxy, the chlorine difluoro-methoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy-, 2-trifluoromethyl-2-propoxy-, 1,1,1-three fluoro-2-propoxy-, perfluor-tert.-butoxy, 2,2,3,3,4,4,4-seven fluoro-1-butoxy, 4,4,4-three fluoro-1-butoxy, 2,2,3,3,3-five fluorine propoxy-, the perfluor oxyethyl group, 1,2, the 2-trifluoro ethoxy, especially 1,1,2,2-tetrafluoro oxyethyl group, 2,2, the 2-trifluoro ethoxy, trifluoromethoxy and difluoro-methoxy preferably.

Single-or two-1-4C-alkyl amine group-1-4C-alkyl carbonyl oxy representative through an above-mentioned list-or 1-4C-alkyl carbonyl oxy of replacing of two-1-4C-alkyl amine group.The example that can mention is dimethyl amido-methyl carbonyl oxygen base and dimethyl amido-ethyl oxy carbonyl.

The above-mentioned 1-4C-alkyl carbonyl oxy that the 1-4C-alkoxyl group-representative of 1-4C-alkyl carbonyl oxy replaces through an above-mentioned 1-4C-alkoxyl group.The example that can mention is a methoxyl methyl carbonyl oxygen base.

The especially all acid salt of possible salt (deciding) of formula 1 or formula 2 compounds according to metalepsy.What can special one carry is permissible inorganic and organic acid salt on the pharmacology commonly used in the pharmaceutics.Suitable salt is water-soluble and water-insoluble acid salt, described acid for example be hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, acetate, citric acid, maltonic acid, phenylformic acid, 2-(4-hydroxy benzoyl) phenylformic acid, butyric acid, sulphosalicylic acid, toxilic acid, lauric acid, oxysuccinic acid, fumaric acid, succsinic acid, oxalic acid, tartrate,

(embonic acid), stearic acid, toluenesulphonic acids, methylsulfonic acid or 3-hydroxyl-2-naphthoic acid, wherein said acid are to prepare to wait molal quantity ratio or other ratio to be used for salt, and this depends on whether relate to monoprotic acid or polyprotonic acid and need which kind of salt.

By the known method of those skilled in the art the salt (for example can obtain as process product at first) that can not tolerate on the pharmacology is changed into the salt that can tolerate on the pharmacology in according to the industrial-scale production of compound of the present invention.

It will be understood by one of ordinary skill in the art that compound according to the present invention and its salt can contain (for example separating with crystallized form) solvent of various amounts.Therefore, the present invention also comprises all solvates and especially all hydrates of the salt of all solvates of formula I compound and especially all hydrates and formula I compound.

(embodiment a) comprises formula 1 compound to one embodiment, wherein

R1 is singly-or two-1-4C-alkyl amine group, and

R2, R3, X and Y have in the foregoing invention content given implication;

Its restricted condition is to represent-CH as Y ₂When-Ar and R2 represented hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, R3 did not have the implication of hydrogen or halogen and the salt of these compounds.

One embodiment (embodiment b) comprises formula 1 compound, and wherein R1 is 1-4C-alkyl carbonyl oxy-1-4C-alkyl, and R2, R3, X and Y have in the foregoing invention content given implication and the salt of these compounds.

Another embodiment (embodiment c) comprises formula 1 compound, and wherein R2 is hydroxyl or 1-4C-alkoxyl group, and

R1, R3, X and Y have in the foregoing invention content given implication and the salt of these compounds.

Another embodiment (embodiment d) comprises formula 1 compound, and wherein R3 is cyano group, SO ₂-NR31R32 group or Het group, and

Wherein

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, or wherein

Wherein

R33 is hydrogen, 1-4C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group, 2-4C-alkene oxygen base, 1-4C-alkyl-carbonyl, carboxyl, 1-4C-carbalkoxy, carboxyl-1-4C-alkyl, 1-4C-carbalkoxy-1-4C-alkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxyl group, trifluoromethyl, nitro, amido, list-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, 1-4C-alcoxyl

Base-1-4C-carbalkoxy amido or alkylsulfonyl,

Wherein

R1, R2, X and Y have in the foregoing invention content given implication and the salt of these compounds.

Another embodiment (embodiment e) comprises formula 1 compound, wherein R1 is a hydrogen, the 1-4C-alkyl, the 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, the 1-4C-carbalkoxy, the 2-4C-thiazolinyl, the 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxyl-1-4C-alkyl, R2 is a hydrogen, the 1-4C-alkyl, aryl, the 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, the 1-4C-carbalkoxy, single-or two-1-4C-alkyl amine group-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxyl group-1-4C-alkyl, R3 is a hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl or-the CO-NR31R32 group

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or 3-7C-cycloalkyl, and

Or wherein

R31 and R32 together with the nitrogen-atoms of their common bonds be pyrrolidyl, piperidyl,

Piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl, '-aziridino or azetidine base, X is O (oxygen) or NH, and Y has implication-CH ₂-Ar,

Wherein

Wherein

Z have implication-CHR8-or-CHR8-CHR9-

Wherein, Ar and/or in the gp group

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl is phenyl or the phenyl that replaces through one, two or three identical or different substituting group, described substituting group is to be selected from the group that is made up of 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-carbalkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group, and its restricted condition is to represent-CH as Y ₂During-Ar, R3 does not have the implication of hydrogen or halogen and the salt of these compounds.

Another embodiment (embodiment f) comprises formula 1 compound, wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-carbalkoxy, 2-4C-thiazolinyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-carbalkoxy, list-or two-1-4C-alkyl amine group-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl or fluoro-2-4C-alkyl,

R3 be hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl ,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl or-the CO-NR31R32 group

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl

Or wherein

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base or morpholinyl together with the nitrogen-atoms of their common bonds,

X is O (oxygen) or NH, and

Y has implication-CH ₂-Ar,

Wherein

Wherein

Z have implication-CHR8-or-CHR8-CHR9-

Wherein, in Ar and/or gp group

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

R8 is a hydrogen, the 1-7C-alkyl, the 2-7C-thiazolinyl, hydroxyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group through the oxygen replacement, the 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-4C-alkoxyl group, hydroxyl-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkoxyl group, 3-7C-cycloalkyloxy-1-4C-alkoxyl group, 3-7C-cycloalkyl-1-4C-alkoxyl group-1-4C-alkoxyl group, the 1-4C-alkyl carbonyl oxy, halo-1-4C-alkoxyl group, amido, single-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, single-or two-1-4C-alkyl amine group-1-4C-alkyl carbonyl oxy or 1-4C-alkoxyl group-1-4C-carbalkoxy amido

R9 is a hydrogen, the 1-7C-alkyl, the 2-7C-thiazolinyl, hydroxyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group through the oxygen replacement, the 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-4C-alkoxyl group, hydroxyl-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkoxyl group, 3-7C-cycloalkyloxy-1-4C-alkoxyl group, 3-7C-cycloalkyl-1-4C-alkoxyl group-1-4C-alkoxyl group, the 1-4C-alkyl carbonyl oxy, halo-1-4C-alkoxyl group, amido, single-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, single-or two-1-4C-alkyl amine group-1-4C-alkyl carbonyl oxy or 1-4C-alkoxyl group-1-4C-carbalkoxy amido

And wherein

In one aspect, the present invention relates to formula 1a compound

Wherein

Or wherein

Wherein

X is O (oxygen) or NH, and

Ar is list or the bicyclic aromatic residue that replaces through R4, R5, R6 and R7, it is to be selected from by phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2, the group that 3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl are formed

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

In yet another aspect, the present invention relates to formula 1a compound,

Wherein

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-carbalkoxy, list-or two-1-4C-alkyl amine group-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxyl group-1-4C-alkyl

R3 be fluoro-1-4C-alkyl, carboxyl ,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl or-the CO-NR31R32 group

Wherein

Or wherein

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl, '-aziridino or azetidine base together with the nitrogen-atoms of their common bonds,

X is O (oxygen) or NH, and

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl is phenyl or the phenyl that replaces through one, two or three identical or different substituting group, described substituting group is to be selected from the group that is made up of 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-carbalkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group and the salt of these compounds.

In yet another aspect, the present invention relates to formula 1a compound,

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl together with the nitrogen-atoms of their common bonds,

X is O (oxygen) or NH, and

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

In yet another aspect, the present invention relates to formula 1b compound

Wherein

R35 is hydrogen, 14C-alkyl, 1-4C-alkoxyl group, 1-4C-carbalkoxy, halogen, trifluoromethyl or hydroxyl,

X is O (oxygen) or NH, and

Z have implication-CHR8-or-CHR8-CHR9-,

Wherein

And wherein

Aryl is phenyl or the phenyl that replaces through one, two or three identical or different substituting group, described substituting group is to be selected from the group that is made up of 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-carbalkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group

Salt with these compounds.

In yet another aspect, the present invention relates to formula 1b compound,

Wherein

R31 and R32 are pyrrolidyl together with the nitrogen-atoms of their common bonds; piperidyl; piperazinyl; N-1-4C-alkylpiperazine base; morpholinyl; '-aziridino or azetidine base; R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; the 1-4C-alkyl-carbonyl; carboxyl; the 1-4C-carbalkoxy; carboxyl-1-4C-alkyl; 1-4C-carbalkoxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryloxy; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amido; single-or two-1-4C-alkyl amine group; 1-4C-alkyl-carbonyl amido; 1-4C-carbalkoxy amido; 1-4C-alkoxyl group-1-4C-carbalkoxy amido or alkylsulfonyl

X is O (oxygen) or NH, and

Z have implication-CHR8-or-CHR8-CHR9-,

Wherein

And wherein

In yet another aspect, the present invention relates to formula 1b compound,

Wherein

X is O (oxygen) or NH, and

Z have implication-CHR8-or-CHR8-CHR9-,

Wherein

And wherein

Formula 1b compound has on its parent structure up to three chiral centres.Therefore the present invention relates to mutually with any all steric isomers that can conceive of desired mixture ratio blended (comprising pure enantiomer), it is a preferred theme of the present invention.

In formula 1a compound, preferred compound is a formula 1a-1 compound

Wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxyl group or aryl-1-4C-alkoxyl group-1-4C-alkyl,

R3 be carboxyl ,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, cyano group ,-CO-NR31R32 group, SO ₂-NR31R32 group or Het group,

Wherein

R31 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 3-7C-cycloalkyl or amido, and

R32 is hydrogen or 1-7C-alkyl,

Or wherein

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl, '-aziridino or azetidine base together with the nitrogen-atoms of their common bonds, and Het is the heterocycle residue through R33, R34 and R35 replacement, it is to be selected from the group that is made up of oxadiazole, dihydro-oxazole and glyoxalidine

Wherein

R33 is hydrogen or 1-4C-alkyl,

R34 is hydrogen or 1-4C-alkyl,

R35 is hydrogen or 1-4C-alkyl,

R4 is hydrogen, 1-4C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-carbalkoxy, trifluoromethyl, amido, list-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido or 1-4C-alkoxyl group-1-4C-carbalkoxy amido

R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group, and

X is O (oxygen) or NH,

Salt with these compounds.

In formula 1a compound, especially preferred compound is a formula 1a-1 compound

Wherein

R1 is hydrogen, 1-4C-alkyl or hydroxyl-1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

R3 be carboxyl ,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or-the CO-NR31R32 group,

Wherein

R31 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or 3-7C-cycloalkyl, and

R32 is hydrogen or 1-7C-alkyl,

Or wherein

R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group, and

X is O (oxygen) or NH,

Salt with these compounds.

Especially preferred formula 1a-1 compound is those following compounds, wherein

R1 is the 1-4C-alkyl,

R2 is the 1-4C-alkyl,

R3 be carboxyl ,-CO-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl or-the CO-NR31R32 group,

Wherein

R31 is hydrogen, 1-4C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or 3-7C-cycloalkyl, and

R32 is hydrogen or 1-4C-alkyl,

R4 is 1-4C-alkyl or 1-4C-alkyl-carbonyl amido,

R5 is the 1-4C-alkyl,

X is O (oxygen) or NH,

With its salt.

In formula 1b compound, formula 1b-1 compound preferably

Preferred exemplary formula 1b-1 compound is those following compounds, wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is hydrogen or 1-4C-alkyl,

R3 be carboxyl ,-CO-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl or-the CO-NR31R32 group,

Wherein

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is hydrogen or 1-4C-alkyl,

R8 is a hydroxyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group through the oxygen replacement, the 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-4C-alkoxyl group, hydroxyl-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkoxyl group, 3-7C-cycloalkyloxy-1-4C-alkoxyl group, 3-7C-cycloalkyl-1-4C-alkoxyl group-1-4C-alkoxyl group, the 1-4C-alkyl carbonyl oxy, halo-1-4C-alkoxyl group, amido, single-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, single-or two-1-4C-alkyl amine group-1-4C-alkyl carbonyl oxy, 1-4C-alkoxyl group-1-4C-carbalkoxy amido or 1-4C-alkoxyl group-1-4C-alkyl carbonyl oxy

X is O (oxygen) or NH,

With its salt.

Especially preferred exemplary formula 1b-1 compound is those following compounds, wherein

R1 is the 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

Wherein

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is a hydrogen or alkyl,

X is O (oxygen) or NH,

With its salt.

R1 is the 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

Wherein

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is a hydrogen,

X is O (oxygen) or NH,

With its salt.

Preferred compound is those formulas 1a-1 compound.

Especially preferred is the salt of the compound that provides as formula 1 end product in example and these compounds.

Embodiment

Can be from the synthetic compound of the present invention of corresponding initial compounds, for example according to the following reaction process of giving.Synthesize in the known mode of professional, for example as the detailed description in the following example.

Initial compounds can be from for example M.W.Lovell, S.G.Schulman, and Anal.Chem.1983,55, learn among the 963-965 (for example 4-bromo-6-nitro-1,2-phenylenediamine).Through the 6-halogen, the benzoglyoxaline that the 4-nitro replaces is known in the literature, and for example 6-chloro-2-methyl-4-nitro-1 (3) H-benzoglyoxalines people such as (, J.Org.Chem.1960,25,942) Gillespie or its can prepare by using similar operation.1,2-epoxy indane is that (for example) is described in W.F.Whitmore; A.I.Gebhart, J.Am.Chem.Soc.1942 is in 64,912.By and large, the alkyl that is substituted-, alkoxyl group-or halogen-epoxy indane can prepare by the method (for example epoxidation) from document, learnt the indenes that is substituted by correspondence.Can react and obtain general formula 1a compound by making formula I be substituted the formula II compound described in benzoglyoxaline and the flow process 1.

Flow process 1:

Similarly, react the compound (referring to the flow process 2 that is used for compound 1b-1) that obtains general formula 1b by the benzoglyoxaline that is substituted that makes formula I with the epoxy indane III that has any desired substituent R 4 and R5.

Flow process 2:

Carry out above-mentioned reactions steps in a manner known way, for example in example, describe in more detail.The derivatization of carrying out equally in a manner known way according to above flow process 1 and 2 compounds that obtained (if existence) (for example changes into radicals R 3 another radicals R 3, or R2=H changed into another radicals R 2, or hydroxyl is changed into alkoxyl group or ester group).The compound of R3=-CO-1-4C-alkoxyl group or R3=-CO-NR31R32 wherein if desired, then the formula I benzoglyoxaline stage (flow process 1 and 2) or preferably after a while certain time point place in a manner known way (for example the metal catalytic carbonylation effect of Dui Ying bromo compound or ester are converted into acid amides transformation) carry out suitable derivatization.

Following example is intended to illustrate in greater detail the present invention and unrestricted the present invention.Similarly, can use the universal method technology to prepare other formula 1 compound that those clearly do not describe its preparation as the mode that the those skilled in the art was familiar with in a similar manner or originally.Abbreviation min representative minute, h representative hour and m.p. represent fusing point.

Example

I. parent material

A.2-benzyloxy-4-bromo-6-nitro-aniline

In 50g (325mmol) 2-amido-3-nitrophenol, 45g (325mmol) salt of wormwood and the suspension of 2g (13mmol) sodium iodide in 400ml ethanol, add 47ml (408mmol) benzyl chloride and with mixture heating up to 80 ℃.After 2 hours, allow reaction mixture cool off and evaporating solvent.Resistates is dissolved in the ethyl acetate and with water to extract.Organic layer is also evaporated through anhydrous magnesium sulfate drying.With the methylene dichloride coevaporation, obtain dun oily resistates, it is dissolved in the 400ml acetonitrile.Add 63.4g (356mmol) N-bromosuccinimide, made reaction mixture refluxed subsequently 1 hour.After the cooling, add 400g silica gel, and mixture is evaporated to dried.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (4: 1) comes purifying gained solid.Evaporation of eluate stays solid, with its from ethyl acetate/normal heptane recrystallize to generate the solid title compound that takes on a red color (90 ℃ of fusing points) of 62g (59%).

B.N-ethanoyl-N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-ethanamide

20g (62mmol) 2-benzyloxy-suspension of 4-bromo-6-nitro-aniline in 120ml diacetyl oxide and 2ml methylsulfonic acid is heated to 120 ℃.After complete reaction (15 minutes), with unnecessary diacetyl oxide evaporation.Resistates is dissolved in methylene dichloride/water, and neutralizes with the 6N aqueous sodium hydroxide solution.Isolate organic layer, through anhydrous magnesium sulfate drying and evaporation.Crystallization goes out resistates from ethyl acetate/normal heptane, obtains 23.2g (92%) and is beige solid title compound (148 ℃ of fusing points).

C.N-(2-amido-6-benzyloxy-4-bromo-phenyl)-ethanamide

23g (56mmol) N-ethanoyl-N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-ethanamide, 5.5g (34mmol) iron(ic) chloride (III) and the suspension of 13.8g gac in 600ml methyl alcohol are heated to backflow.Adding 28ml hydrazine hydrate (95%) in reaction mixture refluxes to keep relaxing.Back (2 hours) is finished in reaction, and thing to be mixed cools off and through diatomite filtration.With the thorough washing leaching cake of methylene chloride and filtrate is evaporated to dried.It is molten that resistates is divided between methylene chloride and water.Organic layer with the salt water washing, is also evaporated through anhydrous magnesium sulfate drying.Make resistates recrystallize from ebullient ethyl acetate/normal heptane, obtain the title compound (185 ℃ of fusing points) that 12.3g (65%) is colorless solid.

D.N-(2-benzyloxy-4-bromo-6-dimethyl amido-phenyl)-ethanamide

5.0g (15mmol) N-(2-amido-6-benzyloxy-4-bromo-the phenyl)-suspension of ethanamide in 80ml methyl alcohol and 34ml formaldehyde (37%) with the acidifying of saturated methyl alcohol hydrogenchloride, is generated clear yellow solution.In solution, add 1.5g (24mmol) sodium cyanoborohydride by aliquot.After question response is finished (15 minutes), with the sodium bicarbonate aqueous solution neutralise mixt and with dichloromethane extraction.Organic layer is also evaporated through anhydrous magnesium sulfate drying.Crystallization goes out resistates from ethyl acetate/normal heptane, obtains the title compound (177 ℃ of fusing points) that 4.3g (79%) is colorless solid.

E.4-benzyloxy-6-bromo-1,2-dimethyl-1H-benzoglyoxaline

26.2g (72mmol) N-(2-benzyloxy-4-bromo-6-dimethyl amido-phenyl)-suspension of ethanamide in the 180ml phosphoryl chloride is heated to 70 ℃, lasts 24 hours.After question response is finished, the phosphoryl chloride of evaporating surplus.Resistates is suspended in the methylene dichloride, and carefully with 6N potassium hydroxide aqueous solution and water neutralization.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Crystallization goes out resistates from ethyl acetate, obtains the title compound (fusing point 177-179 ℃) that 15.1g (63%) is colorless solid.

F.4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

With 12.0g (37mmol) 4-benzyloxy-1, (50 ℃, 5 cling to H to the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in 100ml ethanol through 1g10%Pd/C ₂) hydrogenation 16 hours.Leach catalyzer and evaporated filtrate.Crystallization goes out resistates from ethanol/ether, obtains the title compound (fusing point 272-273 ℃) that 5.91g (69%) is colorless solid.

G.4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylate methyl ester

With 8.5 g (27mmol) 4-benzyloxy-1, (30 ℃, 1 clings to H to the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylate methyl ester in 100ml methyl alcohol through 0.7g10%Pd/C ₂) hydrogenation 2 hours.Leach catalyzer, wash several times and evaporated filtrate with hot methanol.Crystallization goes out resistates from methanol, obtains the title compound (286 ℃ of fusing points) that 6g (99%) is colorless solid.

H.4-hydroxyl-6-methoxyl methyl-1,2-dimethyl-1H-benzoglyoxaline

With 1.2g (4.1mmol) 4-benzyloxy-6-methoxyl methyl-1, the 2-dimethyl-solution of 1H-benzoglyoxaline in 12ml methyl alcohol is through 0.12g10%Pd/C (1 crust H ₂) hydrogenation 16 hours.Leach catalyzer and evaporated filtrate.Crystallization goes out resistates from ethyl acetate/light sherwood oil, obtains the title compound (fusing point 219-220 ℃) that 0.83g (99%) is colorless solid.

I.6-(N, N-dimethyl amido carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline

With 2.3g (7.1mmol) 4-benzyloxy-6-(N, N-dimethyl amido carbonyl)-1, the 2-dimethyl-solution of 1H-benzoglyoxaline in 80ml methyl alcohol is with 0.3g10%Pd/C (1 crust H ₂) hydrogenation 16 hours.Leach catalyzer and evaporated filtrate.Crystallization goes out resistates from acetone, obtains the title compound (248 ℃ of fusing points) that 1.2g (71%) is colorless solid.

J.6-bromo-2-methyl-4-nitro-1 (3) H-benzoglyoxalines

To 65g (0.28mol) 5-bromo-3-nitro-1, add 140ml5N hydrochloric acid in the suspension of 2-phenylenediamine in 600ml ethanol.Reaction mixture is heated to backflow, and once add 58ml (0.56mol) 2,4-diacetylmethane.After 1 hour, thing to be mixed cools off, and pours in the 500ml water and with dense ammonia to neutralize.The collecting precipitation thing with the thorough washing of water and through the Vanadium Pentoxide in FLAKES drying, obtains 70.8g (99%) title compound body (fusing point 229-231 ℃).

K.6-bromo-4-nitro-1 (3) H-benzoglyoxalines

To 14.25g (61.4mmol) 5-bromo-3-nitro-1, add 4.65ml (123mmol) formic acid in the suspension of 2-phenylenediamine in 120ml4N hydrochloric acid.Reaction mixture is heated to 120 ℃.1.5 after hour, thing to be mixed cools off and neutralizes with dense ammonia.The collecting precipitation thing is with water washing and through the Vanadium Pentoxide in FLAKES drying.Recrystallize from ethanol and gac obtains 9.79g (66%) title compound (249 ℃ of fusing points).

L.6-bromo-2-methoxyl methyl-4-nitro-1 (3) H-benzoglyoxalines

With 1g (4.3mmol) 5-bromo-3-nitro-1, the suspension of 2-phenylenediamine in the 4ml methoxyacetic acid is heated to 110 ℃ and continues 16 hours.Mixture is poured in the frozen water, with the neutralization of 6N aqueous sodium hydroxide solution and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Come the purifying resistates by crystallization from ethyl acetate and gac, obtain the title compound (173 ℃ of fusing points) that 0.9g (73%) is colorless solid.

M.6-bromo-1-methyl-4-nitro-1H-benzoglyoxaline

Suspension in 200ml acetone stirred 30 minutes with 5.12g (21.2mmol) 6-bromo-4-nitro-1 (3) H-benzoglyoxalines and 4.6g (33.3mmol) salt of wormwood, added 1.54ml (24.7mmol) methyl iodide then.After stirring 18 hours at ambient temperature, with unnecessary solvent evaporation and that resistates is divided between methylene dichloride and water is molten.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Come the purifying resistates by crystallization from ethyl acetate, obtain the title compound (198 ℃ of fusing points) that 2.7g (50%) is colorless solid.

N.6-bromo-2-methoxyl methyl-1-methyl-4-nitro-1H-benzoglyoxaline

In 13g (45.4mmol) 6-bromo-2-methoxyl methyl-4-nitro-1 (3) H-benzoglyoxalines and the suspension of 12.6g (90.9mmol) salt of wormwood in 130ml acetone, add 6.8g (47.7mmol) methyl iodide, and at ambient temperature mixture was stirred 18 hours.Dense thick suspension is poured in the 200ml water and with dichloromethane extraction.Organic layer is also evaporated through anhydrous magnesium sulfate drying.Come the purifying resistates by crystallization from isopropyl ether, obtain the title compound (fusing point 145-147 ℃) that 13.6g (99%) is yellow solid.

O.1-benzyloxymethyl-6-bromo-2-methyl-4-nitro-1H-benzoglyoxaline

Under 0 ℃ to 0.26g (6.4mmol) sodium hydride (60% dispersion liquid in the mineral oil) in 10mlN, slowly add 1.5g (5.9mmol) 6-bromo-2-methyl-4-nitro-1 (3) H-benzoglyoxalines in the suspension in the dinethylformamide in 5ml N, the solution in the dinethylformamide.After 1 hour, added 2.29g (8.8mmol) benzyloxymethyl chlorine (60%) in experience under 0 ℃ through 20 minutes.When (1 hour) is finished in reaction, carefully add 10ml water and mixture divided between methylene dichloride and water molten.Organic layer is also evaporated through anhydrous magnesium sulfate drying.By using ethyl acetate: the silica gel column chromatography of triethylamine (95: 5) comes the purifying resistates, generates oily matter, with its crystallization from isopropyl ether, obtains the title compound (fusing point 106-109 ℃) that 1.16g (53%) is yellow solid.

P.6-bromo-1,2-dimethyl-4-nitro-1H-benzoglyoxaline

Under 0 ℃ to 4.3g (107mmol) sodium hydride (60% dispersion liquid in the mineral oil) in 25mlN, slowly add 25g (98mmol) 6-bromo-2-methyl-4-nitro-1 (3) H-benzoglyoxalines in the suspension in the dinethylformamide in 100mlN, the solution in the dinethylformamide.After 30 minutes, added 15.2g (107mmol) methyl iodide in experience under 0 ℃ through 20 minutes.When (45 minutes) are finished in reaction, carefully add 200ml water and also at ambient temperature mixture was stirred 1 hour.The collecting precipitation thing is with the thorough washing of water and through the Vanadium Pentoxide in FLAKES drying.Recrystallize from methyl alcohol obtains the title compound (fusing point 193-195 ℃) that 19.6g (74%) is colorless solid.

Q.4-amido-6-bromo-1-methyl isophthalic acid H-benzoglyoxaline

In 10g (39mmol) the 6-bromo-1-methyl-4-nitro-suspension of 1H-benzoglyoxaline in 100ml methyl alcohol, add 7.6g (46.9mmol) iron(ic) chloride (III) and 2.5g gac.Reaction mixture is heated to 80 ℃ and the slow 9.5ml hydrazine hydrate (95%) that adds.Reflux after 2 hours, add 2ml hydrazine hydrate (95%) in addition.After 5 hours, with the reaction mixture of heat through diatomite filtration and with methyl alcohol and washed with dichloromethane filter cake.Evaporated filtrate is to stay solid, and by using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.6: 0.4) is with the solid purifying.Crystallization from isopropyl ether obtains the title compound (170 ℃ of fusing points) that 6.8g (77%) is faint yellow solid.

R.4-amido-6-bromo-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline

In 8.5g (28.3mmol) the 6-bromo-2-methoxyl methyl-1-methyl-4-nitro-suspension of 1H-benzoglyoxaline in 150ml methyl alcohol, add 5.51g (34mmol) iron(ic) chloride (III), 2.5g gac and 6.9ml hydrazine hydrate (95%).Reflux after 2 hours, add 4ml hydrazine hydrate (95%) in addition.After 4 hours, with the reaction mixture of heat through diatomite filtration, and with methyl alcohol and washed with dichloromethane filter cake.Evaporated filtrate, and by using methylene dichloride: the silica gel column chromatography of methyl alcohol (20: 1) is with residue purified.Crystallization from isopropyl ether obtains the title compound (fusing point 138-140 ℃) that 5.5g (72%) is colorless solid.

S.4-amido-1-benzyloxymethyl-6-bromo-2-methyl isophthalic acid H-benzoglyoxaline

In 10g (26.6mmol) 1-benzyloxymethyl-6-bromo-2-methyl-4-nitro-1H-benzoglyoxaline and the suspension of 1g gac in 150ml methyl alcohol, add 5.2g (31.9mmol) iron(ic) chloride (III) and 6.5ml hydrazine hydrate (95%).Reflux after 1 hour, add 3ml hydrazine hydrate (95%) in addition.After 6 hours, with the reaction mixture of heat through diatomite filtration and with the hot methanol washing leaching cake.Evaporated filtrate stays yellow solid, and by using methylene dichloride: the silica gel column chromatography of methyl alcohol (9: 1) is with the solid purifying.Crystallization from isopropyl ether obtains the title compound (142 ℃ of fusing points) that 6.68g (73%) is faint yellow solid.

T.4-amido-6-bromo-1,2-dimethyl-1H-benzoglyoxaline

To 19g (70mmol) 6-bromo-1, add 13.7g (84mmol) iron(ic) chloride (III) and 6g gac in the 2-dimethyl-4-nitro-solution of 1H-benzoglyoxaline in 250ml methyl alcohol.Reaction mixture is heated to 80 ℃ and the slow 17ml hydrazine hydrate (95%) that adds.Reflux after 3 hours, with the reaction mixture of heat through diatomite filtration, and with methyl alcohol and washed with dichloromethane filter cake.Evaporated filtrate is handled it with normal heptane to stay suspension.The collecting precipitation thing with normal heptane washing and dry, generates 13.3g (79%) solid title compound (fusing point 206-209 ℃).

U.6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 12g (50mmol) 4-amido-6-bromo-1, add 5.5g (52mmol) yellow soda ash and 1.5g (10mmol) sodium iodide in 2-dimethyl-1H-benzoglyoxaline and 8.8g (52mmol) 2-ethyl-suspension of 6-methyl-benzyl chloride in 220ml acetone.After stirring 3 hours under 45 ℃, reaction mixture is poured in the 400ml water and with ethyl acetate extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 3) and with the normal heptane crystallization with residue purified, obtain the title compound (fusing point 145-147 ℃) that 15.6g (84%) is colorless solid.

V.6-bromo-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 0.97g (4mmol) 4-amido-6-bromo-1,2-dimethyl-1H-benzoglyoxaline and 0.66g (4.2mmol) 2 add 0.56g (4mmol) salt of wormwood and 70mg (0.4mmol) potassiumiodide in the suspension of 6-dimethyl-benzyl chloride in the 25ml acetonitrile.After stirring 1 hour under 65 ℃, add 1N ammoniacal liquor and the evaporation reaction mixture of 2ml.It is molten that resistates is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (185 ℃ of fusing points) that 0.93g (64%) is colorless solid.

W.1-benzyloxymethyl-6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline

In 6.5 (18.8mmol) 4-amido-1-benzyloxymethyl-6-bromo-2-methyl isophthalic acid H-benzoglyoxaline and 3.32g (19.7mmol) 2-ethyl-suspension of 6-methyl-benzyl chloride in the 120ml acetonitrile, add 3.0g (28.2mmol) yellow soda ash and 0.56g (3.75mmol) sodium iodide.Reflux after 3 hours, reaction mixture is poured in the 300ml water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column layer of light sherwood oil (2: 3) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 117-119 ℃) that 6.88g (77%) is colorless solid.

X.6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline

In 2.0g (8.9mmol) 4-amido-6-bromo-1-methyl isophthalic acid H-benzoglyoxaline and 1.6g (9.5mmol) 2-ethyl-suspension of 6-methyl-benzyl chloride in the 40ml acetonitrile, add 1.4g (13.1mmol) yellow soda ash and 0.3g (2mmol) sodium iodide.Experience is after 1 hour down at 70 ℃, and mixture divides molten between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 1) obtains the title compound (fusing point 132-134 ℃) that 2.0g (63%) is colorless solid with residue purified.

Y.6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H benzoglyoxaline

In the 2-ethyl-suspension of 6-methyl-benzyl chloride in the 70ml acetonitrile, add the potassiumiodide of 7.0g (50.3mmol) salt of wormwood and catalytic amount to 6.8g (25.2mmol) 4-amido-6-bromo-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline and 4.46g (26.4mmol).Reaction mixture is poured in the 200ml water and with dichloromethane extraction after 5 hours in experience under 70 ℃.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 110-112 ℃) that 5.46g (54%) is colorless solid.

Z.6-bromo-4-(2,6-dimethyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline

To 2.5g (9.25mmol) 4-amido-6-bromo-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline and 1.52g (9.72mmol) 2, add the potassiumiodide of 2.56g (18.5mmol) salt of wormwood and catalytic amount in the suspension of 6-dimethyl-benzyl chloride in the 50ml acetonitrile.Reaction mixture is poured in the 150ml water and with dichloromethane extraction after 3 hours in experience under 70 ℃.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 1) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 143-145 ℃) that 0.84g (23%) is colorless solid.

AA.4-amido-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

To 3g (12.5mmol) 4-amido-6-bromo-1, add 280mg (1.25mmol) acid chloride (II) and 2g (7.5mmol) triphenylphosphine in the suspension of 2-dimethyl-1H-benzoglyoxaline in 100ml dimethylamine (2M is in tetrahydrofuran (THF)).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.The cooling of question response mixture is poured in 200ml water and the 100ml saturated aqueous ammonium chloride, and with dichloromethane extraction.Separate organic layer, with water washing, dry and evaporation on anhydrous magnesium sulfate.Silica gel column chromatography by using ethyl acetate/methanol (4: 1) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 230-234 ℃) that 0.7g (24%) is colorless solid.

BB. cyclopropane-carboxylic acid (2-benzyloxy-4-bromo-6-nitro-phenyl)-acid amides

Suspension in the 130ml diox is heated to 100 ℃ with 20.0g (61.9mmol) 2-benzyloxy-4-bromo-6-nitro-aniline and 11.2ml (123.4mmol) cyclopropane carbonyl chlorine.After 5 hours, flask is immersed in the ice bath, the collecting precipitation thing with toluene wash and vacuum-drying, obtains the title compound (191 ℃ of fusing points) that 21.2g (87%) is yellow solid.

CC. cyclopropane-carboxylic acid (2-amido-6-benzyloxy-4-bromo-phenyl)-acid amides

11.0g (28.1mmol) cyclopropane-carboxylic acid (2-benzyloxy-4-bromo-6-nitro-phenyl)-acid amides, 3.0g (18.5mmol) iron(ic) chloride (III) and the suspension of 7.4g gac in 140ml methyl alcohol are heated to backflow.Adding 14.7ml hydrazine hydrate (95%) in reaction mixture refluxes to keep to relax.Back (1 hour) is finished in reaction, and thing to be mixed cools off and through diatomite filtration.With the thorough washing leaching cake of hot methanol/acetone, and filtrate is evaporated to dried.Crystallization goes out resistates from ethyl acetate, obtains the title compound (fusing point 207-208 ℃) that 7.5g (73%) is colorless solid.

DD.4-benzyloxy-6-bromo-2-cyclopropyl-1-methyl isophthalic acid H-benzoglyoxaline

7.5g (20.8mmol) cyclopropane-carboxylic acid (2-amido-6-benzyloxy-4-bromo-the phenyl)-suspension of acid amides in 80ml methyl alcohol and 13.3ml formaldehyde (37%) with the acidifying of saturated methyl alcohol hydrogenchloride, is obtained clear yellow solution.In solution, add 0.75g (11.9mmol) sodium cyanoborohydride by aliquot.After reaction is finished (4 hours), mixture poured in the water and with 40% aqueous sodium hydroxide solution neutralize.The collecting precipitation thing, with water washing and through the Vanadium Pentoxide in FLAKES drying to obtain the 5.3g colorless solid.Solid suspension is continued 2 hours in the 10ml phosphoryl chloride and with mixture heating up to 90 ℃.After reaction is finished, with methylene dichloride diluted mixture thing, and with 6N potassium hydroxide aqueous solution and water neutralization.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using toluene/diox (10: 1) and from ether crystallization residue purified is obtained the title compound (fusing point 153-154 ℃) that 2.97g (40%) is colorless solid.

EE.2-cyclopropyl-4-hydroxyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester

(25 ℃, 1 clings to H with 0.27g 10%Pd/C with 2.3g (6.6mmol) 4-benzyloxy-2-cyclopropyl-1-methyl isophthalic acid H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in 23ml methyl alcohol ₂) hydrogenation 5 hours.Leach catalyzer and evaporated filtrate.Crystallization goes out resistates from ethyl acetate, obtains the title compound (fusing point 201-202 ℃) that 1.5g (88%) is colorless solid.

FF.4-amido-N, N-dimethyl-3,5-dinitrobenzene-benzsulfamide

With 5.0g (27.3mmol) 2, the suspension of 6-dinitraniline in the 40ml chlorsulfonic acid is heated to 100 ℃.2.5 after hour, the cooling of question response mixture is also poured in the 1000ml trash ice carefully.With dichloromethane extraction suspension.With organic layer through anhydrous magnesium sulfate drying and be evaporated to dried.Resistates is dissolved in the 100ml tetrahydrofuran (THF), and slowly adds the solution of 25ml dimethylamine in the 25ml tetrahydrofuran (THF).After 20 minutes, evaporate suspension and resistates divided between methylene dichloride and water molten.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 169-170 ℃) that 6.7g (85%) is orange solids by crystallization from ethanol.

GG.3,4-two amidos-N, N-dimethyl-5-nitro-benzsulfamide

Under 0 ℃, make 50ml2N ammoniacal liquor saturated with hydrogen sulfide.With 50ml alcohol dilution solution and add 5.58g (19.2mmol) 4-amido-N, N-dimethyl-3,5-dinitrobenzene-benzsulfamide.60 ℃ of following experience after 40 minutes, with mixture with the water dilution and through diatomite filtration.With ebullient methylene dichloride and methanol wash filter cake several times.Evaporation obtains 1.18g (24%) the solid title compound (fusing point 211-213 ℃) that takes on a red color through the extract of combination and with resistates recrystallize from ethanol/ether.

HH.2-methyl-7-nitro-3H-benzoglyoxaline-5-sulfonic acid dimethylformamide

With 1.0g (3.84mmol) 3,4-two amidos-N, the suspension of N-dimethyl-5-nitro-benzsulfamide in 20ml ethanol and 5ml5N hydrochloric acid is heated to 80 ℃.In reaction mixture, added 1.6ml (15.4mmol) 2,4-diacetylmethane through 1 hour by two parts.Treat solution cooling and neutralize with the 6N aqueous sodium hydroxide solution.The collecting precipitation thing with water washing and through Vanadium Pentoxide in FLAKES vacuum-drying, obtains 0.99g (90%) beige solid (fusing point 254-255 ℃).

II.2,3-dimethyl-7-nitro-3H-benzoglyoxaline-5-sulfonic acid dimethylformamide

With 1.87g (6.6mmol))))) 2-methyl-7-nitro-3H-benzoglyoxaline-5-sulfonic acid dimethylformamide, 1.82g (13.2mmol) salt of wormwood and 0.71ml (11.5mmol))))) suspension of methyl iodide in 50ml acetone stirred 3 hours at ambient temperature.It is molten that mixture is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and be evaporated to dried.Make resistates recrystallize from the ebullient ethyl acetate, obtain 1.5g (76%) and be beige solid title compound (fusing point 194-196 ℃).

JJ.7-amido-2,3-dimethyl-3H-benzoglyoxaline-5-sulfonic acid dimethylformamide

With 1.2g (4.0mmol) 2, the 3-dimethyl-7-nitro-3H-benzoglyoxaline-suspension of 5-sulfonic acid dimethylformamide in 15ml methyl alcohol and 5ml acetate is heated to 60 ℃, and adds 1.1g (20mmol) iron filings.1.5 after hour, leach solid and several times with the ebullient dichloromethane extraction.Evaporation through the combination extract and from ethyl acetate/normal heptane crystallization go out resistates, obtain 0.99g (92%) and be beige solid title compound (fusing point 255-258 ℃).

KK.N-(4-bromo-2,6-dinitrobenzene-phenyl)-ethanamide

With 5.0g (19.1mmol) 4-bromo-2, the suspension of 6-dinitraniline in 50ml diacetyl oxide and 1ml methylsulfonic acid stirred 3 hours down at 30 ℃.The collecting precipitation thing with ether washing and dry, obtains the title compound (fusing point 238-239 ℃) that 4.8g (83%) is colorless solid.LL.4- -6-bromo-1-hydroxy-2-methyl-1H-benzoglyoxaline

Under 60 ℃, carried in the suspension of ruthenium (5%) in 80ml ethanol to 2.0g (6.6mmol) N-(4-bromo-2,6-dinitrobenzene-phenyl)-ethanamide and 0.4g charcoal and add 1.2ml (24.7mmol) hydrazine hydrate (95%) through 1.5 hours.Leach catalyzer and filtrate is evaporated to dry state.With ebullient ethyl acetate extraction resistates, stay 1.23g (77%) and be light gray solid title compound (fusing point 257-258 ℃).

MM.N-[5-bromo-2-(2-chloro-acetamido)-3-nitro-phenyl]-2-chloro-ethanamide

To 46.4g (200mmol) 4-bromo-2, the 6-dinitraniline slowly adds 80ml (1000mmol) chloroacetyl chloride in 500mlN in the solution in dinethylformamide and the 20ml pyridine.After 3 hours, reaction mixture is poured in the 600ml frozen water, and with in the 6N aqueous sodium hydroxide solution and gained suspension.The collecting precipitation thing with water washing and vacuum-drying, obtains 74.1g (96%) and is beige solid title compound (fusing point 172-173 ℃).

NN.6-bromo-2-chloromethyl-4-nitro-1H-benzoglyoxaline

With 1.0g (2.59mmol) N-[5-bromo-2 (2-chloro-acetamido)-3-nitro-phenyl]-suspension of 2-chloro-ethanamide in 25ml4N hydrochloric acid and 20ml ethanol is heated to backflow.After 4 hours, reaction mixture is poured in the 75ml water, and neutralized with saturated sodium bicarbonate aqueous solution.The collecting precipitation thing with water washing and through the Vanadium Pentoxide in FLAKES drying, obtains the title compound (fusing point 148-150 ℃) that 0.65g (86%) is orange solids.

OO.6-bromo-2-chloromethyl-1-methyl-4-nitro-1H-benzoglyoxaline

In 39.3g (135.3mmol) the 6-bromo-2-chloromethyl-4-nitro-solution of 1H-benzoglyoxaline in 500ml acetone, add 26.0g (206.1mmol) methyl-sulfate and 50.0g (362mmol) salt of wormwood.After at room temperature stirring 1.25 hours, reaction mixture is poured in the 1000ml water.The collecting precipitation thing, with water washing and from methyl alcohol recrystallize, obtain 32.5g (63%) and be beige solid title compound (fusing point 154-155 ℃).

PP.2-acetyl-o-methyl-6-bromo-1-methyl-4-nitro-1H-benzoglyoxaline

In 30.0g (98.5mmol) the 6-bromo-2-chloromethyl-1-methyl-4-nitro-solution of 1H-benzoglyoxaline in 200ml acetone, add 16.4g (98.5mmol) potassiumiodide.Gained suspension was stirred 1 hour at ambient temperature, and add 14.5g (147.8mmol) potassium acetate.Reaction mixture is poured in the 500ml water and with dichloromethane extraction after 2 hours in experience under 40 ℃.Separate organic layer, through anhydrous magnesium sulfate drying and be evaporated to dry state.Make resistates recrystallize from boiling ethanol, obtain the title compound (fusing point 143-145 ℃) that 23.9g (74%) is orange solids.

QQ.2-acetyl-o-methyl-4-amido-6-bromo-1-methyl isophthalic acid H-benzoglyoxaline

In 10.0g (30.5mmol) 2-acetyl-o-methyl-6-bromo-1-methyl-4-nitro-suspension of 1H-benzoglyoxaline in 40ml acetate, add 6.8g (122mmol) iron filings, and reaction mixture is heated to 60 ℃.After 4 hours, add 1.0g (18mmol) iron filings in addition and continue heating 1.25 hours.The collecting precipitation thing is dissolved in the methylene dichloride and with water and extracts.Separate organic layer, through anhydrous magnesium sulfate drying and be evaporated to dried.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (7: 3) and from ethyl acetate/normal heptane crystallization residue purified is obtained 4.6g (51%) and is beige solid title compound (fusing point 104-106 ℃).

RR.4-amido-6-bromo-2-methylol-1-methyl isophthalic acid H-benzoglyoxaline

(25 ℃, 1 clings to H with Raney's nickel with 7.5g (22.9mmol) 2-acetyl-o-methyl-6-bromo-1-methyl-4-nitro-suspension of 1H-benzoglyoxaline in 180ml methyl alcohol ₂) hydrogenation 2.5 hours.Leach catalyzer and filtrate divided between water and methylene dichloride molten.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Crystallization goes out resistates from ethanol/isopropyl ether, obtains 1.32g (22%) solid title compound (fusing point 216-218 ℃).

SS.2,6-two bromo-1-methyl-4-nitro-1H-benzoglyoxaline

In 1.0g (3.9mmol) the 6-bromo-1-methyl-4-nitro-solution of 1H-benzoglyoxaline in the 25ml ethylene dichloride, add 5g silica gel and 0.94g (5.3mmol) N-bromosuccinimide.Experience is after 2.5 hours down at 85 ℃, and thing cooling to be mixed is also filtered.With saturated sodium bicarbonate aqueous solution extraction filtrate, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 235-236 ℃) that 0.745g (57%) is yellow solid.

TT.6-bromo-2-(N, N-dimethyl amido)-1-methyl-4-nitro-1H-benzoglyoxaline

In 3.0g (11.7mmol) the 6-bromo-1-methyl-4-nitro-solution of 1H-benzoglyoxaline in the 75ml ethylene dichloride, add 25g silica gel and 2.5g (14.1mmol) N-bromosuccinimide.Experience is after 3 hours down at 85 ℃, and thing cooling to be mixed is also filtered.Evaporated filtrate also is dissolved in resistates in the 100ml tetrahydrofuran (THF).The slowly solution of interpolation 10ml dimethylamine in the 20ml tetrahydrofuran (THF), and stirred solution 4 hours.Mixture is evaporated to 1/4 volume and between saturated sodium bicarbonate aqueous solution and methylene dichloride, divides molten.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 206-207 ℃) that 1.6g (46%) is orange solids by crystallization from ethyl acetate.

UU.4-amido-6-bromo-2-(N, N-dimethyl amido)-1-methyl isophthalic acid H-benzoglyoxaline

Under 65 ℃, in 1.0g (3.3mmol) 6-bromo-2-(N, N-the dimethyl amido)-1-methyl-suspension of 4-nitro-1H-benzoglyoxaline in 25ml methyl alcohol and 8ml acetate, add 0.85g (15.2mmol) iron powder.After 2 hours, leach solid and with washed with dichloromethane.With water extraction filtrate, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using ethyl acetate and from ether crystallization residue purified is obtained the title compound (137 ℃ of fusing points) that 0.2g (22%) is colorless solid.

VV.6-bromo-1,2-dimethyl-4-(2-methyl-benzyl amido)-1H-benzoglyoxaline

In the solution of 0.9ml (6.4mmol) 2-methyl-benzyl chloride in 20ml acetone, add 1.1g (6.6mmol) sodium iodide, and mixture was stirred under room temperature 1.5 hours.Leach solid and with 1.5g (4.4mmol) 4-amido-6-bromo-1,2-dimethyl-1H-benzoglyoxaline and 1.3g (9.4mmol) salt of wormwood add in the filtrate.Reflux after 3 hours, it is molten that mixture is divided between water and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (30: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 128-129 ℃) that 1.28g (61%) is colorless solid.

WW.6-bromo-4-(2,4-dimethyl-furans-3-base-methyl amido)-1,2-dimethyl-1H-benzoglyoxaline

At room temperature in the suspension of the high iodine alkyl of 1.95g (4.6mmol) Dess-Martin-in 10ml methylene dichloride and 0.5ml pyridine, dropwise add 0.5g (4.0mmol) (2,4-dimethyl-furans-3-the yl)-solution of methyl alcohol in the 5ml methylene dichloride.After 30 minutes, add the water and the 1ml saturated sodium sulfite aqueous solution, and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Ethyl acetate is used in the evaporation back: light sherwood oil (9: 1) stays colorless oil by the filtered through silica gel resistates.Crude product is dissolved in 10ml methyl alcohol and the 0.5ml acetate.Adding 0.48g (2mmol) 4-amido-6-bromo-1, behind 2-dimethyl-1H-benzoglyoxaline, adding 0.3g (4.8mmol) sodium cyanoborohydride by three parts through 2.5 hours.After 2 hours, add saturated sodium bicarbonate aqueous solution and with the dichloromethane extraction mixture.Organic layer is also evaporated through anhydrous magnesium sulfate drying.Silica gel column chromatography by using ethyl acetate and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 207-208 ℃) that 0.45g (65%) is colorless solid.

XX.6-bromo-4-(2-methylol-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

In 0.8g (5.4mmol) 7-methyl-3H-isobenzofuran-solution of 1-ketone in the 15ml dry toluene, slowly adding 4.3ml (6.5mmol) diisobutyl aluminium hydride (1.5M is in toluene) under-78 ℃.After 1 hour, arrive room temperature with 1ml methyl alcohol stopped reaction mixture and temperature.It is molten that mixture is divided between saturated sodium tartrate aqueous solutions of potassium and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.The oily matter that so obtains is dissolved in 20ml methyl alcohol and the 1ml acetate.After adding excessive sodium cyanoborohydride, under 45 ℃, stirred the mixture 4 hours.It is molten that mixture is divided between water and methylene dichloride, neutralizes with the 6N aqueous sodium hydroxide solution.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using ethyl acetate and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 215-216 ℃) that 0.35g (24%) is colorless solid.

YY.6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-2-methylol-1-methyl isophthalic acid H-benzoglyoxaline

The suspension of potassiumiodide in the 15ml acetonitrile of 1.25g (4.88mmol) 4-amido-6-bromo-2-methylol-1-methyl isophthalic acid H-benzoglyoxaline, 0.86g (5.12mmol) 2-ethyl-6-methyl-benzyl chloride, 1.35g (9.76mmol) salt of wormwood and catalytic amount is heated to 70 ℃.After 6 hours, pour into reaction mixture in the water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 3) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 206-208 ℃) that 0.54g (29%) is colorless solid.

ZZ.6-bromo-2-(N, N-dimethyl amido)-4-(2,6-dimethyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline

To 0.46g (1.7mmol) 4-amido-6-bromo-2-(N, the N-dimethyl amido)-and 1-methyl isophthalic acid H-benzoglyoxaline and 0.3g (2.2mmol) 2, add 0.6g (2.8mmol) sodium triacetoxy borohydride in the solution of 6-dimethyl-phenyl aldehyde in 10ml methylene dichloride and 2.5ml acetate.After experiencing 1 hour at ambient temperature, add saturated sodium bicarbonate aqueous solution and continue and stirred 30 minutes.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using ethyl acetate and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 157-158 ℃) that 0.46g (70%) is colorless solid.

AAA.1-benzyloxymethyl-6-bromo-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline

To 7.6g (22mmol) 4-amido-1-benzyloxymethyl-6-bromo-2-methyl isophthalic acid H-benzoglyoxaline and 3.56g (23.0mmol) 2, add 3.5g (32.7mmol) yellow soda ash and 0.66g (4.4mmol) sodium iodide in the suspension of 6-dimethyl-benzyl chloride in the 140ml acetonitrile.Reflux after 3.5 hours, it is molten that reaction mixture is divided in water and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (2: 3) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 147-148 ℃) that 6.8g (64%) is colorless solid.

II. the end product of formula 1

1. 4-(2-ethyl-6-methyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylate methyl ester

To 2.0g (9.1mmol) 4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylate methyl ester and 1.7g (10.1mmol) 2-ethyl-6-methyl-benzyl chloride slowly add 0.7g (17.5mmol) sodium hydride (60% dispersion liquid in the mineral oil) in 56mlN in the solution in the dinethylformamide.After 1 hour, add 0.3g (1.8mmol) 2-ethyl-6-methyl-benzyl chloride in addition and stirred the mixture 4 hours.Carefully with the saturated aqueous ammonium chloride hydrolysis, and between water and methylene dichloride, divide molten mixture.Organic layer is also evaporated through anhydrous magnesium sulfate drying.With residue purified, obtain 2.7g (84%) solid title compound (157 ℃ of fusing points) by crystallization from water/acetone.

2. 4-(2-ethyl-6-methyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid

To 2.6g (7.4mmol) 4-(2-ethyl-6-methyl-benzyloxy)-1, add the 15ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylate methyl ester in the 75ml diox.After 3 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=7 in experience under 80 ℃.After adding 50g silica gel, mixture is evaporated to dried, and by using methylene dichloride: the silica gel column chromatography of methyl alcohol (4: 1) is with residue purified.Evaporating solvent goes out solid crystallization from ether to stay solid, obtains 2.67g (quantitatively) title compound (crude product that contains silica gel), and it is not accepted purifying and is directly used in next step.

3. 4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylate methyl ester

Through 2 hours to 3.6g (16.4mmol) 4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylate methyl ester and 2.8g (18.1mmol) 2,6-dimethyl-benzyl chloride slowly adds 1.3g (32.5mmol) sodium hydride (60% dispersion liquid in the mineral oil) in 100mlN in the solution in the dinethylformamide.After reaction is finished, mixture is diluted with the saturated aqueous ammonium chloride hydrolysis and with 500ml water carefully.The collecting precipitation thing with the thorough washing of water and through the Vanadium Pentoxide in FLAKES drying, obtains 4.04g (73%) title compound (fusing point 165-169 ℃).

4. 4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid

To 3.5g (10.3mmol) 4-(2,6-dimethyl-benzyloxy)-1, add the 20ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylate methyl ester in the 100ml diox.After 2 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=7 80 ℃ of experience.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (4: 1) elution.Evaporating solvent goes out solid crystallization from ethylacetate/ether to stay solid, obtains 2.33g (70%) title compound (fusing point 285-286 ℃).

5. 4-benzyloxy-6-methylol-1,2-dimethyl-1H-benzoglyoxaline

In the suspension of 0.7g (18.4mmol) lithium aluminum hydride in the 40ml tetrahydrofuran (THF), slowly add 3g (9.7mmol) 4-benzyloxy-1, the 2-dimethyl-1H-benzoglyoxaline-solution of 6-carboxylate methyl ester in the 10ml tetrahydrofuran (THF).Add finish after, with 0.13ml water, 0.25ml6N potassium hydroxide aqueous solution and 0.13ml water hydrolysis reaction mixture carefully.The interpolation anhydrous magnesium sulfate also stirred 1 hour.Behind diatomite filtration suspension, evaporated filtrate and from acetone crystallization go out resistates, obtain the title compound (fusing point 213-214 ℃) that 1.99g (74%) is colorless solid.

6. 4-benzyloxy-6-methoxyl methyl-1,2-dimethyl-1H-benzoglyoxaline

To 1.5g (5.3mmol) 4-benzyloxy-6-methylol-1,2-dimethyl-1H-benzoglyoxaline is in 12mlN, slowly adds 0.4g (10mmol) sodium hydride (60% dispersion liquid in the mineral oil) in the solution in the dinethylformamide, and with mixture temperature to 50 ℃.After 1 hour, reaction mixture is cooled to-10 ℃ and added 0.4ml (6.4mmol) methyl iodide through 30 minutes.Reaction mixture was stirred 3 hours, then with saturated aqueous ammonium chloride hydrolysis carefully.It is molten that mixture is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain 1.25g (80%) solid title compound (113 ℃ of fusing points) by crystallization from light sherwood oil.

7. 4-benzyloxy-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

To 3.0g (9.1mmol) 4-benzyloxy-6-bromo-1, add 0.3g (1.3mmol) acid chloride (II) and 1.4g (5.3mmol) triphenylphosphine in the solution of 2-dimethyl-1H-benzoglyoxaline in 100ml dimethylamine (3.2M is in tetrahydrofuran (THF)).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.The cooling of question response mixture is evaporated and resistates is dissolved in the methylene dichloride.Organic layer with water washing, is also evaporated through anhydrous magnesium sulfate drying.Silica gel column chromatography by using ethyl acetate obtains the title compound (fusing point 159-160 ℃) that 2.3g (78%) is colorless solid with residue purified.

8. 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline

To 0.35g (1.5mmol) 6-(N, N-dimethyl amido carbonyl)-4-hydroxyl-1, add 0.5g (3mmol) 2-ethyl-6-methyl-benzyl chloride in 2-dimethyl-1H-benzoglyoxaline and the suspension of 0.32g (3mmol) yellow soda ash in 5ml acetone, and mixture was stirred 20 hours at ambient temperature.It is molten that mixture is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using ethyl acetate obtains the title compound (fusing point 161-162 ℃) that 0.38g (68%) is colorless solid with residue purified.

9. 6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline

To 1.0g (3.08mmol) 4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 40ml methylene dichloride and 10ml N, add 1.7g (5.3mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 1 hour, add 3.7ml (18.5mmol) dimethylamine (5M is in tetrahydrofuran (THF)) at ambient temperature.After 30 minutes, it is molten that reaction mixture is divided between 2N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) to generate oily matter, goes out oily matter crystallization from ethyl acetate/light sherwood oil residue purified, obtains the title compound (180 ℃ of fusing points) that 1.0g (91%) is yellow solid.

10. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline oxalate

To 0.5g (2.1mmol) 6-(N, N-dimethyl amido carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline and 1.1g (8.3mmol) 1 add the 0.6ml triethylamine in the suspension of 2-epoxy indane in 5.3ml methyl alcohol and 1.3ml water, and mixture heating up to 70 ℃ is continued 30 minutes.It is molten that refrigerative solution is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) to generate oily matter, is dissolved in the acetone oily matter residue purified, and with the solution-treated of 0.27g (2.1mmol) two oxalic acid hydrates in acetone.The collecting precipitation thing, and, obtain the title compound (fusing point 144-145 ℃) that 0.64g (65%) is colorless solid with washing with acetone.

11. 4-[(1S, 2S)-2,3-dihydro-2-hydroxyl-1-indenes oxygen base]-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline oxalate

To 0.5g (2.1mmol) 6-(N, N-dimethyl amido carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline and 0.75g (5.7mmol) (1R, 2S)-add the 0.6ml triethylamine in the suspension of epoxy indane in 5ml ethanol and 1.25ml water, and mixture heating up to 60 ℃ is continued 48 hours.It is molten that refrigerative solution is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) to generate oily matter, is dissolved in the acetone oily matter residue purified, and with the solution-treated of 0.12g (1mmol) two oxalic acid hydrates in acetone.Collecting precipitation thing, and with washing with acetone, obtain the title compound that 0.14g (14%) is colorless solid (fusing point 126-127 ℃, 92%ee).

12. 4-(anti--2,3-dihydro-2-methoxyl group-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline oxalate

Under 0 ℃ to 0.57g (1.56mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline slowly adds 0.15g (2.3mmol) sodium hydride (60% dispersion liquid in the mineral oil) in 5mlN in the solution in the dinethylformamide.After 5 minutes, add 0.13ml (2mmol) methyl iodide and continue at ambient temperature and stirred 40 minutes.Divide reaction mixture molten carefully with the hydrolysis of 1ml1N ammoniacal liquor and between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3: 1) to generate oily matter, is dissolved in the acetone oily matter residue purified, and with the solution-treated of 0.19g (1.6mmol) two oxalic acid hydrates in acetone.The collecting precipitation thing, and, obtain the title compound (fusing point 126-127 ℃) that 0.51g (70%) is colorless solid with acetone and ether washing.

13. 4-[is anti--2,3-dihydro-2-(methoxyl methyl carbonyl oxygen base)-1-indenes oxygen base]-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

In the solution of 0.2ml (1.9mmol) methoxyacetic acid in the 4ml tetrahydrofuran (THF), add 0.3g (1.9mmol) N, N '-carbonyl dimidazoles.After 15 minutes, add 0.4g (1.1mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline and 0.3ml (2mmol) 1,8-diazabicylo [5.4.0] 11-7-alkene, and continue to stir 1 hour, it is molten that mixture is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.5: 0.5) and from 2-propyl alcohol/ether/normal heptane crystallization residue purified is obtained 0.47g (97%) solid title compound (140 ℃ of fusing points).

14. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-methoxyl methyl-1,2-dimethyl-1H-benzoglyoxaline oxalate

To 0.8g (3.9mmol) 4-hydroxyl-6-methoxyl methyl-1,2-dimethyl-1H-benzoglyoxaline and 1.03g (7.8mmol) 1, add the 1.08ml triethylamine in the suspension of 2-epoxy indane in 9.5ml methyl alcohol and 2.5ml water, and mixture heating up to 50 ℃ is continued 4 hours.It is molten that refrigerative solution is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (20: 1) to generate oily matter, is dissolved in the acetone oily matter residue purified, and with the solution-treated of 0.51g (4mmol) two oxalic acid hydrates in acetone.The collecting precipitation thing, and, obtain the title compound (purity 93%) that 0.72g (42%) is colorless solid with washing with acetone.

15. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

To 5.0g (21.4mmol) 4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester and 5.65g (42.8mmol) 1, add the 6ml triethylamine in the suspension of 2-epoxy indane in 48ml ethanol and 12ml water, and mixture heating up to 60 ℃ is continued 4 hours.It is molten that refrigerative solution is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain 5.66g (72%) title compound by crystallization from ethanol/ether, it is not accepted purifying and is directly used in the next step.

16. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid

To 5.6g (15.3mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1, add the 10ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 50ml diox.After 2.5 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=6 in experience under 80 ℃.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (4: 1) elution.Evaporating solvent goes out solid crystallization from ethyl acetate/normal heptane to stay solid, generates 5.3g (quantitatively) title compound (306 ℃ of fusing points).

17. 4-(anti--5-chloro-2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

To 1.17g (5.0mmol) 4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester and 2.47g (10mmol) 2-bromo-5-chloro-2, add 4.14g (30mmol) salt of wormwood in the 3-dihydro-suspension of 1H-indenes-1-phenol in 20ml ethanol and 5ml water, and with mixture heating up to 50 ℃.After 2 hours, add 1g (4mmol) 2-bromo-5-chloro-2 in addition, 3-dihydro-1H-indenes-1-phenol and 2g (14.5mmol) salt of wormwood, and continue to stir 5 hours.It is molten that refrigerative solution is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 3) obtains 0.52g (26%) title compound with residue purified, and it is not accepted purifying and is directly used in the next step.

18. 4-(anti--5-chloro-2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid

To 0.51g (1.27mmol) 4-(anti--5-chloro-2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1, add the 2.5ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 13ml diox.After 4 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=6 in experience under 80 ℃.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (4: 1) elution.Evaporating solvent goes out solid crystallization from normal heptane to stay solid, generates 0.63g title compound (containing silica gel), and it is not accepted purifying and is directly used in the next step.

19. 4-(anti--5-chloro-2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline oxalate

To 0.63g (1.27mmol, contain silica gel) and 4-(instead-5-chloro-2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 14ml methylene dichloride and 7mlN, add 0.6g (1.9mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 30 minutes, add 1.5ml (7.5mmol) dimethylamine (5M is in tetrahydrofuran (THF)) at ambient temperature.After 30 minutes, it is molten that reaction mixture is divided between 2N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) is with residue purified.Evaporate partly and with resistates is dissolved in the acetone, and with the solution-treated of 0.27g (2.1mmol) two oxalic acid hydrates in acetone.After the cooling, collecting precipitation thing and with washing with acetone obtains the title compound (fusing point 158-159 ℃) that 0.42g is colorless solid.

20. 4-(anti--2,3-dihydro-2-hydroxyl-4,7-dimethyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

To 1.17g (5.0mmol) 4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester and 2.41g (10mmol) 2-bromo-2,3-dihydro-4, add 4.14g (30mmol) salt of wormwood in the 7-dimethyl-suspension of 1H-indenes-1-phenol in 20ml ethanol and 5ml water, and with mixture heating up to 50 ℃.After 1 hour, add 2.41g (10mmol) 2-bromo-2 in addition, 3-dihydro-4,7-dimethyl-1H-indenes-1-phenol and 1.4g (10mmol) salt of wormwood, and continue to stir 1 hour.It is molten that refrigerative solution is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 3) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (184 ℃ of fusing points) that 0.85g (43%) is colorless solid.

21. 4-(anti--2,3-dihydro-2-hydroxyl-4,7-dimethyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid

To 0.8g (2mmol) 4-(anti--2,3-dihydro-2-hydroxyl-4,7-dimethyl-1-indenes oxygen base)-1, add the 4ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 20ml diox.After 4 hours, the cooling of question response mixture is also passed through to add 10% hydrochloric acid pH regulator is arrived pH=6 in experience under 80 ℃.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (4: 1) elution.Evaporating solvent stays 0.8g solid title compound (containing silica gel), and it is not accepted purifying and is directly used in the next step.

22. 4-(anti--2,3-dihydro-2-hydroxyl-4,7-dimethyl-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

To 0.7g (1.8mmol, contain silica gel) 4-(anti--2,3-dihydro-2-hydroxyl-4,7-dimethyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.8g (2.5mmol) O-(1H-benzotriazole-1-yl)-N in 20ml methylene dichloride and 10mlN in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 30 minutes, add 2ml (10mmol) dimethylamine (5M is in tetrahydrofuran (THF)) at ambient temperature.After 20 minutes, it is molten that reaction mixture is divided between 2N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) is with residue purified.Crystallization from ethyl acetate/normal heptane obtains the title compound (134 ℃ of fusing points) that 0.72g is colorless solid.

23. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-6-[(1-pyrrolidyl) carbonyl]-1H-benzoglyoxaline oxalate

To 1.0g (2.96mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1, add 1.45g (4.5mmol) O-(1H-benzotriazole-1-yl)-N in the 2-dimethyl-suspension of 1H-benzoglyoxaline-6-carboxylic acid in 20ml methylene dichloride and 10ml1-N-methyl-2-2-pyrrolidone N-, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 15 minutes, add 0.49ml (6mmol) tetramethyleneimine at ambient temperature.After 2 hours, it is molten that reaction mixture is divided between saturated aqueous ammonium chloride and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) is with residue purified.The oily matter that so obtains is dissolved in the acetone, and with the solution-treated of 0.38g (3mmol) two oxalic acid hydrates in acetone.Collecting precipitation thing and with the washing of acetone and ether obtains the title compound (124 ℃ of fusing points) that 1.06g (74%) is colorless solid.

24. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-[N-(2-methoxyethyl)-N-methyl-amido carbonyl]]]]]]-1,2-dimethyl-1H-benzoglyoxaline oxalate

To 1.0g (2.96mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1, add 1.45g (4.5mmol) O-(1H-benzotriazole-1-yl)-N in the 2-dimethyl-suspension of 1H-benzoglyoxaline-6-carboxylic acid in 20ml methylene dichloride and 10ml1-N-methyl-2-2-pyrrolidone N-, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 15 minutes, add 0.54g (6mmol) N-(2-methoxyethyl)-N-methyl-amine at ambient temperature.After 1 hour, it is molten that reaction mixture is divided between saturated aqueous ammonium chloride and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) is with residue purified.The evaporate part is dissolved in resistates in the acetone and with the solution-treated of 0.19g (1.5mmol) two oxalic acid hydrates in acetone.The collecting precipitation thing, and, obtain the title compound (141 ℃ of fusing points) that 0.55g (38%) is colorless solid with acetone and ether washing.

25. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-6-[(1-piperidyl) carbonyl]-1H-benzoglyoxaline oxalate

To 1.3g (3.84mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 25ml methylene dichloride and 10mlN, add 1.85g (5.76mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 15 minutes, add 0.64ml (7.7mmol) piperidines at ambient temperature.After 1 hour, it is molten that reaction mixture is divided between saturated aqueous ammonium chloride and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) is with residue purified.The oily matter that so obtains is dissolved in the acetone, and with the solution-treated of 0.25g (2mmol) two oxalic acid hydrates in acetone.The collecting precipitation thing, and, obtain the title compound (fusing point 115-116 ℃) that 0.95g (50%) is colorless solid with acetone and ether washing.

26. 6-(cyclopropyl amido carbonyl)-4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline

To 1.0g (2.96mmol) 4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 20ml methylene dichloride and 10mlN, add 1.45g (4.5mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 1 hour, add 0.45ml (6.5mmol) cyclopropylamine at ambient temperature.After 1 hour, it is molten that reaction mixture is divided between 2N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 148-149 ℃) that 0.78g (70%) is colorless solid by crystallization from ethyl acetate/methanol/normal heptane.

27. 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

With 1.0g (2.7mmol) 6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline is dissolved in 15ml ethanol and the 2.5ml triethylamine and transfers in the autoclave.After adding 0.1g (0.45mmol) acid chloride (II) and 0.33g (1.25mmol) triphenylphosphine, with reaction mixture carbonylation (5 crust carbon monoxide pressures, 100 ℃) 16 hours.Question response mixture cooling is filtered also evaporation to stay orange, it is dissolved in ethyl acetate and extracts with water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 171-173 ℃) that 0.8g (81%) is colorless solid by crystallization from ethyl acetate/light sherwood oil.

28. 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

With 8.8g (24.6mmol) 6-bromo-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline is dissolved in 130ml ethanol and the 21.3ml triethylamine and transfers in the autoclave.After adding 0.8g (3.6mmol) acid chloride (II) and 3.2g (12.2mmol) triphenylphosphine, with reaction mixture carbonylation (10 crust carbon monoxide pressures, 100 ℃) 16 hours.The cooling of question response mixture, filtration is also evaporated to stay orange, it is dissolved in the methylene dichloride and with water extract.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) and from ethyl acetate crystallization residue purified is obtained the title compound (190 ℃ of fusing points) that 6.18g (72%) is colorless solid.

29. 4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester

Be dissolved in 3.4g (8.45mmol) 6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline in 80ml ethanol and the 10ml triethylamine and transfer in the autoclave.After adding 0.28g (1.3mmol) acid chloride (II) and 1.1g (4.2mmol) triphenylphosphine, with reaction mixture carbonylation (6 crust carbon monoxide pressures, 100 ℃) 16 hours.The cooling of question response mixture is poured in the 250ml water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (3: 7) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 106-107 ℃) that 2.2g (66%) is colorless solid.

30. 4-(2,6-dimethyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester

Be dissolved in 2.5g (6.43mmol) 6-bromo-4-(2,6-dimethyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline in 60ml ethanol and the 7ml triethylamine and transfer in the autoclave.After adding 0.22g (0.96mmol) acid chloride (II) and 0.84g (3.2mmol) triphenylphosphine, with reaction mixture carbonylation (6 crust carbon monoxide pressures, 110 ℃) 16 hours.The cooling of question response mixture is poured in the 250ml water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 134-135 ℃) that 1.84g (81%) is yellow solid.

31. 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid

To 5.0g (13.7mmol) 4-(2-ethyl-6-methyl-benzyl amido)-1, add the 50ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 80ml diox.After experiencing 2 hours under 100 ℃, the cooling of question response mixture is poured in the 50ml saturated aqueous ammonium chloride and by interpolation 6N hydrochloric acid pH regulator is arrived pH=6.Collect dense thick throw out, with water washing and from ethanol recrystallize, generate the title compound (fusing point 312-314 ℃) that 3.7g (81%) is colorless solid.

32. 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1h-benzoglyoxaline-6-carboxylic acid

To 5.0g (14.2mmol) 4-(2,6-dimethyl-benzyl amido)-1, add the 20ml2N aqueous sodium hydroxide solution in the 2-dimethyl-1h-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 50ml diox.After 16 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=7 in experience under 100 ℃.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (13: 1) elution.Evaporating solvent goes out solid crystallization from acetone to stay solid, obtains 4.15g (90%) title compound (fusing point 315-318 ℃).

33. 4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid

In 1.6g (4.04mmol) 4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid h-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 30ml diox, add the 16ml2N aqueous sodium hydroxide solution.After experiencing 2 hours under 100 ℃, the cooling of question response mixture is poured in the 30ml water and by interpolation 6N hydrochloric acid pH regulator is arrived pH=6.The collecting precipitation thing with water and washing with alcohol and through the Vanadium Pentoxide in FLAKES drying, generates the title compound (fusing point 275-278 ℃) that 1.06g (71%) is colorless solid.

34. 4-(2,6-dimethyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid

In 1.3g (3.4mmol) 4-(2,6-dimethyl-benzyl the amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 25ml diox, add the 13ml2N aqueous sodium hydroxide solution.After experiencing 3 hours under 100 ℃, the cooling of question response mixture is poured in the 75ml water and by interpolation 6N hydrochloric acid pH regulator is arrived pH=6.The collecting precipitation thing with water, ethanol and isopropyl ether washing, generates the title compound (fusing point 269-272 ℃) that 0.96g (80%) is colorless solid.

35. 4-(2-ethyl-6-methyl-benzyl amido)-6-(2-hydroxyethyl-amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

With 1.0g (2.74mmol) 4-(2-ethyl-6-methyl-benzyl amido)-1, the 2-dimethyl-suspension of 1h-benzoglyoxaline-6-carboxylic acid, ethyl ester in 10ml2-amido ethanol is heated to 110 ℃ and continues 30 hours.The cooling of question response mixture is with the saturated aqueous ammonium chloride dilution and with ethyl acetate extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 200-201 ℃) that 0.72g (69%) is colorless solid by crystallization from ethylacetate/ether.

36. 4-(2,6-dimethyl-benzyl amido)-6-(2-hydroxyethyl-amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

With 1.0g (2.85mmol) 4-(2,6-dimethyl-benzyl amido)-1, the 2-dimethyl-suspension of 1H-benzoglyoxaline-6-carboxylic acid, ethyl ester in 15ml2-amido ethanol is heated to 100 ℃ and continues 16 hours.The cooling of question response mixture extracts with the water dilution and with methylene chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 259-260 ℃) that 0.64g (61%) is colorless solid by crystallization from ethyl acetate/methanol and gac.

37. 4-(2,6-dimethyl-benzyl amido)-6-(2-hydroxyethyl-amido carbonyl)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline

0.4g (1.04mmol) 4-(2,6-dimethyl-benzyl the amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in 4ml2-amido ethanol is heated to 140 ℃ continues 3 hours.The cooling of question response mixture is poured in 15ml water and the 10ml saturated aqueous ammonium chloride and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.6: 0.4) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 186-187 ℃) that 0.38g (93%) is colorless solid.

38. 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid amides

To 1.0g (2.96mmol) 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.54g (3.26mmol) N, N '-carbonyl dimidazoles in 10ml tetrahydrofuran (THF) and 5mlN in the suspension in the dinethylformamide.After 1 hour, add the saturated methyl alcohol ammonia of 10ml and continue and stirred 1 hour.Add 25ml saturated aqueous ammonium chloride and 50ml water, and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.8: 0.2) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 240-241 ℃) that 0.8g (80%) is colorless solid.

39. 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid amides

To 1.2g (3.7mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.7g (4.3mmol) N, N '-carbonyl dimidazoles in 10ml tetrahydrofuran (THF) and 5mlN in the suspension in the dinethylformamide.After 1 hour, with the ammonia drum through flask 1 hour.It is molten that mixture is divided between methylene dichloride and 2N aqueous sodium hydroxide solution.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (272 ℃ of fusing points) that 0.4g (34%) is colorless solid by crystallization from ethyl acetate.

40. 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-6-(pyrrolidyl carbonyl)-1H-benzoglyoxaline

To 1.0g (2.96mmol) 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.54g (3.26mmol) N, N '-carbonyl dimidazoles in 10ml tetrahydrofuran (THF) and 3mlN in the suspension in the dinethylformamide.After 2 hours, add 0.63g (3.26mmol) tetramethyleneimine and continue and stir.After 1 hour, add 20ml saturated aqueous ammonium chloride and 50ml water, and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.9: 0.1) and from ethyl acetate/normal heptane crystallization residue purified is obtained 0.91g (79%) solid title compound (126 ℃ of fusing points).

41. 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-6-(morpholinyl carbonyl)-1H-benzoglyoxaline

To 1.5g (4.44mmol) 4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 20ml tetrahydrofuran (THF) and 5mlN, add 1.48g (8.88mmol) N in the suspension in the dinethylformamide, N '-carbonyl dimidazoles, and with mixture heating up to 60 ℃.After 1 hour, add 1.94g (22.2mmol) morpholine, and made reaction mixture refluxed 1 hour.Mixture is poured in 100ml water and the 20ml saturated sodium bicarbonate aqueous solution then, and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.9: 0.1) and from isopropyl ether/normal heptane crystallization residue purified is obtained the title compound (fusing point 229-231 ℃) that 1.6g (89%) is colorless solid.

42. 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline

To 0.9g (2.44mmol) 4-(2-ethyl-6-methyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid in 10ml tetrahydrofuran (THF) and 3mlN, add 0.8g (4.9mmol) N in the suspension in the dinethylformamide, N '-carbonyl dimidazoles.After 1 hour, add 5ml (5mmol) dimethylamine (5M is in tetrahydrofuran (THF)) and continue and stirred 4 hours.Mixture is poured in the 60ml water and with dichloromethane extraction.Separate organic layer, with water washing, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.9: 0.1) and from isopropyl ether crystallization residue purified is obtained the title compound (154 ℃ of fusing points) that 0.88g (91%) is colorless solid.

43. 6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline

To 0.5g (1.4mmol) 4-(2,6-dimethyl-benzyl amido)-2-methoxyl methyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid is in 8ml tetrahydrofuran (THF) and 3mlN, add 0.46g (2.8mmol) N in the suspension in the dinethylformamide, N '-carbonyl dimidazoles, and mixture heating up to 60 ℃ continued 5 minutes.After experiencing 1 hour at ambient temperature, add 3ml (15mmol) dimethylamine (5M is in tetrahydrofuran (THF)), and continue to stir 1 hour.Mixture is poured in the 40ml water and with dichloromethane extraction.Separate organic layer, with water washing, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.8: 0.2) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 156-157 ℃) that 0.49g (92%) is colorless solid.

44. 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 9.5g (25.5mmol) 6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-1, add 0.85g (2.55mmol) acid chloride (II) and 4g (15.3mmol) triphenylphosphine in the solution of 2-dimethyl-1H-benzoglyoxaline in 225ml dimethylamine (3.2M is in tetrahydrofuran (THF)).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.The cooling of question response mixture is poured in the 400ml water and with dichloromethane extraction.Separate organic layer, with water washing, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 3) and from boiling ethyl acetate crystallization residue purified is obtained the title compound (fusing point 152-153 ℃) that 5.8g (76%) is colorless solid.

45. 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline hydrochloride

In 2.0g (5.6mmol) 6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-solution of 1-methyl-lH-benzoglyoxaline in 30ml dimethylamine (5M is in tetrahydrofuran (THF)), add 0.2g (0.9mmol) acid chloride (II) and 0.7g (2.7mmol) triphenylphosphine.Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 110 ℃) 16 hours.The cooling of question response mixture is with the water dilution and with dichloromethane extraction.Separate organic layer, with water washing, through anhydrous magnesium sulfate drying and evaporation.By at first using methylene dichloride: methyl alcohol (13: 1) and the silica gel column chromatography that uses ethyl acetate subsequently are with residue purified.Evaporate partly and with the saturated hydrogenchloride in the ether is handled, and obtains the title compound (fusing point 183-184 ℃) that 0.3g (14%) is colorless solid.

46. 6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 0.86g (2.4mmol) 6-bromo-4-(2,6-dimethyl-benzyl amido)-1, add 80mg (0.36mmol) acid chloride (II) and 250mg (0.96mmol) triphenylphosphine in the solution of 2-dimethyl-1H-benzoglyoxaline in 30ml dimethylamine (5M is in tetrahydrofuran (THF)).Reaction mixture is transferred in the autoclave and carbonylation (5.5 crust carbon monoxide pressures, 110 ℃) 16 hours.The cooling of question response mixture, evaporation also divides molten between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (20: 1) is with residue purified, and crystallization from ethyl acetate/normal heptane, obtains the title compound (fusing point 142-143 ℃) that 0.4g (48%) is colorless solid.

47. 6-(1-azetidine base carbonyl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 1.1g (3.4mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 20ml methylene dichloride and 5mlN, add 1.2g (3.74mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 1 hour, add the solution of 0.36g (3.74mmol) hydrochloric acid azetidine in 1.14g (11.2mmol) triethylamine.After 45 minutes, mixture is poured in the 120ml water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.6: 0.4) is with residue purified.Crystallization from isopropyl ether obtains the title compound (fusing point 193-195 ℃) that 0.46g (37%) is colorless solid.

48. 1-benzyloxymethyl-6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline oxalate

In 6.5g (13.6mmol) 1-benzyloxymethyl-6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-solution of 2-methyl isophthalic acid H-benzoglyoxaline in 44ml dimethylamine (5M is in tetrahydrofuran (THF)), add 0.3g (1.36mmol) acid chloride (II) and 2.1g (8.1mmol) triphenylphosphine.Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 100 ℃) 16 hours.The cooling of question response mixture is poured in the 200ml water and with ethyl acetate extraction.Separate organic layer, with water washing, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) generates the 3.1g yellow oil with residue purified, is dissolved in it in 20ml acetonitrile and with the solution-treated of 0.8g (6.4mmol) two oxalic acid hydrates in the 5ml acetonitrile.Collecting precipitation thing and with ether washing obtains 1.34g (18%) solid title compound (fusing point 168-169 ℃).

49. 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline

Make that 0.7g (1.25mmol) 1-benzyloxymethyl-6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline oxalate divides molten between methylene dichloride and saturated sodium bicarbonate aqueous solution.Separate organic layer and evaporation.Resistates is dissolved in the 15ml methyl alcohol and with 0.3g10%Pd/C (70 ℃, 1 crust H ₂) hydrogenation 2 hours.Leach catalyzer and evaporated filtrate.By at first using methylene dichloride: methyl alcohol (13: 1) and use ethyl acetate subsequently: the silica gel column chromatography of triethylamine (9: 1) is with residue purified.Crystallization from isopropyl ether obtains 0.1g (23%) solid title compound (fusing point 228-230 ℃).

50. 6-(N, N-dimethyl amido carbonyl)-4-(2-methoxycarbonyl amido-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 0.38g (1.63mmol) 4-amido-6-(N, N-dimethyl amido carbonyl)-1, add 0.35g (3.26mmol) yellow soda ash and 25mg (0.16mmol) sodium iodide in 2-dimethyl-1H-benzoglyoxaline and 0.37g (1.71mmol) the 2-methoxycarbonyl amido-suspension of 6-methyl-benzyl chloride in 20ml acetone.After stirring 3 hours at ambient temperature, reaction mixture is poured in the 80ml water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.8: 0.2) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 193-195 ℃) that 0.37g (55%) is colorless solid.

51. 4-(anti--2,3-dihydro-2-hydroxyl-1-indenyl amido)-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

To 0.6g (2.6mmol) 4-amido-6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline and 1g (7.7mmol) 1 add a triethylamine in the suspension of 2-epoxy indane in 10ml diox and 2ml water, and reaction mixture was stirred 6 hours down in 100 ℃.After cooling, mixture is poured in the 100ml water and with dichloromethane extraction.Separate organic layer, with water washing, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3: 1) and from isopropyl ether crystallization residue purified is obtained the title compound (fusing point 219-221 ℃) that 0.72g (77%) is colorless solid.

52. 4-benzyloxy-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid, ethyl ester

To 15.0g (45.3mmol) 4-benzyloxy-6-bromo-1, add 1.53g (6.8mmol) acid chloride (II) and 5.35g (20.4mmol) triphenylphosphine in the solution of 2-dimethyl-1H-benzoglyoxaline in 200ml ethanol and 50ml triethylamine.Mixture transferred in the autoclave and carbonylation (10 crust carbon monoxide pressures, 100 ℃) 18 hours.The cooling of question response mixture is evaporated and resistates is dissolved in the methylene dichloride.With water extraction organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (152 ℃ of fusing points) that 12.3g (84%) is colorless solid by crystallization from ethyl acetate/normal heptane and gac.

53. 4-benzyloxy-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylate methyl ester

To 27.0g (81mmol) 4-benzyloxy-6-bromo-1, add 2.7g (12mmol) acid chloride (II) and 9.6g (37mmol) triphenylphosphine in the solution of 2-dimethyl-1H-benzoglyoxaline in 340ml methyl alcohol and 90ml triethylamine.Mixture transferred in the autoclave and carbonylation (10 crust carbon monoxide pressures, 100 ℃) 16 hours.The cooling of question response mixture is filtered and evaporation.Resistates is dissolved in the methylene dichloride, with the water extraction, through anhydrous magnesium sulfate drying and evaporation.Resistates is dissolved in the hot ethyl acetate and with gac manages.After the filtration, evaporated filtrate stays the Vandyke brown solid, and by using methylene dichloride: the silica gel column chromatography of methyl alcohol (30: 1) obtains 15.6g (62%) gray solid title compound (166 ℃ of fusing points) with the solid purifying.

54. 6-(1-'-aziridino carbonyl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 1.0g (3.1mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.9g (5.6mmol) N, N '-carbonyl dimidazoles in 20ml tetrahydrofuran (THF) and 10mlN in the suspension in the dinethylformamide.60 ℃ of following experience after 2 hours, solution is cooled to 30 ℃ and added 1.5ml (29mmol) aziridine through 1.5 hours by three parts.Add 50ml water and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using ethyl acetate and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 201-202 ℃) that 0.92g (86%) is colorless solid.

55. 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-6-(N-methyl amido carbonyl)-1H-benzoglyoxaline

To 1.0g (3.1mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.9g (5.6mmol) N, N '-carbonyl dimidazoles in 20ml tetrahydrofuran (THF) and 10mlN in the suspension in the dinethylformamide.60 ℃ of following experience after 1.5 hours, treat that solution is cooled to 40 ℃ and add 3.05ml (6.1mmol) methylamine (2M is in tetrahydrofuran (THF)).After 30 minutes, add saturated aqueous ammonium chloride and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 252-253 ℃) that 1.0g (96%) is colorless solid by crystallization from ethyl acetate.

56. 4-(2,6-dimethyl-benzyl amido)-6-(N-2-hydroxyethyl-N-methyl amido carbonyl)-1,2-dimethyl-1H-benzoglyoxaline

To 1.0g (3.1mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid is in 45ml methylene dichloride and 10ml N, add 1.9g (5.9mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 1 hour, add 0.6ml (8.0mmol) 2-(methyl amido) ethanol at ambient temperature.After 4 hours, it is molten that reaction mixture is divided between 6N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) is with residue purified.Crystallization from acetone alkane obtains the title compound (fusing point 177-178 ℃) that 0.77g (65%) is colorless solid.

57. 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid hydrazides

To 1.0g (3.1mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid adds 0.9g (5.6mmol) N, N '-carbonyl dimidazoles in 20ml tetrahydrofuran (THF) and 10mlN in the suspension in the dinethylformamide.60 ℃ of following experience after 1.5 hours, treat that solution is cooled to 40 ℃ and add 0.3ml (9.4mmol) hydrazine.After 1 hour, the collecting precipitation thing and from the 2-propyl alcohol recrystallize, obtain the title compound (fusing point 277-278 ℃) that 0.88g (85%) is colorless solid.

58. 4-(2,6-dimethyl-benzyl amido)-6-methylol-1,2-dimethyl-1H-benzoglyoxaline

In nitrogen atmosphere, in the suspension of 0.8g (21mmol) lithium aluminum hydride in the 40ml anhydrous tetrahydro furan, slowly adding 4.0g (11.4mmol) 4-(2 under 0 ℃, 6-dimethyl-benzyl amido)-1, the 2-dimethyl-1H-benzoglyoxaline-solution of 6-carboxylic acid, ethyl ester in the 20ml anhydrous tetrahydro furan.After 2 hours, add 0.4g (10.5mmol) lithium aluminum hydride in addition and at room temperature continue and stirred 1 hour.With 0.3ml water, 0.6ml6N potassium hydroxide aqueous solution and 0.3ml water hydrolysis reaction mixture carefully.Add anhydrous magnesium sulfate, through diatomite filtration suspension and with the boiling washed with dichloromethane.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (20: 1) elution.Evaporating solvent with its crystallization from ethyl acetate/normal heptane, obtains the title compound (fusing point 245-246 ℃) that 1.4g (40%) is colorless solid to stay solid.

59. 2-cyclopropyl-4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid

To 1.5g (5.8mmol) 2-cyclopropyl-4-hydroxyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester and 1.5g (11.5mmol) 1, add the 1.6ml triethylamine in the suspension of 2-epoxy indane in 18ml ethanol and 5ml water, and mixture heating up to 50 ℃ is continued 4 hours.It is molten that refrigerative solution is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the 0.8g solid, it is suspended in 20ml diox and the 4ml2N aqueous sodium hydroxide solution.After 3 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=6 in experience under 80 ℃.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (10: 1) elution.Evaporating solvent with its crystallization from ethylacetate/ether, generates 0.68g (32%) title compound (fusing point 132-134 ℃) to stay solid.

60.2-cyclopropyl-4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-6-(N, N-dimethyl amido carbonyl)-1-methyl isophthalic acid H-benzoglyoxaline

To 0.67g (1.8mmol) 2-cyclopropyl-4-(anti--2,3-dihydro-2-hydroxyl-1-indenes oxygen base)-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid is in 30ml methylene dichloride and 7mlN, add 1.0g (3.1mmol) O-(1H-benzotriazole-1-yl)-N in the suspension in the dinethylformamide, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU), and with mixture heating up to 40 ℃.After 1 hour, add 2.3ml (11.4mmol) dimethylamine (5M is in tetrahydrofuran (THF)) at ambient temperature.After 30 minutes, it is molten that reaction mixture is divided between 2N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) obtains 0.63g (87%) colourless foam shape thing with residue purified.

61. 6-(N, N-dimethyl amido carbonyl)-1,2-dimethyl-4-(2-methyl-benzyl amido)-1H-benzoglyoxaline

To 1.2g (3.5mmol) 6-bromo-1, add 0.24g (0.3mmol) two (triphenylphosphine) Palladous chloride (II) in 2-dimethyl 4-(2-methyl-benzyl the amido)-solution of 1H-benzoglyoxaline in 55ml dimethylamine (5M is in tetrahydrofuran (THF)).Mixture transferred in the autoclave and carbonylation (5 crust carbon monoxide pressures, 100 ℃) 16 hours.The cooling of question response mixture is also filtered.It is molten that filtrate is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using toluene ∶ diox: the silica gel column chromatography of methyl alcohol (6: 3.9: 0.1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 158-159 ℃) that 0.37g (31%) is colorless solid.

62. 6-(N, N-dimethyl amido carbonyl)-4-(2,4-dimethyl-furans-3-base-methyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 0.4g (1.15mmol) 6-bromo-4-(2,4-dimethyl-furans-3-base-methyl amido)-1, add 40mg (0.17mmol) acid chloride (II) and 0.12g (0.46mmol) triphenylphosphine in the solution of 2-dimethyl-1H-benzoglyoxaline in 20ml dimethylamine (2M is in tetrahydrofuran (THF)).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.The cooling of question response mixture is also filtered.It is molten that filtrate is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (20: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 163-164 ℃) that 0.1g (26%) is colorless solid.

63. 7-(2,6-dimethyl-benzyl amido)-2,3-dimethyl-3H-benzoglyoxaline-5-sulfonic acid dimethylformamide

At room temperature stir 0.5g (1.86mmol) 7-amido-2,3-dimethyl-3H-benzoglyoxaline-5-sulfonic acid dimethylformamide and 0.3g (1.96mmol) 2, the suspension of 6-dimethyl-benzyl chloride, and add 0.08g (2.05mmol) sodium hydride (60% dispersion liquid in the mineral oil).Add 0.3g (1.96mmol) 2,6-dimethyl-benzyl chloride and 0.13g (3.25mmol) sodium hydrides with reaction mixture temperature to 45 ℃ and through 1.5 hours in addition by two parts.Mixture was stirred 16 hours down in 40 ℃, to be cooled and between methylene dichloride and water, divide molten.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (75: 25) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 237-238 ℃) that 0.35g (49%) is colorless solid.

64. 1-benzyloxymethyl-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester

In 6.5g (14.2mmol) 1-benzyloxymethyl-6-bromo-4-(2,6-dimethyl-benzyl the amido)-solution of 2-methyl isophthalic acid H-benzoglyoxaline in 125ml ethanol and 25ml triethylamine, add 1.0g (1.36mmol) two (triphenylphosphine) Palladous chloride (II).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 100 ℃) 16 hours.The cooling of question response mixture is also filtered.It is molten that filtrate is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 155-156 ℃) that 5.3g (82%) is colorless solid.

65. 1-benzyloxymethyl-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid

In 5.0g (10.9mmol) 1-benzyloxymethyl-4-(2,6-dimethyl-benzyl the amido)-2-methyl isophthalic acid H-benzoglyoxaline-solution of 6-carboxylic acid, ethyl ester in the 30ml diox, add the 15ml2N aqueous sodium hydroxide solution.After 2 hours, the cooling of question response mixture is also passed through to add 6N hydrochloric acid pH regulator is arrived pH=7 in experience under 90 ℃.After adding 50g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (13: 1) elution.Evaporating solvent with its crystallization from ether, generates the 4.36g title compound to stay solid, and it is not accepted purifying and is directly used in the next step.

66. 1-benzyloxymethyl-6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline

To 3.0g (7mmol, crude product) 1-benzyloxymethyl-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid is in 30ml tetrahydrofuran (THF) and 15mlN, adds 1.97g (12.2mmol) N in the suspension in the dinethylformamide, N '-carbonyl dimidazoles.60 ℃ of following experience after 2 hours, treat that solution is cooled to 40 ℃ and add 5.0ml (25mmol) dimethylamine (5M is in tetrahydrofuran (THF)).After 30 minutes, add saturated aqueous ammonium chloride and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (75: 25) obtains the title compound (fusing point 55-56 ℃) that 2.68g (84%) is colourless foam shape thing with residue purified.

67. 6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline

With 2.4g (7.1mmol) 1-benzyloxymethyl-6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline, 4.5g (71mmol) ammonium formiate and 0.5g charcoal carry the suspension of palladium (10%) in 50ml ethanol and be heated to backflow.After 2 hours, mixture is also evaporated through diatomite filtration.It is molten that resistates is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (203 ℃ of fusing points) that 1.4g (59%) is colorless solid by crystallization from ethyl acetate/normal heptane.

68. 1-benzyloxymethyl-6-(N-methyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline

To 1.3g (3mmol, crude product) 1-benzyloxymethyl-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid is in 20ml tetrahydrofuran (THF) and 10mlN, adds 0.8g (4.9mmol) N in the suspension in the dinethylformamide, N '-carbonyl dimidazoles.60 ℃ of following experience after 2.5 hours, treat that solution is cooled to 40 ℃ and add 5.0ml (10mmol) methylamine (2M is in tetrahydrofuran (THF)).After 1 hour, add saturated aqueous ammonium chloride and with the dichloromethane extraction mixture.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 215-216 ℃) that 0.91g (71%) is colorless solid by crystallization from ethyl acetate/normal heptane.

69. 4-(2,6-dimethyl-benzyl amido)-6-(N-methyl amido carbonyl)-2-methyl isophthalic acid H-benzoglyoxaline

0.85g (1.92mmol) 1-benzyloxymethyl-6-(N-methyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methyl isophthalic acid H-benzoglyoxaline, 2.5g (40mmol) ammonium formiate and 0.26g charcoal are carried the suspension of palladium (10%) in 45ml ethanol be heated to backflow.1.5 after hour, mixture is also evaporated through diatomite filtration.It is molten that resistates is divided between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (298 ℃ of fusing points) that 0.47g (76%) is colorless solid by crystallization from ethyl acetate/normal heptane.

70. 6-(N, N-dimethyl amido carbonyl)-4-(2-methylol-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

To 0.45g (1.2mmol) 6-bromo-4-(2-methylol-6-methyl-benzyl amido)-1, add 0.125g (0.18mmol) two (triphenylphosphine) Palladous chloride (II) in the solution of 2-dimethyl-1H-benzoglyoxaline in 5ml dimethylamine and 15ml tetrahydrofuran (THF).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.The cooling of question response mixture is also filtered.It is molten that filtrate is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (20: 1) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 197-198 ℃) that 0.07g (15%) is colorless solid.

71. 6-cyano group-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

With 6.0g (16.8mmol) 6-bromo-4-(2,6-dimethyl-benzyl amido)-1, through degassing N, the suspension in the dinethylformamide is heated to 100 ℃ in 50ml for 2-dimethyl-1H-benzoglyoxaline, 2.1g (17.9mmol) zinc cyanide and 1.94 (1.68mmol) tetrakis triphenylphosphine palladium.After 40 minutes, the cooling of question response mixture is poured in the 300ml saturated aqueous ammonium chloride and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (100: 1) and from ethyl acetate crystallization residue purified is obtained the title compound that 4.56g is colorless solid, it is used for next step without being further purified.

72. 6-(4,5-dihydro-1H-imidazoles-2-yl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

With 0.5g (1.64mmol) 6-cyano group-4-(2,6-dimethyl-benzyl amido)-1, the suspension of thiophosphoric anhydride in the 5ml quadrol of 2-dimethyl-1H-benzoglyoxaline and catalytic amount is heated to 120 ℃.After 1 hour, the cooling of question response mixture also divides molten between water and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 273-274 ℃) that 0.54g (90%) is yellow solid by crystallization from ether.

73. 6-(4,5-dihydro-1-methyl isophthalic acid H-imidazoles-2-yl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

With 0.25g (0.82mmol) 6-cyano group-4-(2,6-dimethyl-benzyl amido)-1, the suspension of the thiophosphoric anhydride of 2-dimethyl-1H-benzoglyoxaline and catalytic amount in 2.5ml N-methyl-quadrol is heated to 120 ℃.After 1 hour, the cooling of question response mixture also divides molten between water and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (4: 1) and from ether crystallization residue purified is obtained the title compound (fusing point 118-119 ℃) that 0.11g (37%) is colorless solid.

74. 6-(4,5-dihydro-oxazoles-2-yl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline

With 0.5g (1.64mmol) 6-cyano group-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline and the suspension of 0.54g (3.9mmol) zinc chloride in the 5ml thanomin are heated to 140 ℃.3.5 after hour, the cooling of question response mixture also divides molten between saturated aqueous ammonium chloride and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using ethyl acetate and from ethylacetate/ether crystallization residue purified is obtained the title compound (235 ℃ of fusing points) that 0.25g (42%) is colorless solid.

75. 4-(2,6-dimethyl-benzyl amido)-N-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-6-carbonamidine

With 0.5g (1.64mmol) 6-cyano group-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline, 0.67g (9.6mmol) oxammonium hydrochloride and 1.04g (9.8mmol) yellow soda ash are in 10mlN, and the suspension in the dinethylformamide is heated to 110 ℃.After 7 hours, the cooling of question response mixture also divides molten between saturated aqueous ammonium chloride and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) and from acetone crystallization residue purified is obtained the title compound (230 ℃ of fusing points) that 0.39g (71%) is colorless solid.

76. 6-bromo-4-(2,6-dimethyl-benzyl amido)-1-hydroxy-2-methyl-1H-benzoglyoxaline

Press aliquot to 4.0g (16.5mmol) 4-amido-6-bromo-1-hydroxy-2-methyl-1H-benzoglyoxaline and 2.5g (18.6mmol) 2, add 3.1g (49.3mmol) sodium cyanoborohydride in the suspension of 6-dimethyl-phenyl aldehyde in 80ml methyl alcohol, and make pH maintain pH=3 by adding methyl alcohol hydrogenchloride by amount.After 3 hours, divide molten with the saturated sodium bicarbonate aqueous solution hydrolysis reaction mixture and between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By from acetone with residue purified, obtain the title compound (277 ℃ of fusing points) that 2.4g (40%) is colorless solid.

77. 6-bromo-4-(2,6-dimethyl-benzyl amido)-1-methoxyl group-2-methyl isophthalic acid H-benzoglyoxaline

In 0.36g (1.0mmol) 6-bromo-4-(2,6-dimethyl-benzyl amido)-1-hydroxy-2-methyl-1H-benzoglyoxaline and the suspension of 0.3g (2.2mmol) salt of wormwood in 3ml acetone, add 0.7ml (1.12mmol) methyl iodide (1.6M is in acetone).After 4 hours, it is molten that mixture is divided between methylene dichloride and saturated aqueous ammonium chloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 171-172 ℃) that 0.2g (53%) is colorless solid by crystallization from ether/normal heptane.

78. 4-(2,6-dimethyl-benzyl amido)-1-methoxyl group-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester

In 1.5g (4.0mmol) 6-bromo-4-(2,6-dimethyl-benzyl the amido)-1-methoxyl group-solution of 2-methyl isophthalic acid H-benzoglyoxaline in 60ml ethanol and 3.3ml triethylamine, add 0.35g (0.5mmol) two (triphenylphosphine) Palladous chloride (II).Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.Question response mixture cooling and through diatomite filtration.Evaporated filtrate also divides molten between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (1: 1) obtains the title compound (fusing point 165-166 ℃) that 0.44g (29%) is colorless solid with residue purified.

79. 4-(2,6-dimethyl-benzyl amido)-1-methoxyl group-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid

In 0.43g (1.17mmol) 4-(2,6-dimethyl-benzyl the amido)-1-methoxyl group-2-methyl isophthalic acid H-benzoglyoxaline-suspension of 6-carboxylic acid, ethyl ester in the 10ml diox, add the 2ml2N aqueous sodium hydroxide solution.80 ℃ of following experience 8 hours and at ambient temperature after the stirred overnight, the cooling of question response mixture also by add 2N hydrochloric acid with pH regulator to pH=7.After adding 25g silica gel, mixture is evaporated to dried, resistates is placed on the post and with methylene dichloride: methyl alcohol (13: 1) elution.Evaporating solvent goes out solid crystallization from acetone to stay solid, generates the title compound (fusing point 248-249 ℃) that 0.3g (75%) is colorless solid.

80. 6-(N, N-dimethyl amido-carbonyl)-4-(2,6-dimethyl-benzyl amido)-1-methoxyl group-2-methyl isophthalic acid H-benzoglyoxaline

To 0.28g (0.8mmol) 4-(2,6-dimethyl-benzyl amido)-1-methoxyl group-2-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid is in 15ml methylene dichloride and 3.5mlN, suspension in the dinethylformamide adds 0.5g (1.6mmol) O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl--Tetrafluoroboric acid urea (TBTU).Add 2.4ml (4.8mmol) dimethylamine (2M is in tetrahydrofuran (THF)) in experience under 40 ℃ at ambient temperature after 1 hour.After 30 minutes, it is molten that reaction mixture is divided between 2N aqueous sodium hydroxide solution and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 128-129 ℃) that 0.24g (80%) is colorless solid by crystallization from ether.

81. 2-acetyl-o-methyl-6-bromo-4-(2,6-dimethyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline

With 1.0g (3.35mmol) 2-acetyl-o-methyl-4-amido-6-bromo-1-methyl isophthalic acid H-benzoglyoxaline, 0.54g (3.5mmol) 2, the suspension of potassiumiodide in the 15ml acetonitrile of 6-dimethyl-benzyl chloride, 0.93g (6.7mmol) salt of wormwood and catalytic amount is heated to 70 ℃.After 4 hours, add 0.27g (1.75mmol) 2 in addition, 6-dimethyl-benzyl chloride also continues to stir 2 hours.Reaction mixture is poured in the 50ml water and with dichloromethane extraction.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using ethyl acetate: the silica gel column chromatography of light sherwood oil (7: 3) and from ethyl acetate/normal heptane crystallization residue purified is obtained the title compound (fusing point 188-190 ℃) that 0.58g (42%) is colorless solid.

82. 6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-2-methylol-1-methyl isophthalic acid H-benzoglyoxaline

In the solution of 30ml dimethylamine (2M is in tetrahydrofuran (THF)), add 0.67g (0.95mmol) two (triphenylphosphine) Palladous chloride (II) to 2.0g (4.8mmol) 2-acetyl-o-methyl-6-bromo-4-(2,6-dimethyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline.Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 25 hours.The cooling of question response mixture is also filtered.It is molten that filtrate is divided between saturated aqueous ammonium chloride and methylene dichloride.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Be dissolved in resistates in the 20ml methyl alcohol and add the 0.1g cesium carbonate.Mixture was refluxed 30 minutes cooling and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (13: 1) and from ethyl acetate crystallization residue purified is obtained the title compound (fusing point 171-172 ℃) that 0.5g (26%) is colorless solid.

83. 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-2-methylol-1-methyl isophthalic acid H-benzoglyoxaline

In 0.5g (1.28mmol) 6-bromo-4-(2-ethyl-6-methyl-benzyl amido)-2-methylol-solution of 1-methyl isophthalic acid H-benzoglyoxaline in 10ml dimethylamine (2M is in tetrahydrofuran (THF)) and 20ml tetrahydrofuran (THF), add 0.03g (0.128mmol) acid chloride (II) and 0.2g (0.77mmol) triphenylphosphine.Mixture transferred in the autoclave and carbonylation (6 crust carbon monoxide pressures, 120 ℃) 16 hours.Question response mixture cooling is poured in the water and with dichloromethane extraction.Organic layer is also evaporated through anhydrous magnesium sulfate drying.Silica gel column chromatography by using ethyl acetate and from ethyl acetate/isopropyl ether crystallization residue purified is obtained the title compound (fusing point 138-141 ℃) that 0.28g (58%) is colorless solid.

84. 4-(2,6-dimethyl-benzyl amido)-6-(the 5-ethyl-[and 1,3,4] oxadiazole-2 bases)-1,2-dimethyl-1H-benzoglyoxaline

With 0.1g (0.3mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid hydrazides is suspended in the 5ml triethyl orthopropionate.Experience is after 1 hour down at 140 ℃, and the cooling of question response mixture also divides molten between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.With residue purified, obtain the title compound (fusing point 246-247 ℃) that 0.08g (71%) is yellow solid by crystallization from normal heptane.

85. 4-(2,6-dimethyl-benzyl amido)-6-(the 5-methyl-[and 1,3,4] oxadiazole-2 bases)-1,2-dimethyl-1H-benzoglyoxaline

With 0.5g (1.48mmol) 4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzoglyoxaline-6-carboxylic acid hydrazides is suspended in the 7ml triethly orthoacetate.Experience is after 2 hours down at 140 ℃, and the cooling of question response mixture also divides molten between methylene dichloride and water.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.By using methylene dichloride: the silica gel column chromatography of methyl alcohol (20: 1) and from ether crystallization residue purified is obtained the title compound (fusing point 256-257 ℃) that 0.2g (37%) is colorless solid.

86. 4-benzyloxy-2-cyclopropyl-1-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid, ethyl ester

In 2.9g (8.1mmol) 4-benzyloxy-6-bromo-2-cyclopropyl-solution of 1-methyl isophthalic acid H-benzoglyoxaline in 100ml ethanol and 7ml triethylamine, add 0.6g (0.86mmol) two (triphenylphosphine) Palladous chloride (II).Mixture transferred in the autoclave and carbonylation (10 crust carbon monoxide pressures, 100 ℃) 18 hours.The cooling of question response mixture is filtered and evaporation.Resistates is dissolved in the methylene dichloride and with water extracts.Separate organic layer, through anhydrous magnesium sulfate drying and evaporation.Silica gel column chromatography by using toluene ∶ diox (10: 1) and from ethyl acetate/light sherwood oil crystallization residue purified is obtained the title compound (120 ℃ of fusing points) that 2.33g (83%) is colorless solid.

Use the similar reactions steps described in above example can obtain following compounds in a similar manner:

A) 6-(N, N-dimethyl amido carbonyl)-2-(N, N-dimethyl amido)-4-(2,6-dimethyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline

B) 6-(N, N-dimethyl amido carbonyl)-2-(N, N-dimethyl amido)-4-(2-ethyl-6-methyl-benzyl amido)-1-methyl isophthalic acid H-benzoglyoxaline

Commercial use

Formula 1 and formula 2 compounds and salt thereof have important pharmacological characteristics, make it have commercial utility.Particular words it, they particularly produce significant gastric acid secretion restraining effect and fabulous stomach and intestine provide protection in the human body warm-blooded animal.In this article, according to the distinguishing feature of compound of the present invention be that time length of selectivity height, effect of its effect is favourable, it is active in the good intestines to have, non-evident effect and have very big therapeutic domain.

" stomach and intestine protection " is interpreted as meaning prevention and treatment gastrointestinal illness in this article; especially gastrointestinal inflammation and pathology (for example stomach ulcer, duodenal ulcer, gastritis, hyperchlorhydria or the functional dyspepsia relevant with medicine), it can be caused by (for example) microorganism (for example helicobacter pylorus Pseudomonas bacterium (Helicobacter pylori)), bacteriotoxin, medicine (for example some antiphlogistic drug and antirheumatic), chemical (for example ethanol), hydrochloric acid in gastric juice or stress situation.

In its excellent characteristic, shockingly find: in the various models of measuring antiulcer agent generation and secretion inhibitor characteristic, obviously be better than compound known from previous technology according to compound of the present invention.Since these characteristics, so acceptable salt significantly is applicable in people and the veterinary medicine on formula 1 and 2 compounds and the pharmacology thereof, and it is specially adapted to treat and/or prevent stomach and/or intestines deficiency disorder.

Therefore, another theme of the present invention is the compound that is used for the treatment of and/or prevents above-mentioned disease according to of the present invention.

The present invention comprises that equally compound according to the present invention is used to produce the purposes that is used for the treatment of and/or prevents the medicine of above-mentioned disease.

The present invention comprises that also compound according to the present invention is used for the treatment of and/or prevents the purposes of above-mentioned disease.

Another theme of the present invention is the medicine that comprises acceptable salt on one or more formula 1 compound and/or its pharmacology.

Described medicine is known and method that the those skilled in the art was familiar with and making with itself.As medicine, according to the active compound of tool (=active compound) on the pharmacology of the present invention is to use or preferably use with suitable medical auxiliary agent or excipient composition with tablet, sugar coated tablet, capsule, suppository, paster (for example as TTS), emulsion, suspension or solution form, active compound content and may obtain to be suitable for active compound fully and/or the medical form of medication of the time length (for example sustained release form or intestines form) that will show effect and/or act on by suitable selection auxiliary agent and vehicle preferably between 0.1 and 95%.

Be applicable to that the auxiliary agent of the pharmaceutical formulation of wanting and vehicle are the those skilled in the art based on known to its expertise.Desolventize, outside gelatinizing agent, suppository host, sheet agent aid and other active compound excipients, may also use (for example) antioxidant, dispersion agent, emulsifying agent, defoamer, smell corrigent, sanitas, solubilizing agent, tinting material or especially be penetration enhancer and recombiner (for example cyclodextrin).

But described active compound per os, without intestines or percutaneous dosing.

By and large, confirm in the human medicine advantageously under the oral administration situation with about 0.01 per daily dose administration active compound to about 20, preferably 0.05 to 5, especially 0.1 to 1.5mg/kg body weight (when suitable with several, preferably 1 to 4 individually dosed) wanted the result to reach.Under situation, can use the general lower dosage of similar dosage or (especially under the situation of intravenous administration active compound) without the intestines treatment.The establishment of the optimal dose of active compound and administering mode in all cases all can easily be carried out based on its expertise by the those skilled in the art.

If use according to compound of the present invention and/or the above-mentioned disease of its salts for treating, then pharmaceutical formulation also can contain the active constituent on the pharmacology of one or more other medicines group, for example: tranquillizer is (for example from the: benzodiazepine group, diazepam (diazepam) for example), spasmolytic (for example bietamiverine (bietamiverine) or bank Miroprofen (camylofine)), anticholinergic (for example oxyphencyclimine (oxyphencyclimine) or phencarbamide (phencarbamide)), local anesthetic (for example tetracaine (tetracaine) or PROCAINE HCL, PHARMA GRADE (procaine)), and also can be enzyme suitably the time, VITAMIN or Amino acid.

Stress in particular in this article according to compound of the present invention and the combination that suppresses sour excretory medicament, described medicament for example is H2 blocker (for example Cimitidine Type A/AB (cimetidine), Ranitidine HCL (ranitidine)), H+/K+ATP enzyme inhibitors (for example omeprazole (omeprazole), pantoprazole (pantoprazole)); Or further with so-called periphery anticholinergic (for example pirenzepine (pirenzepine), telenzepine (telenzepine)) and be used to increase the main effect and/or the elimination of additive or super additive aspect or reduce the tert-Amyloxycarbonyltetragastrin antagonist of side effect; Or further with the combination of the antibacterial substance that is used to control helicobacter pylori (for example cynnematin, tsiklomitsin, penicillin, macrolide, nitroimidazole or bismuth salt).The suitable antibiotic component altogether that can mention is for example mezlocillin (mezlocillin), Ampicillin Trihydrate (ampicillin), amoxycilline Trihydrate bp (amoxicillin), cephalosporin (cefalothin), cefoxitin (cefoxitin), cefotaxime (cefotaxime), imipenum (imipenem), gentamicin (gentamycin), amikacin (amikacin), erythromycin (erythromycin), Ciprofloxacin (ciprofloxacin), metronidazole (metronidazole), clarithromycin (clarithromycin), Azythromycin (azithromycin) and combination (for example clarithromycin+metronidazole) thereof.

In view of the splendid stomach and intestine provide protection of formula 1 compound, its be applicable to known have specificly cause those medicines that ulcer renders a service (for example some antiphlogistic drug and antirheumatic, such as NSAID) arbitrarily or fixed combination.

Pharmacology

Good stomach provide protection and gastric acid secretion restraining effect according to compound of the present invention can be confirmed in the research to animal experimental model.For the compound of in following model, being studied according to the present invention provide corresponding to example in the numbering of numbering of these compounds.

Test is to the secretion inhibition through the perfusion rat stomach

Be presented at intraduodenal administration in following Table A after, compound according to the present invention is to the secretory influence of Peptavlon pungency acid through the perfusion rat stomach.

Table A

Biological data

Numbering	In dosage (μ mol/kg) duodenum (i.d.)	Acid excretory inhibiting rate (%)
Numbering	In dosage (μ mol/kg) duodenum (i.d.)	Acid excretory inhibiting rate (%)	8	1	＞50
10	1	＞50	8	1	＞50
10	1	＞50	11	1	＞50
13	1	＞50	11	1	＞50
13	1	＞50	19	1	＞50
35	1	＞50	19	1	＞50
35	1	＞50	38	1	＞50
40	1	＞50	38	1	＞50
40	1	＞50	41	1	＞50
42	1	＞50	41	1	＞50
42	1	＞50	43	1	＞50
44	1	＞50	43	1	＞50
44	1	＞50	45	1	＞50
46	1	＞50	45	1	＞50
46	1	＞50	49	1	＞50
55	1	＞50	49	1	＞50

Method

After tracheotomy by upper middle belly cutting will through the rat of anesthesia (the CD rat, female, 200-250g; 1.5k/ abdominal incision minute intramuscular urethane), and pass and mouthful be fixed on the PVC conduit in the esophagus and another conduit passes pylorus and makes the two tubes end just in time charge in the gastral cavity.Pass side opening from the outside derivation of the conduit of pylorus derivation and enter right stomach wall.

Behind cleaning down (about 50-100ml), with temperature (37 ℃) physiology NaCl solution continue by stomach (0.5ml/ minute, pH6.8-6.9; Braun-Unita I).In the effluent liquid of under each situation, collecting with 15 minutes interval, measure pH (pH meter 632, glass electrode EA147; φ=5mm; Metrohm) and secreted HCl (being titrated to pH7 (Dosimat 665 Metrohm)) by 0.01NNaOH solution with prepared fresh.

The intravenously Peptavlon (left femoral vein) that continues infusion 1 μ g/kg (=1.65ml/ hour) by (promptly in 2 preparation parts of mensuration back) after finishing about 30 minutes in operation stimulates gastric secretion.Before lasting Peptavlon infusion begins 60 minutes with the 2.5ml/kg liquid volume through intraduodenal administration material to be tested.

By infrared radiation and heating cushion (by means of the automatic stepless control of rectal temperature transmitter) animal heat is remained on constant 37.8-38 ℃.

Claims

1. formula 1 compound

Wherein

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-carbalkoxy, list-or two-1-4C-alkyl amine group-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxyl group-1-4C-alkyl, hydroxyl or 1-4C-alkoxyl group

R3 be hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl ,-CO-1-4C-alkoxyl group, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, cyano group ,-CO-NR31R32 group, SO ₂-NR31R32 group or Het group,

Wherein

Or wherein

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl, '-aziridino or azetidine base together with the nitrogen-atoms of their common bonds, and

Het is that it is selected from the group that is made up of oxadiazole base, dihydro-oxazole base, glyoxalidine Ji, oxazolyl, imidazolyl, isoxazolyl, dihydro-isoxazole base, pyrazolyl and tetrazyl through the heterocycle residue of R33, R34 and R35 replacement,

Wherein

X is O (oxygen) or NH, and

Y has implication-CH ₂-Ar

Wherein

Ar is list or the bicyclic aromatic residue that replaces through R4, R5, R6 and R7, it is selected from by phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2, the group that 3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl are formed

Perhaps Y represents the gp group

Wherein

Z have implication-CHR8-or-CHR8-CHR9-

Wherein, in Ar and/or gp group

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

R9 is a hydrogen, the 1-7C-alkyl, the 2-7C-thiazolinyl, hydroxyl, the 1-4C-alkoxyl group, 1-4C-alkoxyl group through the oxygen replacement, the 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-4C-alkoxyl group, hydroxyl-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkoxyl group, 3-7C-cycloalkyloxy-1-4C-alkoxyl group, 3-7C-cycloalkyl-1-4C-alkoxyl group-1-4C-alkoxyl group, the 1-4C-alkyl carbonyl oxy, halo-1-4C-alkoxyl group, amido, single-or two-1-4C-alkyl amine group, 1-4C-alkyl-carbonyl amido, 1-4C-carbalkoxy amido, single-or two-1-4C-

Alkyl amine group-1-4C-alkyl carbonyl oxy, 1-4C-alkoxyl group-1-4C-carbalkoxy amido or 1-4C-alkoxyl group-1-4C-alkyl carbonyl oxy,

And wherein

Aryl is phenyl or the phenyl that replaces through one, two or three identical or different substituting group, described substituting group is selected from the group that is made up of 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-carbalkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group

Its restricted condition is to represent-CH as Y ₂When-Ar and R2 represented hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, R3 did not have the implication of hydrogen or halogen,

Or one salt.

2. compound according to claim 1,

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Or wherein

X is O (oxygen) or NH, and

Y has implication-CH ₂-Ar,

Wherein

Perhaps Y represents the gp group

Wherein

Z have implication-CHR8-or-CHR8-CHR9-

Wherein, in Ar and/or gp group

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Its restricted condition is to represent-CH as Y ₂During-Ar, R3 does not have the implication of hydrogen or halogen,

Or one salt.

3. compound according to claim 1 is characterized by formula 1a

Wherein

Or wherein

Wherein

X is O (oxygen) or NH, and

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Or one salt.

4. compound according to claim 1 is characterized by formula 1b

Wherein

Or wherein

Wherein

X is O (oxygen) or NH, and

Z have implication-CHR8-or-CHR8-CHR9-,

Wherein

And wherein

Or one salt.

5. formula 1a compound according to claim 3 is characterized by formula 1a-1

Wherein

R32 is hydrogen or 1-7C-alkyl,

Or wherein

Het is that it is selected from the group that is made up of oxadiazole base, dihydro-oxazole base and glyoxalidine base through the heterocycle residue of R33, R34 and R35 replacement,

Wherein

R33 is hydrogen or 1-4C-alkyl,

R34 is hydrogen or 1-4C-alkyl,

R35 is hydrogen or 1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group, and

X is O (oxygen) or NH,

Or one salt.

6. formula 1b compound according to claim 4 is characterized by formula 1b-1

Wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is hydrogen or 1-4C-alkyl,

Wherein

Or wherein

R31 and R32 are pyrrolidyl, piperidyl, piperazinyl, N-1-4C-alkylpiperazine base, morpholinyl, '-aziridino or azetidine base together with the nitrogen-atoms of their common bonds, and R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is hydrogen or 1-4C-alkyl,

X is O (oxygen) or NH,

Or one salt.

7. formula 1b-1 compound according to claim 6, wherein

R1 is the 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

Wherein

Or wherein

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

R5 is a hydrogen,

X is O (oxygen) or NH,

Or one salt.

8. formula 1a-1 compound according to claim 5, wherein

R1 is the 1-4C-alkyl,

R2 is the 1-4C-alkyl,

Wherein

R32 is hydrogen or 1-4C-alkyl,

R4 is 1-4C-alkyl or 1-4C-alkyl-carbonyl amido,

R5 is the 1-4C-alkyl,

X is O (oxygen) or NH,

Or one salt.

9. a 6-(N, N-dimethyl amido carbonyl)-4-(2-ethyl-6-methyl-benzyl amido)-1,2-dimethyl-1H-benzimidazole compound or one salt.

10. a 6-(N, N-dimethyl amido carbonyl)-4-(2,6-dimethyl-benzyl amido)-1,2-dimethyl-1H-benzimidazole compound or one salt.

11. a medicine, it comprises acceptable salt and medical auxiliary agent commonly used and/or vehicle on compound according to claim 1 and/or its pharmacology.

12. acceptable salt is in the purposes of prevention and treatment gastrointestinal disorder disease on a compound according to claim 1 and its pharmacology.