CN101160306B - Benzimidazole compound - Google Patents

Benzimidazole compound Download PDF

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CN101160306B
CN101160306B CN2006800126056A CN200680012605A CN101160306B CN 101160306 B CN101160306 B CN 101160306B CN 2006800126056 A CN2006800126056 A CN 2006800126056A CN 200680012605 A CN200680012605 A CN 200680012605A CN 101160306 B CN101160306 B CN 101160306B
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methyl
salt
benzoglyoxaline
mixture
group
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CN101160306A (en
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宫泽修平
篠田昌信
川原哲也
渡边信久
原田均
饭田大介
寺内广毅
永川纯一
藤崎秀明
窪田笃彦
上田正人
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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Abstract

The present invention provides a novel chemical compound useful as a therapeutic or prophylactic agent for acid-related diseases, having an excellent inhibitory effect against gastric acid secretion, an excellent effect of maintaining the inhibitory effect against gastric acid secretion, thereby maintaining intragastric pH high for a long time, and having more safety and appropriate physicochemical stability. Provided is a compound represented by general formula (1), a salt thereof or a solvate of these, where R<1> and R<3> may be the same or different and each represent a hydrogen atom or a C1-C6 alkyl group; R<2> represents (5,5-dimethyl-1,3-dioxan-2-yl)methoxy group, 5,7-dioxaspiro[2.5]oct-6-ylmethoxy group, 1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy group, or (2,2-dimethyl-1,3-dioxan-5-yl)methoxy group; R<4>, R<5>, R<6> and R<7> represent a hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group or C1-C6 haloalkoxy group; and W<1> represents a single bond, methylene or ethylene group.

Description

Benzimidazole compound
Technical field
The present invention relates to benzimidazole compound or its salt or their solvate as gastric acid secretion inhibitor.
The invention still further relates to and be used as and sour diseases associated or the therapeutical agent of symptom (particularly gastroesophageal reflux disease, Symptomatic gastroesophageal reflux disease, stomach ulcer and duodenal ulcer) or benzimidazole compound or its salt or their solvate of preventive.
Background technology
Peptide ulceration such as stomach ulcer and duodenal ulcer are to cause that owing to the balance between attack factor such as acid and stomach en-and defense factor such as mucus and the blood flow is damaged it has caused autodigestion.
Peptide ulceration is mainly treated by the method for internal medicine, and therefore having attempted various pharmacotherapys carries out medical treatment.Particularly, developed in recent years and a kind ofly can suppress H specifically +/ K +-ATP enzyme (a kind of enzyme that is present in the final stage of parietal cell and responsible gastric acid secretion) thus gastric acid inhibitory secretion and the medicine and this medicine that suppress autodigestion have entered clinical application.The example of described medicine comprises omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole.
These medicines have good result of treatment; Yet, still need to develop gastric acid inhibitory secretion more enduringly, safety and medicine that have suitable physical and chemical stability.Especially, somebody's curative ratio of proposing gastroesophageal reflux disease can improve (non-patent literature 1) by keeping the high pH value in the stomach for a long time.
The compound relevant especially with the present invention described in patent documentation 1 and 2 to some extent.Yet the compound that is disclosed in these patent documentations is different with the concrete disclosed compound of the present invention on chemical structure.
Patent documentation 1:WO 91/19712
Patent documentation 2:JP-A-59-181277
Non-patent literature 1:Digestion 1992; 51 (suppl 1): 59-67
Disclosure of the Invention
The problem to be solved in the present invention
The purpose of this invention is to provide a kind of new compound, this new compound has good inhibition effect, can be used as and the treatment of sour diseases associated or symptom or preventive and very outstanding on the inhibition effect that keeps gastric acid secretion gastric acid secretion, can keep the high pH in the stomach thus for a long time.
The method of dealing with problems
The present inventor has carried out going deep into careful research to achieve the above object.The result, they find that the benzimidazole compound that a class has a new chemical structure has good inhibition effect to gastric acid secretion, very outstanding on the inhibition effect that keeps gastric acid secretion, the high pH value in the stomach be can keep thus for a long time, and the treatment or the preventive of gastroesophageal reflux disease, Symptomatic gastroesophageal reflux disease, stomach ulcer and duodenal ulcer especially can be used as.On the basis of these discoveries, finished the present invention.
Or rather, the invention provides the compound or its salt of (1) that has following formula or their solvate.
[formula 1]
Figure S2006800126056D00021
In addition, the present invention also provides the medicine that contains following formula (1) compound or its salt or their solvate.
The present invention also provides the gastric acid secretion inhibitor that contains following formula (1) compound or its salt or their solvate.
The present invention further provides the pharmaceutical composition that contains following formula (1) compound or its salt or their solvate, or following formula (1) compound or its salt or their solvate are used for the purposes of pharmaceutical compositions.
In addition, the invention still further relates to be used for sour diseases associated or symptom such as stomach ulcer, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux disease (comprising the gastroesophageal reflux disease that shows effect repeatedly and occur), Zollinger-Ellison syndrome, Symptomatic gastroesophageal reflux disease, the gastroesophageal reflux disease of splanchnoscopy feminine gender, the non-aggressive gastroesophageal reflux disease, gastroesophageal reflux, NUD (non-ucler dyspepsia), the throat paresthesia, Barrett esophagus, the ulcer that NSAID-brings out, gastritis, gastrorrhagia, hemorrhagic gastritis, gastrointestinal hemorrhage, peptide ulceration, hemorrhagic ulcer, stress ulcer, hyperchlorhydria, maldigestion, gastroparesis, senile ulcer, intractable ulcer, acute gastric mucosal lesion, pyrosis, the pyrosis of sleep apnea syndrome, bruxism, stomachache, the stomach sense of heaviness, vomiting, feel sick, the therapeutical agent of hyposiagonarthritis or erosive gastritis or preventive, it contains the compound or its salt of above general formula (1) or their solvate.
Preferred example with sour diseases associated or symptom comprises gastroesophageal reflux disease, non-aggressive gastroesophageal reflux disease and the acute gastric mucosal lesion of stomach ulcer, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux disease, Zollinger-Ellison syndrome, Symptomatic gastroesophageal reflux disease, splanchnoscopy feminine gender.Preferred example comprises gastroesophageal reflux disease, Symptomatic gastroesophageal reflux disease, stomach ulcer and duodenal ulcer.Further preferred example comprises (1) gastroesophageal reflux disease or Symptomatic gastroesophageal reflux disease and (2) stomach ulcer or duodenal ulcer.
On the other hand, the present invention relates to resist the sterilant or the assisting sterilisation agent of Hp, it contains the compound or its salt of following formula (1) or their solvate.
Should be noted that above-described " preventive " except being used at disease or paresthesia epilepsy or the preventive of using before occurring, also comprise and keep therapeutical agent and anti-recurrence agent behind the disease cured.
In addition, above-described " assisting sterilisation agent " be meant and be controlled at the Working environment that is difficult to the sterilant that plays a role under the acidic conditions so that produce the material of rendeing a service.
In formula (1), R 1And R 3Can be identical or different and expression hydrogen atom or C1 to C6 alkyl; R 2With [formula 2] expression, it has 1 to 4 group that is selected from following A1 group.
[formula 2]
The A1 group is selected from halogen atom, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Haloalkyl, C 1-C 6Alkoxy-C 1-C 6Alkyl and hydroxyl.
R 4, R 5, R 6And R 7Can represent hydrogen atom, hydroxyl, halogen atom, C identical or different and separately 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group or C 1-C 6Halogenated alkoxy, or R 5And R 6Combination represent methylene radical dioxy base or ethylidene dioxy base, and W 1Expression singly-bound or C1 to C8 straight or branched alkylidene group.
W 2Expression hydrogen atom, C 1-C 6(condition is W for alkyl or halogen atom 2Can on phenyl ring, occur 1 to 3 time, and can be identical or different);
N1 represents 1 to 5, n2 represent 1 to 4 and n3 represent 1 to 6.
" C used herein 1-C 6Alkyl " be meant the straight or branched alkyl that contains 1 to 6 carbon atom; such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethyl-butyl or 2-ethyl-butyl.
" halogen atom " used herein is meant fluorine atom, chlorine atom, bromine atoms or iodine atom.
" C used herein 1-C 6Alkoxyl group " be meant the straight or branched alkoxyl group that contains 1 to 6 carbon atom; such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, 2-methyl butoxy, neopentyl oxygen, hexyloxy, 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 3; 3-dimethyl butoxy, 2; 2-dimethyl butoxy, 1; 1-dimethyl butoxy, 1; 2-dimethyl butoxy, 1,3-dimethyl butoxy or 2,3-dimethyl butoxy.
" C used herein 1-C 6Haloalkyl " be meant C with 1 to 5 above-described halogenic substituent 1-C 6Alkyl, for example comprise single methyl fluoride, monochloro methyl, single brooethyl, single iodomethyl, difluoromethyl, dichloromethyl, two brooethyls, diiodomethyl, trifluoromethyl, trichloromethyl, trisbromomethyl, three iodomethyls, 1-fluoro ethyl, 2-fluoro ethyl, 2,2,2-trifluoroethyl, 1-chloroethyl, 2-chloroethyl, 2,2,2-three chloroethyls, 1-fluoropropyl, 2-bromopropyl, 1-brombutyl, 1-chlorine amyl group and 1-fluorine hexyl.
" C used herein 1-C 6Halogenated alkoxy " be meant C with 1 to 5 above-described halogenic substituent 1-C 6Alkoxyl group, for example comprise single fluorine methoxyl group, monochloro methoxyl group, single bromine methoxyl group, single iodine methoxyl group, difluoro-methoxy, dichloro methoxyl group, dibromo methoxyl group, diiodo-methoxyl group, trifluoromethoxy, trichlorine methoxyl group, tribromo methoxyl group, triiodo methoxyl group, 1-fluorine oxyethyl group, 2-fluorine oxyethyl group, 2,2,2-trifluoro ethoxy, 1-chloroethoxy, 2-chloroethoxy, 2,2,2-three chloroethoxies, 1-fluorine propoxy-, 2-bromine propoxy-, 1-bromine butoxy, 1-chlorine pentyloxy and 1-fluorine hexyloxy.
" C used herein 1-C 6Alkoxy-C 1-C 6Alkyl " be meant to have single above-described C 1-C 6The C of alkoxy substituent 1-C 6Alkyl for example comprises methoxymethyl, ethoxyl methyl, propoxy-methyl, 2-methoxy ethyl, 2-ethoxyethyl group, 1-methoxy ethyl, 3-methoxy-propyl, 3-ethoxycarbonyl propyl, 4-methoxyl group butyl, 4-oxyethyl group butyl, 4-propoxy-butyl, 5-methoxyl group amyl group, 5-oxyethyl group amyl group, 5-propoxy-amyl group, 6-methoxyl group hexyl and 6-oxyethyl group hexyl.
" C used herein 1-C 8Straight chain and branched alkylidene chain " be meant methylene radical, ethylidene, trimethylene, tetramethylene, pentamethylene, hexa-methylene, propylidene (1-methyl ethylidene), 1-methyl trimethylene or 2-methyl trimethylene.
Above-described R 1" C 1-C 6Alkyl " methyl preferably.
Above-described R 3" C 1-C 6Alkyl " methyl preferably.
Above-described R 4, R 5, R 6And R 7" halogen atom " preferably fluorine or chlorine atom, more preferably fluorine atom.
Above-described R 4, R 5, R 6And R 7" C 1-C 6Alkyl " preferably methyl or ethyl, more preferably methyl.
Above-described R 4, R 5, R 6And R 7" C 1-C 6Haloalkyl " preferably single methyl fluoride, difluoromethyl or trifluoromethyl, more preferably single methyl fluoride.
Above-described R 4, R 5, R 6And R 7" C 1-C 6Alkoxyl group " preferably methoxy or ethoxy, more preferably methoxyl group.
Above-described R 4, R 5, R 6And R 7" C 1-C 6Halogenated alkoxy " preferably single fluorine methoxyl group, monochloro methoxyl group, difluoro-methoxy, dichloro methoxyl group, trifluoromethoxy or trichlorine methoxyl group, more preferably single fluorine methoxyl group or difluoro-methoxy.
" halogen atom " of A1 group be fluorine atom preferably.
" the C of above-described A1 group 1-C 6Alkyl " preferably methyl, ethyl or propyl group, more preferably methyl or ethyl, most preferable.
" the C of above-described A1 group 1-C 6Alkoxyl group " preferably methoxy or ethoxy, more preferably methoxyl group.
" the C of above-described A1 group 1-C 6Haloalkyl " preferably methyl fluoride or difluoromethyl, more preferably methyl fluoride.
" the C of above-described A1 group 1-C 6Alkoxy-C 1-C 6Alkyl " preferably methoxymethyl or ethoxyl methyl.
Above-described W 1Preferably singly-bound, methylene radical or ethylidene, more preferably methylene radical.
Above-described W 2" C 1-C 6Alkyl " methyl preferably.
Above-described W 2" halogen atom " preferably fluorine atom or chlorine atom, more preferably fluorine atom.
At above-described W 2Phenyl ring on preferably one of the substituent number that exists.
Above-described W 2Hydrogen atom preferably.
Above-described n1 preferably 1 to 3, and more preferably 1 or 2.
Above-described n2 preferably 1 or 2, and more preferably 1.
Above-described n3 preferably 1 to 4, and more preferably 1 or 2.
In specification sheets, for convenience's sake, the structural formula of compound is sometimes represented specific isomer; Yet, present invention resides in all isomer such as the geometrical isomer that produces on the structure, optically active isomer, rotational isomer, steric isomer, tautomer and composition thereof, the restriction of the exemplary configurations formula shown in therefore not being subjected to.Any isomer or mixture of isomers all are acceptable.Therefore, The compounds of this invention can exist with optically active substance or racemic form, and they can not limit the present invention and include in the present invention.Compound can have the crystallization polymorphic sometimes, but the present invention is not limited.The mixture of monocrystalline material and crystalline material also is acceptable.In addition, the example of The compounds of this invention can comprise anhydride and solvate (especially hydrate).And the so-called metabolite that the vivo degradation by The compounds of this invention (1) produces is also included within the present invention.In addition, the present invention also comprises the compound (so-called prodrug) that can produce The compounds of this invention (1) in vivo by metabolism such as oxidation, reduction, hydrolysis and combinations.
In the The compounds of this invention shown in the above-described formula (1), salt forms on first or tertiary NH group of benzoglyoxaline skeleton.
" salt " is had no particular limits, as long as it is pharmaceutically useful.The example of described salt comprises the salt of mineral alkali and the salt of organic bases.
The example of the salt of preferred mineral alkali comprises an alkali metal salt such as sodium salt, sylvite and lithium salts; Alkaline earth salt such as calcium salt and magnesium salts; Transition metal salt is such as zinc salt; Aluminium salt; And ammonium salt.The example of preferred organic salt comprises diethyl amine salt, diethanolamine salt, meglumine salt and N, N '-dibenzyl ethylenediamine salt.
" solvate " of the present invention had no particular limits, as long as it is pharmaceutically useful.The example of described solvate comprises hydrate, alcohol solvent compound and acetone solvate.Preferred examples is a hydrate.
In the compound shown in the formula of the present invention (1), preferred compound comprises
(2) R wherein 1Be the compound or its salt of hydrogen atom or methyl or their solvate;
(3) R wherein 1Be compound or its salt or their solvate of methyl;
(4) R wherein 2Be the compound or its salt of group of formula 3 expression or their solvate
[formula 3]
Figure S2006800126056D00081
W wherein 2Expression hydrogen atom, C 1-C 6(condition is W for alkyl or halogen atom 2Can on phenyl ring, occur 1 to 3 time, and can be identical or different); N1 represents 1 to 5, and n2 represents 1 to 4; And n3 represents 1 to 6, and described group randomly has 1 or 2 group that is selected from the A2 group, and described A2 group is made up of fluorine atom, methyl, ethyl, propyl group, methoxyl group and single methyl fluoride;
(5) R wherein 2Compound or its salt as shown in Equation 4 or their solvate
[formula 4]
Figure S2006800126056D00091
Figure S2006800126056D00092
Or
Figure S2006800126056D00093
(6) R wherein 2Compound or its salt as shown in Equation 5 or their solvate
[formula 5]
Figure S2006800126056D00094
Or
(7) R wherein 3Be compound or its salt or their solvate of hydrogen atom or methyl;
(8) R wherein 3Be compound or its salt or their solvate of methyl;
(9) R wherein 4Be compound or its salt or their solvate of hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom;
(10) R wherein 4Be compound or its salt or their solvate of hydrogen atom, methyl or fluorine atom;
(11) R wherein 4Be compound or its salt or their solvate of hydrogen atom;
(12) R wherein 5Be compound or its salt or their solvate of hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom;
(13) R wherein 5Be compound or its salt or their solvate of hydrogen atom, methyl or fluorine atom;
(14) R wherein 5Be compound or its salt or their solvate of hydrogen atom;
(15) R wherein 6Be compound or its salt or their solvate of hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom;
(16) R wherein 6Be compound or its salt or their solvate of hydrogen atom, methyl or fluorine atom;
(17) R wherein 6Be compound or its salt or their solvate of hydrogen atom;
(18) R wherein 7Be compound or its salt or their solvate of hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom;
(19) R wherein 7Be compound or its salt or their solvate of hydrogen atom, methyl or fluorine atom;
(20) R wherein 7Be compound or its salt or their solvate of hydrogen atom;
(21) W wherein 1Be compound or its salt or their solvate of singly-bound, methylene radical or ethylidene;
(22) W wherein 1Be compound or its salt or their solvate of methylene radical;
(23) W wherein 2Be compound or its salt or their solvate of hydrogen atom;
(24) n1 wherein is 1 to 3 compound or its salt or their solvate;
(25) n1 wherein is 1 or 2 compound or its salt or their solvate;
(26) n2 wherein is 1 or 2 compound or its salt or their solvate;
(27) n3 wherein is 1 to 4 compound or its salt or their solvate; With
(28) n3 wherein is 1 or 2 compound or its salt or their solvate.
In addition, preferred use is selected from (2) or (3) with compound or its salt or their solvate: the R1 that arbitrary combination satisfies following condition; R2 is selected from (4) or (6); R3 is selected from (7) or (8); R4 is selected from (9) to (11); R5 is selected from (12) to (14); R6 is selected from (15) to (17); R7 is selected from (18) to (20); And W 1Be selected from (21) or (22), W 2Be selected from (23), n1 and be selected from that (24) or (25), n2 are selected from (26), n3 is selected from (27) or (28).
In particular compound or its salt or their solvate, suitable The compounds of this invention comprise 2-(((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_7
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline;
2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_8
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline;
2-(((3-methyl-4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((4-(1,3-dioxolane-4-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((4-((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_9
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline;
2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
(((((2-methoxyl group-1,3-two for 4-for 2- Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline;
2-(((3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy) pyridine-2-yl) methyl) sulfinyl-1 H-benzimidazole; Or
2-(((4-((5,5-two fluoro-1,3-two
Figure 2006800126056_11
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline; Or its salt, or their solvate (the especially hydrate of their sodium salt anhydride or their sodium salt).
The compound of present invention further optimization comprises
2-(((4-((5,5-dimethyl-1,3-two
Figure 2006800126056_12
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline;
2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline;
2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline; Or
2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_13
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline; Or its salt, or their solvate (the especially anhydride of their sodium salt or hydrate).
In the optically active isomer of the above compound (existing at present), more preferably use gastric acid secretion is shown the compound of better inhibition effect or the inhibition effect of gastric acid secretion is had better persistent compound.
Advantage of the present invention
The compounds of this invention has good inhibition effect, the inhibition effect of gastric acid secretion is had better persistence gastric acid secretion, can keep the high pH in the stomach for a long time and have security and suitable physical and chemical stability.Therefore, this compound useful as drug, especially as with the therapeutical agent or the preventive of sour diseases associated or symptom, and as the sterilant or the assisting sterilisation agent of antagonism Hp.
Implement best mode of the present invention
The compounds of this invention can be by any the making in the following stated method; Yet preparation method of the present invention is not limited to these methods.
Compound of the present invention (1) can make by following method A.
[formula 6]
Method A
Figure S2006800126056D00131
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7And W 1With defined above identical, X 2The expression leavings group.
X 2The example of leavings group comprise sulfonyloxy such as mesyloxy, tolysulfonyl oxygen base and trifluoro-methanesulfonyl oxy; Halogen group such as chlorine, bromine and iodine; Acyloxy such as acetoxyl group, trifluoroacetyl oxygen base and propionyloxy preferably use mesyloxy and tolysulfonyl oxygen base, chlorine or acetoxyl group.
To explain below each step of method A.
The introducing or the halogenation of (A-1 step) leavings group
(1) reaction of introducing leavings group
In this step, compound (3) and leavings group are introduced agent reacting to make compound (3a) or its salt under the condition that does not have solvent or in inert solvent and in the presence of alkali.
The solvent used for this step has no particular limits, if it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; Aromatic hydrocarbons such as benzene, toluene and phenylfluoroform; Ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), two
Figure 2006800126056_14
Alkane, glycol dimethyl ether and diethylene glycol dimethyl ether; Amides such as methane amide, N, dinethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide; And pyridine; And the solvent mixture of these solvents.Preferred solvent is the solvent mixture of halohydrocarbon, ether or ether and aromatic hydrocarbons, most preferably the solvent mixture of methylene dichloride, tetrahydrofuran (THF) or tetrahydrofuran (THF) and toluene.
Here the example that used leavings group is introduced agent comprises sulphonating agent such as methylsulfonyl chloride, Tosyl chloride, trifluoromethanesulfchloride chloride, N-phenyl-two (fluoroform sulfimide).Preferred methylsulfonyl chloride or Tosyl chloride most preferably use methylsulfonyl chloride.
The example of used here alkali comprises alkyl amine such as Trimethylamine 99 and triethylamine; Pyridine, salt of wormwood, yellow soda ash, sodium hydroxide and potassium hydroxide.Preferred triethylamine or sodium hydroxide most preferably use triethylamine.
Temperature of reaction changes along with raw material, solvent, leavings group introducing agent and alkali.Temperature of reaction is normally-50 ℃ to 100 ℃, preferred-20 ℃ to 40 ℃.
Reaction times is along with raw material, solvent, leavings group are introduced agent, alkali and temperature of reaction and changed.Normally 15 minutes to 12 hours reaction times, more preferably 30 minutes to 2 hours.
The compound that this step obtains does not need special separation and can directly carry out next step.
(2) halogenation (with chlorination as representational example)
In this step, with compound (3) and chlorizating agent under the condition that does not have solvent or in inert solvent and exist or do not exist under the condition of alkali reaction to make compound (3a).
Here used solvent is had no particular limits, if it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; Aromatic hydrocarbons such as benzene, toluene and phenylfluoroform; Ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), two
Figure 2006800126056_15
Alkane, glycol dimethyl ether and diethylene glycol dimethyl ether.Preferred halohydrocarbon or aromatic hydrocarbons most preferably use methylene dichloride, chloroform or toluene.
The example of used here chlorizating agent comprises methylsulfonyl chloride, oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride and hydrochloric acid; Preferred thionyl chloride or the hydrochloric acid of using.
The example of used here alkali comprises alkyl amine such as Trimethylamine 99 and triethylamine; With pyridine etc.The preferred triethylamine that uses.
Temperature of reaction changes along with raw material, solvent and chlorizating agent.Temperature of reaction is normally-20 ℃ to 30 ℃, preferred 0 ℃ to 10 ℃.
Reaction times changes along with raw material, solvent, chlorizating agent and temperature of reaction.Normally 10 minutes to 6 hours reaction times, preferred 10 minutes to 2 hours.
The compound that this step obtains does not need special separation and can directly carry out next step.
Bromination utilizes reagent such as bromine/red phosphorus, phosphorus tribromide and phosphorus pentabromide to carry out.Iodate utilizes reagent such as iodine/red phosphorus to carry out.Perhaps, bromide and iodide can by with reagent such as Sodium Bromide and sodium iodide respectively with the A-1 step in the synthetic leavings group react and obtain.
(A-2 step) thioetherification
In this step, with compound (2) and compound (3a) or its salt (especially hydrochloride) under the condition that does not have solvent or in inert solvent and exist or do not exist under the condition of alkali reaction to make compound (4).
Here used solvent is had no particular limits, if it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises that alcohol is such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, Diethylene Glycol, glycerol, octanol, hexalin and methylcyclohexane; Halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; Ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), two
Figure 2006800126056_16
Alkane, glycol dimethyl ether and diethylene glycol dimethyl ether; Aromatic hydrocarbons such as benzene and toluene; N, dinethylformamide; Dimethyl sulfoxide (DMSO); Water; Solvent mixture with these solvents.The solvent mixture of preferred methylene dichloride, alcohol, ether or ether and toluene most preferably uses the solvent mixture of methyl alcohol, tetrahydrofuran (THF) or tetrahydrofuran (THF) and toluene.
The example of used here alkali comprises mineral alkali such as sodium hydride, potassium hydride KH, Quilonum Retard, yellow soda ash, salt of wormwood, lithium hydroxide, sodium hydroxide and potassium hydroxide; Organic bases such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropyl ethyl amine, dicyclohexylamine, N-methyl piperidine, pyridine, 4-pyrrolidyl pyridine, picoline, 4-(N, the N-dimethylamino) pyridine, 2,6-two (tertiary butyl)-4-picoline, quinoline, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 1,4-diazabicylo [2.2.2] octane (DABCO) and 1,8-diazabicylo [5.4.0] undecane-7-alkene (DBU).Preferred mineral alkali such as sodium hydride, potassium hydride KH, lithium hydroxide, sodium hydroxide or potassium hydroxide or triethylamine most preferably use sodium hydroxide or triethylamine.
Temperature of reaction changes along with raw material, solvent and alkali; Normally 0 ℃ to 100 ℃, preferred 10 ℃ to 50 ℃.
Reaction times changes along with raw material, solvent, alkali and temperature of reaction; Normally 30 minutes to 3 days.
(A-3 step) oxidation
In this step, compound (4) and oxygenant are reacted to make compound (1) under the condition that has or do not exist solvent.
Here used solvent is had no particular limits, if it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises that alcohol is such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, Diethylene Glycol, glycerol, octanol, hexalin and methylcyclohexane; Aromatic hydrocarbons such as benzene and toluene; Halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; Amides such as methane amide, N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphoramide; Nitrile is such as acetonitrile.The solvent mixture of preferred aromatic hydrocarbons, alcohol, halohydrocarbon or these solvents most preferably uses toluene, toluene and methanol solvent mixture or methylene dichloride.
The example of used here oxygenant comprises hydrogen peroxide, tertbutyl peroxide, cumene hydroperoxide, sodium periodate, peracetic acid, peroxybenzoic acid, 3-chlorine peroxybenzoic acid, hydroperoxidation urea addition compound ((NH 2) 2COH 2O 2).Preferred 3-chlorine peroxybenzoic acid or the cumene hydroperoxide of using.
Should be noted that asymmetric oxidation can carry out according to the described method of following document: WO96/02535, WO2001/83473, WO2004/087702, WO2004/052881, WO2004/052882, Adv.Synth.Catal.2005,347,19-31., Chem.Rev.2003,103,3651-3705., Tetrahedron Lett.2004,45,9249-9252., Angew.Chem.Int.Ed.2004,43,4225-4228. and Tetrahedron Asymmetry 2003,14,407-410.
More particularly, asymmetric oxidation is undertaken by compound (4) and oxygenant are reacted in the presence of asymmetric induction agent or asymmetric induction catalyzer.
The example of oxygenant comprises superoxide such as hydrogen peroxide, tertbutyl peroxide, hydroperoxidation urea and cumene hydroperoxide.Especially when containing titanium, zirconium or hafnium in asymmetric induction agent or the asymmetric induction catalyzer, use the hydroxyl cumene peroxide.When it contains vanadium, use hydrogen peroxide.
Here the amount that used oxygenant can surpass compound (4) exists, preferably in the scope of 1.01 to 10 molar equivalents.Especially when asymmetric induction agent or asymmetric induction catalyzer contain titanium, use 1.05 normal oxygenants.When asymmetric induction agent or asymmetric induction catalyzer contain zirconium or hafnium, use 1.2 normal oxygenants.When it contains vanadium, use 1.1 normal oxygenants usually.
The example of described asymmetric induction agent or asymmetric induction catalyzer comprises
(1) mixture of two of opticity titanium mixture such as opticity pure and mild pure titaniums (IV) and water or alcohol;
(2) mixture of two of opticity zirconium composite such as opticity pure and mild pure zirconiums (IV) (can have or not exist water);
(3) mixture of two of opticity hafnium mixture such as opticity pure and mild pure hafniums (IV);
(4) mixture of the Schiff of opticity vanadium mixture such as opticity and vanadyl methyl ethyl diketone;
(5) mixture of the Schiff alkali of opticity iron complexes such as opticity and ferric acetyl acetonade (III);
(6) opticity manganese mixture (for example salen-manganese mixture) is such as the Schiff alkali of opticity and the mixture of manganese; With
(7) mixture of the Cinchona alkaloid of opticity tungsten mixture such as opticity and tungsten (III).
The example of the glycol of opticity comprises
(1) alkyl diol such as tartrate, for example (+) or (-) dimethyl tartrate, diethyl tartrate, tartrate diisopropyl ester and dibutyl tartrate; With tartramide such as the tetramethyl-tartramide; With
(2) aromatic glycol such as (R)-or (S)-dinaphthol.
The example of the Schiff alkali of opticity comprises Schiff alkali such as (S)-(-)-2-(3 derived from the salicylic aldehyde that replaces, 5-two-tertiary butyl salicylidene amino)-3,3-dimethyl-1-butanols and (1R, 2S)-1-((2-hydroxyl-3,5-two-tertiary butyl benzylidene) amino) the pure and mild salen type of indane-2-Schiff alkali.
When carrying out asymmetric oxidation, if necessary, can add alkali.The example of used alkali has no particular limits, as long as it can inhibited reaction, and comprises mineral alkali and organic bases, preferred tertiary amine such as diisopropyl ethyl amine and triethylamine, most preferably diisopropyl ethyl amine.With respect to compound (4), the add-on of alkali is 0.1 to 1 equivalent normally.
Should be noted that when using the asymmetric induction agent contain vanadium or asymmetric induction catalyzer, do not use alkali usually.
The example of the solvent that asymmetric oxidation is used comprises aromatic hydrocarbons such as toluene, benzene and dimethylbenzene; Halohydrocarbon such as methylene dichloride and chloroform; With ester such as ethyl acetate.Especially, when the asymmetric induction agent of using titaniferous, zirconium or hafnium or asymmetric induction catalyzer, preferably use toluene or t-butyl methyl ether.When use contains the asymmetric induction agent of vanadium or asymmetric induction catalyzer, preferably use acetonitrile or methylene dichloride.When using titaniferous asymmetric induction catalyzer, the adding of water is effective.Water, the amount that comprises the water that contains in solvent, reaction reagent (not comprising oxygenant) and the substrate with respect to compound (4) preferably in 0.1 to 0.33 normal scope, 0.13 to 0.25 equivalent most preferably.Water content can be controlled by molecular sieve 3a.
When the mixture of synthol titanium (IV) and alcohol, Virahol usually by effectively as alcohol, usually use with 1.2 normal amounts with respect to titanium.
Temperature of reaction changes along with raw material, solvent and oxygenant; Normally-100 ℃ to 100 ℃, preferred-70 ℃ to 70 ℃.
Reaction times changes along with raw material, solvent, oxygenant and temperature of reaction; Normally 15 minutes to 72 hours, more preferably 30 minutes to 24 hours.
The compound that more than obtains can transform salify by ordinary method.More specifically incite somebody to action, compound (1) and alkali are reacted under the condition that has or do not exist solvent.About solvent, can use acetonitrile; Alcohol is such as methyl alcohol or ethanol; The solvent mixture of water or these solvents, the solvent mixture of preferred alcohol and water.About alkali, can use alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; Alkaline earth metal hydroxides is such as magnesium hydroxide; With alkoxide such as sodium methylate, sodium tert-butoxide, sodium tert-amyl alcohol or magnesium methylate.The preferred aqueous solution that uses sodium hydroxide.Temperature of reaction is selected 10 to 40 ℃ normally-50 to 50 ℃.Normally 1 minute to 2 hours reaction times, preferred 1 minute to 1 hour.
Perhaps, an alkali metal salt such as sodium salt and sylvite can carry out the salt permutoid reaction to change into corresponding metal salt such as barium salt, magnesium salts and zinc salt with metal chloride or metal sulfate such as bariumchloride, magnesium chloride, sal epsom or zinc sulfate under the condition that has or do not exist solvent.
After compound (4) oxidation, can under the condition of not carrying out lock out operation, compound (1) be transformed salify and obtain metal-salt.
About the intermediate among the method A, i.e. compound (2) and compound (3), the compound that can use the compound that can buy or be easy to make from the ordinary method that the compound that can buy carries out usually according to those skilled in the art.Particularly, compound (3) can make according to the method B of the following stated.
[formula 7]
Figure S2006800126056D00201
In formula, R 1, R 2, R 3And W 1With defined above identical; And X 1The expression halogen, preferred chlorine atom, bromine atoms or iodine atom, more preferably chlorine atom.
Below with each step of interpretation procedure B.
(B-1 step) halogenation (with chlorination as representational reaction)
In this step, compound (5) and chlorizating agent are reacted under the condition that does not have solvent or in inert solvent to make compound (6).
In this step, reaction needed is carried out in chlorizating agent, does not use solvent usually.Yet, when using solvent, solvent is had no particular limits, as long as it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; With ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), two
Figure 2006800126056_17
Alkane and glycol dimethyl ether and diethylene glycol dimethyl ether.
The example of chlorizating agent used herein comprises Acetyl Chloride 98Min., oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride and phosphorus pentachloride, preferably uses Acetyl Chloride 98Min..
Temperature of reaction changes along with raw material, solvent and chlorizating agent; Normally-50 ℃ to 30 ℃, preferred-30 ℃ to 10 ℃.
Reaction times changes along with raw material, solvent, chlorizating agent and temperature of reaction; Normally 30 minutes to 8 hours, more preferably 1 to 5 hour.
When carrying out bromination, use reagent such as acetyl bromide, hydrogen bromide, bromine/red phosphorus, phosphorus tribromide and phosphorus pentabromide.When carrying out iodate, use reagent such as iodine/red phosphorus, perhaps carry out bromination, react with sodium iodide then.
(B-2 step) R 2-W 1-O group is introduced reaction
In this step, with compound (6) with alcohol (7), be R 2-W 1-OH group (R wherein 2And W 1With defined above identical) reacting to make compound (8) under the condition that does not have solvent or in inert solvent and in the presence of alkali.
Here used solvent is had no particular limits, if it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises aliphatic hydrocarbon such as hexane, heptane, petroleum naphtha and sherwood oil; Halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; Aromatic hydrocarbons such as benzene and toluene; Ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), two
Figure 2006800126056_18
Alkane, glycol dimethyl ether and diethylene glycol dimethyl ether; Amides such as methane amide, N, dinethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide and N-Methyl pyrrolidone; Dimethyl sulfoxide (DMSO); Water; And the solvent mixture of these solvents.Preferred dimethyl sulfoxide (DMSO), ether or acid amides most preferably use dimethyl sulfoxide (DMSO).
The example of used here alkali comprises alkaline carbonate such as Quilonum Retard, yellow soda ash and salt of wormwood; Alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Metal alkoxide such as lithium methoxide, sodium methylate, sodium ethylate and potassium tert.-butoxide; Alkalimetal hydride such as lithium hydride, sodium hydride and potassium hydride KH; The alkali metal alcoholates that makes by basic metal; N-Butyl Lithium and di-isopropyl lithamide.The preferred alkalimetal hydride that uses most preferably uses sodium hydride.
Temperature of reaction changes along with raw material, solvent and alkali; Alcohol therein (7), be R 2-W 1-OH is under the situation of primary alconol, normally 0 ℃ to 100 ℃, and preferred 10 ℃ to 100 ℃; Alcohol therein is under the situation of secondary alcohol, and temperature of reaction is 50 to 100 ℃.
Reaction times changes along with raw material, solvent, alkali and temperature of reaction; Normally 15 minutes to 48 hours, more preferably 30 minutes to 12 hours.
(B-3 step) reset and generated acetic ester
In this step, there are not solvent in compound (8) and diacetyl oxide and are existing or do not exist under the condition of alkali reaction to make the acetic ester of compound (3).
The example of used here alkali comprises tertiary amine such as Trimethylamine, diisopropyl ethyl amine and triethylamine; With pyridine etc.The preferred triethylamine that uses.
Temperature of reaction is along with raw material and solvent and change; In the presence of alkali normally 20 ℃ to 150 ℃, preferred 20 ℃ to 60 ℃, under the condition that does not have alkali normally 50 to 100 ℃.
Reaction times changes along with raw material, solvent and temperature of reaction; Normally 10 minutes to 6 hours, preferred 30 minutes to 5 hours.
After the reaction, will directly carry out next step by the resistates that the distillation diacetyl oxide obtains usually.Perhaps, acetic ester is carried out the steps A-2 of method A to obtain compound (4).
(B-4 step) hydrolysis reaction
In this step, compound and alkali that the B-3 step is obtained react to make compound (3) under the condition that has or do not exist solvent.
The solvent used to this step has no particular limits, if it can dissolving raw material to a certain degree and can inhibited reaction.The example of described solvent comprises water; Alcohol is such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, Diethylene Glycol, glycerol, octanol, hexalin and methylcyclohexane; Aliphatic hydrocarbon such as hexane, heptane, petroleum naphtha and sherwood oil; Ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), two
Figure 2006800126056_19
Alkane, glycol dimethyl ether and diethylene glycol dimethyl ether; Halohydrocarbon such as chloroform, methylene dichloride, 1,2-ethylene dichloride and tetracol phenixin; Amides such as methane amide, N, dinethylformamide; N,N-dimethylacetamide and hexamethylphosphoramide; Solvent mixture with these solvents.Preferably use the solvent mixture of alcohol or alcohol and water, most preferably use the solvent mixture of first alcohol and water.
The example of used here alkali comprises alkaline carbonate such as Quilonum Retard, yellow soda ash and salt of wormwood; Alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Metal alkoxide such as lithium methoxide, sodium methylate, sodium ethylate and potassium tert.-butoxide; With ammonia such as ammoniacal liquor and dense ammonia-methyl alcohol etc.The preferred alkali metal hydroxide that uses most preferably uses sodium hydroxide.
Temperature of reaction changes along with raw material, solvent and alkali; Normally 0 ℃ to 60 ℃, preferred 10 ℃ to 40 ℃.
Reaction times changes along with raw material, solvent, alkali and temperature of reaction; Normally 10 minutes to 6 hours.
In the whole bag of tricks, after the reaction of each step was finished, target compound can obtain according to ordinary method from reaction mixture.
For example, at the entire reaction mixture is under the situation of solution, target compound obtains by the following method: with the temperature of reaction mixture turn back to room temperature (if necessary) or with reaction mixture at cooled on ice, neutralizing acid, alkali, oxygenant or reductive agent, then add entry and organic solvent such as with the water unmixing and not with the ethyl acetate of target compound reaction, separate the layer that contains target compound thus, add then with the layer unmixing that obtains and not with the solvent of target compound reaction, washing contains the layer of target compound, layering then.In addition, if the layer that obtains is an organic layer, then required compound can be by with dewatering agent such as salt of wormwood, anhydrous magnesium sulfate or anhydrous sodium sulfate drying organic layer, steaming desolventizes and obtains then.On the other hand, if the layer that obtains is a water layer, then required compound can be by carrying out electric desalting with this layer and lyophilize obtains.
Perhaps, when the entire reaction mixture was solution, if possible, target compound can or remove other compound (for example solvent, reagent) under reduced pressure by normal pressure and obtain.
In addition, when having only target compound to separate out or the entire reaction mixture is a liquid and when having only target compound precipitate in removal process to separate out with solid form precipitation, target compound can by filtration, with the target compound behind the appropriate solvent washing and filtering then drying obtain.In addition, target compound also can be from filtrate according to being that the identical mode of the situation of solution obtains with the entire reaction mixture.
In addition, when reagent or catalyzer are present in the reaction mixture with solid form separately, be under the situation of solution perhaps at the entire reaction mixture, have only reagent or catalyzer in removal process, to separate out and target compound when being dissolved in the solvent with solid form precipitation, target compound can obtain by the following method: leach reagent or catalyzer, with reagent or the catalyzer after the suitable organic or inorganic solvent wash filtration, merge washings and filtrate, according to being the identical mode treating mixture of situation of solution with the entire reaction mixture.
Particularly, other compound except that target compound that contains in reaction mixture can not suppress under the situation of reaction of next step, and this mixture can be directly used in next step and not separate target compound.
In order to improve the purity of the target compound that above-mentioned steps obtains, can suitably use recrystallization method, various chromatographic process and distillating method.
When the target compound that obtains was solid, the purity of target compound improved by recrystallization method usually.In recrystallization method, can use not and the single solvent of the target compound reaction perhaps solvent mixture of multi-solvent.More particularly, target compound can carry out crystallization by the following method: at first target compound at room temperature or under heating is dissolved in the perhaps solvent mixture of multi-solvent of single solvent, then with the solution that forms by coolings such as frozen water, stir or at room temperature leave standstill, perhaps add the low solvent of target compound solubleness therein, from solution, reclaim the crystalline target compound thus.
The purity of target compound can improve by various chromatographic processes.Usually use the silica gel 60 (70 to 230 orders or 340 to 400 orders) of silica gel column chromatography such as the Merck Ltd. production that utilizes slightly acidic silica gel, the BW-300 (300 order) of Fuji Silysia Chemical Ltd. production or the disposable silica gel column casing that is used for medium pressure liquid chromatography (High Frash post) that YamazenCorporation produces.When target compound be alkalescence and when excessively being adsorbed by above-described silica gel, can use the silica gel that scribbles propylamine (200 to 350 order) of FujiSilysia Chemical Ltd. production or the used NH silica gel (High Frash, amino) of the disposable silica gel column casing that is used for medium pressure liquid chromatography that YamazenCorporation produces.Perhaps, when target compound has bipolarity maybe must be by high polar solvent such as methanol-eluted fractions the time, can use NAM-200H or NAM-300H (by NAM Laboratory production).When with target compound by utilizing any in these silica gel and not carrying out wash-out and remove when desolvating with the single solvent of the target compound reaction perhaps solvent mixture of multi-solvent, can obtain the target compound that purity improves.
When the target compound that obtains was liquid, the purity of target compound can improve by distillating method.In distillating method, target compound is being distilled under room temperature or heating under normal pressure or the decompression.
The representational preparation method of compound (1) has been described in the front.Be used to prepare the initial compounds of The compounds of this invention and reagent and can be salt or solvate such as hydrate, it changes along with used raw material and solvent, and does not have concrete restriction, as long as they can inhibited reaction.Certainly, used solvent changes along with raw material and reagent, and does not have concrete restriction, if it can inhibited reaction and the solubilized raw material to a certain degree.When The compounds of this invention (1) when obtaining with free form, it can change into salt or the solvate that compound (1) can change into according to ordinary method.
When The compounds of this invention (1) existed with the salt of compound (1) or solvate forms, described salt or solvate can change into the compound (1) of free form according to ordinary method.
In addition, the various isomer of The compounds of this invention (1) (such as geometrical isomer, optically active isomer, rotational isomer, steric isomer and tautomer) can by conventional separation method purifying with separate for example method of recrystallization method, diastereoisomeric salt, enzyme separation method, various chromatographic process (such as thin-layer chromatography, column chromatography and gas-chromatography).
When The compounds of this invention is used as medicine, by this compound and suitable additive are mixed mutually to make spendable preparation.Yet, do not discharge the situation that The compounds of this invention directly is used as medicine yet.
The example of described additive comprises vehicle, tackiness agent, lubricant, disintegrating agent, tinting material, the gentle improving agent of correctives, emulsifying agent, tensio-active agent, solubilizing agent, suspending agent, isotonic agent, buffer reagent, sanitas, antioxidant, stablizer and is generally used for the absorption enhancer of medicine.If necessary, their uses capable of being combined.
The example of vehicle comprises lactose, white sugar, glucose, W-Gum, N.F,USP MANNITOL, sorbyl alcohol, starch, Alpha-starch, dextrin, crystalline cellulose, light anhydrous silicic acid, pure aluminium silicate, Calucium Silicate powder, magnesium aluminum silicate and secondary calcium phosphate.
The example of tackiness agent comprises polyvinyl alcohol, methylcellulose gum, ethyl cellulose, gum arabic, tragacanth gum, gelatin, shellac, HPMC, hydroxypropylcellulose, Xylo-Mucine, polyvinylpyrrolidone and polyoxyethylene glycol.
The example of lubricant comprises Magnesium Stearate, calcium stearate, stearyl-sodium fumarate, talcum, polyoxyethylene glycol and colloidal silica.
Examples of disintegrants comprises hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, carboxymethyl starch, the sodium starch glycolate of crystalline cellulose, agar, gelatin, lime carbonate, sodium bicarbonate, citrate of lime, dextrin, pectin, low replacement degree.
The example of tinting material comprises pharmaceutically useful tinting material such as ferric oxide, yellow ferric oxide, famille rose, caramel, β-Hu Luobusu, titanium oxide, talcum, riboflavin sodium phosphate and yellow aluminium color lake.
The example of the gentle improving agent of correctives comprises cocoa powder, menthol, empasm, menthol oil, Borneo camphor and Cortex Cinnamomi powder.
The example of emulsifying agent or tensio-active agent comprises stearyl-trolamine, Sodium Lauryl Sulphate BP/USP, lauryl alanine, Yelkin TTS, Zerol, sucrose fatty ester and glycerol fatty acid ester.
The example of solubilizing agent comprises polyoxyethylene glycol, propylene glycol, peruscabin, ethanol, cholesterol, trolamine, yellow soda ash, Trisodium Citrate, polysorbate80 and niacinamide.
The example of suspending agent also comprises hydrophilic polymer such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose gum, Walocel MT 20.000PV, Natvosol and hydroxypropylcellulose except above-mentioned tensio-active agent.
The example of isotonic agent comprises glucose, sodium-chlor, N.F,USP MANNITOL and sorbyl alcohol.
The example of buffer reagent comprises phosphoric acid salt, acetate, carbonate and citrate buffer solution.
Examples of preservatives comprises methyl p-hydroxybenzoate, propylparaben, butylene-chlorohydrin, benzylalcohol, phenylethyl alcohol, dehydroacetic acid (DHA) and Sorbic Acid.
Examples of antioxidants comprises sulphite, ascorbate salt and alpha-tocopherol.
As the example of stablizer, can should be mentioned that those that are generally used for medicine.
As the example of absorption enhancer, can should be mentioned that those that are generally used for medicine.
The example of preparation comprises per os preparation such as tablet, pulvis, granula, capsule, syrup, lozenge and inhalation; External preparation such as suppository, ointment, ophthalmic ointment, adhesive tape agent, eye drops, nasal drop, ear drop, paste and lotion; And injection.
Above-described per os preparation can make by The compounds of this invention is suitably mixed mutually with above-described additive.Should be noted that if necessary the surface of preparation can be by dressing.
External preparation can make by The compounds of this invention is suitably mixed mutually with above-mentioned additive, especially vehicle, tackiness agent, the gentle improving agent of correctives, emulsifying agent, tensio-active agent, solubilizing agent, suspending agent, isotonic agent, sanitas, antioxidant, stablizer and absorption enhancer.
Injection can make by The compounds of this invention is suitably mixed mutually with above-mentioned additive, especially emulsifying agent, tensio-active agent, solubilizing agent, suspending agent, isotonic agent, buffer reagent, sanitas, antioxidant, stablizer and absorption enhancer.
When The compounds of this invention is used as medicine, dosage will change according to symptom and age; Yet, 0.15 to 5000mg (preferred 0.5 to 1500mg) normally under the situation of per os preparation, 0.5 to 1500mg (preferred 1.5 to 500mg) normally under the situation of external application preparation, 0.3 to 5000mg (preferred 1 to 500mg) normally under the situation of injection.Described dosage can single-dose or is divided into 2 to 6 administrations every day.Should be noted that under the situation of per os preparation and injection dosage is actual dosage, yet under the situation of external application preparation, dosage represents that actual absorption arrives biological intravital amount.
The compounds of this invention (1) can make by the method shown in following examples.The effect of this compound can be confirmed by the described method of experimental example (following).These embodiment are described by way of example, but can limit the present invention by any way.
The raw material of buying that embodiment is used and the title of reagent and manufacturer thereof are as shown below.The title of document is shown in available manufacturer one hurdle, and this is meant that this compound forms according to the method described in the document.
Benzyloxy acetaldehyde (Aldrich),
2 (Kanto Chemical Co., Inc.),
The tosic acid monohydrate (Tokyo Kasei Kogyo Co., Ltd.),
20% palladium hydroxide (Aldrich),
The oil solution of sodium hydride (Wako Pure Chemical Industries Ltd.),
Acetone (Wako Pure Chemical Industries Ltd.)
4-chloro-2,3 dimethyl pyridine 1-oxide compound (derives from Sanyo Fine Co., Ltd.; Yet it is to be disclosed in J.Med.Chem.1998,41, and the known compound of 1777-1788),
Diacetyl oxide (Kanto Chemical Co., Inc.),
5N aqueous sodium hydroxide solution (Wako Pure Chemical Industries Ltd.),
1N aqueous sodium hydroxide solution (Wako Pure Chemical Industries Ltd.),
Triethylamine (Kanto Chemical Co., Inc., or Wako Pure Chemical Industries Ltd.),
Methylsulfonyl chloride (Tokyo Kasei Kogyo Co., Ltd.),
2-mercaptobenzimidazole (Tokyo Kasei Kogyo Co., Ltd.),
3-chlorine peroxybenzoic acid (Tokyo Kasei Kogyo Co., Ltd.),
1,1-two (methylol) cyclopropane (Aldrich)
3-oxo ethyl hexanoate (ACROS)
Ethylene glycol (Tokyo Kasei Kogyo Co., Ltd.),
Lithium aluminum hydride (Wako Pure Chemical Industries Ltd.),
1,3-benzyloxy-2-propyl alcohol (Aldrich)
Sulfur trioxide pyridine complex (Aldrich)
Triethyl orthoformate (Wako Pure Chemical Industries Ltd.),
Trimethyl orthoformate (Tokyo Kasei Kogyo Co., Ltd.),
Propionyl methyl acetate (Aldrich)
Pyruvic alcohol (Wako Pure Chemical Industries Ltd.),
Benzoyl chloride (Tokyo Kasei Kogyo Co., Ltd.),
D-(-)-diethyl tartrate (Tokyo Kasei Kogyo Co., Ltd.),
Toluene (anhydrous) (Kanto Chemical Co., Inc.),
Titanium isopropylate (IV) (Kanto Chemical Co., Inc. or Aldrich),
N, N-diisopropyl ethyl amine (Aldrich or Nakarai Tesque)
Cumene hydroperoxide (Nakarai Tesque, Inc. or Aldrich)
L-(+)-diethyl tartrate (Tokyo Kasei Kogyo Co., Ltd. or Aldrich),
2-(methylol)-1, ammediol (E-MERCK or Aldrich),
Tetrahydrofuran (THF) (anhydrous) (Kanto Chemical Co., Inc.),
1,3-difluoro acetone (SYNQUEST)
1, ammediol (Wako Pure Chemical Industries Ltd.),
((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methyl alcohol (Aldrich) 2,2-dimethyl-1,3-two Alkane-5-ketone (Tokyo Kasei Kogyo Co., Ltd.),
Bromotoluene (E-MERCK)
Tetrabutylammonium iodide (Tokyo Kasei Kogyo Co., Ltd.),
DOWEX(R)50W-X8(Muromachi?Kagaku?Kogyo?Kaisha，Ltd.)
Cyclobutanone (AVOCADO)
Tetrahydrochysene-4H-pyrans-4-ketone (Tokyo Kasei Kogyo Co., Ltd.),
Methylene dichloride (anhydrous) (Kanto Chemical Co., Inc.),
70% perchloric acid (Wako Pure Chemical Industries Ltd.),
2,3,5-collidine (ACROS),
Sulfuric acid (Junsei Chemical Co., Ltd.),
Nitrosonitric acid (Wako Pure Chemical Industries Ltd.),
Acetyl Chloride 98Min. (Junsei Chemical Co., Ltd.),
N, dinethylformamide (Wako Pure Chemical Industries Ltd.),
0.1N aqueous sodium hydroxide solution (Wako Pure Chemical Industries Ltd.),
Sodium hydroxide (Wako Pure Chemical Industries Ltd.),
Tosyl chloride (Tokyo Kasei Kogyo Co., Ltd.),
Thionyl chloride (Wako Pure Chemical Industries Ltd.),
Potassium tert.-butoxide (Tokyo Kasei Kogyo Co., Ltd.),
Tetramethylolmethane (Tokyo Kasei Kogyo Co., Ltd.),
Triethly orthoacetate (Tokyo Kasei Kogyo Co., Ltd.),
Triethyl orthopropionate (Tokyo Kasei Kogyo Co., Ltd.),
Propione (Tokyo Kasei Kogyo Co., Ltd.),
Cyclopentanone (Tokyo Kasei Kogyo Co., Ltd.),
Pimelinketone (Tokyo Kasei Kogyo Co., Ltd.),
1,4-cyclohexanedione list ethylidene ketal (Tokyo Kasei Kogyo Co., Ltd.),
The cyclopropane formonitrile HCN (Tokyo Kasei Kogyo Co., Ltd.),
Tetramethylene formonitrile HCN (AVOCADO),
Benzyloxy acetaldehyde (Aldrich),
1-benzyloxy-2-acetone (Aldrich),
Pyridine carboxylic acid (Tokyo Kasei Kogyo Co., Ltd.),
1,3-pentanediol (Wako Pure Chemical Industries Ltd.),
2 (Kanto Chemical Co., Inc.)
Methyl aceto acetate (Tokyo Kasei Kogyo Co., Ltd.),
4-methoxyl group methyl acetoacetate (Tokyo Kasei Kogyo Co., Ltd.),
Iodoethane (Wako Pure Chemical Industries Ltd.)
Thionyl chloride (Wako Pure ChemicalIndustries Ltd.),
Diisopropylamine (Aldrich),
N-Butyl Lithium (Kanto Chemical Co., Inc.),
Lithium aluminum hydride (Wako Pure Chemical Industries Ltd.),
Sodium borohydride (Kanto Chemical Co., Inc.),
2N aqueous sodium hydroxide solution (Wako Pure Chemical Industries Ltd.),
Hydrogen (TOMOE SHOKAI Co., LTD),
Hydrochloric acid gas (TOMOE SHOKAI Co., LTD),
3-oxopentanoic acid ethyl ester (Aldrich),
1-bromine fourth-2-ketone (Trans World Chemicals, Inc.),
Potassium acetate (Wako Pure Chemical Industries Ltd.),
Salt of wormwood (Kanto Chemical Co., Inc.),
4-methoxyl group methyl acetoacetate (Tokyo Kasei Kogyo Co., Ltd.)
Otan (E-MERCK),
Pyridine (Wako Pure Chemical Industries Ltd.),
Benzoyl chloride (Tokyo Kasei Kogyo Co., Ltd.),
1,8-diazabicylo [5.4.0] undecane-7-alkene (Aldrich),
Nine fluoro-1-butane sulfonic acid fluoride (Tokyo Kasei Kogyo Co., Ltd.),
Sodium Benzoate (Kanto Chemical Co., Inc.),
(diethylamino) sulfur trifluoride (FLUKA),
The methanol solution of 28% sodium methylate (Wako Pure Chemical Industries Ltd.),
Benzyloxy acetaldehyde (Aldrich),
3-hydroxy-2-methyl pyridine (Aldrich)
N-phenyl trifluoromethanesulfonate Toluidrin (Tokyo Kasei Kogyo Co., Ltd.),
(trimethyl silyl) acetylene (Aldrich),
Two (triphenylphosphine) Palladous chloride (II) (N.E.CHEMCAT),
Cuprous iodide (I) (Kanto Chemical Co., Inc.),
Tetrabutyl ammonium fluoride (1N tetrahydrofuran solution) (Aldrich),
10% palladium/carbon (N.E.CHEMCAT),
3,4-diaminostilbene-fluorobenzene (Lancaster),
Dithiocarbonic anhydride (Wako Pure Chemical Industries Ltd.),
The formaldehyde dimethylacetal (Tokyo Kasei Kogyo Co., Ltd.),
Lithiumbromide (Aldrich)
The tosic acid monohydrate (Tokyo Kasei Kogyo Co., Ltd.),
2-methyl-6-N-methyl-p-nitroaniline (Wako Pure Chemical Industries Ltd.),
4-nitro-2-PICOLINE N-OXIDES (Lancaster),
0.1N aqueous sodium hydroxide solution (Wako Pure Chemical Industries Ltd.),
Sodium hydroxide (Wako Pure Chemical Industries Ltd.),
Tosyl chloride (Tokyo Kasei Kogyo Co., Ltd.),
Potassium tert.-butoxide (Tokyo Kasei Kogyo Co., Ltd.),
5,5-dimethyl-1,3-two
Figure 2006800126056_21
Alkane-2-ethanol (Aldrich),
Sericosol N (Tokyo Kasei Kogyo Co., Ltd.),
2-methylol-1,4-benzo two
Figure 2006800126056_22
Alkane (Aldrich),
2-(allyloxy) ethanol (Tokyo Kasei Kogyo Co., Ltd.),
Iodine (Wako Pure Chemical Industries Ltd.),
18-is preced with-6 (Wako Pure Chemical Industries Ltd.),
Zirconium iso-propoxide (IV)/Virahol mixture (Aldrich),
(-)-tetramethyl--(D)-tartramide (Tokyo Kasei Kogyo Co., Ltd.),
Four butanols hafniums (Aldrich),
Vanadyl Acetyl Acetone (Aldrich),
(S)-(-)-and 2-(3,5-two-tertiary butyl salicylidene amino)-3,3-dimethyl-1-butanols (Aldrich),
30% hydrogen peroxide (Kanto Chemical Co., Inc.),
3-amino-4-nitrotoluene (Aldrich),
2-methoxyl group-6-N-methyl-p-nitroaniline (J.of Chem.Soc. (1954) 2977-2978),
4-amino-3-nitro-trifluoromethyl toluene (ACROS),
4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich),
DL-α-0-benzyl group glycerol (SIGMA),
Propione (Tokyo Kasei Kogyo Co., Ltd.),
1-benzyloxy-2-acetone (Aldrich),
(+)-1,4-dioxo spiro [4,5] decane-2-methyl alcohol (Aldrich)
4-benzyloxy-2-butanone (FLUKA),
(R)-(+)-1,2,4-trihydroxybutane (Wako Pure Chemical Industries Ltd.),
(S)-(-)-1,2,4-trihydroxybutane (Wako Pure Chemical Industries Ltd.),
Methyl acetoacetate (Tokyo Kasei Kogyo Co., Ltd.)
6,7-dihydro-1H-[1,4] dioxine also [2 ', 3 ': 4,5] benzo [D] imidazoles-2-mercaptan (MAYBRIDGE),
5-nitro-1,3-benzo dioxole (Tokyo Kasei Kogyo Co., Ltd.),
Tetramethyl-ammonium nitrate (Aldrich),
Trifluoromethanesulfanhydride anhydride (Aldrich),
2-cyclopentanone methyl-formiate (Aldrich),
1,4-cyclohexanedione list-2,2-dimethyl trimethylene ketal (Aldrich).
4-pimelinketone ethyl formate (Tokyo Kasei Kogyo Co., Ltd.)
Hydroxy-acetaldehyde diethyl acetal (Lancaster),
1,1-tetramethylene dicarboxylate (Lancaster)
Embodiment
In the described chemical formula of embodiment, represent asymmetric atom with the atom of reference symbol * mark.
(embodiment 1) 2-(((4-((5,5-monomethyl-1,3-two
Figure 2006800126056_23
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 8]
Figure S2006800126056D00341
(1a) 2-((benzyloxy) methyl)-5,5-dimethyl-1,3-two
Figure 2006800126056_24
Alkane
[formula 9]
Figure S2006800126056D00342
To benzyloxy acetaldehyde (5g, 33.3mmol), 2,2-dimethyl-1, ammediol (4.16g, (287mg 1.51mmol) and refluxed 4 hours, removes by the Dean-Stark device simultaneously and anhydrates to add the tosic acid monohydrate 40mmol) and in the mixture of toluene (70ml).After reaction mixture is cooled to room temperature, joins triethylamine (4ml) in the reaction mixture and remove and desolvate by evaporation.Resistates is passed through silica gel chromatography (silica gel: 200g, eluting solvent: ethyl acetate/heptane=1/9) obtain title compound (7.6g, yield: 96.6%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.73(3H，s)，1.19(3H，s)，3.46(2H，d，J＝10Hz)，3.55(2H，d，J＝4Hz)，3.64(2H，d，J＝10Hz)，4.60(2H，s)，4.66(1H，t，J＝4Hz)，7.26-7.35(5H，m)。
(1b) (5,5-dimethyl-1,3-two
Figure 2006800126056_25
Alkane-2-yl) methyl alcohol
[formula 10]
Figure S2006800126056D00351
With the 2-((benzyloxy) methyl)-5 that step (1a) obtains, 5-dimethyl-1,3-two
Figure 2006800126056_26
(7.6g 32.2mmol) mixes with 20% palladium hydroxide (700mg) and ethyl acetate (70ml) alkane mutually.Mixture stirred under nitrogen atmosphere spend the night.Reaction mixture was continued to leave standstill 5 days under identical nitrogen atmosphere.With the reaction vessel nitrogen purge, leach catalyzer, steam solvent and obtain title compound (4g, yield: 85%), be white solid.
1H?NMR(400MHz，CDCl 3)δ?ppm；0.75(3H，s)，1.20(3H，s)，1.88-1.95(1H，br)，3.47(2H，d，J＝10Hz)，3.63-3.66(4H，m)，4.54(1H，t，J＝4Hz)。
(1c) 4-((5,5-dimethyl-1,3-two
Figure 2006800126056_27
Alkane-2-yl) methoxyl group)-2,3 dimethyl pyridine 1-oxide compound
[formula 11]
With step (1b) obtain (5,5-dimethyl-1,3-two
Figure 2006800126056_28
Alkane-2-yl) (2g, 13.7mmol) oil solution (content is by 60% for 822mg, 20.6mmol) with sodium hydride mixes with dimethyl sulfoxide (DMSO) (20ml) methyl alcohol mutually.Mixture was at room temperature stirred 30 minutes.(2.16g 13.7mmol) and 50 ℃ of following stirrings spends the night, and at room temperature continues then to leave standstill 1 day to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in reaction mixture.After steaming dimethyl sulfoxide (DMSO), methyl alcohol and NH silica gel are joined in the resistates, steam methyl alcohol then.The mixture of reaction mixture and NH silica gel is passed through silica gel chromatography (NH silica gel: 200g, eluting solvent: ethyl acetate/heptane=1/1 is to 4/1 → methanol/ethyl acetate=1/9) obtain title compound (3.1g, yield: 84.6%), be light yellow oil.
1H?NMR(400MHz，DMSO-d 6)δppm；0.70(3H，s)，1.12(3H，s)，2.12(3H，s)，2.34(3H，s)，3.49(2H，d，J＝11Hz)，3.59(2H，d，J＝11Hz)，4.06(2H，d，J＝4Hz)，4.82(1H，t，J＝4Hz)，6.96(1H，d，J＝7Hz)，8.05(1H，d，J＝7Hz)。
(1d) (4-((5,5-dimethyl-1,3-two
Figure 2006800126056_29
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol
[formula 12]
Figure S2006800126056D00361
The 4-that step (1c) is obtained ((5,5-dimethyl-1,3-two
Figure 2006800126056_30
Alkane-2-yl) methoxyl group)-(3.1g, 11.6mmol) (9.87ml 104mmol) mixes 2,3 dimethyl pyridine 1-oxide compound mutually with diacetyl oxide.Mixture is removed diacetyl oxide after stirring 45 minutes under 85 ℃.Resistates is dissolved in methyl alcohol (40ml), and (5.1ml 25.5mmol) joins in the mixture, simultaneously in cooled on ice with the 5N aqueous sodium hydroxide solution.Mixture was at room temperature stirred 1 hour.Steam methyl alcohol and frozen water is joined in the resistates, use ethyl acetate extraction then.Organic layer is washed with saturated brine solution, use anhydrous magnesium sulfate drying.After steaming solvent, the mixture that forms is obtained title compound (1.23g, yield: 39.7%), be light yellow oil by silica gel chromatography (silica gel: 120g, eluting solvent: ethyl acetate/heptane=1/4 is to 4/1).
1H?NMR(400MHz，CDCl 3)δppm；0.77(3H，s)，1.23(3H，s)，2.07(3H，s)，3.52(2H，d，J＝12Hz)，3.69(2H，d，J＝12Hz)，4.12(2H，d，J＝4Hz)，4.65(2H，s)，4.85(1H，t，J＝4Hz)，6.73(1H，d，J＝6Hz)，8.30(1H，d，J＝6Hz)。
(1e) 2-(((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_31
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 13]
Figure S2006800126056D00362
With step (1d) obtain (4-((5,5-dimethyl-1,3--two
Figure 2006800126056_32
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) (500mg, 1.87mmol) (1.04ml 7.48mmol) mixes with tetrahydrofuran (THF) (15ml) methyl alcohol mutually with triethylamine.With this mixture be cooled to-19 ℃ and to wherein adding methylsulfonyl chloride (217 μ l 2.81mmol), stirred 30 minutes down at-19 ℃ then.Under identical condition, (309mg 2.06mmol) joins in the reaction mixture with 2-mercaptobenzimidazole.With reaction mixture at room temperature stir spend the night after, methyl alcohol and NH silica gel are joined in the mixture, steam solvent then.The mixture of reaction mixture and NH silica gel is passed through silica gel chromatography (silica gel: 80g, eluting solvent: ethyl acetate/heptane=1/1 is to 4/1 → methanol/ethyl acetate=1/9) obtain title compound (599mg, yield: 80.2%), be the light red foam.
1H?NMR(400MHz，DMSO-d 6)δppm；0.71(3H，s)，1.13(3H，s)，2.21(3H，s)，3.50(2H，d，J＝11Hz)，3.59(2H，d，J＝11Hz)，4.09(2H，d，J＝4Hz)，4.69(2H，s)，4.84(1H，t，J＝4Hz)，6.98(1H，d，J＝6Hz)，7.11(2H，dd，J＝3，6Hz)，7.36-7.51(2H，br)，8.22(1H，d，J＝6Hz)。
(1f) 2-(((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_33
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline
[formula 14]
The 2-that step (1e) is obtained (((4-((5,5-dimethyl-1,3-two
Figure 2006800126056_34
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-(599mg 1.5mmol) mixes with methyl alcohol (5ml) and toluene (15ml) the 1H-benzoglyoxaline mutually, then mixture is cooled to-50 ℃.The 3-chlorine peroxybenzoic acid (content is by 65% for 358mg, 1.35mmol) that will be dissolved in the solvent mixture of methyl alcohol and toluene slowly is added drop-wise in the mixture and at-47 ℃ to-70 ℃ and stirred 3 hours down.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture, use ethyl acetate extraction then.Organic layer is washed with saturated brine solution, dry and steam solvent with salt of wormwood.With resistates silica gel chromatography (NH silica gel: 40g, eluting solvent: methylene dichloride/heptane=7/3 → ethanol/methylene=3/97 is to 1/9).In the product that obtains, add heptane (20ml) and diethyl ether (2ml), obtain throw out by filtration.Obtain title compound (475mg, yield: 76.2%), be the light orange solid according to this mode.
1H?NMR(400MHz，DMSO-d 6)δppm；0.71(3H，s)，1.12(3H，s)，2.14(3H，s)，3.49(2H，d，J＝11Hz)，3.59(2H，d，J＝11Hz)，4.09(2H，d，J＝4Hz)，4.70(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，4.84(1H，t，J＝4Hz)，6.98(1H，d，J＝6Hz)，7.25-7.32(2H，m)，7.60-7.66(2H，m)，8.20(1H，d，J＝6Hz)。
(1g) 2-(((4-((and 5,5-dimethyl-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 15]
The 2-that step (1f) is obtained (((4-((5,5-dimethyl-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-(475mg 1.14mmol) mixes with ethanol (15ml) the 1H-benzoglyoxaline mutually.In mixture, add the 1N aqueous sodium hydroxide solution (1.14ml, 1.14mmol) and steam solvent.Ethanol is joined in the resistates, dissolve and steam.Should operate and repeat 2 times.Diethyl ether is joined in the resistates and the mixture that forms is carried out supersound process.Obtain throw out by filtration, drain and obtain title compound (445mg, yield: 89.2%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.70(3H，s)，1.13(3H，s)，2.18(3H，s)，3.50(2H，d，J＝11Hz)，3.59(2H，d，J＝11Hz)，4.08(2H，d，J＝4Hz)，4.39(1H，d，J＝13Hz)，4.76(1H，d，J＝13Hz)，4.84(1H，t，J＝4Hz)，6.85(2H，dd，J＝3，6Hz)，6.95(1H，d，J＝6Hz)，7.43(2H，dd，J＝3，6Hz)，8.27(1H，d，J＝6Hz)。
(embodiment 2) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 16]
Figure S2006800126056D00391
(2a) 6-((benzyloxy) methyl)-5,7-dioxo spiro [2.5] octane
[formula 17]
Figure S2006800126056D00392
With benzyloxy acetaldehyde (5g, 33.3mmol), 1,1-two (hydroxymethyl) cyclopropane (4.08g, 40mmol), tosic acid monohydrate (287mg, 1.51mmol) and the mixture of toluene (70ml) refluxed 2 hours, remove by the Dean-Stark device simultaneously and anhydrate.After reaction mixture is cooled to room temperature, joins triethylamine (4ml) in the reaction mixture and steam solvent.Resistates is obtained title compound (6.1g, yield: 78.2%), be light yellow oil by silica gel chromatography (silica gel: 200g, eluting solvent: ethyl acetate/heptane=5/95 is to 1/9).
1H?NMR(400MHz，CDCl 3)δppm；0.31-0.35(2H，m)，0.67-0.71(2H，m)，3.26(2H，d，J＝12Hz)，3.57(2H，d，J＝4Hz)，4.14(2H，d，J＝12Hz)，4.60(2H，s)，4.82(1H，t，J＝4Hz)，7.27-7.34(5H，m)。
(2b) 5,7-dioxo spiro [2.5] suffering-6-base methyl alcohol
[formula 18]
With the 6-((benzyloxy) methyl)-5 that step (2a) obtains, (6.1g 26mmol) mixes with 20% palladium hydroxide (800mg) and ethyl acetate (70ml) and mixture was stirred 24 hours under nitrogen atmosphere 7-dioxo spiro [2.5] octane mutually.Reaction vessel with nitrogen purge and leach catalyzer, is steamed solvent then and obtains title compound (3.7g, yield: 98.7%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.33-0.37(2H，m)，0.68-0.72(2H，m)，3.28(2H，d，J＝12Hz)，3.68(2H，d，J＝4Hz)，4.16(2H，d，J＝12Hz)，4.73(1H，t，J＝4Hz)。
(2c) 4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-2,3 dimethyl pyridine 1-oxide compound
[formula 19]
With step (2b) obtain 5,7-dioxo spiro [2.5] suffering-6-base methyl alcohol (1.7g, 11.8mmol) mix mutually with dimethyl sulfoxide (DMSO) (20ml) with the oil solution (content is by 60% for 708mg, 17.7mmol) of sodium hydride and mixture was at room temperature stirred 30 minutes.(1.86g 11.8mmol) and 50 ℃ of following stirrings spends the night to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in reaction mixture.After steaming dimethyl sulfoxide (DMSO), join methyl alcohol and NH silica gel in the resistates and steam methyl alcohol.The mixture of reaction mixture and NH silica gel is passed through silica gel chromatography (NH silica gel: 200g, eluting solvent: ethyl acetate/heptane=1/1 to 4/1 → methanol/ethyl acetate=1/9 is to 1/4) obtain title compound (1.8g, yield: 57.5%), be reddish oil.
1H?NMR(400MHz，CDCl 3)δppm；0.36-0.40(2H，m)，0.69-0.74(2H，m)，2.22(3H，s)，2.53(3H，s)，3.30(2H，d，J＝12Hz)，4.11(2H，d，J＝4Hz)，4.19(2H，d，J＝12Hz)，5.00(1H，t，J＝4Hz)，6.68(1H，d，J＝7Hz)，8.13(1H，d，J＝7Hz)。
(2d) (4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl alcohol
[formula 20]
Figure S2006800126056D00402
(1.8g, 6.78mmol) (5.77ml 61mmol) mixes 4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-2,3 dimethyl pyridine 1-oxide compound that step (2c) is obtained mutually with diacetyl oxide.Mixture was stirred 45 minutes down at 85 ℃, steam diacetyl oxide then.With resistates in cooled on ice and be dissolved in methyl alcohol.(2.98ml 14.9mmol) and with mixture at room temperature stirred 2 hours to wherein adding the 5N aqueous sodium hydroxide solution under the cooling of ice.Steam methyl alcohol and water is joined in the resistates, use ethyl acetate extraction then.Organic layer is washed with saturated brine solution, use anhydrous magnesium sulfate drying, steam solvent then.Carry out purifying (silica gel: 100g, eluting solvent: ethyl acetate/heptane=1/4 is to 4/1) by silica gel column chromatography.Add heptane (15ml) in the product behind purifying and mixture is refluxed.After confirming that solution reaches even attitude, it is cooled off gradually.Obtain precipitating the product of separating out by filtration.Obtain title compound (520mg, yield: 28.9%), be white solid according to this mode.
1H?NMR(400MHz，CDCl 3)δppm；0.36-0.40(2H，m)，0.70-0.74(2H，m)，2.07(3H，s)，3.30(2H，d，J＝11Hz)，4.14(2H，d，J＝4Hz)，4.20(2H，d，J＝11Hz)，4.64(2H，s)，4.86(1H，brs)，5.02(1H，t，J＝4Hz)，6.73(1H，d，J＝6Hz)，8.29(1H，d，J＝6Hz)。
(2e) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 21]
Figure S2006800126056D00411
With step (2d) obtain (4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-and 3-picoline-2-yl) methyl alcohol (520mg, 1.96mmol) with triethylamine (1.09ml, 7.84mmol) mix mutually with tetrahydrofuran (THF) (10ml) and with formation mixture be cooled to-19 ℃.(228 μ l 2.94mmol) join in the mixture, stir 30 minutes down at-19 ℃ then with methylsulfonyl chloride.Under identical condition, (324mg 2.16mmol) joins in the reaction mixture with 2-mercaptobenzimidazole.After reaction mixture at room temperature stirred 2 days, join methyl alcohol and NH silica gel in the mixture and steam solvent.The mixture of reaction mixture and NH silica gel is passed through silica gel chromatography (silica gel: 80g, eluting solvent: ethyl acetate/heptane=4/6 is to 7/3 → methanol/ethyl acetate=1/9) obtain title compound (629mg, yield: 80.7%), be colourless foam.
1H?NMR(400MHz，DMSO-d 6)δppm；0.31-0.36(2H，m)，0.56-0.61(2H，m)，2.21(3H，s)，3.26(2H，d，J＝12Hz)，4.10-4.13(4H，m)，4.69(2H，s)，5.02(1H，t，J＝5Hz)，6.99(1H，d，J＝6Hz)，7.11(2H，dd，J＝3，6Hz)，7.39-7.49(2H，br)，8.23(1H，d，J＝6Hz)。
(2f) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 22]
Figure S2006800126056D00421
(((4-(5 with 2-that step (2e) obtains, 7-dioxo spiro [2.5] suffering-6-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfenyl)-(629mg 1.58mmol) mixes with methyl alcohol (5ml) and toluene (15ml) and mixture is cooled to-50 ℃ the 1H-benzoglyoxaline mutually.The 3-chlorine peroxybenzoic acid (content is by 65% for 378mg, 1.42mmol) that will be dissolved in the solvent mixture of methyl alcohol and toluene then slowly is added drop-wise in the mixture and at-47 ℃ to-70 ℃ and stirred 4 hours down.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture, use ethyl acetate extraction then.Organic layer is washed with saturated brine solution, dry and steam solvent with salt of wormwood.Resistates is obtained title compound (623mg, yield: 95.4%), be colourless foam with silica gel chromatography (NH silica gel: 40g, eluting solvent: methylene dichloride/heptane=7/3 → ethanol/methylene=3/97 is to 1/9).
1H?NMR(400MHz，DMSO-d 6)δppm；0.31-0.36(2H，m)，0.56-0.61(2H，m)，2.14(3H，s)，3.26(2H，d，J＝11Hz)，4.11-4.13(4H，m)，4.70(1H，d，J＝14Hz)，4.79(1H，d，J＝14Hz)，5.02(1H，t，J＝4Hz)，6.99(1H，d，J＝6Hz)，7.29(2H，dd，J＝3，6Hz)，7.59-7.67(2H，br)，8.21(1H，d，J＝6Hz)。
(2g) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 23]
(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-(623mg 1.51mmol) mixes with ethanol (15ml) the 1H-benzoglyoxaline 2-that step (2f) is obtained mutually.In mixture, add the 1N aqueous sodium hydroxide solution (1.51ml, 1.51mmol) and steam solvent.Join ethanol in the resistates and steam.Should operate and repeat 2 times.Diethyl ether is joined in the resistates and the mixture that forms is carried out supersound process.Obtain throw out by filtration, drain and obtain title compound (553mg, yield: 84.1%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.31-0.35(2H，m)，0.57-0.61(2H，m)，2.19(3H，s)，3.26(2H，d，J＝11Hz)，4.10(2H，d，J＝5Hz)，4.12(2H，d，J＝11Hz)，4.37(1H，d，J＝13Hz)，4.82(1H，d，J＝13Hz)，5.02(1H，t，J＝5Hz)，6.84(2H，dd，J＝3，6Hz)，6.95(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.27(1H，d，J＝6Hz)。
(embodiment 3) 2-(((3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 24]
Figure S2006800126056D00432
(3a) (2-propyl group-1,3-dioxolane-2-yl) ethyl acetate
[formula 25]
Figure S2006800126056D00441
With 3-oxo ethyl hexanoate (5g, 31.6mmol), ethylene glycol (3.92g, 63.2mmol), (4.68g, 31.6mmol) (544mg, mixture 2.86mmol) at room temperature stirred 29 hours 10 minutes triethyl orthoformate with the tosic acid monohydrate.In reaction mixture, add entry and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine solution, with dried over mgso and filtration.Filtrate decompression concentrated obtain title compound (6.2g, 97%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.93(3H，t，J＝7Hz)，1.27(3H，t，J＝7Hz)，1.39-1.48(2H，m)，1.78(2H，t，J＝8Hz)，2.64(2H，s)，3.94-4.02(4H，m)，4.15(2H，q，J＝7H)。
(3b) 2-(2-propyl group-1,3-dioxolane-2-yl) ethanol
[formula 26]
Figure S2006800126056D00442
To lithium aluminum hydride (1.17g, 30.7mmol) tetrahydrofuran (THF) (100ml) suspension in ice cooling under add (the 2-propyl group-1 that step (3a) obtains, 3-dioxolane-2-yl) ethyl acetate (6.2g, tetrahydrofuran (THF) 30.7mmol) (20ml) solution.Mixture was stirred 30 minutes under the cooling of ice, add entry (1.17ml) and 15% aqueous sodium hydroxide solution (1.17ml) and water (3.51ml) then successively and stirred 10 minutes.Sodium sulfate is joined in the mixture, stir and carry out filtered through silica gel.Filtrate decompression is concentrated, resistates is dissolved in the solution mixture that contains normal heptane/ethyl acetate with 2: 1 ratio, carry out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=2/1) obtain title compound (3.82 g, 77.7%), be water white oil then.
1H?NMR(400MHz，CDCl 3)δppm；0.93(3H，t，J＝8Hz)，1.33-1.43(2H，m)，1.60-1.65(2H，m)，1.92(2H，t，J＝6Hz)，2.83(1H，t，J＝6Hz)，3.74(2H，q，J＝6Hz)，3.95-4.03(4H，m)。
(3c) 2,3-dimethyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine 1-oxide compound
[formula 27]
Figure S2006800126056D00451
2-(the 2-propyl group-1 that obtains to step (3b), 3-dioxolane-2-yl) ethanol (1.5g, 9.35mmol) dimethyl sulfoxide (DMSO) (22.5ml) solution under nitrogen gas stream, add the oil solution (561mg of sodium hydride, 14mmol, content is by 60%) and 4-chloro-2, (1.33g 8.42mmol) and at 60 ℃ stirred 2 hours down 3-lutidine 1-oxide compound.Mixture was at room temperature left standstill 3 days and concentrating under reduced pressure.Resistates is suspended in the tetrahydrofuran (THF).NH silica gel is joined in the mixture of formation, be concentrated into dried then, carry out NH silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate/methanol=1/1/0 → 0/1/0 → 0/10/1) obtain title compound (1.53g, yield: 58.2%), be shallow brown oil.
1H?NMR(400MHz，CDCl 3)δppm；0.94(3H，t，J＝7Hz)，1.38-1.49(2H，m)，1.62-1.67(2H，m)，2.14-2.20(2H，m)，2.19(3H，s)，2.53(3H，s)，3.92-4.01(4H，m)，4.10(2H，t，J＝7Hz)，6.64(1H，d，J＝7Hz)，8.13(1H，d，J＝7Hz)。
(3d) acetate (3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl ester
[formula 28]
Figure S2006800126056D00452
With step (3c) obtain 2, (1.53g 5.44mmol) mixes with diacetyl oxide (30ml) and mixture is stirred down at 80 ℃ spend the night 3-dimethyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine 1-oxide compound mutually.Be dissolved in ethyl acetate with the reaction mixture concentrating under reduced pressure and with resistates, carry out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1) obtain title compound (1.19g, 67.6%), be light yellow oil then.
1H?NMR(400MHz，CDCl 3)δppm；0.94(3H，t，J＝7Hz)，1.39-1.49(2H，m)，1.64-1.69(2H，m)，2.12(3H，s)，2.16-2.20(2H，m)，2.18(3H，s)，3.93-4.00(4H，m)，4.12(2H，t，J＝7Hz)，5.20(2H，s)，6.73(1H，d，J＝6Hz)，8.31(1H，d，J＝6Hz)。
(3e) (3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl alcohol
[formula 29]
Figure S2006800126056D00461
(1.19g 3.68mmol) mixes with 1N aqueous sodium hydroxide solution (5ml) and methyl alcohol (10ml) methyl ester the acetate (3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) that step (3d) is obtained mutually.Mixture was at room temperature stirred 3 hours and concentrating under reduced pressure.Resistates is suspended in the tetrahydrofuran (THF), joins in the suspension sodium sulfate and filtration.Filtrate decompression is concentrated.Resistates is dissolved in the solution mixture that contains heptane and ethyl acetate with 2: 1 ratio, carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=2/1) obtain title compound (0.88g, 85%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.94(3H，t，J＝7Hz)，1.39-1.49(2H，m)，1.64-1.69(2H，m)，2.03(3H，s)，2.18(2H，t，J＝7Hz)，3.93-4.01(4H，m)，4.14(2H，t，J＝7Hz)，4.65(2H，s)，4.89(1H，brs)，6.73(1H，d，J＝6Hz)，8.29(1H，d，J＝6Hz)。
(3f) 2-(((3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 30]
Figure S2006800126056D00471
(450mg 1.6mmol) mixes with tetrahydrofuran (THF) (10ml) methyl alcohol (3-methyl-4-(2-(2-propyl group-1, the 3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) that step (3e) is obtained mutually.With mixture under nitrogen gas stream in cooled on ice.To wherein add triethylamine (0.446ml, 3.2mmol) and methylsulfonyl chloride (0.186ml 2.4mmol) and under the cooling of ice stirred 50 minutes.(240mg 1.6mmol), at room temperature stirs then and spends the night to add 2-mercaptobenzimidazole in reaction mixture.In reaction mixture, add sodium bicarbonate aqueous solution and use ethyl acetate extraction.Organic layer is washed with saturated brine solution, with dried over mgso and filtration.Filtrate decompression is concentrated.Resistates is dissolved in ethyl acetate.After joining silica gel in the solution, with solution concentration.The exsiccant resistates is carried out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1 → 0/1) obtain title compound (528mg, 79.8%), be colourless thick oil.
1H?NMR(400MHz，CDCl 3)δppm；0.94(3H，t，J＝7Hz)，1.39-1.50(2H，m)，1.63-1.68(2H，m)，2.20(2H，t，J＝7Hz)，2.26(3H，s)，3.93-4.01(4H，m)，4.16(2H，t，J＝7Hz)，4.37(2H，s)，6.78(1H，d，J＝6Hz)，7.16-7.20(2H，m)，7.50-7.59(2H，m)，8.35(1H，d，J＝6Hz)。
(3g) 2-(((3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 31]
Figure S2006800126056D00472
2-(((3-methyl-4-(2-(2-propyl group-1 that step (3f) is obtained, 3-dioxolane-2-yl) sulfenyl methyl pyridine-2-yl oxyethyl group))))-(482mg 1.17mmol) is dissolved in the solvent mixture of toluene (30ml) and methyl alcohol (3ml) to the 1H-benzoglyoxaline.Mixture is cooled off under nitrogen atmosphere.Be lower than under-70 ℃ the methanol solution (1.3ml) that in this mixture, adds 3-chlorine peroxybenzoic acid (content is by 65% for 311mg, 1.17mmol) at internal temperature and stirring 2 hours below-60 ℃.In reaction mixture, add sodium bicarbonate aqueous solution and ethyl acetate.Isolate organic layer, with the saturated brine solution washing, with anhydrous sodium sulfate drying and filtration.Filtrate decompression is concentrated.Resistates is dissolved in methylene dichloride and carries out silica gel column chromatography (eluting solvent: methylene chloride=1/0 → 100/1 → 100/5) obtain title compound (323mg, yield: 64.3%) with NH silica gel.
1H?NMR(400MHz，DMSO-d 6)δppm；0.85(3H，t，J＝7Hz)，1.28-1.39(2H，m)，1.55-1.60(2H，m)，2.04(2H，t，J＝7Hz)，2.10(3H，s)，3.89-3.90(4H，m)，4.08(2H，t，J＝7Hz)，4.68(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.95(1H，d，J＝6Hz)，7.26-7.32(2H，m)，7.59-7.67(2H，m)，8.20(1H，d，J＝6Hz)。
(3h) 2-(((3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 32]
Figure S2006800126056D00481
2-(((3-methyl-4-(2-(2-propyl group-1 that step (3g) is obtained; 3-dioxolane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline (323mg; 0.752mmol) with ethanol (15ml) and 1N aqueous sodium hydroxide solution (0.752ml, 0.752mmol) mixing and mixture at room temperature stirred 10 minutes mutually.Steam solvent and the resistates that forms is dissolved in ethanol, and then steam solvent.Diethyl ether-ethanol-normal heptane is joined in the resistates, at room temperature stir, filter then and obtain solid.Obtain title compound (315mg, 92.8%) according to this mode, be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.85(3H，t，J＝7Hz)，1.29-1.39(2H，m)，1.56-1.63(2H，m)，2.05(2H，t，J＝7Hz)，2.15(3H，s)，3.83-3.91(4H，m)，4.07(2H，t，J＝7Hz)，4.40(1H，d，J＝13Hz)，4.76(1H，d，J＝13Hz)，6.84-6.90(2H，m)，6.92(1H，d，J＝5Hz)，7.41-7.47(2H，m)，8.25(1H，d，J＝5Hz)。
(embodiment 4) 2-(((4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt.
[formula 33]
Figure S2006800126056D00491
(4a) 1,3-two (benzyloxy) acetone
[formula 34]
Figure S2006800126056D00492
To 1,3-benzyloxy-2-propyl alcohol (52g, 191mmol), triethylamine (130ml, 933mmol) and dimethyl sulfoxide (DMSO) (65ml, add sulfur trioxide pyridine complex (131g down in 0 ℃ in methylene dichloride 916mmol) (200ml) solution, 823mmol), stirred 2 hours to room temperature at 0 ℃ then.In mixture, add entry and ethyl acetate.Organic layer with 2N hydrochloric acid, water and salt brine solution washing, is also concentrated with anhydrous sodium sulfate drying.Obtain brown oily title compound (52.01g, quantitative yield).
1H?NMR(400MHz，DMSO-d 6)δppm；4.26(4H，s)，4.49(4H，s)，7.25-7.38(10H，m)。
(4b) 2,2-two ((benzyloxy) methyl)-1,3-dioxolane
[formula 35]
With step (4a) obtain 1,3-two (benzyloxy) acetone (30g, 111mmol) with ethylene glycol (64ml, 1,148mmol), triethyl orthoformate (19ml, 114mmol) and the tosic acid monohydrate (591mg 3.11mmol) mixes mutually.Mixture was stirred 14 hours down at 50 ℃.In mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.With organic layer water and salt brine solution washing, with anhydrous sodium sulfate drying and concentrated.With the crude product that obtains by silica gel chromatography (eluting solvent: heptane/ethyl acetate=1/0-4/1 gradient), required fraction concentrated obtain title compound (28.46g, yield: 81.6%), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；3.45(4H，s)，3.88(4H，s)，4.50(4H，s)，7.22-7.35(10H，m)。
(4c) 1,3-dioxolane-2,2-two basic dimethanols
[formula 36]
Figure S2006800126056D00501
To step (4b) obtain 2,2-two ((benzyloxy) methyl)-1,3-dioxolane (28.5g, 90.7mmol) ethyl acetate (300ml) solution in add palladium hydroxide (20wt%Pd (based on dry weight) carbon, wet (maximum water holding capacity 50%)) (2.5g) and under nitrogen atmosphere, at room temperature stirred 39 hours.With reaction mixture with nitrogen purge after, from reaction mixture, leach catalyzer and wash with ethyl acetate.Filtrate is concentrated.In the resistates that obtains, add ethyl acetate (300ml) and palladium hydroxide (20wt%Pd (based on dry weight) carbon, wet (maximum water holding capacity 50%)) (2.5g) and under nitrogen atmosphere, at room temperature stirred 26 hours.With reaction mixture with nitrogen purge after, leach catalyzer and wash with ethyl acetate.Filtrate concentrating obtained title compound (11.97g, yield: 98.4%), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；3.32(4H，d，J＝6Hz)，3.85(4H，s)，4.63(2H，t，J＝6Hz)。
(4d) (8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl acetate
[formula 37]
Figure S2006800126056D00511
With 1; 3-dioxolane-2; 2-two basic dimethanol (4g; 29.8mmol) (its can according to obtaining with the described identical method of step (4a)-(4c)) and propionyl methyl acetate (5.6ml; 44.6mmol), triethyl orthoformate (5.2ml; 31.3mmol) and tosic acid monohydrate (163mg, 0.856mmol) mixing mutually.Mixture was at room temperature stirred 3 hours.In mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.Wash organic layer with water water 2 times, then with the salt brine solution washing, with anhydrous sodium sulfate drying and concentrated.With the crude product that obtains by silica gel chromatography (eluting solvent: concentrate heptane/ethyl acetate=1/0-3/1-1/1 gradient) and with required fraction and to obtain title compound (2.63g, yield: 35.8%), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；0.84(3H，t，J＝7Hz)，1.75(2H，q，J＝7Hz)，2.76(2H，s)，3.56(3H，s)，3.58(2H，d，J＝12Hz)，3.68(2H，d，J＝12Hz)，3.80-3.89(4H，m)。
(4e) 2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) ethanol
[formula 38]
Figure S2006800126056D00512
(the 8-ethyl-1 that obtains to step (4d), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl acetate (2.63g, 10.7mmol) THF (40ml) solution in add down lithium aluminum hydride in 0 ℃ (487mg 12.8mmol) and at 0 ℃ stirred 4 hours to room temperature.Add entry (0.5ml), 2N aqueous sodium hydroxide solution (0.5ml), water (1.5ml) successively with termination reaction.Then anhydrous sodium sulphate and diatomite are joined in the mixture, the mixture that forms is filtered by glass filter and washs with ethyl acetate.Filtrate concentrating obtained title compound (2.34g, quantitative yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；0.79(3H，t，J＝7Hz)，1.62(2H，q，J＝7Hz)，1.81(2H，t，J＝8Hz)，3.41(2H，dt，J＝6，8Hz)，3.57(4H，s)，3.83(4H，s)，4.29(1H，t，J＝6Hz)。
(4f) 4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-2,3 dimethyl pyridine 1-oxide compound
[formula 39]
Figure S2006800126056D00521
To 2-(8-ethyl-1,4,7 that step (4e) obtains, 9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) ethanol (1.34g, 6.14mmol) dimethyl sulfoxide (DMSO) (20ml) solution at room temperature under nitrogen atmosphere, add the oil solution (content is by 60% for 295mg, 7.37mmol) of sodium hydride.Mixture was stirred 30 minutes under identical condition.(1.06g 6.75mmol) and with the mixture that forms stirred 5.5 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in reaction mixture under room temperature.Reaction mixture concentrated and with resistates by silica gel chromatography (NH silica gel, eluting solvent: heptane, ethyl acetate/methanol=1/0-4/1 gradient), then with the concentrated title compound (948mg that obtains of required fraction, yield: 45.5%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.83(3H，t，J＝7Hz)，1.73(2H，q，J＝7Hz)，2.09(3H，s)，2.12(2H，t，J＝6Hz)，2.32(3H，s)，3.62(4H，s)，3.80-3.88(4H，m)，4.06(2H，t，J＝6Hz)，6.89(1H，d，J＝8Hz)，8.05(1H，d，J＝8Hz)。
(4g) (4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl alcohol
[formula 40]
Figure S2006800126056D00531
(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-(947mg 2.79mmol) mixes with diacetyl oxide (10ml) 2,3 dimethyl pyridine 1-oxide compound the 4-that step (4f) is obtained mutually.(0.6ml 4.3mmol) and at 50 ℃ stirred 2 hours down to add triethylamine in mixture.Reaction mixture is concentrated and methyl alcohol (10ml) is joined in the resistates, add 5N aqueous sodium hydroxide solution (7ml) then and also at room temperature stirred 1 hour.In mixture, add saturated aqueous ammonium chloride (7ml), with the pH regulator of the solution that forms to being about 10.Reaction mixture is washed with 2N aqueous sodium hydroxide solution, water and salt brine solution with the ethyl acetate dilution and with organic layer, with anhydrous sodium sulfate drying and concentrated.With the crude product that obtains by silica gel chromatography (eluting solvent: concentrate ethyl acetate/methanol=1/0-4/1 gradient) and with required fraction and to obtain title compound (564mg, yield: 59.6%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.84(3H，t，J＝7Hz)，1.74(2H，q，J＝7Hz)，2.08(3H，s)，2.14(2H，t，J＝6Hz)，3.63(4H，s)，3.78-3.89(4H，m)，4.08(2H，t，J＝6Hz)，4.50(2H，d，J＝6Hz)，4.96(1H，t，J＝6Hz)，6.90(1H，d，J＝6Hz)，8.20(1H，d，J＝6Hz)。
(4h) 2-(((4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 41]
Figure S2006800126056D00532
(4-(2-(the 8-ethyl-1 that obtains to step (4g), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-and 3-picoline-2-yl) methyl alcohol (560mg, 1.65mmol) THF (10ml) solution under room temperature, add triethylamine (0.48ml 3.44mmol), add methylsulfonyl chloride (0.19ml under the refrigerative condition then in cryosel is bathed, 2.45mmol), under identical condition, stirred 30 minutes then.After removing the cryosel bath, (248mg 1.65mmol) also at room temperature stirred 22 hours to add 2-mercaptobenzimidazole.After reaction mixture concentrated, NH silica gel joined in the resistates and dry.Thick material is concentrated by silica gel chromatography (eluting solvent: heptane/ethyl acetate=1/0,1/1-0/1 gradient) and with required fraction.The spumescence product that obtains is dissolved in chloroform and to wherein adding diethyl ether.The solid by filtration collection that forms is obtained title compound (410 mg, yield: 52.7%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.84(3H，t，J＝7Hz)，1.75(2H，q，J＝7Hz)，2.15(2H，t，J＝6Hz)，2.18(3H，s)，3.63(4H，s)，3.80-3.90(4H，m)，4.09(2H，t，J＝6Hz)，4.67(2H，s)，6.93(1H，d，J＝6Hz)，7.07-7.13(2H，m)，7.35-7.51(2H，m)，8.22(1H，d，J＝6Hz)，12.60(1H，brs)。
(4i) 2-(((4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 42]
Figure S2006800126056D00541
2-(((4-(2-(the 8-ethyl-1 that obtains to step (4h), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (380mg, 0.81mmol) toluene (10.8ml) and methyl alcohol (1.2ml) solution in 10 minutes, under nitrogen atmosphere, drip 3-chlorine peroxybenzoic acid (192mg under in-70 to-60 ℃, 0.73mmol content is by 65%) toluene (2.7ml) and methyl alcohol (0.3ml) solution.Mixture was stirred 1 hour under identical condition.Come termination reaction by under identical temperature, adding saturated aqueous solution of sodium bicarbonate (15ml).With mixture chloroform extraction (50ml) 2 times, organic layer is also concentrated with anhydrous sodium sulfate drying.The crude product that obtains is passed through silica gel chromatography (NH silica gel: eluting solvent: ethyl acetate/methanol=1/0-4/1 gradient) and with required fraction concentrate.The spumescence product that obtains precipitated again with chloroform and diethyl ether separate out, filter then.Should operate and repeat four times, the solid that obtains is washed with diethyl ether, drying obtains title compound (188mg, 47.9% yield) then, is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.83(3H，t，J＝7Hz)，1.74(2H，q，J＝7Hz)，2.10(3H，s)，2.14(2H，t，J＝6Hz)，3.63(4H，s)，3.79-3.90(4H，m)，4.09(2H，t，J＝6Hz)，4.68(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.93(1H，d，J＝6Hz)，7.23-7.32(2H，m)，7.54-7.68(2H，m)，8.20(1H，d，J＝6Hz)。
(4j) 2-(((4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 43]
Figure S2006800126056D00551
2-(((4-(2-(the 8-ethyl-1 that obtains to step (4i); 4; 7; 9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (188mg; 0.39mmol) ethanol (2ml) solution under room temperature, add 1N aqueous sodium hydroxide solution (386 μ l; 0.39mmol) and with mixture stirring 10 minutes, concentrate then.Join methyl alcohol in the resistates and concentrate.After repeating this operation, diethyl ether joined in the resistates and with the suspension that obtains leave standstill.After removing supernatant liquor, resistates is obtained title compound (190mg, 96.6% yield) by the vacuum pump drying, be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.84(3H，t，J＝8Hz)，1.75(2H，q，J＝8Hz)，2.09-2.20(5H，m)，3.63(4H，s)，3.80-3.90(4H，m)，4.08(2H，t，J＝6Hz)，4.36(1H，d，J＝13Hz)，4.79(1H，d，J＝13Hz)，6.78-6.88(2H，m)，6.89(1H，d，J＝5Hz)，7.36-7.46(2H，m)，8.26(1H，d，J＝5Hz)。
(embodiment 5) 2-(((3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 44]
Figure S2006800126056D00561
(5a) 2-oxopropyl benzoic ether
[formula 45]
Figure S2006800126056D00562
(5g, (12ml 103mmol) and with mixture at room temperature stirred 43 hours in add Benzoyl chloride under 0 ℃ under nitrogen atmosphere in pyridine 67.5mmol) (25ml) and THF (10ml) solution to pyruvic alcohol.Ice is joined in the reaction mixture, dilute with ethyl acetate then.Organic layer with 1N hydrochloric acid, water and salt brine solution washing, is also concentrated with anhydrous sodium sulfate drying.The crude product that obtains is passed through silica gel chromatography (eluting solvent: heptane/ethyl acetate=1/0-1/1 gradient).Required fraction concentrated obtain title compound (10.56g, 87.8% yield), be light yellow oil.
1H?NMR(400MHz，DMSO-d 6)δppm；2.14(3H，s)，5.01(2H，s)，7.51-7.58(2H，m)，7.65-7.70(1H，m)，7.95-8.00(2H，m)。
(5b) (8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl benzoate
[formula 46]
Figure S2006800126056D00563
The 2-oxopropyl benzoic ether (4g that step (5a) is obtained, 22.4mmol) with step (4c) obtain 1,3-dioxolane-2,2-two basic dimethanol (3g, 22.4mmol), triethyl orthoformate (3.8ml, 22.8mmol) and tosic acid monohydrate (200mg, 1.05mmol) mixing mutually.Mixture was at room temperature stirred 13.5 hours.In mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.Organic layer is washed with water 2 times, then with the salt brine solution washing, with anhydrous sodium sulfate drying and concentrated.With the crude product that obtains heptane/ethyl acetate=1/0-1/1 gradient) and will required fraction is concentrated obtain title compound (1.92 g, 29.1% yield) by silica gel chromatography (eluting solvent:, be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.41(3H，s)，3.64-3.76(4H，m)，3.80-3.88(4H，m)，4.33(2H，s)，7.50-7.57(2H，m)，7.64-7.70(1H，m)，7.92-8.00(2H，m)。
(5c) (8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl alcohol
[formula 47]
Figure S2006800126056D00571
(the 8-methyl isophthalic acid that obtains to step (5b), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl benzoate (1.92g, 6.52mmol) THF (10ml) and methyl alcohol (5ml) solution in add the 1N aqueous sodium hydroxide solution (10ml, 10mmol) and at room temperature stirred 1 hour.With reaction mixture dichloromethane extraction (50ml) four times, concentrate then with anhydrous sodium sulfate drying.With the crude product that obtains heptane/ethyl acetate=1/1-0/1 gradient) and will required fraction is concentrated obtain title compound (1.12g, 90.0% yield) by silica gel chromatography (eluting solvent:, be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.24(3H，s)，3.33(2H，d，J＝6Hz)，3.60(4H，s)，3.80-3.85(4H，m)，4.81(1H，t，J＝6Hz)。
(5d) 2,3-dimethyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine 1-oxide compound
[formula 48]
Figure S2006800126056D00581
To (8-methyl isophthalic acid, 4,7 that step (5c) obtains, 9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl alcohol (1.11g, 5.82mmol) dimethyl sulfoxide (DMSO) (15ml) solution in the oil solution (content is by 60% for 326mg, 8.15mmol) that in nitrogen atmosphere, adds sodium hydride under the room temperature.Mixture was stirred 30 minutes under identical condition.(917mg 5.82mmol) and with reaction mixture stirred 4.5 hours down at 70 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in reaction mixture under room temperature.Reaction mixture is concentrated, with resistates by silica gel chromatography (eluting solvent: ethyl acetate/methanol=1/0-5/2 gradient) and with required fraction is concentrated obtain title compound (1.20g, 66.1% yield), be brown oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.42(3H，s)，2.12(3H，s)，2.33(3H，s)，3.65-3.75(4H，m)，3.85(4H，s)，4.07(2H，s)，7.00(1H，d，J＝7Hz)，8.07(1H，d，J＝7Hz)。
(5e) (3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl alcohol
[formula 49]
Figure S2006800126056D00582
With step (5d) obtain 2, (1.20g 3.84mmol) mixes with diacetyl oxide (10ml) pyridine 1-oxide compound 3-dimethyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) mutually.(0.8ml 5.74mmol) and with mixture stirred 2 hours down at 50 ℃ to add triethylamine in mixture.Reaction mixture is concentrated and methyl alcohol (10ml) is joined in the resistates.Then 5N aqueous sodium hydroxide solution (7ml) is joined in the mixture and also at room temperature stirred 30 minutes.In reaction mixture, add saturated aqueous ammonium chloride (7ml) and with pH regulator to being about 10.Reaction mixture is diluted with ethyl acetate, and organic layer is washed with 2N aqueous sodium hydroxide solution, water and salt brine solution, with anhydrous sodium sulfate drying and concentrated.With the crude product that obtains ethyl acetate/methanol=1/0-4/1 gradient) and will required fraction is concentrated obtain title compound (312mg, 26.1% yield) by silica gel chromatography (eluting solvent:, be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.44(3H，s)，2.11(3H，s)，3.65-3.75(4H，m)，3.85(4H，s)，4.08(2H，s)，4.51(2H，d，J＝5Hz)，4.97(1H，t，J＝5Hz)，6.99(1H，d，J＝6Hz)，8.20(1H，d，J＝6Hz)。
(5f) 2-(((3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 50]
Figure S2006800126056D00591
(3-methyl-4-((the 8-methyl isophthalic acid that obtains to step (5e), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl alcohol (312mg pyridine-2-yl methoxyl group)), 1.00mmol) THF (7ml) solution under room temperature, add triethylamine (0.30ml, 2.15mmol), (0.12ml 1.55mmol) and under identical condition stirred 30 minutes to add methylsulfonyl chloride then under the cooling that cryosel is bathed.In reaction mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.With the water layer ethyl acetate extraction.Organic layer is merged, and water and salt brine solution washing are with anhydrous sodium sulfate drying and concentrated.The resistates that obtains is dissolved in ethanol (6ml).In the solution that forms, add 2-mercaptobenzimidazole (150mg, 1.00mmol) and sodium hydroxide (160mg 4.00mmol) also at room temperature stirred 16.5 hours.After reaction mixture concentrated, join NH silica gel in the resistates and with the mixture drying.The crude product that obtains by silica gel chromatography (eluting solvent: heptane/ethyl acetate=1/0,1/1-0/1 gradient) and will required fraction is concentrated obtain title compound (377mg, 85.0% yield), is white foam.
1H?NMR(400MHz，DMSO-d 6)δppm；1.43(3H，s)，2.21(3H，s)，3.66-3.76(4H，m)，3.85(4H，s)，4.09(2H，s)，4.68(2H，s)，7.02(1H，d，J＝6Hz)，7.07-7.14(2H，m)，7.37-7.50(2H，m)，8.22(1H，d，J＝6Hz)，12.59(1H，brs)。
(5g) 2-(((3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 51]
2-(((3-methyl-4-((the 8-methyl isophthalic acid that obtains to step (5f), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) sulfenyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline (372mg, 0.84mmol) toluene (8.1ml) and methyl alcohol (0.9ml) solution under-55 ℃ to-50 ℃, in 10 minutes, under nitrogen atmosphere, drip 3-chlorine peroxybenzoic acid (200mg, 0.76mmol content is by 65%) toluene (2.7ml) and methyl alcohol (0.3ml) solution.Mixture was stirred 1.5 hours down at-60 ℃ to-50 ℃.Come termination reaction by under identical temperature, adding the 12ml saturated sodium bicarbonate aqueous solution.With mixture 50ml chloroform extraction 2 times, then organic layer is also concentrated with anhydrous sodium sulfate drying.The crude product that obtains is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol=1/0-4/1 gradient) and with required fraction concentrate.To obtain white foam and precipitate again, filter then with chloroform and diethyl ether.Should operate repetition and obtain title compound (148mg, 38.4% yield) 2 times, be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.43(3H，s)，2.14(3H，s)，3.65-3.77(4H，m)，3.85(4H，s)，4.09(2H，s)，4.69(1H，d，J＝14Hz)，4.78(1H，d，J＝14Hz)，7.02(1H，d，J＝6Hz)，7.20-7.32(2H，m)，7.53-7.70(2H，m)，8.20(1H，d，J＝6Hz)。
(5h) 2-(((3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 52]
Figure S2006800126056D00611
2-(((3-methyl-4-((the 8-methyl isophthalic acid that obtains to step (5g); 4; 7; 9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) sulfinyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline (147mg; 0.32mmol) ethanol (4ml) solution under room temperature, add 1N aqueous sodium hydroxide solution (320 μ l; 0.32mmol) and stirred 10 minutes, then mixture is concentrated.Join in the resistates methyl alcohol also concentrated.Repeat to add diethyl ether after this operation 2 times and the suspension that obtains is left standstill.The reject supernatant liquor obtains title compound (147mg, 95.4% yield) with resistates by the vacuum pump drying, is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.43(3H，s)，2.18(3H，s)，3.66-3.76(4H，m)，3.85(4H，s)，4.07(2H，s)，4.36(1H，d，J＝13Hz)，4.81(1H，d，J＝13Hz)，6.78-6.88(2H，m)，6.99(1H，d，J＝6Hz)，7.38-7.46(2H，m)，8.27(1H，d，J＝6Hz)。
(((((2-methoxyl group-1,3-two for 4-for (embodiment 6) 2-
Figure 2006800126056_37
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 53]
Figure S2006800126056D00612
(6a) (2-methoxyl group-1,3-two
Figure 2006800126056_38
Alkane-5-yl) methyl alcohol
[formula 54]
Figure S2006800126056D00613
With 2-(hydroxymethyl)-1, and ammediol (1.7g, 16mmol), (7ml, 64.1mmol) (275mg, mixture 1.6mmol) at room temperature stirred 22 hours trimethyl orthoformate with the tosic acid monohydrate.In reaction mixture, add triethylamine (447 μ l) and mixture is concentrated.(eluting solvent: heptane/ethyl acetate) obtain title compound (1.4g, 59.1% yield), it is cis and trans (1: 1) mixture, is light yellow oil by silica gel chromatography with resistates.
1H?NMR(400MHz，CDCl 3)δppm；1.85-1.92(0.5H，m)，1.93-2.04(0.5H，m)，3.34(1.5H，s)，3.41(1.5H，s)，3.62-3.84(3H，m)，3.90(1H，dd，J＝4，12Hz)，4.03(1H，dd，J＝6，12Hz)，4.27(1H，dd，J＝4，12Hz)，5.22(0.5H，s)，5.25(0.5H，s)。
(6b) ((2-methoxyl group-1,3-two for 4-
Figure 2006800126056_39
Alkane-5-yl) methoxyl group)-2,3 dimethyl pyridine 1-oxide compound
[formula 55]
Figure S2006800126056D00621
To obtain according to the mode identical with step (6a) (2-methoxyl group-1,3-two
Figure 2006800126056_40
Alkane-5-yl) (2.0g adds the oil solution (content is by 55% for 770mg, 14.9mmol) of sodium hydride to methyl alcohol under room temperature in dimethyl sulfoxide (DMSO) 13.5mmol) (10ml) solution.(2.13g 13.5mmol) and with mixture stirred 2.5 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.Reaction mixture is cooled to after the room temperature concentrates.(NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (1.8g, 49.5% yield), it is cis and trans (1: 1) mixture, is yellow oil by silica gel chromatography with resistates.
1H?NMR(400MHz，CDCl 3)δppm；2.12-2.30(1H，m)，2.20(3H，s)，2.54(3H，s)，3.41(1.5H，s)，3.45(1.5H，s)，3.77(1H，dd，J＝4，12Hz)，4.01(1H，dd，J＝4，12Hz)，4.08-4.26(3H，m)，4.39(1H，dd，J＝4，12Hz)，5.28(0.5H，s)，5.29(0.5H，s)，6.65(0.5H，d，J＝8Hz)，6.69(0.5H，d，J＝8Hz)，8.15(0.5H，d，J＝8Hz)，8.16(0.5H，d，J＝8Hz)。
(6c) (((2-methoxyl group-1,3-two for 4-
Figure 2006800126056_41
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol
[formula 56]
Figure S2006800126056D00631
((2-methoxyl group-1,3-two with 4-that step (6b) obtains
Figure 2006800126056_42
Alkane-5-yl) methoxyl group)-(1.8g 6.68ml) mixes with diacetyl oxide (8ml) 2,3 dimethyl pyridine 1-oxide compound mutually.Mixture was stirred 2 hours down at 100 ℃.After being cooled to room temperature, with the reaction mixture concentrating under reduced pressure.In resistates, add methyl alcohol (10ml) and 5N aqueous sodium hydroxide solution (5ml) and mixture was at room temperature stirred 15 hours.Reaction mixture is concentrated and resistates is separated with ethyl acetate with saturated brine solution.With the organic layer anhydrous magnesium sulfate drying, filter, concentrate and with resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol) obtains title compound (0.41g, yield: 22.8%), it is cis and trans (1: 1) mixture, is yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；2.04(3H，s)，2.12-2.22(0.5H，m)，2.24-2.32(0.5H，m)，3.41(1.5H，s)，3.44(1.5H，s)，3.79(1H，dd，J＝4，12Hz)，4.01(1H，dd，J＝4，12Hz)，4.10-4.20(2H，m)，4.23(1H，d，J＝8Hz)，4.38(1H，dd，J＝4，12Hz)，4.66(2H，s)，4.86(1H，bs)，5.28(0.5H，s)，5.29(0.5H，s)，6.73(0.5H，d，J＝8Hz)，6.76(0.5H，d，J＝8Hz)，8.31(0.5H，d，J＝8Hz)，8.32(0.5H，d，J＝8Hz)。
(6d) (((((2-methoxyl group-1,3-two for 4-for 2-
Figure 2006800126056_43
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 57]
To step (6c) obtain (((2-methoxyl group-1,3-two for 4-
Figure 2006800126056_44
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol (0.41g, 1.52mmol) and triethylamine (1.06ml, 7.61mmol) tetrahydrofuran (THF) (anhydrous) (10ml) under the cooling of ice, in nitrogen atmosphere, drip in the solution methylsulfonyl chloride (176 μ l, 2.27mmol).Mixture was stirred 1.5 hours under identical condition.(228mg 1.52mmol) also at room temperature stirred 20 hours to add 2-mercaptobenzimidazole in mixture.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.(eluting solvent: heptane/ethyl acetate) obtain title compound (324mg, 53.1% yield), it is cis and trans (1: 1) mixture, is light yellow foam by silica gel chromatography with resistates.
1H?NMR(400MHz，CDCl 3)δppm；2.12-2.24(1H，m)，2.27(3H，s)，3.41(1.5H，s)，3.44(1.5H，s)，3.79(1H，dd，J＝4，12Hz)，4.02(1H，dd，J＝4，12Hz)，4.12-4.20(2H，m)，4.27(1H，d，J＝8Hz)，4.38(2H，s)，4.36-4.44(1H，m)，5.27(0.5H，s)，5.29(0.5H，s)，6.78(0.5H，d，J＝8Hz)，6.82(0.5H，d，J＝8Hz)，7.15-7.24(2H，m)，7.43-7.50(1H，m)，7.58-7.67(1H，m)，8.35-8.44(1H，m)。
(6e) (((((2-methoxyl group-1,3-two for 4-for 2-
Figure 2006800126056_45
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline
[formula 58]
Figure S2006800126056D00641
(((((2-methoxyl group-1,3-two for 4-to 2-that step (6d) obtains
Figure 2006800126056_46
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (324mg, 807 μ mol) toluene and methanol (10: 1) (20ml) dripped 3-chlorine peroxybenzoic acid (528mg in the solution in nitrogen atmosphere in 5 minutes under-50 ℃ to-60 ℃, 1.99mmol content is by 65%) (5ml) solution of toluene and methanol (10: 1).Mixture was stirred 2 hours under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution and with the mixture ethyl acetate extraction that forms.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.With resistates by silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (337mg, 65.9% yield), it is cis and trans (1: 1) mixture,, be light yellow foam.
MS?m/e(ESI)418(MH) +，440(MNa) +
(6f) (((((2-methoxyl group-1,3-two for 4-for 2- Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 59]
Figure S2006800126056D00651
(((((2-methoxyl group-1,3-two for 4-to 2-that step (6e) obtains
Figure 2006800126056_48
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-under room temperature, add 1N aqueous sodium hydroxide solution (532 μ l, 532 μ mol) in ethanol (10ml) solution of 1H-benzoglyoxaline (222mg, 532 μ mol) and stirred 1 hour.Mixture is concentrated and resistates is dissolved in ethanol.Diethyl ether is joined in the mixture and then the mixture supersound process.The solid that forms is collected by filtering under nitrogen atmosphere.The solid drying under reduced pressure is obtained title compound, and (234mg, yield: 83.4%), it is cis and trans (1: 1) mixture, is light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.14-2.21(1H，m)，2.18(3H，s)，3.66-3.74(1H，m)，3.27(1.5H，s)，3.28(1.5H，s)，3.66-3.76(1H，m)，3.88-4.04(2H，m)，4.09(1H，dd，J＝4，12Hz)，4.16-4.23(1H，m)，4.35(1H，d，J＝13Hz)，4.82(1H，d，J＝13Hz)，5.24(0.5H，s)，5.27(0.5H，s)，6.83(2H，dd，J＝3，6Hz)，6.93(1H，d，J＝6Hz)，7.41(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
MS?m/e(ESI)440(MNa) +
(embodiment 7) 2-(((4-((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_49
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt.
[formula 60]
Figure S2006800126056D00652
(7a) (2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_50
Alkane-5-yl) methyl alcohol
[formula 61]
Figure S2006800126056D00661
With 2-(hydroxymethyl)-1, and ammediol (2.2g, 20.7mmol), 1,3-difluoro acetone (3.89g, 41.4mmol), trimethyl orthoformate (3.44ml, 20.7mmol) and the tosic acid monohydrate (356mg, mixture 2.07mmol) stirred 10 hours down at 60 ℃.After reaction is finished triethylamine (577 μ l) is joined in the reaction mixture, concentrate then.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (1.6g, yield: 43.4%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δ?ppm；1.97-2.10(1H，m)，3.72-3.82(2H，m)，3.87(2H，dd，J＝4，12Hz)，4.10(2H，dd，J＝4，12Hz)，4.46(2H，dd，J＝2，48Hz)，4.57(2H，dd，J＝2，48Hz)。
(7b) 4-((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_51
Alkane-5-yl) methoxyl group)-2,3 dimethyl pyridine 1-oxide compound
[formula 62]
Figure S2006800126056D00662
To step (7a) obtain (2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_52
Alkane-5-yl) (1.6g adds the oil solution (content is by 55% for 431mg, 9.88mmol) of sodium hydride to methyl alcohol under room temperature in dimethyl sulfoxide (DMSO) 8.98mmol) (10ml) solution.(1.42g 8.98mmol) and with mixture stirred 2 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.Reaction mixture is cooled to concentrating under reduced pressure after the room temperature.With resistates by silica gel chromatography (eluting solvent: ethyl acetate/methanol) obtain title compound (1.63g, yield: 60.6%), be yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；2.19(3H，s)，2.26-2.36(1H，m)，2.54(3H，s)，3.99(2H，dd，J＝4，12Hz)，4.13(2H，d，J＝8Hz)，4.21(2H，dd，J＝4，12Hz)，4.45(2H，dd，J＝2，48Hz)，4.62(2H，dd，J＝2，48Hz)，6.64(1H，d，J＝8Hz)，8.14(1H，d，J＝8Hz)。
(7c) (4-((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_53
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol
[formula 63]
Figure S2006800126056D00671
The 4-that step (7b) is obtained ((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_54
Alkane-5-yl) methoxyl group)-(1.63g 5.37mmol) mixes with diacetyl oxide (8ml) 2,3 dimethyl pyridine 1-oxide compound mutually.Mixture was stirred 2 hours down at 100 ℃, be cooled to room temperature, then concentrating under reduced pressure.In resistates, add methyl alcohol (10ml) and 5N aqueous sodium hydroxide solution (5ml) and mixture was at room temperature stirred 3 hours.Reaction mixture is concentrated and resistates is distributed between saturated brine solution and ethyl acetate.With the organic layer anhydrous magnesium sulfate drying, filter, concentrate and resistates is obtained title compound (385mg, yield 23.6%) by silica gel chromatography (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol), be yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；2.04(3H，s)，2.32-2.40(1H，m)，4.01(2H，dd，J＝4，12Hz)，4.16(2H，d，J＝8Hz)，4.21(2H，dd，J＝4，12Hz)，4.48(2H，dd，J＝2，48Hz)，4.62(2H，dd，J＝2，48Hz)，4.66(2H，s)，4.84(1H，bs)，6.73(1H，d，J＝8Hz)，8.31(1H，d，J＝8Hz)。
(7d) 2-(((4-((and 2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_55
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 64]
Figure S2006800126056D00672
To step (7c) obtain (4-((2,2-two (methyl fluoride)-1,3-two Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol (385mg, 1.27mmol) and triethylamine (885 μ l, 6.35mmol) tetrahydrofuran (THF) (anhydrous) (20ml) under the cooling of ice, in nitrogen atmosphere, drip in the solution methylsulfonyl chloride (177 μ l, 2.29mmol).Mixture was stirred 1.0 hours under identical condition.(191mg 1.27mmol) also at room temperature stirred 10 hours to add 2-mercaptobenzimidazole in reaction mixture.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (305mg, yield: 55.1%), be light yellow foam.
1H?NMR(400MHz，CDCl 3)δppm；2.26(3H，s)，2.30-2.38(1H，m)，4.01(2H，dd，J＝4，12Hz)，4.18(2H，d，J＝8Hz)，4.22(2H，dd，J＝4，12Hz)，4.38(2H，s)，4.46(2H，dd，J＝2，48Hz)，4.62(2H，dd，J＝2，48Hz)，6.79(1H，d，J＝8Hz)，7.15-7.23(2H，m)，7.42-7.50(1H，m)，7.56-7.66(1H，m)，8.37(1H，d，J＝8Hz)。
(7e) 2-(((4-((and 2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_57
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline
[formula 65]
Figure S2006800126056D00681
The 2-that obtains to step (7d) (((4-((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_58
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (305mg, 700 μ mol) toluene and methanol (10: 1) (20ml) dripped 3-chlorine peroxybenzoic acid (167mg in the solution in nitrogen atmosphere in 5 minutes under-50 ℃ to-60 ℃, 630mmol, content is by 65%) (5ml) solution of toluene and methanol (10: 1).Mixture was stirred 2 hours under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution and with the mixture ethyl acetate extraction that forms.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (215mg, yield: 68%), be light yellow foam.
MS?m/e(ESI)452(MH) +，474(MNa) +
(7f) 2-(((4-((and 2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_59
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 66]
Figure S2006800126056D00691
The 2-that obtains to step (7e) (((4-((2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_60
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-under room temperature, add 1N aqueous sodium hydroxide solution (476 μ l, 476 μ mol) in ethanol (10ml) solution of 1H-benzoglyoxaline (215mg, 476 μ mol) and stirred 1 hour.After mixture concentrated, resistates is dissolved in ethanol, diethyl ether is joined in the mixture.Mixture is collected by filtering under nitrogen atmosphere with supersound process and with the solid that forms.The solid drying under reduced pressure is obtained title compound (193mg, yield: 85.6%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.17(3H，s)，2.18-2.28(1H，m)，3.84-3.94(2H，m)，4.06-4.18(2H，m)，4.12(2H，d，J＝8Hz)，4.37(1H，d，J＝12Hz)，4.50(2H，d，J＝47Hz)，4.58(2H，d，J＝47Hz)，4.81(1H，d，J＝12Hz)，6.80-6.90(2H，m)，6.94(1H，d，J＝8Hz)，7.38-7.48(2H，m)，8.27(1H，d，J＝8Hz)。
(((((2-propyl group-1,3-two for 2-for 3-methyl-4-for (embodiment 8) 2-
Figure 2006800126056_61
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline sodium salt
[formula 67]
Figure S2006800126056D00701
(8a) (2-propyl group-1,3-two
Figure 2006800126056_62
Alkane-2-yl) ethyl acetate
[formula 68]
Figure S2006800126056D00702
With 3-oxo ethyl hexanoate (5g, 31.6mmol), 1, ammediol (3.61g, 47.4mmol), (5.78ml, 34.8mmol) (272mg, mixture 1.58mmol) at room temperature stirred 22 hours trimethyl orthoformate with the tosic acid monohydrate.(881 μ l 6.32mmol) joined in the reaction mixture then and concentrate with triethylamine after reaction was finished.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (5.5g, yield: 80.5%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；0.94(3H，t，J＝7Hz)，1.27(3H，t，J＝7Hz)，1.40-1.54(2H，m)，1.55-1.68(2H，m)，1.74-1.90(2H，m)，2.82(2H，s)，3.87-4.06(4H，m)，4.15(2H，q，J＝7Hz)。
(8b) (2-propyl group-1,3-two for 2-
Figure 2006800126056_63
Alkane-2-yl) ethanol
[formula 69]
Figure S2006800126056D00703
To step (8a) obtain (2-propyl group-1,3-two
Figure 2006800126056_64
Alkane-2-yl) ethyl acetate (5.5g, tetrahydrofuran (THF) 25.4mmol) (anhydrous) (30ml) under the cooling of ice, drip in the solution lithium aluminum hydride (578mg, 15.2mmol) and stirred 1 hour.In reaction mixture, add entry (0.6ml), 2N aqueous sodium hydroxide solution (0.6ml) and water (1.8ml) successively, inclusion is passed through diatomite filtration.Filtrate decompression concentrated obtain title compound (4.4g, yield 99.4%), be light yellow oily crude product.
1H?NMR(400MHz，CDCl 3)δppm；0.97(3H，t，J＝7Hz)，1.22-1.42(4H，m)，1.82-2.00(4H，m)，3.78-3.96(4H，m)，3.96-4.08(2H，m)。
(8c) 2, ((2-propyl group-1,3-two for 2-for 3-dimethyl-4-
Figure 2006800126056_65
Alkane-2-yl) pyridine 1-oxide compound oxyethyl group)
[formula 70]
Figure S2006800126056D00711
To step (8b) obtain ((2-propyl group-1,3-two for 2-
Figure 2006800126056_66
Alkane-2-yl) (4.4g 25.3mmol) adds the oil solution (content is by 55% for 1.1g, 25.3mmol) of sodium hydride to ethanol under room temperature in, dimethyl sulfoxide (DMSO) (20ml) solution.(3.19g 20.2mmol) and with mixture stirred 1.5 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.After being cooled to room temperature, with the mixture concentrating under reduced pressure.Resistates is obtained title compound (3.9g, yield: 52.2%), be light yellow oil by silica gel chromatography (NH silica gel, eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol).
1H?NMR(400MHz，CDCl 3)δppm；0.96(3H，t，J＝7Hz)，1.34-1.48(2H，m)，1.76-1.88(2H，m)，2.14-2.26(4H，m)，2.54(3H，s)，2.62(3H，s)，3.82-3.90(2H，m)，3.92-4.04(2H，m)，4.17(2H，t，J＝7Hz)，6.69(1H，d，J＝8Hz)，8.14(1H，d，J＝8Hz)。
(8d) (((2-propyl group-1,3-two for 2-for 3-methyl-4-
Figure 2006800126056_67
Alkane-2-yl) methyl alcohol pyridine-2-yl oxyethyl group))
[formula 71]
Figure S2006800126056D00712
With step (8c) obtain 2, ((2-propyl group-1,3-two for 2-for 3-dimethyl-4-
Figure 2006800126056_68
Alkane-2-yl) oxyethyl group) (3.9g 13.2mmol) mixes with diacetyl oxide (16ml) pyridine 1-oxide compound mutually.Mixture was stirred 2 hours down at 90 ℃.After being cooled to room temperature, with the reaction mixture concentrating under reduced pressure.In resistates, add methyl alcohol (20ml) and 5N aqueous sodium hydroxide solution (10ml) and mixture was at room temperature stirred 2 hours.Reaction mixture is concentrated and resistates is separated with ethyl acetate with saturated brine solution.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate, resistates is obtained title compound (1.69g, yield: 43.3%), be yellow oil by silica gel chromatography (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol).
1H?NMR(400MHz，CDCl 3)δppm；0.96(3H，t，J＝7Hz)，1.35-1.48(2H，m)，1.52-1.66(2H，m)，1.72-1.88(2H，m)，2.03(3H，s)，2.22(2H，t，J＝7Hz)，3.82-4.04(4H，m)，4.19(2H，t，J＝7Hz)，4.65(2H，s)，6.77(1H，d，J＝8Hz)，8.29(1H，d，J＝8Hz)。
(8e) (((((2-propyl group-1,3-two for 2-for 3-methyl-4-for 2-
Figure 2006800126056_69
Alkane-2-yl) sulfenyl methyl pyridine-2-yl oxyethyl group))))-the 1H-benzoglyoxaline
[formula 72]
Figure S2006800126056D00721
To step (8d) obtain (((2-propyl group-1,3-two for 2-for 3-methyl-4-
Figure 2006800126056_70
Alkane-2-yl) methyl alcohol (445ml pyridine-2-yl oxyethyl group)), 1.51mmol) and triethylamine (1.05ml, 7.55mmol) tetrahydrofuran (THF) (anhydrous) (30ml) under the cooling of ice, in nitrogen atmosphere, drip methylsulfonyl chloride in the solution (210 μ l 2.72mmol) and with mixture stirred 1 hour under identical condition.(227mg 1.51mmol) also at room temperature stirred 3 days to add 2-mercaptobenzimidazole in reaction mixture.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.Resistates is obtained title compound (417mg, yield: 64.6%), be light yellow foam by silica gel chromatography (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol).
1H?NMR(400MHz，CDCl 3)δppm；0.96(3H，t，J＝7Hz)，1.35-1.47(2H，m)，1.76-1.88(4H，m)，2.22(2H，t，J＝7Hz)，2.25(3H，s)，3.82-3.91(2H，m)，3.92-4.00(2H，m)，4.22(2H，t，J＝7Hz)，4.37(2H，s)，6.82(1H，d，J＝8Hz)，7.14-7.24(2H，m)，7.50-7.62(2H，m)，8.35(1H，d，J＝8Hz)。
(8f) (((((2-propyl group-1,3-two for 2-for 3-methyl-4-for 2-
Figure 2006800126056_71
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-the 1H-benzoglyoxaline
[formula 73]
Figure S2006800126056D00731
(((((2-propyl group-1,3-two for 2-for 3-methyl-4-to 2-that step (8e) obtains
Figure 2006800126056_72
Alkane-2-yl) sulfenyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline (417mg, 975 μ mol) toluene-methyl alcohol (10: 1) (30ml) dripped 3-chlorine peroxybenzoic acid (233mg in the solution in nitrogen atmosphere in 5 minutes under-50 ℃ to-60 ℃, 878mmol, content is by 65%) (5ml) solution of toluene and methanol (10: 1).Reaction mixture was stirred 2 hours under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction.After organic layer concentrated, with resistates by silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (311mg, yield: 71.9%), be light yellow foam.
1H?NMR(400MHz，CDCl 3)δppm；0.95(3H，t，J＝7Hz)，1.34-1.47(2H，m)，1.70-1.88(4H，m)，2.17(3H，s)，2.20(2H，t，J＝7Hz)，3.82-3.92(2H，m)，3.92-4.00(2H，m)，4.17(2H，t，J＝7Hz)，4.65(1H，d，J＝14Hz)，4.82(1H，d，J＝14Hz)，6.78(1H，d，J＝8Hz)，7.28-7.38(2H，m)，7.30-7.62(2H，m)，8.30(1H，d，J＝8Hz)。
(8g) (((((2-propyl group-1,3-two for 2-for 3-methyl-4-for 2-
Figure 2006800126056_73
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline sodium salt
[formula 74]
Figure S2006800126056D00732
(((((2-propyl group-1,3-two for 2-for 3-methyl-4-to 2-that step (8f) obtains Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-under room temperature, add 1N aqueous sodium hydroxide solution (701 μ l, 701 μ mol) in ethanol (6ml) solution of 1H-benzoglyoxaline (311mg, 701 μ mol) and stirred 1 hour.Mixture is concentrated and resistates is dissolved in ethanol.After joining diethyl ether in the solution, with the solution supersound process.The solid that produces is obtained title compound (283mg, yield: 86.7%), be light yellow solid by the filtration collection and with the solid drying under reduced pressure under nitrogen atmosphere.
1H?NMR(400MHz，DMSO-d 6)δppm；0.87(3H，t，J＝7Hz)，1.26-1.38(2H，m)，1.48-1.64(2H，m)，1.67-1.74(2H，m)，2.12-2.20(2H，m)，2.16(3H，s)，3.81(4H，t，J＝7Hz)，4.07(2H，t，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.79(1H，d，J＝13Hz)，6.82-6.90(2H，m)，6.91(1H，d，J＝8Hz)，7.36-7.50(2H，m)，8.25(1H，d，J＝8Hz)。
MS?m/e(ESI)466(MNa) +。
(embodiment 9) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt.
[formula 75]
(9a) 2,2-dimethyl-1,3-two Alkane-5-alcohol
[formula 76]
Figure S2006800126056D00742
To 2,2-dimethyl-1,3-two Alkane-5-ketone (15g, under 0 to 8 ℃, in 1 hour, in nitrogen atmosphere, add in diethyl ether 0.115mol) (150ml) solution lithium aluminum hydride (4.38g, 0.115mol).In reaction mixture, under 0 to 10 ℃, add entry (4.2ml), 5N aqueous sodium hydroxide solution (4.2ml) and water (12.8ml) successively.With the mixture anhydrous sodium sulfate drying, filtration and concentrating under reduced pressure obtain title compound (14.2g, 93.4%), are water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.44(3H，s)，1.46(3H，s)，2.75-2.95(1H，br)，3.51-3.55(1H，m)，3.74-3.79(2H，m)，4.05-4.10(2H，m)。
(9b) 5-(benzyloxy)-2,2-dimethyl-1,3-two
Figure 2006800126056_77
Alkane
[formula 77]
Figure S2006800126056D00751
To step (9a) obtain 2,2-dimethyl-1,3-two
Figure 2006800126056_78
(7.1g, N 0.054mol) also stir in 0 ℃ of oil solution (content is by 55% for 2.81g, 0.064mol) that adds sodium hydride down in dinethylformamide (200ml) solution alkane-5-alcohol.Under identical temperature with bromotoluene (12.9ml, 0.108mol) and tetrabutylammonium iodide (220mg, 0.001mol) join in the mixture after, mixture was at room temperature stirred 1.5 hours.Water is joined in the reaction mixture, use ethyl acetate extraction then 3 times.Organic layer is merged, wash with water 5 times, with saturated brine solution washing 1 time, with anhydrous sodium sulfate drying and filtration.After carrying out NH silica gel, the mixture that forms is concentrated and obtain title compound (6.5g, 54.5%), be water white oil by silica gel chromatography (eluting solvent: heptane, heptane/ethyl acetate=9/1,4/1, ethyl acetate).
1H?NMR(400MHz，CDCl 3)δppm；1.40(3H，s)，1.45(3H，s)，3.50-3.56(1H，m)，3.77(2H，dd，J＝7，12Hz)，3.95(2H，dd，J＝4，12Hz)，4.58(2H，s)，7.28-7.38(5H，m)。
(9c) 2-(benzyloxy) the third-1, the 3-glycol
[formula 78]
Figure S2006800126056D00752
To the 5-(benzyloxy)-2 that step (9b) obtains, 2-dimethyl-1,3-two (6.5g adds DOWEX (R) 50W-X8 (5g) and stirring at room temperature to alkane in methyl alcohol 29.2mmol) (50ml) solution.After 2 hours, reaction mixture filtered and concentrate obtain title compound (5.0g, 93.8%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；3.60-3.65(1H，m)，3.74(2H，dd，J＝5，12Hz)，3.82(2H，dd，J＝4，12Hz)，4.67(2H，s)，7.29-7.40(5H，m)。
(9d) 7-(benzyloxy)-5,9-dioxo spiro [3.5] nonane
[formula 79]
Figure S2006800126056D00761
To containing in steps the 2-(benzyloxy) the third-1 that (9c) obtains, 3-glycol (5.0g, 27.4mmol) the round-bottomed flask of benzene (50ml) solution in add cyclobutanone (2.33ml, 30.6mmol) and tosic acid monohydrate (100mg, 0.53mmol), connect the reflux condensing tube that is equipped with the Dean-Stark water separator.Mixture was refluxed 2 hours.(0.4ml concentrates 0.72mmol) and with mixture and to obtain crude product to add triethylamine in reaction mixture.Crude product is obtained title compound (6.3g, yield: 98.2%), be light yellow oil by silica gel chromatography (NH silica gel, eluting solvent: heptane, heptane/ethyl acetate=5/1).
1H?NMR(400MHz，CDCl 3)δppm；1.70-1.79(2H，m)，2.20-2.29(4H，m)，3.44-3.50(1H，m)，3.64-3.69(2H，m)，3.92(2H，dd，J＝4，12Hz)，4.58(2H，s)，7.27-7.39(5H，m)。
(9e) 5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-alcohol
[formula 80]
Figure S2006800126056D00762
To the 7-(benzyloxy)-5 that step (9d) obtains, (6.3g adds 20% palladium hydroxide (630mg) and stirred 13 hours under nitrogen atmosphere 9-dioxo spiro [3.5] nonane in methyl alcohol 26.9mmol) (269ml) solution.With reaction vessel with nitrogen purge and by removing by filter insolubles.Filtrate concentrating obtained crude product.Crude product is obtained title compound (3.42g, yield: 88.2%), be water white oil by silica gel chromatography (NH silica gel, eluting solvent: heptane, heptane/ethyl acetate=5/1).
1H?NMR(400MHz，CDCl 3)δppm；1.72-1.82(2H，m)，2.21-2.31(4H，m)，2.71-2.88(1H，br)，3.50-3.56(1H，m)，3.71-3.76(2H，m)，3.93-3.98(2H，m)。
(9f) 4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-2,3 dimethyl pyridine 1-oxide compound
[formula 81]
Figure S2006800126056D00771
To step (9e) obtain 5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-alcohol, (1.68g added the oil solution (content is by 55% for 587mg, 13.5mmol) of sodium hydride under room temperature in dimethyl formamide 11.7mmol) (30ml) solution.Mixture was at room temperature stirred 50 minutes.To wherein add 4-chloro-2,3 dimethyl pyridine 1-oxide compound (1.84g, 11.7mmol) after, mixture was stirred 2 hours down at 80 ℃.Reaction mixture is concentrated and, stir down at 80 ℃ then to wherein adding dimethyl sulfoxide (DMSO) (30ml).Oil solution (content is by 55% for 587mg, 13.5mmol) with sodium hydride after 12 hours joins in the reaction mixture and stirring under 80 ℃.After 1 hour reaction mixture is concentrated and resistates is obtained title compound (2.00g, yield: 64.4%), be light yellow oil by silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate, ethyl acetate/methanol=9/1).
1H?NMR(400MHz，CDCl 3)δppm；1.76-1.82(2H，m)，2.24(3H，s)，2.27-2.32(4H，m)，2.54(3H，s)，3.85(2H，dd，J＝6，12Hz)，4.07(2H，dd，J＝3，12Hz)，4.24-4.30(1H，m)，6.62(1H，d，J＝7Hz)，8.16(1H，d，J＝7Hz)。
(9g) (4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl alcohol
[formula 82]
Figure S2006800126056D00781
(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-(1.25g, 4.71mmol) (4.45ml 47.1mmol) mixes 2,3 dimethyl pyridine 1-oxide compound the 4-that step (9f) is obtained mutually with diacetyl oxide.After mixture at room temperature stirred 1 hour, it is cooled to 0 ℃.Add triethylamine (656 μ l, 4.71mmol) after, mixture stirred 1 hour and at room temperature continued stirred 1 hour.50 ℃ down stir 2 hours after, reaction mixture concentrated and with resistates by silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/heptane=1/3).(2.24ml 11.2mmol) and with reaction mixture at room temperature stirred 1 hour to add methyl alcohol (30ml) and 5N aqueous sodium hydroxide solution in the product that obtains.Saturated aqueous ammonium chloride is joined in the reaction mixture pH with regulator solution to being about 9, concentrate then.Resistates ethyl acetate extraction 3 times with forming merge organic layer, with the saturated brine solution washing, use anhydrous sodium sulfate drying, filter and concentrate to obtain title compound (630mg, yield: 49.6%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.77-1.85(2H，m)，2.08(3H，s)，2.26-2.35(4H，m)，3.85(2H，dd，J＝6，12Hz)，4.1?1(2H，dd，J＝4，12Hz)，4.38-4.44(1H，m)，4.68(2H，s)，6.72(1H，d，J＝6Hz)，8.31(1H，d，J＝6Hz)。
(9h) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 83]
Figure S2006800126056D00782
(4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl alcohol that step (9g) is obtained (630mg, 2.37mmol) and triethylamine (0.66ml, tetrahydrofuran (THF) 4.74mmol) (20ml) solution is-10 ℃ of stirrings down.After 10 minutes, (275 μ l 3.56mmol) and with the mixture that forms stirred 30 minutes under identical condition to add methylsulfonyl chloride under identical temperature.In reaction mixture, pour saturated sodium bicarbonate aqueous solution into.Reaction mixture is merged with ethyl acetate extraction 2 times and with organic layer,, use anhydrous sodium sulfate drying, filter and concentrate with the saturated brine solution washing.Methylene dichloride (30ml) is joined in the resistates to form solution, under room temperature, add then 2-mercaptobenzimidazole (354mg, 2.36mmol).Then, add triethylamine (0.493ml, 3.54mmol) and add methyl alcohol and dissolve until 2-mercaptobenzimidazole.After reaction mixture at room temperature stirred 2 hours, NH silica gel is joined in the reaction mixture, concentrate then.Resistates is carried out silica gel column chromatography (eluting solvent: heptane/ethyl acetate=1/1, ethyl acetate) obtain title compound (690mg, yield: 73.6%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.61-1.70(2H，m)，2.13-2.25(4H，m)，2.22(3H，s)，3.77(2H，dd，J＝4，12Hz)，4.02(2H，dd，J＝2，12Hz)，4.44-4.48(1H，m)，4.68(2H，s)，6.97(1H，d，J＝6Hz)，7.07-7.13(2H，m)，7.37-7.50(2H，m)，8.21(1H，d，J＝6Hz)。
(9i) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 84]
Figure S2006800126056D00791
(((4-(5 to 2-that step (9h) obtains, 9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (290mg, 0.73mmol) toluene (30ml)/methyl alcohol (3ml) solution under-70 ℃, in nitrogen atmosphere, add 3-chlorine peroxybenzoic acid (174mg, 0.65mmol content is by 65%) toluene and methanol (10: 1) solution.Mixture is added saturated sodium bicarbonate aqueous solution after stirring 1 hour under-50 ℃.After mixture is warming up to room temperature, with mixture with ethyl acetate extraction 2 times.Organic layer is merged, use anhydrous sodium sulfate drying then, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate, ethyl acetate/methanol=9/1).The fraction that will contain title compound is collected and is concentrated with ethyl acetate.After joining diethyl ether in the resistates, steam solvent and obtain title compound (230mg, yield: 76.2%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.70(2H，m)，2.15(3H，s)，2.12-2.25(4H，m)，3.73-3.81(2H，m)，3.98-4.06(2H，m)，4.44-4.49(1H，m)，4.70(1H，d，J＝14Hz)，4.78(1H，d，J＝14Hz)，6.97(1H，d，J＝6Hz)，7.25-7.32(2H，m)，7.56-7.70(2H，m)，8.19(1H，d，J＝6Hz)。
(9j) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 85]
Figure S2006800126056D00801
(((4-(5 to 2-that step (9i) obtains; 9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (230mg; 0.56mmol) ethanol (20ml) solution under room temperature, add the 1N aqueous sodium hydroxide solution (0.56ml, 0.56mmol).The mixture stirring was concentrated in 1 hour then.After resistates and ethanol carried out component distillation 2 times, it is suspended in the diethyl ether, the solid by filtration that forms is collected and drying obtains title compound (190mg, yield: 91%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.70(2H，m)，2.13-2.27(4H，m)，2.22(3H，s)，3.74-3.81(2H，m)，3.99-4.06(2H，m)，4.37(1H，d，J＝13Hz)，4.42-4.50(1H，m)，4.85(1H，d，J＝13Hz)，6.82-6.88(2H，m)，6.94(1H，d，J＝6Hz)，7.40-7.46(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 10) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 86]
Figure S2006800126056D00811
(10a) 1,5,9-trioxa spiral shell [5.5] undecane-3-base methyl alcohol
[formula 87]
Figure S2006800126056D00812
With 2-(hydroxymethyl)-1, ammediol (3.3 g, 31.1mmol), tetrahydrochysene-4H-pyrans-4-ketone (3.12g, 31.2mmol), the tosic acid monohydrate (268mg, 1.41mmol) and benzene (68.3ml) in the flask that is equipped with prolong and Dean-Stark water trap, refluxed 6 hours.After being cooled to room temperature, triethylamine (1ml) being joined in the reaction mixture and mixture is concentrated.Resistates is obtained title compound (3.80g, yield: 64.9%), be water white oil by silica gel chromatography (silica gel: 200g, eluting solvent: heptane, heptane/ethyl acetate=1/1,1/3).
1H?NMR(400MHz，DMSO-d 6)δppm；1.67-1.82(5H，m)，3.35-3.42(2H，m)，3.49-3.57(4H，m)，3.65(2H，dd，J＝7，12Hz)，3.86(2H，dd，J＝4，12Hz)，4.56(1H，t，J＝5Hz)。
(10b) 2,3-dimethyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine 1-oxide compound
[formula 88]
Figure S2006800126056D00813
To step (10a) obtain 1,5, (3.80g adds the oil solution (content is by 60% for 770mg, 19.3mmol) of sodium hydride to 9-trioxa spiral shell [5.5] undecane-3-base methyl alcohol under room temperature in dimethyl sulfoxide (DMSO) 20.2mmol) (30ml) solution.Mixture was at room temperature stirred 30 minutes under nitrogen atmosphere.(2.6g 16.5mmol), stirs mixture 2.5 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.After being cooled to room temperature, reaction mixture is concentrated.Resistates is obtained title compound (3.38g, yield: 66.2%), be light yellow natural gum by silica gel chromatography (NH silica gel: 200g, eluting solvent: heptane, heptane/ethyl acetate=1/1,1/3, ethyl acetate, ethyl acetate/methanol=10/1).
1H?NMR(400MHz，DMSO-d 6)δppm；1.78(2H，t，J＝5Hz)，1.85(2H，t，J＝5Hz)，2.07-2.20(1H，m)，2.13(3H，s)，2.35(3H，s)，3.52-3.60(4H，m)，3.80(2H，dd，J＝6，12Hz)，4.04(2H，dd，J＝4，12Hz)，4.11(2H，d，J＝7Hz)，6.97(1H，d，J＝7Hz)，8.08(1H，d，J＝7Hz)。
(10c) (3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl alcohol
[formula 89]
Figure S2006800126056D00821
With step (10b) obtain 2, (3.31g, 10.7mmol) (30ml 331mmol) mixes 3-dimethyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine 1-oxide compound mutually with diacetyl oxide.Mixture was stirred 1 hour 55 minutes down at 85 ℃.After being cooled to room temperature, reaction mixture is concentrated.(30ml 150mmol) and with mixture at room temperature stirred 1 hour to add methyl alcohol (50ml) and 5N aqueous sodium hydroxide solution in resistates.Reaction mixture is concentrated and resistates is distributed between water and ethyl acetate.Organic layer is washed 2 times with the 1N aqueous sodium hydroxide washes, used anhydrous magnesium sulfate drying, filter and concentrated title compound (1.97g, the yield: 59.5%), be brown oil of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.78(2H，t，J＝5Hz)，1.85(2H，t，J＝5Hz)，2.09-2.20(1H，m)，2.12(3H，s)，3.50-3.62(4H，m)，3.82(2H，dd，J＝6，12Hz)，4.05(2H，dd，J＝4，12Hz)，4.14(2H，d，J＝7Hz)，4.53(2H，d，J＝6Hz)，4.99(1H，t，J＝6Hz)，6.97(1H，d，J＝6Hz)，8.24(1H，d，J＝6Hz)。
(10d) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 90]
Figure S2006800126056D00831
(3-methyl-the 4-(1 that obtains to step (10c), 5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) methyl alcohol (1.26g pyridine-2-yl), 4.07mmol) and triethylamine (1.13ml, 8.14mmol) methylene dichloride (anhydrous) (20ml) under 1 ℃ to 4 ℃, in 20 minutes, in nitrogen atmosphere, drip in the solution methylsulfonyl chloride (473 μ l, 6.11mmol).Mixture was stirred 40 minutes under identical condition.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution.With the water layer dichloromethane extraction.Organic layer is merged, use anhydrous sodium sulfate drying, filter and concentrate.With resistates and 2-mercaptobenzimidazole (595mg, 3.96mmol) mixing mutually.Mixture was stirred 17 hours 45 minutes under room temperature in methyl alcohol (15ml).NH silica gel (10g) is joined in the reaction mixture and mixture is concentrated.Resistates is carried out silica gel column chromatography (silica gel: 15g, eluting solvent: heptane/ethyl acetate=50/50,25/75, ethyl acetate, ethyl acetate/methanol=10/1) to obtain the mixture of title compound and 2-mercaptobenzimidazole.Mixture is further passed through silica gel chromatography (silica gel: 15g, eluting solvent: heptane/ethyl acetate=50/50,25/75, ethyl acetate, ethyl acetate/methanol=10/1).The oil that obtains is suspended in the hexane, concentrates and obtain title compound (994mg, yield; 56.8%), is colourless foam.
1H?NMR(400MHz，DMSO-d 6)δppm；1.78(2H，t，J＝5Hz)，1.85(2H，t，J＝5Hz)，2.10-2.20(1H，m)，2.22(3H，s)，3.52-3.60(4H，m)，3.82(2H，dd，J＝6，12Hz)，4.05(2H，dd，J＝4，12Hz)，4.15(2H，d，J＝7Hz)，4.70(2H，s)，6.99(1H，d，J＝6Hz)，7.09-7.16(2H，m)，7.38-7.53(2H，br)，8.25(1H，d，J＝6Hz)，12.62(1H?brs)。
(10e) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 91]
Figure S2006800126056D00841
2-(((3-methyl-the 4-(1 that obtains to step (10d), 5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfenyl methyl pyridine-2-yl)))-1H-benzoglyoxaline (974mg, 2.21mmol) toluene (30ml)-methyl alcohol (3ml) solution in in 5 minutes inherent nitrogen atmosphere, dripping 3-chlorine peroxybenzoic acid (528mg under-65 ℃, 1.99mmol content is by 65%) toluene (1ml)-methyl alcohol (1ml) solution.Mixture was stirred 55 minutes under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 20g, eluting solvent: methylene dichloride, methylene chloride=10/1).The fraction that will contain title compound is collected and is concentrated with ethyl acetate.After joining diethyl ether in the resistates, steam solvent and obtain title compound (725mg, yield: 71.7%), be light gray solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.78(2H，t，J＝5Hz)，1.85(2H，t，J＝5Hz)，2.05-2.21(1H，m)，2.14(3H，s)，3.48-3.62(4H，m)，3.81(2H，dd，J＝6，12Hz)，4.05(2H，dd，J＝4，12Hz)，4.15(2H，d，J＝7Hz)，4.71(1H，d，J＝14Hz)，4.80(1H，d，J＝14Hz)，6.99(1H，d，J＝6Hz)，7.26-7.36(2H，m)，7.58-7.72(2H，br)，8.23(1H，d，J＝6Hz)。
(10f) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 92]
2-(((3-methyl-the 4-(1 that obtains to step (10e); 5; 9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfinyl methyl pyridine-2-yl)))-1H-benzoglyoxaline (708mg; 1.55mmof) ethanol (15ml) solution under room temperature, add 1N aqueous sodium hydroxide solution (1.54ml; 1.55mmol concentration is 1.004M) and mixture is concentrated.Resistates and ethanol are carried out component distillation 2 times.Resistates is suspended with diethyl ether, and supersound process leaves standstill then and supernatant liquor is removed.This washing process is repeated 2 times again.The resistates drying under reduced pressure is obtained title compound (635mg, yield: 85.4%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.79(2H，t，J＝5Hz)，1.85(2H，t，J＝5Hz)，2.10-2.23(1H，m)，2.19(3H，s)，3.50-3.62(4H，m)，3.78-3.87(2H，m)，4.05(2H，dd，J＝4，12Hz)，4.14(2H，d，J＝7Hz)，4.40(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，6.82-6.90(2H，m)，6.96(1H，d，J＝6Hz)，7.42-7.48(2H，m)，8.29(1H，d，J＝6Hz)。
(embodiment 11) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_80
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 93]
Figure S2006800126056D00851
(11a) (2,2-dimethyl-1,3-two
Figure 2006800126056_81
Alkane-5-yl) methyl alcohol
[formula 94]
Figure S2006800126056D00852
With 2-(hydroxymethyl)-1, and ammediol (4.09g, 38.5mmol), (130ml, 1768mmol) (1.37g, mixture 9.55mmol) at room temperature stirred 21 hours acetone with 70% perchloric acid.The pH of reaction mixture is adjusted to 9 with strong aqua, reaction mixture is concentrated.Resistates is obtained title compound (4.83g, yield: 85.8%), be water white oil by silica gel chromatography (silica gel: 100g, eluting solvent: heptane, heptane/ethyl acetate=1/3).
1H?NMR(400MHz，DMSO-d 6)δppm；1.29(3H，s)，1.30(3H，s)，1.64-1.74(1H，m)，3.35-3.41(2H，m)，3.61(2H，dd，J＝7，12Hz)，3.82(2H，dd，J＝4，12Hz)，4.54(1H，t，J＝5Hz)。
(11b) 2,3,5-trimethylpyridine 1-oxide compound
[formula 95]
Figure S2006800126056D00861
To 2,3, (11.0g, methylene dichloride 90.8mmol) (anhydrous) (150ml) add 3-chlorine peroxybenzoic acid (content is by 65% for 24.8g, 93.4mmol) in the solution to the 5-collidine in nitrogen atmosphere under 1 ℃.Mixture is stirred, in 13.5 hours, temperature is warming up to room temperature gradually simultaneously.After reaction mixture concentrated, resistates is obtained the crude product of title compound by silica gel chromatography (NH silica gel: 200g, eluting solvent: heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=20/1), be light yellow oil.After crude product usefulness ethyl acetate and saturated sodium bicarbonate aqueous solution dilution, mixture is concentrated.Resistates is obtained title compound (11.0g, yield: 88.3%), be white solid by silica gel chromatography (NH silica gel: 300g, eluting solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=20/1).
1H?NMR(400MHz，DMSO-d 6)δppm；2.15(3H，s)，2.23(3H，s)，2.27(3H，s)，6.97(1H，s)，7.99(1H，s)。
(11c) 2,3,5-trimethylammonium-4-nitropyridine 1-oxide compound
[formula 96]
With step (11b) obtain 2,3, (11.0g, 80.2mmol) (34.1g 348mmol) mixes 5-trimethylpyridine 1-oxide compound mutually with sulfuric acid.At room temperature (5.50ml 133mmol) is added drop-wise in this mixture, and mixture was stirred 9 hours down at 80 ℃ with nitrosonitric acid.Reaction mixture is cooled to room temperature, pours in the ice then.To obtain aqueous solution chloroform extraction 3 times, organic layer will be merged, use anhydrous magnesium sulfate drying then, filter and concentrated title compound (13.6g, the yield: 93.1%), be yellow solid of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；2.16(3H，s)，2.20(3H，s)，2.36(3H，s)，8.35(1H，s)。
(11d) the 4-chloro-2,3,5-trimethylpyridine 1-oxide compound
[formula 97]
Figure S2006800126056D00871
With step (11c) obtain 2,3,5-trimethylammonium-4-nitropyridine 1-oxide compound (13.4g, 73.6mmol) under-30 ℃, in nitrogen atmosphere, join Acetyl Chloride 98Min. (80ml, 1,125mmol) in.Mixture was stirred 4 hours 20 minutes to room temperature at-30 ℃.After reaction mixture concentrated, resistates is carried out silica gel column chromatography (NH silica gel: 300g, eluting solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=10/1) obtain containing title compound pure products fraction and contain the fraction of the crude product of title compound.
The fraction that will contain the crude product of title compound concentrates.Resistates is suspended in the ethyl acetate and the throw out that forms is collected by filtering, wash with ethyl acetate and diethyl ether and obtain title compound (Lot A 1.58g), is white solid.Filtrate is concentrated.Resistates is dissolved in chloroform,, uses anhydrous sodium sulfate drying, filter and concentrate with the saturated sodium bicarbonate aqueous solution washing.Resistates is suspended in the diethyl ether.The throw out that forms is collected by filtering, and (Lot B 2.69g), is the light brown solid to obtain title compound with the diethyl ether washing.
The fraction that will contain the pure products of title compound concentrates.Resistates is dissolved in chloroform,, use anhydrous sodium sulfate drying, filter and concentratedly obtain title compound (LotC 6.56g), is shallow white solid with saturated sodium bicarbonate aqueous solution washing.
The total recovery of 3 parts of gained title compounds is 85.7%.
Lot?A： 1H?NMR(400MHz，DMSO-d 6)δppm；2.24(3H，s)，2.35(3H，s)，2.39(3H，s)，8.25(1H，s)。
Lot?B： 1H?NMR(400MHz，DMSO-d 6)δppm；2.24(3H，s)，2.35(3H，s)，2.39(3H，s)，8.25(1H，s)。
Lot?C： 1H?NMR(400MHz，DMSO-d 6)δppm；2.24(3H，s)，2.35(3H，s)，2.39(3H，s)，8.25(1H，s)。
(11e) 4-((2,2-dimethyl-1,3-two
Figure 2006800126056_82
Alkane-5-yl) methoxyl group)-2,3,5-trimethylpyridine 1-oxide compound
[formula 98]
Figure S2006800126056D00881
To step (11a) obtain (2,2-dimethyl-1,3-two
Figure 2006800126056_83
Alkane-5-yl) (4.78g adds the oil solution (1,26g, 31.5mmol, content is by 60%) of sodium hydride to methyl alcohol under room temperature in dimethyl sulfoxide (DMSO) 32.7mmol) (50ml) solution.Mixture was at room temperature stirred 15 minutes in nitrogen atmosphere.Add the 4-chloro-2,3 that step (11d) obtains in mixture, (Lot C, 4.50g 26.2mmol) and with mixture stirred 8 hours 10 minutes down at 60 ℃ 5-trimethylpyridine 1-oxide compound.After being cooled to room temperature, reaction mixture is concentrated.Resistates is obtained title compound (5.06g, yield: 68.6%), be yellow oil by silica gel chromatography (NH silica gel: 300g, eluting solvent: heptane, heptane/ethyl acetate=1/1,1/3, ethyl acetate, ethyl acetate/methanol=10/1).
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.13(1H，m)，2.14(3H，s)，2.17(3H，s)，2.31(3H，s)，3.77-3.86(4H，m)，4.01(2H，dd，J＝4，12Hz)，8.07(1H，s)。
(11f) (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_84
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl alcohol
[formula 99]
Figure S2006800126056D00891
The 4-that step (11e) is obtained ((2,2-dimethyl-1,3-two
Figure 2006800126056_85
Alkane-5-yl) methoxyl group)-2,3, (5.06g, 18mmol) (50ml 529mmol) mixes and mixture was stirred 1.5 hours down at 85 ℃ 5-trimethylpyridine 1-oxide compound mutually with diacetyl oxide.After being cooled to room temperature, reaction mixture is concentrated.(50ml 250mmol) joins in the resistates and with mixture and at room temperature stirred 30 minutes with methyl alcohol (50ml) and 5N aqueous sodium hydroxide solution.Reaction mixture is concentrated and resistates is distributed between water and ethyl acetate.Organic layer is washed 2 times with the 1N aqueous sodium hydroxide washes, used anhydrous magnesium sulfate drying then, filter and concentrated title compound (3.02g, the yield: 59.6%), be brown oil of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.37(3H，s)，2.05-2.16(1H，m)，2.20(6H，s)，3.82(2H，dd，J＝6，12Hz)，3.86(2H，d，J＝8Hz)，4.02(2H，dd，J＝4，12Hz)，4.51(2H，d，J＝6Hz)，4.98(1H，t，J＝6Hz)，8.16(1H，s)。
(11g) 2-(((4-((and 2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 100]
Figure S2006800126056D00892
To step (11f) obtain (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_87
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl alcohol (504mg, 1.79mmol) and triethylamine (500 μ l, under 1 ℃ to 3 ℃, in 15 minutes, in nitrogen atmosphere, drip in tetrahydrofuran (THF) 3.58mmol) (15ml) solution methylsulfonyl chloride (208 μ l, 2.69mmol).Reaction mixture was stirred under identical condition 1 hour 25 minutes.(271mg at room temperature stirred mixture 64 hours 20 minutes after 1.8mmol) to add 2-mercaptobenzimidazole.Reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.Resistates is obtained title compound (442mg, yield: 59.7%), be colourless foam by silica gel chromatography (silica gel: 30g, eluting solvent: heptane/ethyl acetate=42/58,22/78, ethyl acetate).
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.16(1H，m)，2.20(3H，s)，2.28(3H，s)，3.81(2H，dd，J＝6，12Hz)，3.87(2H，d，J＝7Hz)，4.02(2H，dd，J＝4，12Hz)，4.69(2H，s)，7.09-7.16(2H，m)，7.41-7.50(2H，m)，8.18(1H，s)。
(11h) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_88
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline
[formula 101]
The 2-that obtains to step (11g) (((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_89
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) sulfenyl methyl))-1H-benzoglyoxaline (424mg, 1.03mmol) toluene (20ml)-methyl alcohol (2ml) solution in 5 minutes, in nitrogen atmosphere, dripping 3-chlorine peroxybenzoic acid (246mg under-65 ℃, 0.927mmol content is by 65%) toluene (1ml)-methyl alcohol (1ml) solution.Mixture was stirred 45 minutes under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution and with the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 20g, eluting solvent: methylene dichloride, methylene chloride=10/1).The fraction that will contain title compound is collected and is concentrated with ethyl acetate.In resistates, add diethyl ether.The throw out that forms is obtained title compound (274mg, yield: 61.9%), be white solid by the filtration collection and with the diethyl ether washing.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.36(3H，s)，2.02-2.13(1H，m)，2.16(3H，s)，2.20(3H，s1)，3.74-3.84(4H，m)，4.00(2H，dd，J＝4，12Hz)，4.70(1H，d，J＝14Hz)，4.79(1H，d，J＝14Hz)，7.26-7.33(2H，m)，7.60-7.70(2H，m)，8.18(1H，s)。
(11i) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_90
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 102]
Figure S2006800126056D00911
The 2-that obtains to step (11h) (((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_91
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-1H-benzoglyoxaline (274mg; 0.638mmol) ethanol (10ml) solution under room temperature, add 1N aqueous sodium hydroxide solution (concentration is by 1.004M for 635 μ l, 0.638mmol) and mixture concentrated.With resistates and ethanol component distillation 2 times.After being suspended in resistates in the diethyl ether, with mixture with supersound process and concentrate and to obtain title compound (260mg, yield: 90.3%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.03-2.14(1H，m)，2.20(3H，s)，2.21(3H，s)，3.76-3.87(4H，m)，4.00(2H，dd，J＝4，11Hz)，4.39(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.81-6.91(2H，m)，7.40-7.48(2H，m)，8.23(1H，s)。
(embodiment 12) 2-(((4-((2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 103]
Figure S2006800126056D00912
(12a) 4-((2,2-dimethyl-1,3-two
Figure 2006800126056_93
Alkane-5-yl) methoxyl group)-2,3 dimethyl pyridine 1-oxide compound
[formula 104]
Figure S2006800126056D00921
To obtain according to the mode identical with the step (11a) of embodiment 11 (2,2-dimethyl-1,3-two Alkane-5-yl) (3.27g adds the oil solution (content is by 60% for 837mg, 20.9mmol) of sodium hydride to methyl alcohol under room temperature in dimethyl sulfoxide (DMSO) 22.4mmol) (30ml) solution.Mixture was at room temperature stirred 15 minutes in nitrogen atmosphere.(3.03g 19.2mmol) and with mixture stirred 3 hours 20 minutes down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.After being cooled to room temperature, reaction mixture is concentrated.Resistates is obtained title compound (3.84g, yield: 74.8%), be the light brown solid by silica gel chromatography (NH silica gel: 250g, eluting solvent: ethyl acetate, ethyl acetate/methanol=10/1).
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，1.35(3H，s)，2.00-2.12(1H，m)，2.12(3H，s)，2.33(3H，s)，3.74(2H，dd，J＝6，12Hz，3.97(2H，dd，J＝4，12Hz)，4.08(2H，d，J＝7Hz)，6.94(1H，d，J＝7Hz)，8.05(1H，d，J＝7Hz)。
(12b) (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_95
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol
[formula 105]
Figure S2006800126056D00922
The 4-that step (12a) is obtained ((2,2-two. and methyl isophthalic acid, 3-two
Figure 2006800126056_96
Alkane-5-yl) methoxyl group)-(3.84g, 14.4mmol) (50ml 530mmol) mixes 2,3 dimethyl pyridine 1-oxide compound mutually with diacetyl oxide.Mixture was stirred 1.5 hours down at 85 ℃.After being cooled to room temperature, reaction mixture is concentrated.(20ml 100mmol) and with mixture at room temperature stirred 2.5 hours to add methyl alcohol (50ml) and 5N aqueous sodium hydroxide solution in resistates.Reaction mixture is concentrated and resistates is distributed between water and ethyl acetate.Organic layer is washed 2 times with the 1N aqueous sodium hydroxide washes, used anhydrous sodium sulfate drying, filter and concentrated title compound (2.97g, the yield: 77.2%), be brown solid of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，1.34(3H，s)，2.03-2.14(1H，m)，2.10(3H，s)，3.76(2H，dd，J＝6，12Hz)，3.98(2H，dd，J＝4，12Hz)，4.10(2H，d，J＝7Hz)，4.51(2H，d，J＝5Hz)，4.97(1H，t，J＝5Hz)，6.95(1H，d，J＝6Hz)，8.22(1H，d，J＝6Hz)。
(12c) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_97
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 106]
To step (12b) obtain (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_98
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol (1.03g, 3.85mmol) and triethylamine (1.07ml, 7.7mmol) methylene dichloride (anhydrous) (20ml) under 1 ℃ to 4 ℃, in 10 minutes, in nitrogen atmosphere, drip in the solution methylsulfonyl chloride (447 μ l, 5.78mmol).Mixture was stirred under identical condition 1 hour 25 minutes.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution.With the water layer dichloromethane extraction.Organic layer is merged, use anhydrous sodium sulfate drying, filter and concentrate.(586mg 3.9mmol) mixes mutually and mixture was stirred 2 hours 40 minutes under room temperature in methyl alcohol (20ml) with resistates and 2-mercaptobenzimidazole.(15g) joins in the reaction mixture with NH silica gel, concentrates then.Resistates is carried out the mixture that silica gel column chromatography (NH silica gel: 20g, eluting solvent: heptane/ethyl acetate=1/1,1/3, ethyl acetate) obtains title compound and 2-mercaptobenzimidazole.Mixture is further obtained title compound (771mg, yield: 50.1%), be colourless foam by silica gel chromatography (silica gel: 30g, eluting solvent: heptane/ethyl acetate=50/50,25/75, ethyl acetate).
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，1.34(3H，s)，2.03-2.15(1H，m)，2.20(3H，s)，3.76(2H，dd，J＝6，12Hz)，3.98(2H，dd，J＝4，12Hz)，4.11(2H，d，J＝7Hz)，4.68(2H，s)，6.97(1H，d，J＝6Hz)，7.06-7.14(2H，m)，7.35-7.51(2H，br)，8.23(1H，d，J＝6Hz)，12.60(1H，brs)。
(12d) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_99
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline
[formula 107]
Figure S2006800126056D00941
The 2-that obtains to step (12c) (((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_100
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (766mg, 1.92mmol) toluene (45ml)-methyl alcohol (5ml) solution in 5 minutes, in nitrogen atmosphere, dripping 3-chlorine peroxybenzoic acid (459mg under-65 ℃, 1.73mmol content is by 65%) toluene (0.5ml)-methyl alcohol (0.5ml) solution.Mixture was stirred under identical condition 1 hour 20 minutes.In reaction mixture, add saturated sodium bicarbonate aqueous solution.With water layer ethyl acetate and chloroform extraction (3 times).Organic layer is merged, use anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 30g, eluting solvent: methylene dichloride, methylene chloride=20/1).Collection contains the fraction of title compound, concentrates to obtain title compound (688mg, yield: 86.2%), be the light brown foam.
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，1.34(3H，s)，2.03-2.12(1H，m)，2.12(3H，s)，3.75(2H，dd，J＝6，12Hz)，3.98(2H，dd，J＝4，12Hz)，4.11(2H，d，J＝7Hz)，4.69(1H，d，J＝14Hz)，4.78(1H，d，J＝14Hz)，6.97(1H，d，J＝6Hz)，7.24-7.34(2H，m)，7.57-7.70(2H，m)，8.20(1?H，d，J＝6Hz)。
(12e) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_101
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 108]
Figure S2006800126056D00951
The 2-that obtains to step (12d) (((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_102
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (688mg; 1.66mmol) ethanol (10ml) solution under room temperature, add 1N aqueous sodium hydroxide solution (1.65ml; 1.66mmol concentration is by 1.004M) and mixture is concentrated.Resistates and ethanol are carried out component distillation 2 times.After being suspended in resistates in the diethyl ether, with mixture with supersound process and leave standstill.Remove supernatant liquor then.This washing process is continued to repeat 2 times and the resistates drying under reduced pressure is obtained title compound (701mg, yield: 96.5%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.34(3H，s)，2.04-2.13(1H，m)，2.17(3H，s)，3.72-3.81(2H，m)，3.98(2H，dd，J＝4，12Hz)，4.10(2H，d，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.76(1H，d，J＝13Hz)，6.80-6.89(2H，m)，6.94(1H，d，J＝5Hz)，7.39-7.47(2H，m)，8.28(1H，d，J＝5Hz)。
(embodiment 13) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 109]
(13a) 5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base methyl alcohol
[formula 110]
Figure S2006800126056D00961
With 2-(hydroxymethyl)-1, ammediol (5.58g, 52.6mmol), cyclobutanone (3.69g, 52.6mmol), the tosic acid monohydrate (550mg, 2.89mmol) and the mixture of benzene (92.9ml) in the round-bottomed flask that is equipped with prolong and Dean-Stark water trap, refluxed 8 hours 35 minutes.After reaction mixture is cooled to room temperature, triethylamine (1ml) joined in the reaction mixture and with mixture concentrates.Resistates is passed through silica gel chromatography (silica gel: 300g, eluting solvent: heptane, heptane/ethyl acetate=1/1).The fraction that will contain title compound is collected and is concentrated with ethyl acetate.Resistates is dissolved in diethyl ether, mixture is concentrated obtain title compound (6.08g, yield: 73.1%), be light yellow oil then.
1H?NMR(400MHz，DMSO-d 6)δppm；1.58-1.68(2H，m)，1.68-1.77(1H，m)，2.07-2.16(4H，m)，3.32-3.39(2H，m)，3.52(2H，dd，J＝7，12Hz)，3.78(2H，dd，J＝4，12Hz)，4.56(1H，t，J＝5Hz)。
(13b) 4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-2,3,5-trimethylpyridine 1-oxide compound
[formula 111]
Figure S2006800126056D00962
To step (13a) obtain 5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base methyl alcohol, (2.20g added the oil solution (content is by 60% for 524mg, 13.1mmol) of sodium hydride under room temperature in dimethyl sulfoxide (DMSO) 13.9mmol) (20ml) solution.Mixture was at room temperature stirred 45 minutes in nitrogen atmosphere.The 4-chloro-2,3 that the step (11d) of adding embodiment 11 obtains in mixture, (LotC, 1.94g 11.3mmol), stir mixture 2 hours 50 minutes down at 60 ℃ 5-trimethylpyridine 1-oxide compound.After being cooled to room temperature, reaction mixture is concentrated.Resistates is obtained title compound (1.97g, yield: 59.4%), be brown oil by silica gel chromatography (NH silica gel: 100g, eluting solvent: heptane, heptane/ethyl acetate=1/1, ethyl acetate, ethyl acetate/methanol=20/1).
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.71(2H，m)，2.07-2.22(5H，m)，2.12(3H，s)，2.16(3H，s)，2.30(3H，s)，3.74(2H，dd，J＝7，12Hz)，3.78(2H，d，J＝7Hz)，3.94(2H，dd，J＝4，12Hz)，8.05(1H，s)。
(13c) (4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) methyl alcohol
[formula 112]
Figure S2006800126056D00971
The 4-that step (13b) is obtained (5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-2,3, (1.97g, 6.72mmol) (20ml 212mmol) mixes 5-trimethylpyridine 1-oxide compound mutually with diacetyl oxide.Mixture was stirred 1.5 hours down at 85 ℃.After being cooled to room temperature, reaction mixture is concentrated.(20ml 100mmol) and with mixture at room temperature stirred 45 minutes to add methyl alcohol (20ml) and 5N aqueous sodium hydroxide solution in resistates.Reaction mixture is concentrated and resistates is distributed between water and ethyl acetate.Organic layer is washed with the 2N aqueous sodium hydroxide washes, used anhydrous magnesium sulfate drying, filter and concentrated title compound (1.69g, the yield: 85.7%), be brown oil of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.70(2H，m)，2.08-2.25(5H，m)，2.18(6H，s)，3.75(2H，dd，J＝6，12Hz)，3.83(2H，d，J＝7Hz)，3.95(2H，dd，J＝4，12Hz)，4.50(2H，d，J＝5Hz)，4.97(1H，t，J＝5Hz)，8.14(1H，s)。
(13d) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 113]
To step (13c) obtain (4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) methyl alcohol (450mg, 1.53mmol) and triethylamine (427 μ l, 3.06mmol) methylene dichloride (anhydrous) (15ml) and under 1 ℃ to 4 ℃, in 10 minutes, in nitrogen atmosphere, drip in tetrahydrofuran (THF) (5ml) solution methylsulfonyl chloride (178 μ l, 2.3mmol).Mixture was stirred 50 minutes under identical condition.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution.With the water layer dichloromethane extraction.Organic layer is merged, use anhydrous sodium sulfate drying, filter and concentrate.(235mg 1.56mmol) mixes mutually and mixture was at room temperature stirred in methyl alcohol (20ml) 2 hours 30 minutes with resistates and 2-mercaptobenzimidazole.(15g) joins in the reaction mixture with NH silica gel, concentrates then.Resistates is carried out silica gel column chromatography (silica gel: 30g, eluting solvent: heptane/ethyl acetate=42/58,22/78, ethyl acetate) obtain title compound (507mg, yield: 77.9%), be colourless foam.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.71(2H，m)，2.08-2.22(5H，m)，2.19(3H，s)，2.28(3H，s)，3.76(2H，dd，J＝6，12Hz)，3.84(2H，d，J＝7Hz)，3.95(2H，dd，J＝4，12Hz)，4.69(2H，s)，7.06-7.19(2H，m)，7.37-7.56(2H，br)，8.18(1H，s)，12.60(1H，brs)。
(13e) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 114]
(((4-(5 to 2-that step (13d) obtains, 9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) sulfenyl methyl))-1H-benzoglyoxaline (499mg, 1.17mmol) toluene (20ml)-methyl alcohol (2ml) solution in 5 minutes, in nitrogen atmosphere, dripping 3-chlorine peroxybenzoic acid (280mg under-65 ℃, 1.05mmol content is by 65%) toluene (1ml)-methyl alcohol (1ml) solution.Mixture was stirred 55 minutes under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution.With the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 20g, eluting solvent: methylene dichloride, methylene chloride=20/1).The fraction that will contain title compound is collected and is concentrated with ethyl acetate.In resistates, add diethyl ether, mixture is concentrated obtain title compound (445mg, yield: 86.1%), be colourless foam then.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.70(2H，m)，2.06-2.23(5H，m)，2.14(3H，s)，2.18(3H，s)，3.67-3.82(4H，m)，3.93(2H，dd，J＝4，12Hz)，4.70(1H，d，J＝14Hz)，4.78(1H，d，J＝14Hz)，7.25-7.34(2H，m)，7.58-7.70(2H，m)，8.18(1H，s)。
(13f) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3,5-lutidine-2-yl) methyl) sulfinyl)-1 H-benzoglyoxaline sodium salt
[formula 115]
Figure S2006800126056D00991
(((4-(5 to 2-that step (13e) obtains; 9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3; 5-lutidine-2-yl) sulfinyl methyl))-1H-benzoglyoxaline (445mg; 1.01mmol) ethanol (10ml) solution under room temperature, add 1N aqueous sodium hydroxide solution (1.01ml; 1.01mmol concentration is by 1.004M) and mixture is concentrated.Resistates and ethanol are carried out component distillation 2 times.After resistates suspended with diethyl ether, with mixture with supersound process and concentrate and obtain title compound (420mg, yield: 89.7%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.58-1.70(2H，m)，2.07-2.25(5H，m)，2.19(6H，s)，3.68-3.82(4H，m)，3.94(2H，dd，J＝4，12Hz)，4.34-4.41(1H，m)，4.70-4.77(1H，m)，6.82-6.89(2H，m)，7.41-7.47(2H，m)，8.22(1H，s)。
(embodiment 14) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 116]
Figure S2006800126056D01001
(14a) 4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-2,3 dimethyl pyridine 1-oxide compound
[formula 117]
Figure S2006800126056D01002
(4.87g adds the oil solution (content is by 55% for 1.73g, 39.6mmol) of sodium hydride under room temperature in dimethyl sulfoxide (DMSO) 39.7mmol) (48ml) solution to ((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methyl alcohol.(4.8g 30.5mmol), stirs mixture 2 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.After being cooled to room temperature, with the reaction mixture concentrating under reduced pressure.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (10.5g, yield: 136%), be yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.40(3H，s)，1.45(3H，s)，2.21(3H，s)，2.54(3H，s)，3.93(1H，dd，J＝6，8Hz)，4.01(1H，dd，J＝5，10Hz)，4.07(1H，dd，J＝5，10Hz)，4.17(1H，dd，J＝6，8Hz)，4.48(1H，quint，J＝6Hz)，6.65(1H，d，J＝8Hz)，8.15(1H，d，J＝8Hz)。
(14b) (4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl alcohol
[formula 118]
Figure S2006800126056D01011
(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-(10.5g 41.5mmol) mixes with diacetyl oxide (20ml) 2,3 dimethyl pyridine 1-oxide compound the 4-that step (14a) is obtained mutually.Mixture was stirred 1 hour down at 80 ℃.After being cooled to room temperature, with the reaction mixture concentrating under reduced pressure.In resistates, add methyl alcohol (40ml) and 5N aqueous sodium hydroxide solution (20ml) and mixture was at room temperature stirred 1.5 hours.Reaction mixture is concentrated and resistates is distributed between saturated brine solution and ethyl acetate.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate and with resistates by silica gel chromatography (eluting solvent: ethyl acetate/methanol) obtain title compound (3.77g, yield: 41.9%), be yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.41(3H，s)，1.46(3H，s)，2.05(3H，s)，3.95(1H，dd，J＝6，8Hz)，4.03(1H，dd，J＝5，10Hz)，4.1?1(1H，dd，J＝5，10Hz)，4.18(1H，dd，J＝6，8Hz)，4.49(1H，quint，J＝6Hz)，4.65(2H，s)，4.84(1H，bs)，6.71(1H，d，J＝8Hz)，8.29(1H，d，J＝8Hz)。
(14c) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 119]
Figure S2006800126056D01012
To (4-(((4R)-2 that step (14b) obtains, 2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol (3.77g, 14.9mmol) and triethylamine (4.15ml, 29.8mmol) tetrahydrofuran (THF) (anhydrous) (50ml) under the cooling of ice, in nitrogen atmosphere, drip methylsulfonyl chloride in the solution (1.73ml 22.4mmol) and with mixture stirred 1.5 hours under identical condition.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.With organic layer with anhydrous magnesium sulfate drying and steam solvent.(3.8g, the yield of crude product: take out 1.2g (3.62mmol) 77%), be dissolved in ethanol (20ml) then, (598mg 3.98mmol) and with mixture at room temperature stirred 14 hours to wherein adding 2-mercaptobenzimidazole from the resistates that obtains.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: heptane/ethyl acetate) obtain title compound (580mg, yield: 41.6%), be light yellow foam.
1H?NMR(400MHz，CD 3?OD)δppm；1.37(3H，s)，1.39(3H，s)，2.33(3H，s)，3.94(1H，dd，J＝6，8Hz)，4.19(1H，dd，J＝6，8Hz)，4.32(1H，dd，J＝5，11Hz)，4.40(1H，dd，J＝4，11Hz)，4.52-4.60(1H，m)，4.75(2H，s)，7.25(2H，dd，J＝3，6Hz)，7.39(1H，d，J＝8Hz)，7.53(2H，dd，J＝3，6Hz)，8.47(1H，d，J＝8Hz)。
(14d) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 120]
Figure S2006800126056D01021
To 2-(((4-(((4R)-2 that step (14c) obtains, 2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (580mg, 1.5mmol) toluene-methyl alcohol (10: 1) (22ml) under-50 ℃ to-60 ℃, in 5 minutes, in nitrogen atmosphere, drip 3-chlorine peroxybenzoic acid (353mg in the solution, 1.33mmol content is by 65%) (11ml) solution of toluene-methyl alcohol (10: 1).Mixture was stirred 3 hours under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.Organic layer concentrated and with resistates by silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (330mg, yield: 54.8%), be light yellow foam.This compound is changed into sodium salt and confirms its structure according to following operation.
(14e) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 121]
Figure S2006800126056D01031
To 2-(((4-(((4R)-2 that step (14d) obtains; 2-dimethyl-1; 3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (330mg; 822 μ mol) under room temperature, add 1N aqueous sodium hydroxide solution (822 μ l, 822 μ mol) in ethanol (6ml) solution and mixture was stirred 30 minutes.After mixture concentrated diethyl ether is joined in the resistates, with the mixture supersound process.The solid that produces is collected by filtering under nitrogen atmosphere.The solid drying under reduced pressure is obtained title compound (314mg, yield: 90.2%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.30(3H，s)，1.36(3H，s)，2.19(3H，s)，3.80(1H，dd，J＝6，8Hz)，4.02-4.14(3H，m)，4.37(1H，d，J＝14Hz)，4.43(1H，quint，J＝6Hz)，4.79(1H，d，J＝14Hz)，6.83(2H，dd，J＝3，6Hz)，6.93(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.36(1H，d，J＝6Hz)。
(14f) optically active isomer of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is short)
[formula 122]
Figure S2006800126056D01032
To 2-(((4-(((4R)-2 that step (14c) obtains, 2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (84mg, 218 μ mol) toluene (anhydrous) (0.5ml) and water (1.73 μ l, 95.9 add L (+)-diethyl tartrate (32.9 μ l, 192 μ mol) in mixing solutions μ mol) and under 50 ℃, in nitrogen atmosphere, stirred 15 minutes.Titanium isopropylate (IV) (28.3 μ l, 95.9 μ mol) joined in the reaction mixture and continue stirred 1 hour.Reaction mixture after cooled on ice, is dripped N in nitrogen atmosphere, N-diisopropyl ethyl amine (33.4 μ l, 192 μ mol) and cumene hydroperoxide (content is by 80% for 121 μ l, 654mmol) also stirred 17 hours to the room temperature at 0 ℃.Join saturated sodium bicarbonate aqueous solution in the reaction mixture and with the mixture ethyl acetate extraction.Organic layer is steamed solvent with anhydrous sodium sulfate drying and decompression.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (45mg, yield: 51.4%), be light yellow foam.This compound is changed into sodium salt and confirms its structure according to following operation.
(14g) sodium salt of the optically active isomer of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is short)
[formula 123]
Figure S2006800126056D01041
To 2-(((4-(((4R)-2 that step (14f) obtains; 2-dimethyl-1; 3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (45mg; under room temperature, add 1N aqueous sodium hydroxide solution (112 μ l, 112 μ mol) in ethanol (3ml) solution of optically active isomer 112 μ mol) (retention time short) and mixture was stirred 30 minutes.After mixture concentrated and joining diethyl ether in the resistates, with the mixture supersound process.The solid that produces is collected by filtering under nitrogen atmosphere.The solid drying under reduced pressure is obtained title compound (22mg, yield: 46.4%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.30(3H，s)，1.35(3H，s)，2.19(3H，s)，3.80(1H，dd，J＝6，8Hz)，4.02-4.14(3H，m)，4.37(1H，d，J＝13Hz)，4.42(1H，quint，J＝5Hz)，4.79(1H，d，J＝13Hz)，6.83(2H，dd，J＝3，6Hz)，6.93(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.3ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 31.6 minutes, diastereomeric excess: 92%de
(14h) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline optically active isomer (retention time is long)
[formula 124]
Figure S2006800126056D01051
To 2-(((4-(((4R)-2 that step (14c) obtains, 2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (170mg, 441 μ mol) toluene (anhydrous) (1.0ml) and water (3.5 μ l, 194 μ mol) add D-(-)-diethyl tartrate (66.6 μ l, 389 μ mol) and under 50 ℃, in nitrogen atmosphere, stirring 15 minutes in the solution.In reaction mixture, add titanium isopropylate (IV) (57.3 μ l, 194 μ mol) and continue and stirred 1 hour.With reaction mixture after cooled on ice, with N, N-diisopropyl ethyl amine (67.6 μ l, 389 μ mol) join in the reaction mixture, then in nitrogen atmosphere to wherein dripping cumene hydroperoxide (245 μ l, 1.32mmol content is by 80%) and mixture stirred 17 hours to the room temperature at 0 ℃.Join saturated sodium bicarbonate aqueous solution in the reaction mixture and use ethyl acetate extraction.With organic layer with dried over sodium sulfate after, decompression steams solvent.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (104mg, yield: 58.7%), be light yellow foam.This compound is changed into sodium salt and confirms its structure according to following operation.
(14i) sodium salt of the optically active isomer of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is long)
[formula 125]
Figure S2006800126056D01061
To 2-(((4-(((4R)-2 that step (14h) obtains; 2-dimethyl-1; 3-dioxolane-4-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (104mg; under room temperature, add 1N aqueous sodium hydroxide solution (259 μ l, 259 μ mol) in ethanol (3ml) solution of optically active isomer 259 μ mol) (retention time long) and mixture was stirred 30 minutes.Mixture is concentrated, join diethyl ether in the resistates after, with the mixture supersound process.The solid that produces is collected by filtering under nitrogen atmosphere.The solid drying under reduced pressure is obtained title compound (99mg, yield: 90%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.30(3H，s)，1.35(3H，s)，2.19(3H，s)，3.80(1H，dd，J＝6，8Hz)，4.02-4.14(3H，m)，4.37(1H，d，J＝13Hz)，4.42(1H，quint，J＝5Hz)，4.79(1H，d，J＝13Hz)，6.82-6.88(2H，m)，6.93(1H，d，J＝6Hz)，7.38-7.46(2H，m)，8.26(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.3ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 35.9 minutes, diastereomeric excess: 89%de.
(embodiment 15) 2-(((4-((5,5-dimethyl-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-sodium salt of the optically active isomer of 1H-benzoglyoxaline (retention time is long)
[formula 126]
Figure S2006800126056D01062
(15a) 2-(((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_104
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-optically active isomer of 1H-benzoglyoxaline (retention time is long)
[formula 127]
Figure S2006800126056D01071
Will according to the 2-that obtains with the identical mode of step (1a) to (1e) of embodiment 1 (((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_105
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (250mg, 0.626mmol) toluene (anhydrous) (2.8ml)-water (1.4 μ l, 0.0777mmol) (47 μ l 0.275mmol) stirred 30 minutes in nitrogen atmosphere under 50 ℃ for suspension and D-(-)-diethyl tartrate.Adding toluene (anhydrous) in mixture (1.2ml) and under identical condition stirred 30 minutes.(37 μ l 0.125mmol) and with the mixture that forms stirred 1 hour under identical condition to add titanium isopropylate (IV).Be cooled to room temperature and with N, the N-diisopropyl ethyl amine (35 μ l, 0.201mmol) join in the mixture after, the mixture that forms was stirred 10 minutes under the cooling of ice.After in 5 minutes, dripping cumene hydroperoxide (content is by 80% for 360 μ l, 1.95mmol) under 0 ℃ to 2 ℃ the internal temperature, mixture was stirred 4 hours under 0 ℃ to 3 ℃ internal temperature.After adding the saturated sodium bicarbonate aqueous solution termination reaction, to wherein adding ethyl acetate and water.With the water layer ethyl acetate extraction of telling.Organic layer is merged, and water, saturated brine solution washing are with anhydrous sodium sulfate drying and concentrated.The resistates that obtains is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol=1/0-4/1 gradient).With required fraction concentrate obtain title compound (203mg, content: 88.9%, yield: 69.4%), be the light brown foam.
1H?NMR(400MHz，DMSO-d 6)δppm；0.69(3H，s)，1.11(3H，s)，2.13(3H，s)，3.48(2H，d，J＝11Hz)，3.58(2H，d，J＝11Hz)，4.08(2H，d，J＝4Hz)，4.69(1H，d，J＝14Hz)，4.77(1H，d，J＝14Hz)，4.83(1H，t，J＝4Hz)，6.97(1H，d，J＝6Hz)，7.24-7.32(2H，m)，7.58-7.67(2H，m)，8.20(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 18.9 minutes, enantiomeric excess: 87%ee
(15b) 2-(((4-((and 5,5-dimethyl-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-sodium salt of the optically active isomer of 1H-benzoglyoxaline (retention time is long)
[formula 128]
Figure S2006800126056D01081
The 2-that obtains to step (15a) (((4-((5,5-dimethyl-1,3-two
Figure 2006800126056_107
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (200mg; content: 88.9%; 0.428mmol) ethanol (3ml) solution of optically active isomer (retention time long) under room temperature, add the 1N aqueous sodium hydroxide solution (428 μ l 0.428mmol) and with mixture stirred 10 minutes under identical condition.After mixture concentrated and joining ethanol in the resistates, mixture is carried out component distillation and suspend with diethyl ether.With the suspension supersound process, leave standstill then.Remove supernatant liquor, then the resistates drying is obtained title compound (145mg, 77.4% yield), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.68(3H，s)，1.11(3H，s)，2.17(3H，s)，3.48(2H，d，J＝11Hz)，3.58(2H，d，J＝11Hz)，4.06(2H，d，J＝4Hz)，4.37(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，4.83(1H，t，J＝4Hz)，6.81-6.88(2H，m)，6.93(1H，d，J＝6Hz)，7.39-7.46(2H，m)，8.25(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 18.4 minutes, enantiomeric excess: 87.4%ee specific rotation: α D 25.5=-123.83 (c=0.5, EtOH).
(embodiment 16) 2-(((4-((5,5-dimethyl-1,3-two
Figure 2006800126056_108
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-sodium salt of the optically active isomer of 1H-benzoglyoxaline (retention time is short)
[formula 129]
Figure S2006800126056D01091
(16a) 2-(((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_109
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-optically active isomer of 1H-benzoglyoxaline (retention time is short)
[formula 130]
Figure S2006800126056D01092
Will according to the 2-that obtains with the identical mode of step (1a) to (1e) of embodiment 1 (((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_110
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline (250mg, 0.626mmol) toluene (anhydrous) (4.0ml)-water (1.4 μ l, 0.0777mmol) (47 μ l 0.274mmol) stirred 10 minutes in nitrogen atmosphere under 50 ℃ for suspension and L-(+)-diethyl tartrate.(37 μ l 0.125mmol) and with the mixture that forms stirred 1 hour under identical condition to add titanium isopropylate (IV).Be cooled to after the room temperature N, (35 μ l 0.201mmol) join in the mixture N-diisopropyl ethyl amine, and the mixture that forms was stirred 15 minutes under the cooling of ice.After in 5 minutes, dripping cumene hydroperoxide (content is by 80% for 360 μ l, 1.95mmol) under 0 ℃ to 2 ℃ the internal temperature, mixture was stirred 4 hours under 0 ℃ to 3 ℃ internal temperature.After adding the saturated sodium bicarbonate aqueous solution termination reaction, to wherein adding ethyl acetate and water.With the water layer ethyl acetate extraction of telling.Organic layer is merged, and water and saturated brine solution washing are with anhydrous sodium sulfate drying and concentrated.The resistates that obtains is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol=1/0-4/1 gradient).With required fraction concentrate obtain title compound (208mg, content: 90.9%, yield: 72.7%), be the light brown foam.
1H?NMR(400MHz，DMSO-d 6)δppm；0.69(3H，s)，1.11(3H，s)，2.13(3H，s)，3.48(2H，d，J＝11Hz)，3.58(2H，d，J＝11Hz)，4.08(2H，d，J＝4Hz)，4.68(1H，d，J＝14Hz)，4.77(1H，d，J＝14Hz)，4.83(1H，t，J＝4Hz)，6.97(1H，d，J＝6Hz)，7.22-7.32(2H，m)，7.57-7.68(2H，m)，8.20(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 15.2 minutes, enantiomeric excess: 84.2%ee
(16b) 2-(((4-((and 5,5-dimethyl-1,3-two
Figure 2006800126056_111
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-sodium salt of the optically active isomer of 1H-benzoglyoxaline (retention time is short)
[formula 131]
Figure S2006800126056D01101
The 2-that obtains to step (16a) (((4-((5,5-dimethyl-1,3-two
Figure 2006800126056_112
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (206mg; content: 90.9%; 0.451mmol) ethanol (3ml) solution of optically active isomer (retention time short) under room temperature, add the 1N aqueous sodium hydroxide solution (451 μ l 0.451mmol) and with mixture stirred 15 minutes under identical condition.After reaction mixture concentrated and joining ethanol in the resistates, mixture is carried out component distillation and suspend with diethyl ether.With the suspension supersound process, leave standstill then.Remove supernatant liquor, then the resistates drying is obtained title compound (126mg, 63.9% yield), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.69(3H，s)，1.11(3H，s)，2.17(3H，s)，3.48(2H，d，J＝11Hz)，3.58(2H，d，J＝11Hz)，4.06(2H，d，J＝4Hz)，4.36(1H，d，J＝13Hz)，4.81(1H，d，J＝13Hz)，4.83(1H，t，J＝4Hz)，6.79-6.87(2H，m)，6.93(1H，d，J＝6Hz)，7.37-7.46(2H，m)，8.25(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 15.8 minutes, enantiomeric excess: 85.0%ee specific rotation: α D 26.3=+116.94 (c=0.5, EtOH)
The sodium salt of the optically active isomer of (embodiment 17) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is short)
[formula 132]
Figure S2006800126056D01111
(17a) optically active isomer of 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is short)
[formula 133]
Figure S2006800126056D01112
To according to the 2-(((3-methyl-4-(1 that obtains with the described identical mode of the step (10a) to (10d) of embodiment 10,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfenyl methyl pyridine-2-yl)))-1H-benzoglyoxaline (300mg, 679 μ mol) toluene (anhydrous) (1.5ml)-water (1.47 μ l, 81.5 μ mol) add L-(+)-diethyl tartrate (51.2 μ l, 299 μ mol) and mixture stirred 5 minutes in the solution under 50 ℃ in nitrogen atmosphere.Add titanium isopropylate (IV) (40.1 μ l, 136 μ mol) and the mixture that forms is continued stirring 1 hour.In cooled on ice and add N, behind the N-diisopropyl ethyl amine (37.8 μ l, 217 μ mol), in nitrogen atmosphere, drip cumene hydroperoxide (content is by 80% for 376 μ l, 2.04mmol), mixture was stirred 5.5 hours to room temperature at 0 ℃.After adding saturated sodium bicarbonate aqueous solution, with the reaction mixture ethyl acetate extraction.With the organic layer dried over sodium sulfate, decompression steams solvent.The resistates that obtains is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (256mg, yield: 82.4%), be light yellow foam.
1H?NMR(400MHz，CDCl 3)δppm；1.85(2H，t，J＝5Hz)，2.01(2H，t，J＝5Hz)，2.12-2.21(1H，m)，2.21(3H，s)，3.66-3.78(4H，m)，3.86(2H，dd，J＝4，12Hz)，4.06-4.24(4H，m)，4.64(1H，d，J＝14Hz)，4.83(1H，d，J＝14Hz)，6.77(1H，d，J＝6Hz)，7.26-7.40(2H，m)，7.50-7.80(2H，br)，8.32(1H，d，J＝6Hz)。
(17b) sodium salt of the optically active isomer of 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is short)
[formula 134]
Figure S2006800126056D01121
2-(((3-methyl-the 4-(1 that obtains to step (17a); 5; 9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfinyl methyl pyridine-2-yl)))-1H-benzoglyoxaline (256mg; under room temperature, add 1N aqueous sodium hydroxide solution (559 μ l, 559 μ mol) in ethanol (10ml) solution of optically active isomer 599 μ mol) (retention time short) and stirred 30 minutes.After mixture concentrated and joining diethyl ether in the resistates, with the mixture supersound process.The solid that produces is collected by filtering under nitrogen atmosphere.The solid drying under reduced pressure is obtained title compound (147mg, yield: 54.8%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.74-1.86(4H，m)，2.08-2.23(1H，m)，2.18(3H，s)，3.50-3.62(4H，m)，3.76-3.84(2H，m)，4.02(2H，dd，J＝4，12Hz)，4.11(2H，d，J＝7Hz)，4.37(1H，d，J＝13Hz)，4.81(1H，d，J＝13Hz)，6.80-6.92(2H，m)，6.93(1H，d，J＝6Hz)，7.38-7.48(2H，m)，8.25(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 29.6 minutes, enantiomeric excess: 85.8%ee
The sodium salt of the optically active isomer of (embodiment 18) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is long)
[formula 135]
Figure S2006800126056D01131
(18a) optically active isomer of 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is long)
[formula 136]
Figure S2006800126056D01132
To according to the 2-(((3-methyl-4-(1 that obtains with the described identical mode of the step (10a) to (10d) of embodiment 10,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfenyl methyl pyridine-2-yl)))-1H-benzoglyoxaline (150mg, 340 μ mol) toluene (anhydrous) (1.5ml)-water (1.35 μ l, 74.8 μ mol) add D-(-)-diethyl tartrate (51.2 μ l, 299 μ mol) and mixture stirred 5 minutes in the solution under 50 ℃ in nitrogen atmosphere.Add titanium isopropylate (IV) (44.2 μ l, 150 μ mol) and the mixture that forms is continued stirring 1 hour.Mixture after cooled on ice, is dripped N in nitrogen atmosphere, N-diisopropyl ethyl amine (39.1 μ l, 224 μ mol) and cumene hydroperoxide (content is by 80% for 188 μ l, 1.02mmol) stir mixture 7 hours to room temperature at 0 ℃.After joining saturated sodium bicarbonate aqueous solution in the reaction mixture, with the reaction mixture ethyl acetate extraction.With the organic layer dried over sodium sulfate, decompression steams solvent.The resistates that obtains is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (68mg, yield: 43.7%), be light yellow foam.
1H?NMR(400MHz，CDCl 3)δppm；1.85(2H，t，J＝5Hz)，2.01(2H，t，J＝5Hz)，2.12-2.22(1H，m)，2.21(3H，s)，3.66-3.78(4H，m)，3.89(2H，dd，J＝4，12Hz)，4.06-4.26(4H，m)，4.65(1H，d，J＝14Hz)，4.83(1H，d，J＝14Hz)，6.79(1H，d，J＝6Hz)，7.28-7.42(2H，m)，7.50-7.80(2H，br)，8.33(1H，d，J＝6Hz)。
(18b) sodium salt of the optically active isomer of 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline (retention time is long)
[formula 137]
Figure S2006800126056D01141
2-(((3-methyl-the 4-(1 that obtains to step (18a); 5; 9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfinyl methyl pyridine-2-yl)))-1H-benzoglyoxaline (68mg; under room temperature, add 1N aqueous sodium hydroxide solution (149 μ l in ethanol (10ml) solution of optically active isomer 149 μ mol) (retention time is long); 149 μ mol), stirred 30 minutes.After mixture concentrated and joining diethyl ether in the resistates, with the mixture supersound process.The solid that forms is collected by filtering under nitrogen atmosphere.The solid drying under reduced pressure is obtained title compound (36mg, yield: 54.8%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.77(2H，t，J＝6Hz)，1.83(2H，t，J＝6Hz)，2.08-2.23(1H，m)，2.17(3H，s)，3.50-3.60(4H，m)，3.76-3.86(2H，m)，4.02(2H，dd，J＝4，12Hz)，4.11(2H，d，J＝7Hz)，4.37(1H，d，J＝13Hz)，4.81(1H，d，J＝13Hz)，6.85(2H，dd，J＝3，6Hz)，6.93(1H，d，J＝6Hz)，7.42(1H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALCEL OD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 36.7 minutes, enantiomeric excess: 36%ee
(embodiment 19) 2-(((4-((2,2-dimethyl-1,3-two Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is long) of 1H-benzoglyoxaline
[formula 138]
Figure S2006800126056D01151
(19a) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_114
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-optically active isomer (retention time is long) of 1H-benzoglyoxaline
[formula 139]
Figure S2006800126056D01152
Will according to the 2-that obtains with the described identical mode of the step (11a) to (11g) of embodiment 11 (((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_115
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) sulfenyl methyl))-1H-benzoglyoxaline (444mg, 1.07mmol) toluene (anhydrous) (2.22ml)-water (2.3 μ l, 0.128mmol) (80.6 μ l 0.471mmol) stirred 10 minutes in nitrogen atmosphere under 50 ℃ for solution and D-(-)-diethyl tartrate.(63.2 μ l 0.214mmol) and with the mixture that forms continue to stir 1 hour under identical condition to add titanium isopropylate (IV).Mixture is cooled to room temperature and adds N, the N-diisopropyl ethyl amine (59.6 μ l, 0.342mmol) after, the mixture that forms is cooled to 0 ℃.After under 0 ℃ to 2 ℃, in 5 minutes, dripping cumene hydroperoxide (content is by 80% for 611 μ l, 3.31mmol), mixture was stirred 3 hours 35 minutes in nitrogen atmosphere under 0 ℃ to 7 ℃.After joining saturated sodium bicarbonate aqueous solution in the reaction mixture, with the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 20g, eluting solvent: methylene dichloride, methylene chloride=20/1).The fraction that will contain title compound is collected with ethyl acetate and concentrated title compound (388mg, the yield: 84.4%), be colourless foam of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.36(3H，s)，2.02-2.13(1H，m)，2.16(3H，s)，2.20(3H，s)，3.74-3.85(4H，m)，4.00(2H，dd，J＝4，12Hz)，4.70(1H，d，J＝14Hz)，4.79(1H，d，J＝14Hz)，7.26-7.34(2H，m)，7.59-7.70(2H，m)，8.18(1H，s)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=1/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALPAK AD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 17.8 minutes, enantiomeric excess: 94.4%ee
(19b) 2-(((4-((and 2,2-dimethyl-1,3-two Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is long) of 1H-benzoglyoxaline
[formula 140]
Figure S2006800126056D01161
The 2-that obtains to step (19a) (((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_117
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-1H-benzoglyoxaline (379mg; 0.882mmol) ethanol (10ml) solution of optically active isomer (retention time long) under room temperature, add 1N aqueous sodium hydroxide solution (878 μ l; 0.882mmol concentration is by 1.004M) and mixture is concentrated.Resistates and ethanol are carried out component distillation.Resistates is suspended in the diethyl ether, and supersound process concentrates and obtains title compound (365mg, yield: 91.7%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.03-2.13(1H，m)，2.20(3H，s)，2.21(3H，s)，3.76-3.88(4H，m)，4.00(2H，dd，J＝4，12Hz)，4.38(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.81-6.90(2H，m)，7.40-7.47(2H，m)，8.23(1H，s)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=1/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALPAK AD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 17.0 minutes, enantiomeric excess: 94.9%ee specific rotation: α D 27.4=-76.29 (c=0.5, EtOH).
(embodiment 20) 2-(((4-(2,2-dimethyl-1,3-two
Figure 2006800126056_118
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 141]
Figure S2006800126056D01171
(20a) 2-(((4-((and 2,2-dimethyl-1,3-two Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 142]
Will according to the 2-that obtains with the described identical mode of the step (11a) to (11g) of embodiment 11 (((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_120
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) sulfenyl methyl))-1H-benzoglyoxaline (591mg, 1.43mmol) toluene (anhydrous) (2.96ml)-water (3.09 μ l, 0.172mmol) (108 μ l 0.629mmol) stirred 5 minutes in nitrogen atmosphere under 50 ℃ for solution and L-(+)-diethyl tartrate.(84.4 μ l 0.286mmol) and with the mixture that forms stirred 1 hour under identical condition to add titanium isopropylate (IV).Mixture is cooled to room temperature and adds N, the N-diisopropyl ethyl amine (79.7 μ l, 0.458mmol) after, the mixture that forms is cooled to 0 ℃.Under 0 ℃ to 1 ℃, in 10 minutes, drip cumene hydroperoxide (content is by 80% for 816 μ l, 4.42mmol), mixture was stirred under identical condition 3 hours 10 minutes.After joining saturated sodium bicarbonate aqueous solution in the reaction mixture, with the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 20g, eluting solvent: methylene dichloride, methylene chloride=20/1).The fraction that will contain title compound is collected with ethyl acetate and concentrated title compound (498mg, the yield: 81.1%), be colourless foam of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.36(3H，s)，2.02-2.12(1H，m)，2.16(3H，s)，2.20(3H，s)，3.74-3.84(4H，m)，4.00(2H，dd，J＝4，12Hz)，4.70(1H，d，J＝14Hz)，4.79(1H，d，J＝14Hz)，7.26-7.34(2H，m)，7.58-7.70(2H，m)，8.18(1H，s)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=1/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALPAK AD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 14.6 minutes, enantiomeric excess: 95.4%ee
(20b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_121
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 143]
The 2-that obtains to step (20a) (((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_122
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-1H-benzoglyoxaline (480mg; 1.12mmol) ethanol (10ml) solution of optically active isomer (retention time short) under room temperature, add 1N aqueous sodium hydroxide solution (1.12ml; 1.12mmol concentration is by 1.004M) and mixture is concentrated.Resistates and ethanol are carried out component distillation.Resistates is suspended in the diethyl ether,, concentrates and obtain title compound (447mg, yield: 88.4%), be white solid the suspension supersound process.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.03-2.14(1H，m)，2.21(6H，s)，3.76-3.87(4H，m)，4.00(2H，dd，J＝4，12Hz)，4.39(1H，d，J＝13Hz)，4.74(1H，d，J＝13Hz)，6.82-6.90(2H，m)，7.40-7.48(2H，m)，8.23(1H，s)。
HPLC：
(0.46cm φ * 25cm), eluent: hexane/ethanol=1/1 (v/v), flow velocity: 0.6ml/min detects: UV (254nm) (condition) post: CHIRALPAK AD-H (being produced by Daicel Chemical Industries Ltd.)
(analytical results): retention time: 14.4 minutes, enantiomeric excess: 95.4%ee
(embodiment 21) 2-(((4-(6,10-dioxo spiro [4.5] last of the ten Heavenly stems-8-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 144]
Figure S2006800126056D01191
(21a) 6,10-dioxo spiro [4.5] last of the ten Heavenly stems-8-base methyl alcohol
[formula 145]
Repeat the identical method of step (9d) with embodiment 9, utilize 2-(hydroxymethyl)-1, ammediol and cyclopentanone obtain title compound (2.8g, yield: 87%), be yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.51-1.55(1H，m)，1.62-1.72(4H，m)，1.83-1.94(4H，m)，3.73-3.80(4H，m)，3.99(2H，dd，J＝4，12Hz)。
(21b) 2-(((4-(6,10-dioxo spiro [4.5] last of the ten Heavenly stems-8-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 146]
Figure S2006800126056D01201
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (21a) obtains 6,10-dioxo spiro [4.5] last of the ten Heavenly stems-basic methyl alcohol of 8-obtains title compound (180mg, total recovery: 8.1%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.52-1.62(4H，m)，1.75-1.86(4H，m)，2.08-2.16(1H，m)，2.17(3H，s)，3.72-3.82(2H，m)，3.92-4.02(2H，m)，4.09(2H，d，J＝7Hz)，4.36(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，6.83(2H，dd，J＝3，6Hz)，6.93(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.27(1H，d，J＝6Hz)。
(embodiment 22) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 147]
Repeat and the step (21a) of embodiment 21 and (21b) identical method, utilize 2-(hydroxymethyl)-1, ammediol and cyclobutanone obtain title compound (265mg, total recovery: 6.2%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.58-1.70(2H，m)，2.06-2.22(5H，m)，2.17(3H，s)，3.66-3.76(2H，m)，3.86-3.96(2H，m)，4.07(2H，d，J＝6Hz)，4.37(1H，d，J＝13Hz)，4.79(1H，d，J＝13Hz)，6.85(2H，dd，J＝3，6Hz)，6.93(1H，d，J＝6Hz)，7.44(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 23) 2-(((4-((2,2-diethyl-1,3-two Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 148]
Figure S2006800126056D01211
(23a) (2,2-diethyl-1,3-two
Figure 2006800126056_124
Alkane-5-yl) methyl alcohol
[formula 149]
Figure S2006800126056D01212
Repeat the identical method of step (9d) with embodiment 9, utilize 2-(hydroxymethyl)-1, ammediol and propione obtain title compound (1.5g, yield: 46%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；0.87(3H，t，J＝7Hz)，0.88(3H，t，J＝7Hz)，1.46-1.51(1H，m)，1.70(2H，q，J＝7Hz)，1.78(2H，q，J＝7Hz)，3.70-3.88(4H，m)，3.96-4.10(2H，m)。
(23b) 2-(((4-((and 2,2-diethyl-1,3-two
Figure 2006800126056_125
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 150]
Figure S2006800126056D01221
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (23a) obtains (2,2-diethyl-1,3-two
Figure 2006800126056_126
Alkane-5-yl) methyl alcohol obtains title compound (164mg, total recovery: 9.7%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.80(6H，t，J＝7Hz)，1.63(2H，q，J＝7Hz)，1.70(2H，q，J＝7Hz)，2.01-2.12(1H，m)，2.18(3H，s)，3.50-3.80(2H，m)，3.94-4.20(2H，m)，4.12(2H，d，J＝7Hz)，4.37(1H，d，J＝13Hz)，4.81(1H，d，J＝13Hz)，6.84(2H，dd，J＝3，6Hz)，6.92(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 24) 2-(((3-methyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 151]
Figure S2006800126056D01222
(24a) (1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methyl alcohol
[formula 152]
Figure S2006800126056D01223
With tetramethylolmethane (15g, 110mmol), triethly orthoacetate (20.2ml, 110mmol) and the tosic acid monohydrate (947mg, mixture 5.5mmol) stirred 30 minutes down at 100 ℃.The temperature of mixture is further risen to 130 ℃ and mixture stirred 30 minutes.(1.53ml 11mmol) and with reaction mixture concentrates to add triethylamine in reaction mixture.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (8.5g, yield: 48.2%), be light yellow solid.
1H?NMR(400MHz，CDCl 3)δppm；1.47(3H，s)，3.46(2H，d，J＝4Hz)，4.02(6H，s)。
(24b) 2,3-dimethyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine 1-oxide compound
[formula 153]
Figure S2006800126056D01231
(the 1-methyl-2 that obtains to step (24a), 6,7-trioxa two ring [2.2.2] suffering-4-yls) (4.5g adds the oil solution (1.29g of sodium hydride to methyl alcohol under room temperature in dimethyl sulphoxide solution 28.1mmol) (30ml), 29.5mmol content is by 55%).(3.99g 25.3mmol), stirred 3 hours down at 60 ℃ to add 4-chloro-2,3 dimethyl pyridine 1-oxide compound in mixture.After being cooled to room temperature, with the reaction mixture concentrating under reduced pressure.With resistates by silica gel chromatography (eluting solvent: ethyl acetate/methanol) obtain title compound (7.46g, yield: 81%), be yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.50(3H，s)，2.20(3H，s)，2.54(3H，s)，3.77(2H，s)，4.15(6H，s)，6.53(1H，d，J＝6Hz)，8.14(1H，d，J＝6Hz)。
(24c) (3-methyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine-2-yl) methyl alcohol
[formula 154]
Figure S2006800126056D01232
With step (24b) obtain 2,3-dimethyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine 1-oxide compound (6.4g, 22.8mmol) and the mixture of diacetyl oxide (20ml) 80 ℃ of stirrings 1 hour down.After being cooled to room temperature, with the reaction mixture concentrating under reduced pressure.In resistates, add methyl alcohol (30ml) and 5N aqueous sodium hydroxide solution (10ml) and mixture was at room temperature stirred 15 hours.Reaction mixture is concentrated and ethyl acetate is joined in the resistates.Mixture is washed with saturated brine solution.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.The resistates (solid) that forms is washed with diethyl ether, obtain title compound (1.5g, yield: 28.7%), be yellow solid by filtering to collect.
1H?NMR(400MHz，CDCl 3)δppm；1.50(3H，s)，2.04(3H，s)，3.80(2H，s)，4.15(6H，s)，4.65(2H，s)，4.77(1H，brs)，6.60(1H，d，J＝6Hz)，8.29(1H，d，J＝6Hz)。
(24d) 2-(((3-methyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine-2-yl) methyl) sulfenyl)-1H-benzoglyoxaline
[formula 155]
Figure S2006800126056D01241
(3-methyl-4-((the 1-methyl-2 that obtains to step (24c), 6,7-trioxa two ring [2.2.2] suffering-4-yls) methyl alcohol (0.37g pyridine-2-yl methoxyl group)), 1.32mmol) and triethylamine (0.368ml, 2.64mmol) tetrahydrofuran (THF) (anhydrous, 20ml) in the solution in nitrogen atmosphere 1 ℃ to 4 ℃ drip down methylsulfonyl chloride (153 μ l, 1.98mmol).The mixture that forms was stirred 1.5 hours under identical condition.In addition, (204mg 1.52mmol) joins in the mixture and at room temperature stirred 18 hours with 2-mercaptobenzimidazole.After reaction mixture concentrated, with resistates by silica gel chromatography (eluting solvent: ethyl acetate/methanol) obtain title compound (230mg, yield: 40.9%), be light yellow foam.
1H?NMR(400MHz，CDCl 3)δppm；1.50(3H，s)，2.27(3H，s)，3.80(2H，s)，4.15(6H，s)，4.38(2H，s)，6.65(1H，d，J＝6Hz)，7.15-7.21(2H，m)，7.36-7.68(2H，m)，8.35(1H，d，J＝6Hz)。
(24e) 2-(((3-methyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 156]
Figure S2006800126056D01251
2-(((3-methyl-4-((the 1-methyl-2 that obtains to step (24d), 6,7-trioxa two ring [2.2.2] suffering-4-yls) sulfenyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline (230mg, 556 μ mol) in nitrogen atmosphere, under-50 ℃ to-60 ℃, in 5 minutes, drip 3-chlorine peroxybenzoic acid (133mg in toluene-methyl alcohol (10: 1) solution (20ml), 0.5mmol content is by 65%) toluene-methyl alcohol (10: 1) solution (5ml) and mixture stirred 3.5 hours under identical condition.In reaction mixture, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel, eluting solvent: ethyl acetate/methanol) obtain title compound (143mg, yield: 59.9%), be light yellow foam.
1H?NMR(400MHz，CDCl 3)δppm；1.50(3H，s)，2.17(3H，s)，3.76(2H，s)，4.12(6H，s)，4.63(1H，d，J＝14Hz)，4.79(1H，d，J＝14Hz)，6.60(1H，d，J＝6Hz)，7.30-7.38(2H，m)，7.47-7.56(1H，m)，7.76-7.86(1H，m)，8.30(1H，d，J＝6Hz)，11.05(1H，brs)。
(24f) 2-(((3-methyl-4-((1-methyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 157]
Figure S2006800126056D01252
2-(((3-methyl-4-((the 1-methyl-2 that obtains to step (24e); 6; 7-trioxa two ring [2.2.2] suffering-4-yls) sulfinyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline (143mg; 333 μ mol) under room temperature, add 1N aqueous sodium hydroxide solution (333 μ l, 333 μ mol) in ethanol (5ml) solution and mixture was stirred 0.5 hour.Mixture is concentrated and resistates is dissolved in ethanol.Then diethyl ether is joined in the solution and carry out supersound process.Filtering the solid that generates also in nitrogen atmosphere, drying under reduced pressure obtains title compound (150mg, yield: 100%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，2.19(3H，s)，3.92(2H，s)，4.04(6H，s)，4.35(1H，d，J＝15Hz)，4.82(1H，d，J＝15Hz)，6.82-6.87(3H，m)，7.42(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 25) 2-(((4-(1,5-dioxo spiro [5.5] undecane-3-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 158]
Figure S2006800126056D01261
(25a) 1,5-dioxo spiro [5.5] undecane-3-base methyl alcohol
[formula 159]
Figure S2006800126056D01262
Repeat the identical method of step (1a) with embodiment 1, utilize 2-(hydroxymethyl)-1, ammediol and pimelinketone obtain title compound (2.26g, yield: 65%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.37-1.46(2H，m)，1.47-1.57(4H，m)，1.68-1.76(2H，m)，1.77-1.90(3H，m)，3.74-3.81(4H，m)，4.02(2H，dd，J＝4，12Hz)。
(25b) 2-(((4-(1,5-dioxo spiro [5.5] undecane-3-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 160]
Figure S2006800126056D01271
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (25a) obtains 1, the basic methyl alcohol of 5-dioxo spiro [5.5] undecane-3-obtains title compound (125mg, total recovery: 8.4%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.30-1.48(6H，m)，1.64-1.76(4H，m)，2.06-2.15(1H，m)，2.18(3H，s)，3.73-3.82(2H，m)，3.96-4.03(2H，m)，4.11(2H，d，J＝7Hz)，4.44(1H，d，J＝13Hz)，4.81(1H，d，J＝13Hz)，6.90-6.98(3H，m)，7.47(2H，dd，J＝3，6Hz)，8.25(1H，d，J＝6Hz)。
(embodiment 26) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_127
Alkane-5-yl) oxygen base)-and 3-picoline-2-yl) methyl) sulfinyl)-1 H-benzoglyoxaline sodium salt
[formula 161]
Figure S2006800126056D01272
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (9a) obtains 2,2-dimethyl-1,3-two
Figure 2006800126056_128
Alkane-5-alcohol obtains title compound (530mg, total recovery: 18%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.34(3H，s)，1.40(3H，s)，2.23(3H，s)，3.79(2H，dd，J＝3，12Hz)，4.12(2H，dd，J＝3，12Hz)，4.39(1H，d，J＝13Hz)，4.46-4.54(1H，m)，4.82(1H，d，J＝13Hz)，6.86-6.94(3H，m)，7.42-7.48(2H，m)，8.23(1H，d，J＝6Hz)。
(embodiment 27) 2-(((4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 162]
Figure S2006800126056D01281
(27a) 1,4-dioxo spiro [4.5] decane-8-alcohol
[formula 163]
Figure S2006800126056D01282
Repeat the mode identical with embodiment 9a, utilize 1,4-cyclohexanedione list ethylidene ketal obtains title compound (2.6g, yield: 79%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.53-1.71(4H，m)，1.77-1.93(4H，m)，3.75-3.85(1H，m)，3.93-3.96(4H，m)。
(27b) 2-(((4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 164]
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (27a) obtains 1,4-dioxo spiro [4.5] decane-8-alcohol obtains title compound (230mg, total recovery: 7.3%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.57-1.94(8H，m)，2.17(3H，s)，3.87(4H，s)，4.35(1H，d，J＝13Hz)，4.62-4.68(1H，m)，4.79(1H，d，J＝13Hz)，6.84(2H，dd，J＝3，6Hz)，6.97(1H，d，J＝6Hz)，7.43(2H，dd，J＝3，6Hz)，8.23(1H，d，J＝6Hz)。
(embodiment 28) 2-(((4-(2-(2,2-dimethyl-1,3-two
Figure 2006800126056_129
Alkane-5-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 165]
Figure S2006800126056D01291
(28a) 2-(2,2-dimethyl-1,3-two
Figure 2006800126056_130
Alkane-5-yl) ethanol
[formula 166]
To according to J.Med.Chem., 30 (9), 2-(hydroxymethyl) butane-1 that the described method of 1636-1642 (1987) obtains, 4-glycol (3.4g, 28.3mmol) acetone (30ml) solution under room temperature, add the tosic acid monohydrate (244mg 2.83mmol) and with mixture stirred 15 hours.(394 μ l 2.83mmol) and with mixture concentrate to add triethylamine in reaction mixture.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (1.0g, yield: 22%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.42(6H，s)，1.54-1.62(2H，m)，1.90-2.02(1H，m)，3.58-3.76(4H，m)，3.94(2H，dd，J＝4，12Hz)。
(28b) 2-(((4-(2-(2,2-dimethyl-1,3-two
Figure 2006800126056_131
Alkane-5-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 167]
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize the 2-that step (28a) obtains (2,2-dimethyl-1,3-two
Figure 2006800126056_132
Alkane-5-yl) ethanol obtains title compound (58mg, total recovery: 2.0%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.28(3H，s)，1.34(3H，s)，1.64-1.72(2H，m)，1.83-1.92(1H，m)，2.16(3H，s)，3.54-3.63(2H，m)，3.83(2H，dd，J＝4，16Hz)，4.06(2H，t，J＝6Hz)，4.38(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.85(2H，dd，J＝3，6Hz)，6.91(1H，d，J＝6Hz)，7.43(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 29) 2-(((4-((1-ethyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 168]
Figure S2006800126056D01302
(29a) (1-ethyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methyl alcohol
[formula 169]
Figure S2006800126056D01303
Repeat the mode identical with embodiment 24, (15g 110mmol) obtains title compound (14g, yield: 73%), be light yellow oil to utilize triethyl orthopropionate.
1H?NMR(400MHz，CDCl 3)δppm；0.96(3H，t，J＝7Hz)，1.71(2H，q，J＝7Hz)，3.47(2H，d，J＝4Hz)，4.02(6H，s)。
(29b) 2-(((4-((1-ethyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 170]
Figure S2006800126056D01311
Repeat the mode identical with embodiment 24, (1-ethyl-2,6,7-trioxa two encircles [2.2.2] suffering-4-yls) methyl alcohol that utilizes step (29a) to obtain obtains title compound (145mg, total recovery: 1.7%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.86(3H，t，J＝7Hz)，1.59(2H，q，J＝7Hz)，2.19(3H，s)，3.92(2H，s)，4.04(6H，s)，4.35(1H，d，J＝13Hz)，4.82(1H，d，J＝13Hz)，6.80-6.90(3H，m)，7.42(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
(((((the 2-methyl isophthalic acid, 3-two for 2-for 3-methyl-4-for (embodiment 30) 2-
Figure 2006800126056_133
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline sodium salt
[formula 171]
Figure S2006800126056D01312
(30a) (the 2-methyl isophthalic acid, 3-two for 2-
Figure 2006800126056_134
Alkane-2-yl) ethanol
[formula 172]
Repeat and the step (8a) of embodiment 8 and (8b) identical method, utilize methyl aceto acetate to obtain title compound (5.4g, total recovery: 49%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.49(3H，s)，1.91(2H，t，J＝6Hz)，1.90-2.40(2H，m)，3.00(1H，t，J＝6Hz)，3.80-4.06(6H，m)。
(30b) (((((the 2-methyl isophthalic acid, 3-two for 2-for 3-methyl-4-for 2-
Figure 2006800126056_135
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline sodium salt
[formula 173]
Figure S2006800126056D01322
Repeat the identical method of step (8c) to (8g) with embodiment 8, (the 2-methyl isophthalic acid, 3-two to utilize the 2-that step (30a) obtains
Figure 2006800126056_136
Alkane-2-yl) ethanol obtains title compound (113mg, total recovery: 2.5%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.39(3H，s)，1.46-1.70(2H，m)，2.12-2.19(2H，m)，2.16(3H，s)，3.76-3.90(4H，m)，4.11(2H，t，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.79(1H，d，J＝13Hz)，6.82-6.92(2H，m)，6.90(1H，d，J＝6Hz)，7.38-7.48(2H，m)，8.24(1H，d，J＝6Hz)。
(embodiment 31) 2-(((4-(2-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 174]
Repeat the mode identical, utilize cyclobutanone to obtain title compound (80mg, total recovery: 0.8%), be light yellow solid with embodiment 28.
1H?NMR(400MHz，DMSO-d 6)δppm；1.57-1.67(4H，m)，1.86-1.96(1H，m)，2.05-2.18(4H，m)，2.16(3H，s)，3.40-3.50(2H，m)，3.82(2H，dd，J＝4，11Hz)，4.06(2H，t，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，6.85(2H，dd，J＝3，6Hz)，6.90(1H，d，J＝6Hz)，7.43(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
((((1,3-two for 4-for (embodiment 32) 2-
Figure 2006800126056_137
Alkane-2-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 175]
Figure S2006800126056D01332
(32a) 2-((benzyloxy) methyl)-1,3-two
Figure 2006800126056_138
Alkane
[formula 176]
Figure S2006800126056D01333
With benzyloxy acetaldehyde (3.6g, 24mmol), 1, ammediol (5.2ml, 72mmol), (4ml, 24mmol) (414mg, mixture 2.45mmol) at room temperature stirred 17 hours triethyl orthoformate with the tosic acid monohydrate.(669 μ l 4.8mmol), concentrate then to add triethylamine in reaction mixture.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (2.9g, yield: 58%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.22(1H，t，J＝7Hz)，2.04-2.20(1H，m)，3.49(2H，d，J＝4Hz)，3.80(2H，dt，J＝2，12Hz)，4.14(2H，dd，J＝5，11Hz)，4.59(2H，s)，4.76(1H，t，J＝4Hz)，7.20-7.42(5H，m)。
(32b) 1,3-two
Figure 2006800126056_139
Alkane-2-base methyl alcohol
[formula 177]
Figure S2006800126056D01341
To the 2-((benzyloxy) methyl)-1 that step (32a) obtains, 3-two
Figure 2006800126056_140
(2.9g adds 10% palladium carbon (760mg) and mixture was at room temperature stirred 2 days in nitrogen atmosphere alkane in methyl alcohol 13.9mmol) (50ml) solution.Reaction mixture is washed by diatomite filtration and with ethyl acetate.Solvent decompression with filtrate steams crude product (860mg, the yield: 52.4%), be light yellow oil that obtains title compound then.
1H?NMR(400MHz，CDCl 3)δppm；1.34-1.44(1H，m)，1.86(1H，t，J＝5Hz)，2.04-2.20(1H，m)，3.60(2H，dd，J＝4，6Hz)，3.82(2H，dt，J＝2，12Hz)，4.15(2H，dd，J＝5，11Hz)，4.66(1H，t，J＝5Hz)。
(32c) ((((1,3-two for 4-for 2-
Figure 2006800126056_141
Alkane-2-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 178]
Figure S2006800126056D01342
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (32b) obtains 1,3-two
Figure 2006800126056_142
Alkane-2-base methyl alcohol makes title compound (148mg, total recovery: 10%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33-1.42(1H，m)，1.84-1.98(1H，m)，2.16(3H，s)，3.74-3.84(2H，m)，3.98-4.08(4H，m)，4.37(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，4.92(1H，t，J＝4Hz)，6.84(2H，dd，J＝3，6Hz)，6.91(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.25(1H，d，J＝6Hz)。
(((((the 2-methyl isophthalic acid, 3-two for 3-methyl-4-for (embodiment 33) 2-
Figure 2006800126056_143
Alkane-2-yl) sulfinyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline sodium salt
[formula 179]
(33a) (the 2-methyl isophthalic acid, 3-two Alkane-2-yl) methyl alcohol
[formula 180]
Figure S2006800126056D01352
Repeat and the step (32a) of embodiment 32 and (32b) identical method, utilize 1-benzyloxy-2-acetone to obtain title compound (1.51g, total recovery: 37%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.43(3H，s)，1.92-2.20(2H，m)，3.53(2H，d，J＝6Hz)，3.86-4.06(4H，m)。
(33b) (((((the 2-methyl isophthalic acid, 3-two for 3-methyl-4-for 2-
Figure 2006800126056_145
Alkane-2-yl) sulfinyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline sodium salt
[formula 181]
Figure S2006800126056D01353
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that step (33a) obtains (the 2-methyl isophthalic acid, 3-two
Figure 2006800126056_146
Alkane-2-yl) methyl alcohol makes title compound (220mg, total recovery: 8.6%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.45(3H，s)，1.57-1.67(2H，m)，2.19(3H，s)，3.88(4H，t，J＝6Hz)，4.09(2H，s)，4.36(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，6.84(2H，dd，J＝3，6Hz)，6.98(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.25(1H，d，J＝6Hz)。
(embodiment 34) 2-(((3-methyl-4-(2-(2,5,5-trimethylammonium-1,3-two
Figure 2006800126056_147
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline sodium salt
[formula 182]
Figure S2006800126056D01361
(34a) 2-(2,5,5-trimethylammonium-1,3-two
Figure 2006800126056_148
Alkane-2-yl) ethanol
[formula 183]
Repeat and the step (8a) of embodiment 8 and (8b) identical method, utilize methyl aceto acetate and 2 to obtain title compound (7.3g, total recovery: 55%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；0.81(3H，s)，1.16(3H，s)，1.44(3H，s)，1.93(2H，t，J＝6Hz)，3.06(1H，t，J＝6Hz)，3.42(2H，d，J＝12Hz)，3.68(2H，d，J＝12Hz)，3.82-3.92(2H，m)。
(34b) 2-(((3-methyl-4-(2-(2,5,5-trimethylammonium-1,3-two
Figure 2006800126056_149
Alkane-2-yl) sulfinyl methyl pyridine-2-yl oxyethyl group))))-1H-benzoglyoxaline sodium salt
[formula 184]
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize the 2-that step (34a) obtains (2,5,5-trimethylammonium-1,3-two Alkane-2-yl) ethanol makes title compound (196mg, total recovery: 7.2%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.83(3H，s)，0.94(3H，s)，1.38(3H，s)，2.12-2.20(2H，m)，2.16(3H，s)，3.39(2H，d，J＝11Hz)，3.51(2H，d，J＝11Hz)，4.13(2H，t，J＝3Hz)，4.38(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，6.84(2H，dd，J＝3，6Hz)，6.88(1H，d，J＝6Hz)，7.42(2H，dd，J＝3，6Hz)，8.25(1H，d，J＝6Hz)。
(embodiment 35) 2-(((3-methyl-4-(2-(6-methyl-5,7-dioxo spiro [2.5] suffering-6-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 185]
Figure S2006800126056D01372
(35a) 2-(6-methyl-5,7-dioxo spiro [2.5] suffering-6-yl) ethanol
[formula 186]
Figure S2006800126056D01373
Repeat and the step (8a) of embodiment 8 and (8b) identical method, utilize methyl aceto acetate and 1,1-two (hydroxymethyl cyclopropane) obtains title compound (2.9g, total recovery: 36%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；0.38(2H，t，J＝6Hz)，0.62(2H，t，J＝6Hz)，1.54(3H，s)，1.96(2H，t，J＝6Hz)，3.04(1H，t，J＝6Hz)，3.16(2H，d，J＝12Hz)，3.84-3.92(2H，m)，4.20(2H，d，J＝12Hz)。
(35b) 2-(((3-methyl-4-(2-(6-methyl-5,7-dioxo spiro [2.5] suffering-6-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 187]
Figure S2006800126056D01381
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, 2-(the 6-methyl-5 that utilizes step (35a) to obtain, 7-dioxo spiro [2.5] suffering-6-yl) ethanol makes title compound (163mg, total recovery: 5.5%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.34-0.50(4H，m)，1.46(3H，s)，2.18(3H，s)，2.22(2H，t，J＝6Hz)，3.45(2H，d，J＝11Hz)，3.76(2H，d，J＝11Hz)，4.16(2H，t，J＝7Hz)，4.39(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，6.86(2H，dd，J＝3，6Hz)，6.91(1H，d，J＝6Hz)，7.43(2H，dd，J＝3，6Hz)，8.26(1H，d，J＝6Hz)。
(((((2-(methoxymethyl)-1,3-two for 2-for 4-for (embodiment 36) 2- Alkane-2-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 188]
Figure S2006800126056D01382
(36a) (2-(methoxymethyl)-1,3-two for 2-
Figure 2006800126056_152
Alkane-2-yl) ethanol
[formula 189]
Repeat and the step (8a) of embodiment 8 and (8b) identical method, utilize 4-methoxyl group methyl acetoacetate to obtain title compound (4.5g, total recovery: 34%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.58-1.70(1H，m)，1.80-1.96(1H，m)，2.03(2H，t，J＝6Hz)，2.86(1H，t，J＝6Hz)，3.43(3H，s)，3.62(2H，s)，3.76-3.84(2H，m)，3.90-4.04(4H，m)。
(36b) (((((2-(methoxymethyl)-1,3-two for 2-for 4-for 2-
Figure 2006800126056_153
Alkane-2-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 190]
Figure S2006800126056D01391
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, (2-(methoxymethyl)-1,3-two to utilize the 2-that step (36a) obtains
Figure 2006800126056_154
Alkane-2-yl) ethanol makes title compound (304mg, total recovery: 7.0%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.50-1.70(2H，m)，2.16(3H，s)，2.20(2H，t，J＝7Hz)，3.29(3H，s)，3.52(2H，s)，3.80-3.90(4H，m)，4.09(2H，t，J＝7Hz)，4.37(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，6.83(2H，dd，J＝3，6Hz)，6.87(1H，d，J＝6Hz)，7.41(2H，dd，J＝3，6Hz)，8.25(1H，d，J＝6Hz)。
(embodiment 37) 2-(((4-((1-cyclopropyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 191]
Figure S2006800126056D01392
(37a) cyclopropane imino-methyl-formiate hydrochloride
[formula 192]
Figure S2006800126056D01401
To the cyclopropane formonitrile HCN (15g, 224mmol), under the cooling of ice, inject hydrogenchloride in the solution mixture of diethyl ether (200ml) and methyl alcohol (10ml) and mixture was at room temperature stirred 17 hours.After the decompression of the solvent of reaction mixture steamed, diethyl ether joined in the resistates and with the solid that generates under nitrogen atmosphere, obtain title compound (29g, yield: 95.5%), be light yellow solid by filtering to collect.
1H?NMR(400MHz，DMSO-d 6)δppm；1.10-1.24(4H，m)，2.06-2.38(1H，m)，3.99(3H，s)，10.8(1H，brs)，12.1(1H，br?s)。
(37b) (trimethoxy methyl) cyclopropane
[formula 193]
Figure S2006800126056D01402
(17.4g, (25.9ml 640mml) and with mixture at room temperature stirred 3.5 days the cyclopropane imino-methyl-formiate hydrochloride that obtains to step (37a) to add methyl alcohol in normal hexane 128mmol) (75ml) solution.The ammonium chloride that precipitation is separated out is by removing by filter and filtrate decompression concentrated crude product (7.5g, the yield: 40%), be light yellow oil that obtains title compound.
1H?NMR(400MHz，CDCl 3)δppm；0.47-0.56(2H，m)，0.58-0.67(2H，m)，0.84-0.94(1H，m)，3.29(9H，s)。
(37c) (1-cyclopropyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methyl alcohol
[formula 194]
Figure S2006800126056D01403
Repeat the identical method of step (24a) with embodiment 24, (9.8g 67.2mmol) makes title compound (11.9g, yield: 95%), be light yellow oil to utilize (trimethoxy methyl) cyclopropane that step (37b) obtains.
1H?NMR(400MHz，CDCl 3)δppm；0.42-0.52(2H，m)，0.58-0.68(2H，m)，0.86-0.96(1H，m)，3.46(2H，s)，4.02(6H，s)。
(37d) 2-(((4-((1-cyclopropyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 195]
Figure S2006800126056D01411
Repeat the identical method of step (24b) to (24f) with embodiment 24, (1-cyclopropyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methyl alcohol that utilizes above step (37c) to obtain makes title compound (147mg, total recovery: 3.2%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.35-0.54(4H，m)，1.06-1.18(1H，m)，2.19(3H，s)，3.92(2H，s)，4.04(6H，s)，4.38(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，6.82-6.94(3H，m)，7.44(2H，dd，J＝3，6Hz)，8.27(1H，d，J＝6Hz)。
(embodiment 38) 2-(((4-((1-cyclobutyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 196]
Figure S2006800126056D01412
(38a) (1-cyclobutyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methyl alcohol
[formula 197]
Figure S2006800126056D01421
Repeat the identical method of step (37a) to (37c) with embodiment 37, utilize the tetramethylene formonitrile HCN to make title compound (15g, total recovery: 51%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.70-2.30(7H，m)，3.47(2H，s)，4.03(6H，s)。
(38b) 2-(((4-((1-cyclobutyl-2,6,7-trioxa two ring [2.2.2] suffering-4-yls) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 198]
Figure S2006800126056D01422
Repeat the identical method of step (24b) to (24f) with embodiment 24, (1-cyclobutyl-2,6,7-trioxa two encircles [2.2.2] suffering-4-yls) methyl alcohol that utilizes above step (38a) to obtain makes title compound (56mg, 2.3%), is light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60-1.86(4H，m)，1.94-2.07(3H，m)，2.19(3H，s)，3.92(2H，s)，4.05(6H，s)，4.33(1H，d，J＝13Hz)，4.83(1H，d，J＝13Hz)，6.78-6.90(3H，m)，7.38-7.48(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 39) 2-(((4-(2-(2-ethyl-1,3-dioxolane-2-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 199]
Figure S2006800126056D01431
(39a) (2-ethyl-1,3-dioxolane-2-yl) ethyl acetate
[formula 200]
Figure S2006800126056D01432
With 3-oxopentanoic acid ethyl ester (5g, 34.7mmol), ethylene glycol (10.8g, 174mmol), (5.14g, 34.7mmol) (598mg, mixture 3.14mmol) at room temperature stir and spend the night triethyl orthoformate with the tosic acid monohydrate.Adding heptane and ethyl acetate obtain dilute solution in reaction mixture, wash with water then.Organic layer is washed with saturated brine solution, use dried over mgso, filter and filtrate decompression is concentrated.Resistates is dissolved in heptane and carries out NH silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/0 → 10/1) obtain title compound (3.85g, yield: 58.9%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.94(3H，t，J＝8Hz)，1.27(3H，t，J＝7Hz)，1.83(2H，q，J＝8Hz)，2.65(2H，s)，3.89-4.03(4H，m)，4.15(2H，q，J＝7Hz)。
(39b) 2-(2-ethyl-1,3-dioxolane-2-yl) ethanol
[formula 201]
Figure S2006800126056D01433
To lithium aluminum hydride (800mg, under the cooling of ice, add in tetrahydrofuran (THF) 21.1mmol) (50ml) suspension (2-ethyl-1,3-dioxolane-2-yl) ethyl acetate (3.85g, 20.5mmol).Mixture at room temperature stirred 1 hour 30 minutes and in cooled on ice.Then water (0.8ml), 15% aqueous sodium hydroxide solution (0.8ml) and water (2.4ml) are joined in the mixture under the cooling of ice successively.Join sal epsom in the mixture and pass through filtered through silica gel.With the concentrated oily title compound (2.76g, 92.1%) that obtains of filtrate decompression.
1H?NMR(400MHz，CDCl 3)δppm；0.92(3H，t，J＝8Hz)，1.68(2H，q，J＝8Hz)，1.93(2H，t，J＝5Hz)，2.82(1H，t，J＝5Hz)，3.76(2H，q，J＝5Hz)，3.96-4.05(4H，m)。
(39c) 2-(((3-methyl-4-(2-(2-propyl group-1,3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 202]
Repeat the identical method of step (3c) to (3h) with embodiment 3, utilize 4-chloro-2,3 dimethyl pyridine 1-oxide compound and 2-(2-ethyl-1,3-dioxolane-2-yl) ethanol to obtain title compound (422mg, 6 steps: 25%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.87(3H，t，J＝8Hz)，1.64(2H，q，J＝8Hz)，2.07(2H，t，J＝7Hz)，2.17(3H，s)，3.85-3.94(4H，m)，4.09(2H，t，J＝7Hz)，4.40(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，6.83-6.90(2H，m)，6.94(1H，d，J＝6Hz)，7.41-7.49(2H，m)，8.27(1H，d，J＝6Hz)。
(embodiment 40) 2-(((4-((2-ethyl-1,3-dioxolane-2-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 203]
Figure S2006800126056D01451
(40a) 2-oxo butylacetic acid ester
[formula 204]
With 1-bromine fourth-2-ketone (10g, 66.2mmol), (7.8g, 79.4mmol) and N, the mixture of dinethylformamide (50ml) at room temperature stirred 5 days potassium acetate.Water joined in the reaction mixture and with diethyl ether extraction 2 times.Organic layer is merged,, use dried over mgso, filter with the saturated brine solution washing.Filtrate decompression concentrated obtain and N the title compound of the form of mixtures of dinethylformamide (8.24g).
1H?NMR(400MHz，CDCl 3)δppm；1.10(3H，t，J＝7Hz)，2.14(3H，s)，2.45(2H，q，J＝7Hz)，4.66(2H，s)。
(40b) (2-ethyl-1,3-dioxolane-2-yl) methyl acetic acid ester
[formula 205]
Figure S2006800126056D01453
The 2-oxo butylacetic acid ester (4g) that step (40a) is obtained, ethylene glycol (7.82g, 126mmol), (3.73g, 25.2mmol) (479mg, mixture 2.52mmol) at room temperature stir and spend the night triethyl orthoformate with the tosic acid monohydrate.In reaction mixture, add entry and ethyl acetate and distribute.Water layer is used ethyl acetate extraction once more.Organic layer is merged, use dried over mgso, filter.Filtrate decompression is concentrated.Resistates is dissolved in heptane-ethyl acetate and carries out NH silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=20/1 → 5/1) obtain title compound (1.4g, the yield of 2 steps: 25%).
1H?NMR(400MHz，CDCl 3)δppm；0.93(3H，t，J＝7Hz)，1.73(2H，q，J＝7Hz)，2.09(3H，s)，3.96-4.03(4H，m)，4.03(2H，s)。
(40c) (2-ethyl-1,3-dioxolane-2-yl) methyl alcohol
[formula 206]
Figure S2006800126056D01461
With (2-ethyl-1,3-dioxolane-2-yl) methyl acetate (1.39g, 7.94mmol), salt of wormwood (2.19g, 15.9mmol), the mixture of tetrahydrofuran (THF) (20ml) and water (10ml) at room temperature stirred 6 hours 50 minutes.With the reaction mixture concentrating under reduced pressure, ethyl acetate is joined in the resistates, carry out the NH silicagel pad and filter.Filtrate decompression concentrated obtain title compound (0.75g, 71.5%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.93(3H，t，J＝8Hz)，1.71(2H，q，J＝8Hz)，1.95-2.03(1H，br)，3.53(2H，d，J＝4Hz)，3.96-4.06(4H，m)。
(40d) 2-(((4-((2-ethyl-1,3-dioxolane-2-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 207]
Figure S2006800126056D01462
Repeat the identical method of step (3c) to (3h) with embodiment 3, utilize 4-chloro-2,3 dimethyl pyridine 1-oxide compound and (2-ethyl-1,3-dioxolane-2-yl) methyl alcohol to obtain title compound (355mg, 6 steps: 9.6%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.87(3H，t，J＝8Hz)，1.74(2H，q，J＝8Hz)，2.17(3H，s)，3.87-4.00(4H，m)，3.96(2H，s)，4.39(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，6.84-6.91(2H，m)，6.94(1H，d，J＝6Hz)，7.41-7.47(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 41) 2-(((4-(2-(2-ethyl-1,3-dioxolane-2-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-4-methyl isophthalic acid H-benzoglyoxaline sodium salt
[formula 208]
Utilize 4-chloro-2,3-lutidine 1-oxide compound and 2-(2-ethyl-1,3-dioxolane-2-yl) ethanol repeats and the identical method of step (39c), 4-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan that different is obtains with the step (54a) of embodiment 54 replaces the 2-mercaptobenzimidazole in the step (39c) of embodiment 39 to make title compound (490mg, 6 steps: 27%), be white powder.
1H?NMR(400MHz，DMSO-d 6)δppm；0.85(3H，t，J＝8Hz)，1.62(2H，q，J＝8Hz)，2.05(2H，t，J＝7Hz)，2.17(3H，s)，2.45(3H，s)，3.83-3.92(4H，m)，4.07(2H，t，J＝7Hz)，4.42(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.63(1H，d，J＝7Hz)，6.73(1H，t，J＝7Hz)，6.91(1H，d，J＝6Hz)，7.24(1H，d，J＝8Hz)，8.25(1H，d，J＝6Hz)。
(((((2-ethyl-1,3-two for 4-for (embodiment 42) 2-
Figure 2006800126056_155
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 209]
Figure S2006800126056D01481
(42a) 2-oxo butylbenzoic acid ester
[formula 210]
Figure S2006800126056D01482
With 1-bromine fourth-2-ketone (7.2g, 47.7mmol), (7.56g, 52.4mmol) and N, the mixture of dinethylformamide (72ml) at room temperature stirred 3 hours 45 minutes Sodium Benzoate.Diethyl ether is joined in the reaction mixture and, use dried over mgso, filtration mixture water and saturated brine solution washing.With the concentrated title compound (9.5g, quantitative) that obtains of filtrate decompression, be shallow brown oil.
1H?NMR(400MHz，CDCl 3)δppm；1.13(3H，t，J＝7Hz)，2.54(2H，q，J＝7Hz)，4.89(2H，s)，7.43-7.49(2H，m)，7.57-7.62(1H，m)，8.08-8.12(2H，m)。(42b) (2-ethyl-1,3-two for phenylformic acid
Figure 2006800126056_156
Alkane-2-yl) methyl esters
[formula 211]
Figure S2006800126056D01483
With 2-oxo butylbenzoic acid ester (5g, 26mmol), 1, ammediol (5.94g, 78mmol), (3.85g, 26mmol) (448mg, mixture 2.36mmol) at room temperature stirred 3 hours 30 minutes triethyl orthoformate with the tosic acid monohydrate.Add ethyl acetate and diethyl ether in reaction mixture and with mixture water and saturated brine solution washing.Organic layer is also filtered with dried over sodium sulfate.Filtrate decompression is concentrated.Resistates is dissolved in heptane/ethyl acetate (12/1) and carries out NH silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=12/1) obtain title compound (4.33g, 65.5%), be colourless thick oil.
1H?NMR(400MHz，CDCl 3)δppm；0.98(3H，t，J＝8Hz)，1.63-1.87(2H，m)，1.89(2H，q，J＝8Hz)，3.90-4.06(4H，m)，4.52(2H，s)，7.42-7.48(2H，m)，7.54-7.60(1H，m)，8.06-8.09(2H，m)。
(42c) (2-ethyl-1,3-two
Figure 2006800126056_157
Alkane-2-yl) methyl alcohol
[formula 212]
(2-ethyl-1,3-two with phenylformic acid
Figure 2006800126056_158
Alkane-2-yl) methyl esters (4.33g, 17.3mmol), salt of wormwood (4.95g, 35.9mmol), the mixture of tetrahydrofuran (THF) (50ml) and water (20ml) at room temperature stirred 11 hours.(2ml) joins in the mixture with the 5N aqueous sodium hydroxide solution, at room temperature stirs 7 hours, to wherein adding methyl alcohol (50ml), at room temperature stirs 4 hours then.With the reaction mixture concentrating under reduced pressure.Join ethyl acetate in the resistates and by removing by filter insolubles.Filtrate decompression is concentrated.Resistates is dissolved in heptane/ethyl acetate and carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=2/1 → 1/1) obtain title compound (2.35g, 92.9%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.89(3H，t，J＝8Hz)，1.52-1.60(1H，m)，1.83-1.95(4H，m)，3.58(2H，d，J＝6Hz)，3.86-4.01(4H，m)。
(42d) (((((2-ethyl-1,3-two for 4-for 2-
Figure 2006800126056_159
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 213]
Figure S2006800126056D01492
Repeat the identical method of step (3c) to (3h) with embodiment 3, utilize 4-chloro-2,3 dimethyl pyridine 1-oxide compound and (2-ethyl-1,3-two
Figure 2006800126056_160
Alkane-2-yl) methyl alcohol makes solid state title compound (305mg, 6 steps: 9.6%).
1H?NMR(400MHz，DMSO-d 6)δppm；0.83(3H，t，J＝8Hz)，1.51-1.71(2H，m)，1.83(2H，q，J＝8Hz)，2.15(3H，s)，3.79-3.94(4H，m)，4.15(2H，s)，4.45(1H，d，J＝13Hz)，4.78(1H，d，J＝13Hz)，6.93-7.00(2H，m)，7.04(1H，d，J＝5Hz)，7.45-7.52(2H，m)，8.26(1H，d，J＝5Hz)。
(embodiment 43) 2-(((4-(2-(2-(methoxymethyl)-1,3-dioxolane-2-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 214]
(43a) 2-(2-(methoxymethyl)-1,3-dioxolane-2-yl) ethanol
[formula 215]
Figure S2006800126056D01502
Repeat and the step (39a) of embodiment 39 and (39b) identical method, utilize 4-methoxyl group methyl aceto acetate to obtain title compound (5.3g, 2 steps: 50%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；2.01(2H，t，J＝5Hz)，2.74-2.80(1H，br)，3.38(2H，s)，3.42(3H，s)，3.74-3.80(2H，br)，4.01-4.06(4H，m)。
(43b) 2-(((4-(2-(2-(methoxymethyl)-1,3-dioxolane-2-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 216]
Figure S2006800126056D01511
Repeat the identical method of step (5d) to (5h) with embodiment 5, utilize 4-chloro-2,3 dimethyl pyridine 1-oxide compound and 2-(2-(methoxymethyl)-1,3-dioxolane-2-yl) ethanol obtains title compound (312mg, 5 steps, 3.9%), be light yellow foam.
1H?NMR(400MHz，DMSO-d 6)δppm；2.10(2H，t，J＝7Hz)，2.15(3H，s)，3.27(3H，s)，3.30(2H，s)，3.86-3.91(4H，m)，4.09(2H，t，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.76(1H，d，J＝13Hz)，6.81-6.88(2H，m)，6.92(1H，d，J＝6Hz)，7.40-7.46(2H，m)，8.26(1H，d，J＝6Hz)。
(((((2-(methyl fluoride)-1,3-two for 4-for (embodiment 44) 2-
Figure 2006800126056_161
Alkane-2-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 217]
Figure S2006800126056D01512
(44a) (2-(hydroxymethyl)-1,3-two for phenylformic acid
Figure 2006800126056_162
Alkane-2-yl) methyl esters
[formula 218]
(20g, (25.8ml 222mmol), at room temperature stirred 4 hours then to add Benzoyl chloride in pyridine 222mmol) (200ml) solution under the cooling of ice to otan.With the reaction mixture concentrating under reduced pressure, add ethyl acetate and water then with its dissolving.Organic layer is taken out, with the water layer ethyl acetate extraction.Organic layer is merged, with the saturated brine solution washing, with dried over mgso and filtration.Filtrate decompression is concentrated.Resistates is suspended in normal heptane/ethyl acetate (1/1) and by removing by filter insolubles.Filtrate concentrating is dissolved in ethyl acetate then.Silica gel is joined in the solution of formation, concentrate and carry out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=3/1 → 2/1 → 1/1 → 0/1) obtain containing the mixture (16.5g) of phenylformic acid 3-hydroxyl-2-oxo propyl ester, be white solid.
The mixture (0.5g), 1 that will contain phenylformic acid 3-hydroxyl-2-oxo propyl ester, ammediol (0.932ml, 12.9mmol), (0.428ml, 2.58mmol) (44.5mg, mixture 0.234mmol) at room temperature stirred 4 days triethyl orthoformate with the tosic acid monohydrate.The mixture (4g), 1 that will contain phenylformic acid 3-hydroxyl-2-oxo propyl ester, ammediol (7.46ml, 12.9mmol), triethyl orthoformate (3.42ml, 20.6mmol) and the tosic acid monohydrate (356mg, 1.87mmol) another part mixture stir down at 40 ℃ and spend the night.Two parts of reaction mixtures are merged, add entry and ethyl acetate and organic layer is taken out.Organic layer is also filtered with dried over mgso.Filtrate decompression is concentrated.Resistates is dissolved in normal heptane/ethyl acetate (2/1) and toluene and carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=3/2) obtain title compound (4.2g).
1H?NMR(400MHz，CDCl 3)δppm；1.58-2.04(2H，m)，3.72(2H，s)，3.92-3.99(2H，m)，4.05-4.13(2H，m)，4.66(2H，s)，7.41-7.48(2H，m)，7.56-7.60(1H，m)，8.02-8.07(2H，m)。
(44b) (2-(methyl fluoride)-1,3-two for phenylformic acid
Figure 2006800126056_163
Alkane-2-yl) methyl esters
[formula 219]
Figure S2006800126056D01521
(2-(hydroxymethyl)-1,3-two to phenylformic acid
Figure 2006800126056_164
Alkane-2-yl) (4.76g adds 1 in toluene 18.8mmol) (100ml) solution to methyl esters, 8-diazabicylo [5.4.0] 11 carbon-7-alkene (8.43ml, 56.4mmol), in cooled on ice, add then nine fluoro-1-butane SULPHURYL CHLORIDE (5.06ml, 28.2mmol).Mixture was stirred 15 minutes under the cooling of ice, stirred 20 hours down at 40 ℃ then, further at room temperature stirred 8 days.With reaction mixture by adding entry and ethyl acetate extracts.Organic layer is washed with saturated brine solution, use dried over mgso, and, then filtrate is concentrated by filtered through silica gel.Resistates is carried out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=4/1) obtain title compound (2.22g, yield: 46.4%) 2 times.
1H?NMR(400MHz，CDCl 3)δppm；1.63-1.74(1H，m)，1.89-2.01(1H，m)，3.93-4.01(2H，m)，4.05-4.13(2H，m)，4.56(2H，d，J＝47Hz)，4.66(2H，d，J＝2Hz)，7.42-7.48(2H，m)，7.54-7.61(1H，m)，8.03-8.08(2H，m)。
(44c) (2-(methyl fluoride)-1,3-two
Figure 2006800126056_165
Alkane-2-yl) methyl alcohol
[formula 220]
Figure S2006800126056D01531
(2-(methyl fluoride)-1,3-two with phenylformic acid
Figure 2006800126056_166
Alkane-2-yl) methyl esters (2.22g, 8.73mmol), the mixture of methyl alcohol (20ml) and 1N aqueous sodium hydroxide solution (13.1ml) at room temperature stirs and spend the night.Ammonium chloride is joined in the reaction mixture, concentrate then.Resistates is suspended in tetrahydrofuran (THF) and the ethyl acetate, adds sal epsom then and mixture was stirred 5 minutes.After carrying out the NH filtered through silica gel, filtrate concentrating obtained title compound (1.17g, 89.3%), be colourless liquid.
1H?NMR(400MHz，CDCl 3)δppm；1.65-1.75(1H，m)，1.85-1.96(1H，m)，3.71(2H，d，J＝3Hz)，3.94-4.05(4H，m)，4.57(2H，d，J＝47Hz)。
(44d) (((((2-(methyl fluoride)-1,3-two for 4-for 2-
Figure 2006800126056_167
Alkane-2-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 221]
Figure S2006800126056D01541
Repeat the identical method of step (1c) to (1g) with embodiment 1, utilize 4-chloro-2,3,5-trimethylpyridine 1-oxide compound is with (2-(methyl fluoride)-1,3-two
Figure 2006800126056_168
Alkane-2-yl) methyl alcohol obtains title compound (331mg, 5 steps: 12%), be yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.61-1.74(2H，m)，2.22(3H，s)，2.25(3H，s)，3.86-3.95(4H，m)，3.96(2H，s)，4.41(1H，t，J＝13Hz)，4.64(2H，d，J＝47Hz)，4.75(1H，d，J＝13Hz)，6.81-6.88(2H，m)，7.39-7.46(2H，m)，8.21(1H，s)。
(embodiment 45) 2-(((4-((2-(methyl fluoride)-1,3-dioxolane-2-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 222]
(45a) (2-(methyl fluoride)-1,3-dioxolane-2-yl) methyl alcohol
[formula 223]
Figure S2006800126056D01543
Utilize otan to repeat and the identical method of step (44a) to (44c), different is that spent glycol replaces 1 among the embodiment 44, and ammediol obtains title compound (543mg, total recovery: 13.8%).
1H?NMR(400MHz，CDCl 3)δppm；1.70-1.82(1H，br)，3.66(2H，d，J＝2Hz)，4.06(4H，s)，4.37(2H，d，J＝47Hz)。
(45b) 2-(((4-((2-(methyl fluoride)-1,3-dioxolane-2-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 224]
Figure S2006800126056D01551
Repeat the identical method of step (3c) to (3h) with embodiment 3, utilize 4-chloro-2,3 dimethyl pyridine 1-oxide compound and (2-(methyl fluoride)-1,3-dioxolane-2-yl) methyl alcohol to obtain title compound (140mg, 6 step s 8.2%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.20(3H，s)，3.95-4.05(4H，m)，4.10(2H，d，J＝2Hz)，4.38(1H，d，J＝13Hz)，4.48(2H，d，J＝47Hz)，4.83(1H，d，J＝13Hz)，6.81-6.88(2H，m)，6.96(1H，d，J＝6Hz)，7.39-7.46(2H，m)，8.27(1H，d，J＝6Hz)。
(embodiment 46) 2-(((4-((5,5-two fluoro-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 225]
Figure S2006800126056D01552
(46a) 2,2-difluoropropane-1,3-two basic diacetate esters
[formula 226]
Figure S2006800126056D01561
With 2-oxo propane-1, (10.6g, 60.8mmol) (24.2ml, mixture 182mmol) at room temperature stirred 4 days 3-two basic diacetate esters with the diethylamino sulfur trifluoride.Reaction mixture is diluted with ethyl acetate,, add saturated sodium bicarbonate solution then and organic layer is taken out in cooled on ice.Organic layer is washed with water 2 times, with dried over mgso and filtration.With the concentrated title compound (10.92g, 91.6%) that obtains of filtrate decompression.
1H?NMR(400MHz，CDCl 3)δppm；2.13(6H，s)，4.35(4H，t，J＝12Hz)。(46b) 2,2-fluoropropane-1,3-glycol
[formula 227]
Figure S2006800126056D01562
With 2,2-difluoropropane-1,3-two basic diacetate esters (10.9g, 55.7mmol), (32.2g, mixture 167mmol) at room temperature stirred 2 hours for the methanol solution of methyl alcohol (300ml) and 28% sodium methylate.DOWEX 50W-X8 (100-200 order, H type) is joined in the reaction mixture to regulate pH to 5.Mixture is filtered and filtrate is concentrated.In resistates, add tetrahydrofuran (THF) and ethyl acetate with its dissolving.Solution with dried over mgso and filtration, is concentrated filtrate then.Resistates is dissolved in ethyl acetate and filters by glass fiber filter paper.With the concentrated title compound (5.3g, 84.9%) that obtains of filtrate decompression.
1H?NMR(400MHz，CDCl 3)δppm；2.07-2.20(2H，br)，3.92(4H，dt，J＝1，12Hz)。
(46c) 2-((benzyloxy) methyl)-5,5-two fluoro-1,3-two
Figure 2006800126056_170
Alkane
[formula 228]
Figure S2006800126056D01571
With 2,2-difluoropropane-1, and the 3-glycol (1g, 8.9mmol), benzyloxy acetaldehyde (1.34g, 8.9mmol), the tosic acid monohydrate (154mg, 0.81mmol) and the condenser reflux of the mixture of toluene (20ml) by being equipped with the Dean-Stark device 1 hour.The mixture that forms at room temperature stirred spend the night, then with the reaction mixture concentrating under reduced pressure.Resistates is dissolved in ethyl acetate and to wherein adding silica gel.The mixture that forms is concentrated into dried, carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=10/1) obtain title compound (930mg, 42.8%) then.
1H?NMR(400MHz，CDCl 3)δppm；3.61(2H，d，J＝5Hz)，3.75-3.88(2H，m)，4.13-4.22(2H，m)，4.61(2H，s)，4.76(1H，t，J＝5Hz)，7.21-7.40(5H，m)。
(46d) (5,5-two fluoro-1,3-two
Figure 2006800126056_171
Alkane-2-yl) methyl alcohol
[formula 229]
Figure S2006800126056D01572
With 2-((benzyloxy) methyl)-5,5-two fluoro-1,3-two
Figure 2006800126056_172
Alkane (930mg, 3.81mmol), the mixture of 20% palladium hydroxide (353mg) and ethyl acetate (30ml) at room temperature stirred in nitrogen atmosphere 4 hours 25 minutes.Reaction mixture filtered and filtrate decompression concentrated and obtain title compound (572mg, 97.4%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；3.72(2H，d，J＝5Hz)，3.78-3.90(2H，m)，4.16-4.23(2H，m)，4.69(1H，t，J＝4Hz)。
(46e) 2-(((4-((and 5,5-two fluoro-1,3-two
Figure 2006800126056_173
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 230]
Figure S2006800126056D01581
Repeat the identical method of step (1c) to (1g) with embodiment 1, utilize 4-chloro-2,3 dimethyl pyridine 1-oxide compound with (5,5-two fluoro-1,3-two
Figure 2006800126056_174
Alkane-2-yl) methyl alcohol makes title compound (375mg, 5 steps: 22.7%), be white powder.
1H?NMR(400MHz，DMSO-d 6)δppm；2.19(3H，s)，4.00-4.25(6H，m)，4.38(1H，d，J＝13Hz)，4.83(1H，d，J＝13Hz)，5.17(1H，t，J＝4Hz)，6.81-6.87(2H，m)，6.96(1H，d，J＝6Hz)，7.39-7.45(2H，m)，8.27(1H，d，J＝6Hz)。
(embodiment 47) 2-(((4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-5-methyl isophthalic acid H-benzoglyoxaline sodium salt
[formula 231]
Figure S2006800126056D01582
(47a) 5-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan
[formula 232]
Figure S2006800126056D01583
At first with 3-amino-4-nitrotoluene (6.3g, 41.4mmol) and 10% palladium carbon (900mg) be suspended in the methyl alcohol (70ml) and and under nitrogen atmosphere, stirred 3 hours mixture.With the reaction vessel nitrogen purge, by removing by filter catalyzer and using washing with alcohol.In reaction mixture, add dithiocarbonic anhydride (20ml) and mixture was at room temperature stirred 5 days.After reaction mixture concentrated, diethyl ether is joined in the resistates.The solid by filtration collection that generates is obtained title compound (6.1g, yield: 89.7%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.33(3H，s)，6.90-6.93(2H，m)，7.00(1H，d，J＝8Hz)。
(47b) 2-(((4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-5-methyl isophthalic acid H-benzoglyoxaline sodium salt
[formula 233]
Figure S2006800126056D01591
Repeat the identical method of step (1e) to (1g) with embodiment 1, the 5-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan (309mg that utilizes step (47a) to obtain, 1.88mmol) and ((2-(2 for 4-, 2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-and 3-picoline-2-yl) methyl alcohol (501mg, 1.88mmol) obtain title compound (118mg), be white solid.Note, be cured the operation of title compound according to following description.Ether is joined in the resistates, the mixture that forms is carried out supersound process.The suspension that obtains is left standstill, remove supernatant liquor then.These operations are repeated 2 times.The throw out that forms blotted obtain title compound.
1H?NMR(400MHz，DMSO-d 6)δppm；1.27(3H，s)，1.33(3H，s)，1.96-2.04(2H，m)，2.18(3H，s)，2.36(3H，s)，3.59(1H，t，J＝8Hz)，4.04-4.14(3H，m)，4.21-4.26(1H，m)，4.37(1H，dd，J＝4，13Hz)，4.80(1H，dd，J＝2，13Hz)，6.69(1H，d，J＝8Hz)，6.92(1H，d，J＝6Hz)，7.22(1H，s)，7.31(1H，d，J＝8Hz)，8.28(1H，d，J＝6Hz)。
(embodiment 48) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_175
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-4-methoxyl group-1H-benzoglyoxaline sodium salt
[formula 234]
(48a) 4-methoxyl group-1H-benzimidazolyl-2 radicals-mercaptan
[formula 235]
Figure S2006800126056D01602
With 2-methoxyl group-6-N-methyl-p-nitroaniline (1g, 5.95mmol), the mixture of 10% palladium carbon (300mg) and methyl alcohol (25ml) stirred in nitrogen atmosphere 4 hours.With reaction vessel with nitrogen purge and by removing by filter catalyzer.In reaction mixture, add dithiocarbonic anhydride (15ml) and mixture at room temperature stirred and spend the night.(1ml) joins in the reaction mixture with triethylamine, and it was stirred 3 hours down at 50 ℃.After reaction mixture concentrated, methyl alcohol (2ml) and diethyl ether (20ml) are joined in the resistates.The solid by filtration collection that generates is obtained title compound (950mg, yield: 88.6%), be the light orange solid.
1H?NMR(400MHz，DMSO-d 6)δppm；3.86(3H，s)，6.74(1H，d，J＝8Hz)，6.75(1H，d，J＝8Hz)，7.05(1H，t，J＝8Hz)。
(48b) 2-(((4-((and 2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-4-methoxyl group-1H-benzoglyoxaline sodium salt
[formula 236]
Figure S2006800126056D01603
Repeat the identical method of step (1e) to (1g) with embodiment 1, utilize 4-methoxyl group-1H-benzimidazolyl-2 radicals-mercaptan that the method according to step (48a) obtains (260mg, 1.44mmol) with (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_177
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) (350mg 1.31mmol) obtains title compound (326mg) to methyl alcohol, is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，t，J＝6Hz)，2.06-2.14(1H，m)，2.20(3H，s)，3.75-3.80(2H，m)，3.88(3H，s)，3.97-4.01(2H，m)，4.10(2H，d，J＝7Hz)，4.35(1H，d，J＝13Hz)，4.83(1H，d，J＝13Hz)，6.33(1H，d，J＝8Hz)，6.74(1H，t，J＝8Hz)，6.94(1H，d，J＝6Hz)，7.05(1H，d，J＝8Hz)，8.27(1H，d，J＝6Hz)。
(embodiment 49) 2-(((4-((5,5-dimethyl-1,3-two
Figure 2006800126056_178
Alkane-2-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-5-(trifluoromethyl)-1H-benzoglyoxaline sodium salt
[formula 237]
Figure S2006800126056D01611
(49a) 5-(trifluoromethyl)-1H-benzimidazolyl-2 radicals-mercaptan
[formula 238]
Figure S2006800126056D01612
With 4-amino-3-nitro-trifluoromethyl toluene (7g, 34mmol), the mixture of 10% palladium carbon (1.3g) and methyl alcohol (70ml) stirred in nitrogen atmosphere 5 hours.With reaction vessel with nitrogen purge and by removing by filter catalyzer.In reaction mixture, add dithiocarbonic anhydride (30ml) and mixture at room temperature stirred and spend the night, then reaction mixture is concentrated.Methyl alcohol (60ml), dithiocarbonic anhydride (20ml) and triethylamine (15ml) joined in the resistates and mixture stirred down at 50 ℃ and spend the night.After reaction mixture concentrated, with resistates by silica gel chromatography (silica gel 200g, eluting solvent: ethyl acetate/heptane=1/3 → 7/3.When ethyl acetate/heptane=7/3, small amount of methanol is joined in the eluting solvent) obtain title compound (5.3g, yield: 71.4%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；7.29(1H，d，J＝8Hz)，7.35(1H，s)，7.45(1H，d，J＝8Hz)，12.86(1H，brs)。
(49b) 2-(((4-((and 5,5-dimethyl-1,3-two Alkane-2-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-5-(trifluoromethyl)-1H-benzoglyoxaline sodium salt
[formula 239]
Figure S2006800126056D01621
Repeat the identical method of step (1e) to (1g) with embodiment 1, utilize 5-(trifluoromethyl)-1H-benzimidazolyl-2 radicals-mercaptan that the method by step (49a) obtains (137mg, 0.626mmol) with (4-((5,5-dimethyl-1,3-two
Figure 2006800126056_180
Alkane-2-yl) methoxyl group)-3,5-lutidine-2-yl) (176mg 0.626mmol) obtains title compound (104mg) to methyl alcohol, is light yellow solid.Note, when title compound solidifies, add heptane (10ml) and diethyl ether (2ml) and carry out supersound process.
1H?NMR(400MHz，DMSO-d 6)δppm；0.70(3H，s)，1.10(3H，s)，2.20(3H，s)，2.21(3H，s)，3.48(2H，d，J＝11Hz)，3.57(2H，d，J＝11Hz)，3.82(2H，d，J＝4Hz)，4.76(1H，t，J＝4Hz)，7.14(1H，dd，J＝2，8Hz)，7.59(1H，d，J＝8Hz)，7.77(1H，s)，8.21(1H，s)。
(embodiment 50) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 240]
Figure S2006800126056D01631
Repeat the identical method of step (10d) to (10f) with embodiment 10, utilize 2-mercaptobenzimidazole (291mg, 1.94mmol) and (4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy) methyl alcohol (443mg pyridine-2-yl), 1.76mmol) obtain title compound (300mg), be white solid.Note, in the method identical, join 2-mercaptobenzimidazole in the reaction mixture and add 2 equivalent triethylamines with step (10d).Mixture was at room temperature stirred 2 days.
1H?NMR(400MHz，DMSO-d 6)δppm；0.30-0.34(2H，m)，0.56-0.60(2H，m)，3.24(2H，d，J＝12Hz)，3.99(2H，t，J＝4Hz)，4.08(2H，d，J＝12Hz)，4.94(1H，t，J＝4Hz)，6.85-6.88(3H，m)，6.92(1H，dd，J＝3，6Hz)，7.45(2H，dd，J＝3，6Hz)，8.37(1H，d，J＝6Hz)。
(embodiment 51) 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-ethylpyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 241]
(51a) 2-picoline-3-base triflate
[formula 242]
Figure S2006800126056D01633
At first (16.2g, 148mmol) (53.2g 149mmol) is dissolved in methylene dichloride (anhydrous) (450ml) with N-phenyl trifluoromethanesulfonate methylsulfonyl imines with 3-hydroxy-2-methyl pyridine.In nitrogen atmosphere, under 1 to 3 ℃, in mixture, add triethylamine (31ml, 222mmol).Mixture was stirred 13 hours 20 minutes, simultaneously temperature is risen to room temperature.Reaction mixture is washed 2 times with the 1N aqueous sodium hydroxide washes, used anhydrous sodium sulfate drying, filter and concentrated title compound (34.3g, the yield: 96.1%), be brown oil of obtaining
1H?NMR(400MHz，DMSO-d 6)δppm；2.54(3H，s)，7.44-7.52(1H，m)，7.90-7.96(1H，m)，8.56-8.60(1H，m)。
(51b) 2-methyl-3-((trimethyl silyl) ethynyl) pyridine
[formula 243]
At first with 2-picoline-3-base triflate (34.3g, 142mmol), trimethyl silyl acetylene (30ml, 212mmol), two (triphenylphosphine) Palladous chloride (II) (10.0g, 14.2mmol) and cuprous iodide (2.75g, 14.4mmol) be dissolved in N, dinethylformamide (150ml).(43ml 309mmol) at room temperature joins in the mixture in nitrogen atmosphere with triethylamine then.Then mixture is stirred 3 hours (generation thermopositive reaction).Reaction mixture is separated with saturated aqueous ammonium chloride by ethyl acetate, then by removing by filter insolubles.The organic layer of filtrate is washed 2 times with saturated aqueous ammonium chloride, use anhydrous magnesium sulfate drying, filter and concentrated title compound (22.6g, the yield: 84.1%), be brown oil of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；0.25(9H，s)，2.57(3H，s)，7.22(1H，dd，J＝5，8Hz)，7.79(1H，dd，J＝2，8Hz)，8.43(1H，dd，J＝2，5Hz)。
(51c) 3-ethyl-2-picoline
[formula 244]
Figure S2006800126056D01651
At first (22.6g 119mmol) is dissolved in tetrahydrofuran (THF) (anhydrous) (200ml) with 2-methyl-3-((trimethyl silyl) ethynyl) pyridine.In mixture, add tetrabutyl ammonium fluoride (1N tetrahydrofuran solution) (150ml, 150mmol).Mixture was at room temperature stirred 1 hour.Reaction mixture is distributed by ethyl acetate and saturated aqueous ammonium chloride.With the water layer ethyl acetate extraction.Organic layer is merged,, distill with anhydrous magnesium sulfate drying and by rotatory evaporator with saturated aqueous ammonium chloride washing 2 times.In the fraction that obtains, add 10% palladium/carbon (900mg), in nitrogen atmosphere, at room temperature stirred 2 hours then.With reaction mixture by anhydrous magnesium sulfate and diatomite filtration.In filtrate, add 10% palladium/carbon (810mg) and mixture was at room temperature stirred in nitrogen atmosphere 4 hours.Reaction mixture by anhydrous magnesium sulfate and diatomite filtration, is obtained title compound (7.25g, yield: 51.1%), be water white oil with filtrate concentrating then.
1H?NMR(400MHz，DMSO-d 6)δppm；1.16(3H，t，J＝8Hz)，2.45(3H，s)，2.60(2H，q，J＝8Hz)，7.14(1H，dd，J＝5，7Hz)，7.51(1H，dd，J＝1，7Hz)，8.26(1H，dd，J＝1，5Hz)。
(51d) 3-ethyl-2-picoline 1-oxide compound
[formula 245]
Figure S2006800126056D01652
At first (7.25g 59.8mmol) is dissolved in methylene dichloride (anhydrous) (100ml), adds 3-chlorine peroxybenzoic acid (content is by 65% for 19.0g, 71.6mmol) then in nitrogen atmosphere under the cooling of ice with 3-ethyl-2-picoline.Mixture was at room temperature stirred 90 hours.In reaction mixture, add saturated sodium bicarbonate aqueous solution.With water layer dichloromethane extraction 2 times, use chloroform extraction 3 times.Organic layer is merged, use anhydrous magnesium sulfate drying, filter and concentrate.Resistates is obtained title compound (7.35g, yield: 89.6%), be the light red solid by silica gel chromatography (silica gel: 100g, eluting solvent: heptane, ethyl acetate/methanol=10/1).
1H?NMR(400MHz，DMSO-d 6)δppm；1.14(3H，t，J＝8Hz)，2.35(3H，s)，2.64(2H，q，J＝8Hz)，7.12-7.24(2H，m)，8.10-8.16(1H，m)。
(51e) 3-ethyl-2-methyl-4-nitropyridine 1-oxide compound
[formula 246]
Figure S2006800126056D01661
Cooling 3-ethyl-2-picoline 1-oxide compound in ice bath (7.35g, 53.6mmol) and sulfuric acid (drip in the time of 22.7g, 231mmol) mixture nitrosonitric acid (3.64ml, 87.9mmol) and with it 80 ℃ of stirrings 8 hours down.Reaction mixture is cooled to room temperature, pours in the ice then.With aqueous solution chloroform extraction 3 times that obtain.Organic layer is merged, use anhydrous magnesium sulfate drying, filter and concentrated title compound (3.37g, the yield: 34.5%), be yellow solid of obtaining.
1H?NMR(400MHz，DMSO-d 6)δppm；1.21(3H，t，J＝7Hz)，2.45(3H，s)，2.80(2H，q，J＝7Hz)，7.88(1H，d，J＝7Hz)，8.36(1H，d，J＝7Hz)。
(51f) 4-chloro-3-ethyl-2-picoline 1-oxide compound
[formula 247]
Figure S2006800126056D01662
At first with 3-ethyl-2-methyl-4-nitropyridine 1-oxide compound (3.37g, 18.5mmol) in nitrogen atmosphere, under-30 ℃, join Acetyl Chloride 98Min. (20ml, 281mmol) in.Mixture was stirred 3 hours down at-30 to 0 ℃.After reaction mixture concentrated, resistates is distributed by chloroform and saturated sodium bicarbonate aqueous solution.After removing by filter insolubles, with water layer chloroform extraction 2 times.Organic layer is merged, and use anhydrous magnesium sulfate drying, filter and concentrate.Resistates is obtained title compound (2.10g, yield: 66.1%), be yellow oil by silica gel chromatography (NH silica gel: 100g, eluting solvent: heptane, heptane/ethyl acetate=50/50).
1H?NMR(400MHz，DMSO-d 6)δppm；1.10(3H，t，J＝8Hz)，2.42(3H，s)，2.77(2H，q，J＝8Hz)，7.41(1H，d，J＝7Hz)，8.16(1H，d，J＝7Hz)。
(51g) 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-ethylpyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 248]
Figure S2006800126056D01671
Repeat and the step (10b) of embodiment 10 and the identical method of step (11f)-(11i) of embodiment 11, utilize contract acetone (solketal) and 2-mercaptobenzimidazole of 4-chloro-3-ethyl-2-picoline 1-oxide compound, glyceryl alcohol to obtain title compound (122mg, yield: 5.6%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.07(3H，t，J＝7Hz)，1.30(3H，s)，1.35(3H，s)，2.60-2.83(2H，m)，3.81(1H，t，J＝7Hz)，4.01-4.18(3H，m)，4.32-4.47(2H，m)，4.67-4.77(1H，m)，6.79-6.89(2H，m)，6.95(1H，d，J＝5H)，7.38-7.49(2H，m)，8.29(1H，d，J＝5Hz)。
(embodiment 52) 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-5-fluoro-1H-benzoglyoxaline sodium salt
[formula 249]
Figure S2006800126056D01681
(52a) 5-fluoro-1H-benzimidazolyl-2 radicals-mercaptan
[formula 250]
With 3,4-diaminostilbene-fluorobenzene (10g, 79.3mmol), dithiocarbonic anhydride (70ml, 1164mmol) and the mixture of methyl alcohol (100ml) at room temperature stirred 86 hours 50 minutes.After reaction mixture concentrated, resistates is suspended in the hexane.The throw out that forms is obtained title compound (13.1g, yield: 98.2%), be brown solid by the filtration collection and with hexane wash.
1H?NMR(400MHz，DMSO-d 6)δppm；6.90-6.99(2H，m)，7.06-7.13(1H，m)，12.58(1H，s)，12.61(1H，s)。
(52b) 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-5-fluoro-1H-benzoglyoxaline sodium salt
[formula 251]
Figure S2006800126056D01683
Repeat and the step (11h) of the step (5f) of the step (14b) of the step (10b) of embodiment 10, embodiment 14, embodiment 5, embodiment 11 and (11i) identical step, utilize glyceryl alcohol contract acetone, 4-chloro-2,3-lutidine 1-oxide compound and 5-fluoro-1H-benzimidazolyl-2 radicals-mercaptan obtain title compound (210mg, yield: 14.1%), be white solid.Note, with step (5f) identical operations in replace ethanol as solvent with methyl alcohol.
1H?NMR(400MHz，DMSO-d 6)δppm；1.29(3H，s)，1.30-1.40(3H，m)，2.17(3H，s)，3.80(1H，dd，J＝6，8Hz)，4.00-4.16(3H，m)，4.37(1H，d，J＝13Hz)，4.42(1H，quint，J＝6Hz)，4.70-4.79(1H，m)，6.62-6.73(1H，m)，6.94(1H，d，J＝5Hz)，7.08-7.16(1H，m)，7.33-7.43(1H，m)，8.27(1H，d，J＝5Hz)。
((((1,3-two for 4-for (embodiment 53) 2-
Figure 2006800126056_181
Alkane-5-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 252]
(53a) 1,3-two
Figure 2006800126056_182
Alkane-5-base methyl alcohol
[formula 253]
With 2-(hydroxymethyl)-1, ammediol (3.06g, 28.8mmol), the formaldehyde dimethylacetal (9ml, 102mmol), lithiumbromide (488mg, 5.62mmol), the tosic acid monohydrate (491mg, 2.58mmol) and methylene dichloride (anhydrous) mixture (15ml) stirred 7 days.After adding triethylamine (1ml), reaction mixture is concentrated.Resistates is obtained title compound (1.37g, yield: 40.3%), be water white oil by silica gel chromatography (silica gel: 100g, eluting solvent: heptane, heptane/ethyl acetate=1/1,1/3).
1H?NMR(400MHz，DMSO-d 6)δppm；1.76-1.86(1H，m)，3.36(2H，t，J＝6Hz)，3.57(2H，dd，J＝8，11Hz)，3.90(2H，dd，J＝4，8Hz)，4.58(1H，t，J＝6Hz)，4.63(1H，d，J＝6Hz)，4.79(1H，d，J＝6Hz)。
(53b) ((((1,3-two for 4-for 2-
Figure 2006800126056_183
Alkane-5-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 254]
Figure S2006800126056D01701
Repeat and the step (10b) of embodiment 10 and the identical method of step (11f)-(11i) of embodiment 11, utilize 1,3-two
Figure 2006800126056_184
Alkane-5-base methyl alcohol, 4-chloro-2,3 dimethyl pyridine 1-oxide compound and 2-mercaptobenzimidazole obtain title compound (927mg, yield: 24.2%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δ?ppm；2.15-2.27(1H，m)，2.19(3H，s)，3.73-3.85(2H，m)，3.98-4.06(2H，m)，4.11(2H，d，J＝7Hz)，4.40(1H，d，J＝13Hz)，4.75(1H，d，J＝6Hz)，4.77(1H，d，J＝13Hz)，4.83(1H，d，J＝6Hz)，6.80-6.91(2H，m)，6.96(1H，d，J＝6Hz)，7.40-7.51(2H，m)，8.30(1H，d，J＝6Hz)。
(embodiment 54) 2-(((4-((2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-4-methyl isophthalic acid H-benzoglyoxaline sodium salt
[formula 255]
Figure S2006800126056D01702
(54a) 4-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan
[formula 256]
Figure S2006800126056D01703
At first (7g 46mmol) is suspended in the methyl alcohol (70ml) with 10% palladium carbon (900mg), and it was stirred in nitrogen atmosphere 5 hours with 2-methyl-6-N-methyl-p-nitroaniline.With reaction vessel with nitrogen purge and by removing by filter catalyzer.In reaction mixture, add dithiocarbonic anhydride (30ml) and mixture at room temperature stirred and spend the night.After decompression steams solvent diethyl ether is joined in the resistates.The solid by filtration collection that generates is obtained title compound (6.9g, yield: 92.7%), be light blue solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.37(3H，s)，6.91(1H，t，J＝8Hz)，6.94(1H，d，J＝8Hz)，7.00(1H，d，J＝8Hz)
(54b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_186
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-4-methyl isophthalic acid H-benzoglyoxaline sodium salt
[formula 257]
Figure S2006800126056D01711
Repeat the identical method of step (11g)-(11i) with embodiment 11, utilize 4-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan with (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_187
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol makes title compound (327mg, yield: 36.5%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.14(1H，m)，2.21(3H，s)，2.48(3H，s)，3.75-3.82(2H，m)，3.97-4.02(2H，m)，4.11(2H，d，J＝7Hz)，4.44(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.65(1H，d，J＝7Hz)，6.75(1H，dd，J＝7，8Hz)，6.95(1H，d，J＝6Hz)，7.26(1H，d，J＝8Hz)，8.29(1H，d，J＝6Hz)。
(embodiment 55) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_188
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-5-methyl isophthalic acid H-benzoglyoxaline sodium salt
[formula 258]
Figure S2006800126056D01721
Repeat the identical method of step (11g)-(11i) with embodiment 11, utilize 5-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan with (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_189
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl alcohol makes title compound (330mg, yield: 35.6%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.06-2.15(1H，m)，2.17(3H，s)，2.36(3H，s)，3.75-3.82(2H，m)，3.97-4.02(2H，m)，4.11(2H，d，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.69(1H，dd，J＝2，8Hz)，6.95(1H，d，J＝6Hz)，7.23(1H，d，J＝2Hz)，7.32(1H，d，J＝8Hz)，8.29(1H，d，J＝6Hz)。
(embodiment 56) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_190
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-5-fluoro-1H-benzoglyoxaline sodium salt
[formula 259]
Repeat the identical method of step (11g)-(11i) with embodiment 11, utilize 5-fluoro-1H-benzimidazolyl-2 radicals-mercaptan with (4-((2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl alcohol makes title compound (169mg, yield: 33.7%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.03-2.13(1H，m)，2.20(6H，s)，3.76-3.87(4H，m)，4.00(2H，dd，J＝4，11Hz)，4.38(1H，d，J＝13Hz)，4.74(1H，d，J＝13Hz)，6.65-6.74(1H，m)，7.10-7.17(1H，m)，7.36-7.43(1H，m)，8.22(1H，s)。
(embodiment 57) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 260]
Figure S2006800126056D01731
(57a) 4-chloro-2-picoline 1-oxide compound
[formula 261]
Figure S2006800126056D01732
With 4-nitro-2-PICOLINE N-OXIDES (20g, 130mmol) in nitrogen atmosphere, under-25 ℃, join Acetyl Chloride 98Min. (120ml, 1688mmol) in.Mixture was stirred 4 hours 15 minutes down at-30 to 5 ℃.After reaction mixture usefulness ethyl acetate (about 150ml) and chloroform (about 100ml) dilution, mixture is concentrated.Resistates is obtained title compound (3.14g) by silica gel chromatography (NH silica gel: 200g, eluting solvent: heptane, heptane/ethyl acetate=75/25,50/50,25/75, ethyl acetate, ethyl acetate/methanol=20/1), be brown oil.Obtain crude product (about 17g) simultaneously.Resulting crude product is further obtained title compound (5.39g) in addition by silica gel chromatography (NH silica gel: 300g, eluting solvent: heptane, heptane/ethyl acetate=75/25,40/60,25/75, ethyl acetate), be brown oil.
1H?NMR(400MHz，DMSO-d 6)δppm；2.33(3H，s)，7.41(1H，dd，J＝3，7Hz)，7.68(1H，d，J＝3Hz)，8.25(1H，d，J＝7Hz)。
(57b) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 262]
Repeat and the step (10b) of embodiment 10 and the identical method of step (11f)-(11i) of embodiment 11, utilize 4-chloro-2-picoline 1-oxide compound, with the method identical with step (13a) obtain 5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base methyl alcohol and 2-mercaptobenzimidazole obtain title compound (274mg, yield: 11.4%), be white solid.Note, with step (11g) identical operations in, join 2-mercaptobenzimidazole in the reaction mixture after, mixture at room temperature stirred 1 day and add 2 equivalent triethylamines based on the amount of alcohol, stirred 8 hours 35 minutes down at 50 ℃ then, at room temperature stirred 84 hours 40 minutes.
1H?NMR(400MHz，DMSO-d 6)δppm；1.64(2H，quint，J＝8Hz)，1.88-1.97(1H，m)，2.13(2H，t，J＝8Hz)，2.15(2H，t，J＝8Hz)，3.47-3.62(3H，m)，3.75-3.85(3H，m)，4.45(1H，d，J＝12Hz)，4.90(1H，d，J＝12?Hz)，6.58(1H，d，J＝2Hz)，6.82(1H，dd，J＝2，6Hz)，6.84-6.91(2H，m)，7.42-7.48(2H，m)，8.31(1H，d，J＝6Hz)。
(embodiment 58) 2-(((4-(6,10-dioxo spiro [4.5] last of the ten Heavenly stems-8-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 263]
Figure S2006800126056D01742
Repeat and the step (10b) of embodiment 10 and the identical method of step (11f)-(11i) of embodiment 11, utilize 4-chloro-2-picoline 1-oxide compound, with the method identical with step (21a) obtain 6,10-dioxo spiro [4.5] last of the ten Heavenly stems-8-base methyl alcohol and 2-mercaptobenzimidazole obtain title compound (427mg, yield: 15.6%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.52-1.63(4H，m)，1.73-1.86(4H，m)，1.88-1.98(1H，m)，3.52-3.66(3H，m)，3.78-3.88(3H，m)，4.45(1H，d，J＝12Hz)，4.59(1H，d，J＝12Hz)，6.60(1H，d，J＝3Hz)，6.82(1H，dd，J＝3，6Hz)，6.84-6.91(2H，m)，7.42-7.49(2H，m)，8.32(1H，d，J＝6Hz)。
(embodiment 59) 2-(((4-((2,2-two (methyl fluoride)-1,3-two Alkane-5-yl) sulfinyl methyl pyridine-2-yl methoxyl group))))-1H-benzoglyoxaline sodium salt
[formula 264]
Figure S2006800126056D01751
Repeat and the step (10b) of embodiment 10 and the identical method of step (11f)-(11i) of embodiment 11, utilize 4-chloro-2-picoline 1-oxide compound, with the method identical with step (7a) obtain (2,2-two (methyl fluoride)-1,3-two
Figure 2006800126056_193
Alkane-5-yl) methyl alcohol and 2-mercaptobenzimidazole obtain title compound (326mg, yield: 12.5%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.02-2.12(1H，m)，3.68-3.78(3H，m)，3.90(1H，dd，J＝7，10Hz)，3.97-4.06(2H，m)，4.40-4.65(6H，m)，6.66(1H，d，J＝2Hz)，6.83-6.92(3H，m)，7.43-7.50(2H，m)，8.34(1H，d，J＝6Hz)。
(embodiment 60) 2-(((4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 265]
Figure S2006800126056D01761
Repeat and the step (10b) of embodiment 10 and the identical method of step (11f)-(11i) of embodiment 11, utilize 4-chloro-2-picoline 1-oxide compound, with the method identical with step (10a) obtain 1,5,9-trioxa spiral shell [5.5] undecane-3-base methyl alcohol and 2-mercaptobenzimidazole obtain title compound (313mg, yield: 7.1%), be white solid.Note, with step (11g) identical operations in, join 2-mercaptobenzimidazole in the reaction mixture after, mixture at room temperature stirred 86 hours 30 minutes and add 2 equivalent triethylamines based on the amount of alcohol, stirred 10 hours down at 50 ℃ then, at room temperature stirred 14 hours 30 minutes.
1H?NMR(400MHz，DMSO-d 6)δppm；1.76(2H，t，J＝5Hz)，1.81(2H，t，J＝5Hz)，1.91-2.02 (1H，m)，3.55(4H，t，J＝5Hz)，3.58-3.75(3H，m)，3.83-3.96(3H，m)，4.44(1H，d，J＝12Hz)，4.58(1H，d，J＝12Hz)，6.64(1H，d，J＝2Hz)，6.82-6.91(3H，m)，7.43-7.49(2H，m)，8.33(1H，d，J＝6Hz)。
(embodiment 61) 2-(((4-(2,3-dihydro-1,4-benzo Dioxins-2-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 266]
Figure S2006800126056D01762
Repeat the identical step of step (8c) to (8g) with embodiment 8, utilize 2-hydroxymethyl-1,4-benzo two
Figure 2006800126056_194
Alkane obtains title compound (141mg, total recovery: 3%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.20(3H，s)，4.19(1H，dd，J＝7，12Hz)，4.30-4.34(2H，m)，4.38(1H，dd，J＝5，13Hz)，4.46(1H，dd，J＝2，12Hz)，4.61-4.63(1H，m)，4.82(1H，dd，J＝5，13Hz)，6.82-6.93(6H，m)，6.98(1H，d，J＝6Hz)，7.43(2H，dd，J＝3，6Hz)，8.29(1H，d，J＝6Hz)。
((((1,4-two for 4-for (embodiment 62) 2-
Figure 2006800126056_195
Alkane-2-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 267]
Figure S2006800126056D01771
(62a) 2-iodomethyl-1,4-two
Figure 2006800126056_196
Alkane
[formula 268]
Figure S2006800126056D01772
To 2-(allyloxy) ethanol (14g, add in acetonitrile 137mmol) (420mL) solution sodium bicarbonate (34.6g, 410mmol) and iodine (104g, 410mmol) and at room temperature stirred 20 hours.In reaction mixture, add entry and use ethyl acetate extraction.Then organic layer is washed with sodium thiosulfate solution and saturated brine solution, filter with dried over mgso and by silicon gel pillar pad.Filtrate concentrating obtained title compound (26.5g, yield 85%), be yellow liquid.
1H?NMR(400MHz，CDCl 3)δppm；3.10(2H，d，J＝8Hz)，3.34(1H，dd，J＝8，13Hz)，3.66-3.98(6H，m)。
(62b) 2-hydroxymethyl-1,4-two
Figure 2006800126056_197
Alkane
[formula 269]
Figure S2006800126056D01773
To the 2-iodomethyl-1 that step (62a) obtains, 4-two Alkane (15g, add in 65.8mmol) potassium acetate (64.6g, 658mmol), (1.74g, 6.58mmol) and N, dinethylformamide (220mL) also stirred 24 hours down at 80 ℃ 18-hat-6.In reaction mixture, add entry and use ethyl acetate extraction.Organic layer is merged, and water and saturated brine solution washing obtain acetoxyl group compound (5g) with dried over mgso.This acetoxyl group compound is dissolved in methyl alcohol (60mL) and dripping hydrochloric acid (1mL).Mixture was at room temperature stirred 1 hour, stirred 1 hour down, then by adding the triethylamine neutralization at 40 ℃.Mixture concentrated and with the resistates extracted with diethyl ether.Leach insolubles and filtrate is concentrated, resistates is obtained title compound (2.15g, yield: 27%), be colourless liquid by silica gel chromatography (silica gel: 500ml, eluting solvent: heptane/ethyl acetate=3/2,1/1,0/1).
1H?NMR(400MHz，CDCl 3)δppm；3.44-3.89(9H，m)。
(62c) (1,4-two for 4-
Figure 2006800126056_199
Alkane-2-ylmethoxy)-2,3 dimethyl pyridine 1-oxide compound
[formula 270]
Figure S2006800126056D01781
With the 2-hydroxymethyl-1 that step (62b) obtains, 4-two
Figure 2006800126056_200
(2.24g, 19mmol) (2.5g, toluene solution 15.8mmol) are heated to 140 ℃ to alkane with 4-chloro-2,3 dimethyl pyridine 1-oxide compound.In this solution, divide and add KOH for 2 times (2g 34.8mmol) and with the mixture that forms reflux 3 hours under identical temperature, utilizes the Dean-Stark device to remove from reaction system simultaneously and anhydrates.In reaction mixture, add NH silica gel also except that desolvating.The mixture of crude reaction product and NH silica gel are carried out purifying (NH silica gel, eluting solvent: ethyl acetate/methanol=9/1 is to 4/1) by silica gel column chromatography obtain title compound (2.9g, yield: 77%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.11(3H，s)，2.32(3H，s)，3.37-3.50(2H，m)，3.58-3.88(5H，m)，4.01-4.02(2H，m)，6.93(1H，d，J＝7Hz)，8.06(1H，d，J＝7Hz)。
(62d) ((((1,4-two for 4-for 2-
Figure 2006800126056_201
Alkane-2-ylmethoxy)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 271]
Figure S2006800126056D01791
Repeat the identical method of step (8d) to (8g) with embodiment 8, ((1,4-two for 4-to utilize the 4-that obtains in the step (62c)
Figure 2006800126056_202
Alkane-2-ylmethoxy))-2,3 dimethyl pyridine 1-oxide compound makes title compound (385mg, total recovery: 24%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.17(3H，s)，3.35-3.51(2H，m)，3.59-3.90(5H，m)，4.02(2H，brs)，4.36(1H，d，J＝12Hz)，4.80(1H，d，J＝12Hz)，6.83(2H，dd，J＝4，6Hz)，6.91(1H，d，J＝6Hz)，7.42(2H，dd，J＝4，6Hz)，8.26(1H，d，J＝6Hz)。
((((1,4-two for 4-for (embodiment 63) 2-
Figure 2006800126056_203
Alkane-2-ylmethoxy)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 272]
Figure S2006800126056D01792
Repeat the identical method of step (62a) to (62d) with embodiment 62, utilize 4-chloro-2,3,5-trimethylpyridine 1-oxide compound obtains title compound (355mg, total recovery: 18%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.18(3H，s)，2.21(3H，d，J＝2Hz)，3.29-3.82(9H，m)，4.36(1H，dd，J＝2，13Hz)，4.75(1H，dd，J＝2，13Hz)，6.82(2H，dd，J＝3，6Hz)，7.41(2H，dd，J＝3，6Hz)，8.19(1H，s)。
(embodiment 64) 2-(((4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 273]
Figure S2006800126056D01801
Repeat the identical step of step (4f) to (4j) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 4, utilize 4-(2-hydroxyethyl)-2,2-dimethyl-1, the 3-dioxolane obtains title compound (412mg, total recovery: 8.7%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.25(3H，s)，1.31(3H，s)，1.90-2.04(2H，m)，2.17(3H，s)，3.57(1H，t，J＝8Hz)，3.98-4.26(4H，m)，4.36(0.5H，d，J＝13Hz)，4.37(0.5H，d，J＝13Hz)，4.78(0.5H，d，J＝13Hz)，4.78(0.5H，d，J＝13Hz)，6.79-6.87(2H，m)，6.91(1H，d，J＝6Hz)，7.37-7.47(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 65) 2-(((4-((2,2-diethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 274]
(65a) 4-((benzyloxy) methyl)-2,2-diethyl-1,3-dioxolane
[formula 275]
Figure S2006800126056D01811
To DL-α-O-benzyl group glycerol (3g, 16.5mmol) tetrahydrofuran (THF) (30ml) solution at room temperature add propione (17.5ml, 165mmol) (300mg 1.58mmol) and with mixture stirred 22 hours under identical temperature with the tosic acid monohydrate.In reaction mixture, add saturated sodium bicarbonate aqueous solution (5ml) to regulate pH to being about 8.With the throw out that produces by removing by filter and filtrate being concentrated.The resistates that obtains is passed through silica gel chromatography (NH silica gel, eluting solvent: heptane/ethyl acetate=1/0 is to 3/1 gradient).Required fraction concentrated obtain title compound (2.77g, 67.1% yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；0.75-0.83(6H，m)，1.46-1.58(4H，m)，3.41-3.50(2H，m)，3.52-3.58(1H，m)，3.96-4.02(1H，m)，4.15-4.23(1H，m)，4.49(2H，s)，7.24-7.36(5H，m)。
(65b) (2,2-diethyl-1,3-dioxolane-4-yl) methyl alcohol
[formula 276]
Figure S2006800126056D01812
The 4-((benzyloxy) methyl)-2 that obtains to above step (65a), 2-diethyl-1,3-dioxolane (2.77g, 11.1mmol) methyl alcohol (40ml) solution in add palladium hydroxide (20wt.%Pd (based on dry weight)/carbon, wet (maximum amount of water 50%)) and (400mg) and with mixture in nitrogen atmosphere, at room temperature stirred 16 hours.Reaction vessel with nitrogen purge and by removing catalyzer with diatomite filtration, is used methanol wash then.The concentrated also drying under reduced pressure of filtrate is obtained title compound (1.593g, 89.6% yield), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.91(3H，t，J＝7Hz)，0.93(3H，t，J＝7Hz)，1.60-1.72(4H，m)，1.86(1H，t，J＝6Hz)，3.55-3.64(1H，m)，3.67-3.84(2H，m)，4.01-4.08(1H，m)，4.20-4.28(1H，m)。
(65c) 2-(((4-((2,2-diethyl-1,3-dioxolane-4-yl) methoxyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 277]
Repeat the identical method of step (4f) to (4j) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 4, utilize that above step (65b) obtains (2,2-diethyl-1,3-dioxolane-4-yl) methyl alcohol makes title compound (418 mg, 14.3% total recovery), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.78-0.88(6H，m)，1.51-1.66(4H，m)，2.18(1.5H，s)，2.18(1.5H，s)，3.76(1H，t，J＝8Hz)，4.02-4.20(3H，m)，4.32-4.48(2H，m)，4.76(0.5H，d，J＝13Hz)，4.78(0.5H，d，J＝13Hz)，6.78-6.88(2H，m)，6.94(1H，d，J＝6Hz)，7.37-7.47(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 66) 2-(((4-(1,3-dioxolane-2-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 278]
Figure S2006800126056D01822
(66a) 2-((benzyloxy) methyl)-1, the 3-dioxolane
[formula 279]
Figure S2006800126056D01831
With benzyloxy acetaldehyde (3g, 20mmol), ethylene glycol (1.23ml, 22mmol), the tosic acid monohydrate (344mg, 1.8mmol) and the mixture of toluene (15ml) stirred 2 hours down at 140 ℃, continue down to stir 3 hours at 150 ℃.After cooled on ice, 2N aqueous sodium hydroxide solution and ethyl acetate are joined in the reaction mixture.Tell organic layer, water (3 times) and saturated brine solution washing.Organic layer is also concentrated with anhydrous sodium sulfate drying.Crude product is passed through silica gel chromatography (NH silica gel, eluting solvent: heptane/ethyl acetate=1/0 is to 9/1 gradient).Required fraction concentrated obtain title compound (3.01g, 77.5% yield), be light yellow oil.
1H?NMR(400MHz，DMSO-d 6)δppm；3.45(2H，d，J＝4Hz)，3.74-3.92(4H，m)，4.51(2H，s)，4.98(1H，t，J＝4Hz)，7.24-7.38(5H，m)。
(66b) 1,3-dioxolane-2-base methyl alcohol
[formula 280]
Figure S2006800126056D01832
The 2-((benzyloxy) methyl)-1 that obtains to above step (66a), 3-dioxolane (3.01g, 15.5mmol) methyl alcohol (100ml) solution in add palladium hydroxide (20wt.%Pd (based on dry weight)/carbon, wet (maximum amount of water 50%)) and (300mg) and with mixture in nitrogen atmosphere, at room temperature stirred 15 hours.Reaction vessel is removed catalyzer with nitrogen purge and by diatomite filtration, use methanol wash then.The concentrated also drying under reduced pressure of filtrate is obtained title compound (1.57g, 97.3% yield), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；1.89(1H，brs)，3.66-3.72(2H，m)，3.88-4.08(4H，m)，5.01(1H，t，J＝3Hz)。
(66c) 2-(((4-(1,3-dioxolane-2-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 281]
Figure S2006800126056D01841
Repeat and the identical method of embodiment 4 described steps (4f) to (4j) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step), utilize that above step (66b) obtains 1,3-dioxolane-2-base methyl alcohol makes title compound (411mg, 17.2% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；2.17(3H，s)，3.80-4.00(4H，m)，4.07(2H，d，J＝4Hz)，4.39(1H，d，J＝13Hz)，4.79(1H，d，J＝13Hz)，5.24(1H，t，J＝4Hz)，6.80-6.89(2H，m)，6.94(1H，d，J＝6Hz)，7.38-7.46(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 67) 2-(((3-methyl-4-((2-methyl isophthalic acid, 3-dioxolane-2-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 282]
Figure S2006800126056D01842
(67a) 2-((benzyloxy) methyl)-2-methyl isophthalic acid, the 3-dioxolane
[formula 283]
Figure S2006800126056D01843
With 1-benzyloxy-2-acetone (4.94g, 30.1mmol), ethylene glycol (20ml, 359mmol), (5ml, 30.1mmol) (130mg, mixture 0.683mmol) at room temperature stirred 61.5 hours triethyl orthoformate with the tosic acid monohydrate.In reaction mixture, add saturated sodium bicarbonate aqueous solution (20ml) and use chloroform (50ml) to extract 2 times in mixture, organic layer is also concentrated with anhydrous sodium sulfate drying.Crude product is passed through silica gel chromatography (NH silica gel, eluting solvent: heptane/ethyl acetate=1/0 is to 4/1 gradient).Required fraction concentrated obtain title compound (5.67g, 90.5% yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.26(3H，s)，3.34(2H，s)，3.85(4H，s)，4.51(2H，s)，7.22-7.38(5H，m)。
(67b) (2-methyl isophthalic acid, 3-dioxolane-2-yl) methyl alcohol
[formula 284]
Figure S2006800126056D01851
2-((benzyloxy) the methyl)-2-methyl isophthalic acid that obtains to above step (67a), 3-dioxolane (5.66g, 27.2mmol) methyl alcohol (100ml) solution in add palladium hydroxide (20wt.%Pd (based on dry weight)/carbon, wet (maximum amount of water 50%)) and (500mg) and with mixture in nitrogen atmosphere, at room temperature stirred 17 hours.Reaction vessel is removed catalyzer with nitrogen purge and by diatomite filtration, use methanol wash then.The concentrated also drying under reduced pressure of filtrate is obtained title compound (2.96g, 92.1% yield), be light green oil.
1H?NMR(400MHz，CDCl 3)δppm；1.35(3H，s)，1.82-1.90(1H，br)，3.54(2H，d，J＝6Hz)，4.01(4H，s)。
(67c) 2-(((3-methyl-4-((2-methyl isophthalic acid, 3-dioxolane-2-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 285]
Figure S2006800126056D01861
Repeat the identical method of step (4f) to (4j) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 4, (the 2-methyl isophthalic acid that utilizes above step (67b) to obtain, 3-dioxolane-2-yl) methyl alcohol makes title compound (263mg, 12.9% total recovery), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.39(3H，s)，2.19(3H，s)，3.88-4.00(4H，m)，3.96(2H，s)，4.37(1H，d，J＝13Hz)，4.79(1H，d，J＝13Hz)，6.78-6.88(2H，m)，6.92(1H，d，J＝6Hz)，7.37-7.46(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 68) 2-(((4-((2S)-1,4-dioxo spiro [4.5] last of the ten Heavenly stems-2-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 286]
Figure S2006800126056D01862
Repeat the identical method of step (4f) to (4j) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 4, utilize (+)-1,4-dioxo spiro [4.5] decane-2-methyl alcohol obtains title compound (500mg, 16.8% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.24-1.63(10H，m)，2.18(3H，s)，3.76-3.84(1H，m)，4.01-4.14(3H，m)，4.37(0.5H，d，J＝13Hz)，4.38(0.5H，d，J＝13Hz)，4.38-4.46(1H，m)，4.77(0.5H，d，J＝13Hz)，4.78(0.5H，d，J＝13Hz)，6.79-6.87(2H，m)，6.94(1H，d，J＝6Hz)，7.37-7.46(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 69) 2-(((3-methyl-4-(2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 287]
Figure S2006800126056D01871
(69a) 2-(2-(benzyloxy) ethyl)-2-methyl isophthalic acid, the 3-dioxolane
[formula 288]
Figure S2006800126056D01872
With 4-benzyloxy-2-butanone (10g, 56.1mmol), ethylene glycol (40ml, 718mmol), (9.3ml, 55.9mmol) (290mg, mixture 1.52mmol) at room temperature stirred 13.5 hours triethyl orthoformate with the tosic acid monohydrate.In reaction mixture, add saturated sodium bicarbonate aqueous solution (40ml) and use chloroform (50ml) to extract 3 times in mixture.Organic layer is also concentrated with anhydrous sodium sulfate drying.Crude product is passed through silica gel chromatography (NH silica gel, eluting solvent: heptane/ethyl acetate=1/0 is to 4/1 gradient).Required fraction concentrated obtain title compound (10.08g, 80.8% yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.23(3H，s)，1.86(2H，t，J＝7Hz)，3.48(2H，t，J＝7Hz)，3.75-3.86(4H，m)，4.42(2H，s)，7.22-7.36(5H，m)。
(69b) 2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) ethanol
[formula 289]
2-(2-(benzyloxy) the ethyl)-2-methyl isophthalic acid that obtains to step (69a), 3-dioxolane (10.1g, 45.4mmol) methyl alcohol (150ml) solution in add palladium hydroxide (20wt.%Pd (based on dry weight)/carbon, wet (maximum amount of water 50%)) and (900mg) and with mixture in nitrogen atmosphere, at room temperature stirred 16 hours.Reaction vessel is removed catalyzer with nitrogen purge and by diatomite filtration, use methanol wash then.Filtrate is concentrated.The resistates that forms is passed through silica gel chromatography (silica gel, eluting solvent: heptane/ethyl acetate=1/0 → 1/1-0/1 gradient).Required fraction concentrated obtain title compound (3.5g, 58.3% yield), be light yellow oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.21(3H，s)，1.73(2H，t，J＝7Hz)，3.40-3.50(2H，m)，3.75-3.86(4H，m)，4.30(1H，t，J＝5Hz)。
(69c) 2-(((3-methyl-4-(2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 290]
Figure S2006800126056D01881
Repeat the identical method of step (4t) to (4j) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 4,2-(the 2-methyl isophthalic acid that utilizes step (69b) to obtain, 3-dioxolane-2-yl) ethanol makes title compound (410mg, 14.4% total recovery), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，2.08(2H，t，J＝7Hz)，2.15(3H，s)，3.87(4H，s)，4.10(2H，t，J＝7Hz)，4.38(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.77-6.89(2H，m)，6.92(1H，d，J＝6Hz)，7.35-7.49(2H，m)，8.26(1H，d，J＝6Hz)。
The sodium salt of the optically active isomer of (embodiment 70) 2-(((3-methyl-4-((2-methyl isophthalic acid, 3-dioxolane-2-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 291]
Figure S2006800126056D01891
Will (((3-methyl-4-((2-methyl isophthalic acid, 3-tetrahydrofuran-2-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-(185 mg) be water-soluble for 1H-benzoglyoxaline sodium salt (racemic modification) according to the 2-that obtains with the identical mode of step (67a) to (67c).In this solution, add methylene dichloride and saturated aqueous ammonium chloride.Water layer is further used dichloromethane extraction.Organic layer is merged, then with anhydrous sodium sulfate drying and concentrated.
In formed free form, add a small amount of diethylamide and mixture is separated (post: CHIRALCEL OD-H2cm by HPLC
Figure 2006800126056_204
* 25cm (by Daicel Chemical Industrises, Ltd. produces), moving phase: hexane/ethanol/diethylamide=80/20/0.1 (v/v/v), flow velocity: 9ml/min detects: 254nm).On the other hand, aqueous sodium hydroxide solution (100 μ l) is placed each test tube in advance.The fraction of the optically active isomer that the fraction of the optically active isomer that retention time is short and retention time are long concentrates respectively, and is then that resistates is water-soluble respectively.In every kind of solution, add methylene dichloride and saturated aqueous ammonium chloride.Water layer is further used dichloromethane extraction respectively.Organic layer is merged respectively, then with anhydrous sodium sulfate drying and concentrated.According to above-described mode, obtain the free form (59mg) of the short optically active isomer of retention time and the free form (56mg) of the optically active isomer that retention time is grown, be light grey foam.
The free form of every kind of optically active isomer operated according to the mode identical with step (4j) (formation of sodium salt) make sodium salt, thereby obtain the sodium salt (58mg) of the short optically active isomer of retention time and the sodium salt (53mg) of the optically active isomer that retention time is grown, be light yellow solid.
1H NMR (400MHz, DMSO-d 6) δ ppm; The chart of two kinds of isomer is identical with 2-(((3-methyl-4-((2-methyl isophthalic acid, 3-dioxolane-2-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt (racemic modification) all.
HPLC; (condition) post: CHIRALCEL OD-H (by Daicel Chemical Industrises, Ltd. produces) (0.46cm
Figure 2006800126056_205
* 25cm), eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.6ml/min detects: UV 254nm).
The retention time of the sodium salt of the optically active isomer that (analytical results) retention time is short: 16 minutes, enantiomeric excess: 100%ee; Retention time with the sodium salt of the long optically active isomer of retention time: 22 minutes, enantiomeric excess: 100%ee.
(embodiment 71) 2-(((4-(2-((4R)-2,2-monomethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 292]
(71a) 2-((4R)-2,2-monomethyl-1,3-dioxolane-4-yl) ethanol
[formula 293]
Figure S2006800126056D01902
With (R)-(+)-1,2, and the 4-trihydroxybutane (30g, 283mmol), (200ml, 2724mmol) (1.4g, mixture 7.36mmol) at room temperature stirred 16.5 hours acetone with the tosic acid monohydrate.In reaction mixture, add triethylamine and mixture is concentrated.Crude product is passed through silica gel chromatography (silica gel, eluting solvent: heptane/ethyl acetate=1/0 → 1/1 → 1/3 gradient).Required fraction concentrated obtain title compound (29.9g, 72.3% yield), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.37(3H，s)，1.43(3H，s)，1.78-1.95(3H，m)，3.60(1H，t，J＝8Hz)，3.76-3.85(2H，m)，4.09(1H，dd，J＝6，8Hz)，4.27(1H，quint，J＝6Hz)。
(71b) 2-(((4-(2-((4R)-2,2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 294]
Figure S2006800126056D01911
Repeat (in the step that obtains piconol, to utilize heptane to carry out recrystallization with the step (4f) to (4j) of embodiment 4, and in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, do not carry out reppd step) identical method, 2-((4R)-2 that utilize step (71a) to obtain, 2-dimethyl-1,3-dioxolane-4-yl) ethanol makes title compound (320mg, 8.5% total recovery), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.26(3H，s)，1.32(3H，s)，1.91-2.04(2H，m)，2.17(3H，s)，3.57(1H，t，J＝7Hz)，3.98-4.28(4H，m)，4.36(0.5H，d，J＝13Hz)，4.37(0.5H，d，J＝13Hz)，4.80(0.5H，d，J＝13Hz)，4.80(0.5H，d，J＝13Hz)，6.78-6.87(2H，m)，6.91(1H，d，J＝6Hz)，7.36-7.46(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 72) 2-(((4-(2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 295]
Figure S2006800126056D01912
(72a) 2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl) ethanol
[formula 296]
Figure S2006800126056D01921
To (S)-(-)-1,2, (30g, (1.4g at room temperature stirs 7.36mmol) and with mixture and to spend the night the 4-trihydroxybutane to add acetone (200ml) and tosic acid monohydrate in 283mmol).In reaction mixture, add triethylamine (4ml) and mixture is concentrated.Resistates is passed through silica gel chromatography (silica gel 350g, eluting solvent: ethyl acetate/heptane=18/82 → 6/4) obtain title compound (30.2g, yield: 73%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.37(3H，s)，1.43(3H，s)，1.83(2H，q，J＝6Hz)，2.20(1H，t，J＝6Hz)，3.60(1H，t，J＝8Hz)，3.80(2H，q，J＝6Hz)，4.09(1H，dd，J＝6，8Hz)，4.27(1H，quint，J＝6Hz)
(72b) 2-(((4-(2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 297]
Figure S2006800126056D01922
Repeat (in the step that obtains piconol, to utilize heptane to carry out recrystallization with the step (4f) to (4j) of embodiment 4, and in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, do not carry out reppd step) identical method, 2-((4S)-2 that utilize above step (72a) to obtain, 2-dimethyl-1,3-dioxolane-4-yl) ethanol makes title compound (386mg, 10.1% total recovery), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.25(3H，s)，1.31(3H，s)，1.90-2.05(2H，m)，2.17(3H，s)，3.57(1H，t，J＝8Hz)，4.00-4.27(4H，m)，4.37(0.5H，d，J＝13Hz)，4.37(0.5H，d，J＝13Hz)，4.78(0.5H，d，J＝13Hz)，4.78(0.5H，d，J＝13Hz)，6.79-6.87(2H，m)，6.91(1H，d，J＝6Hz)，7.38-7.46(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 73) 2-(((3-methyl-4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 298]
Figure S2006800126056D01931
(73a) (8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl acetate
[formula 299]
Will according to the identical mode of step (4a) to (4c) obtain 1,3-dioxolane-2,2-two basic dimethanol (4g, 29.8mmol), methyl acetoacetate (4.9ml, 45.4mmol), triethyl orthoformate (5.2ml, 31.3mmol) and the tosic acid monohydrate (163mg, mixture 0.856mmol) at room temperature stirred 3 hours.In mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.With organic layer water (2 times) and salt brine solution washing, then with anhydrous sodium sulfate drying and concentrated.Crude product is passed through silica gel chromatography (silica gel, eluting solvent: heptane/ethyl acetate=1/0-3/1-1/1 gradient).Required fraction concentrated obtain title compound (3.46g, 50.0% yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.41(3H，s)，2.75(2H，s)，3.57(3H，s)，3.60(2H，d，J＝12Hz)，3.65(2H，d，J＝12Hz)，3.84(4H，s)。
(73b) 2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) ethanol
[formula 300]
(the 8-methyl isophthalic acid that obtains to step (73a), 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methyl acetate (3.46g, 14.9mmol) THF (40ml) solution in add down lithium aluminum hydride at 0 ℃ (679mg 17.9mmol) and with mixture stirred 3 hours to room temperature at 0 ℃.After adding entry (0.68ml), 2N aqueous sodium hydroxide solution (0.68ml) and water (2ml) termination reaction successively, to wherein adding anhydrous sodium sulphate and diatomite.Mixture is filtered by glass fibre.Throw out with ethyl acetate washing and concentrate and obtain title compound (2.96g, 97.3% yield), is water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.27(3H，s)，1.81(2H，t，J＝7Hz)，3.44(2H，dt，J＝6，7Hz)，3.55(2H，d，J＝12Hz)，3.60(2H，d，J＝12Hz)，3.72-3.89(4H，m)，4.31(1H，t，J＝6Hz)。
(73c) 2-(((3-methyl-4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 301]
Repeat the identical method of step (4f)-(4j) with embodiment 4, the 2-(8-methyl isophthalic acid, 4 that utilize above step (73b) to obtain, 7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) ethanol obtains title compound (298mg, 15.1% total recovery), is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.38(3H，s)，2.11-2.20(5H，m)，3.62(2H，d，J＝12Hz)，3.66(2H，d，J＝12Hz)，3.79-3.90(4H，m)，4.11(2H，t，J＝7Hz)，4.37(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.80-6.87(2H，m)，6.90(1H，d，J＝6Hz)，7.38-7.45(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 74) 5-methyl-2-(((3-methyl-4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 302]
Repeat the identical method of step (4f)-(4j) with embodiment 4,2-(the 8-methyl isophthalic acid that utilizes above step (73b) to obtain, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) 5-methyl isophthalic acid H-benzimidazolyl-2 radicals-mercaptan of obtaining of ethanol and step (47a) makes title compound (188mg, 12.4% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.38(3H，s)，2.09-2.20(5H，m)，2.34(3H，s)，3.62(2H，d，J＝12Hz)，3.66(2H，d，J＝12Hz)，3.77-3.92(4H，m)，4.10(2H，t，J＝6Hz)，4.35(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.67(1H，d，J＝8Hz)，6.89(1H，d，J＝6Hz)，7.20(1H，s)，7.29(1H，d，J＝8Hz)，8.25(1H，d，J＝6Hz)。
(embodiment 75) 2-(((4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 303]
Figure S2006800126056D01952
Repeat the identical method of step (5d) to (5h) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 5,2-(the 8-methyl isophthalic acid that utilizes above step (73b) to obtain, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) the 4-chloro-2-picoline 1-oxide compound that obtains of ethanol and step (57a) obtains title compound (860mg, 20.2% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，2.05(2H，t，J＝7Hz)，3.59(2H，d，J＝12Hz)，3.64(2H，d，J＝12Hz)，3.78-4.03(6H，m)，4.45(1H，d，J＝12Hz)，4.54(1H，d，J＝12Hz)，6.71-6.90(4H，m)，7.37-7.48(2H，m)，8.32(1H，d，J＝6Hz)。
(embodiment 76) 2-(((4-(2-(9-methyl isophthalic acid, 5,8,10-four oxaspiros [5.5] undecane-9-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 304]
Figure S2006800126056D01961
(76a) 2,2-two ((benzyloxy) methyl)-1,3-two
Figure 2006800126056_206
Alkane
[formula 305]
Figure S2006800126056D01962
To obtain according to the mode identical with above step (4a) 1,3-two (benzyloxy) acetone (20g, 73.9mmol), 1, ammediol (54ml, 747mmol), triethyl orthoformate (13ml, 78.2mmol) and the tosic acid monohydrate (394mg, mixture 2.07mmol) stirred 14.5 hours down at 50 ℃.In mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.With organic layer water and salt brine solution washing, with anhydrous sodium sulfate drying and concentrated.The crude product that obtains is passed through silica gel chromatography (silica gel, eluting solvent: heptane/ethyl acetate=1/0-3/1 gradient).Required fraction concentrated obtain title compound (17.46g, 71.9% yield), be light yellow oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.60(2H，quint，J＝6Hz)，3.60(4H，s)，3.82(4H，t，J＝6Hz)，4.49(4H，s)，7.22-7.35(10H，m)。
(76b) 1,3-two
Figure 2006800126056_207
Alkane-2,2-two basic dimethanols
[formula 306]
Figure S2006800126056D01971
To above step (76a) obtain 2,2-two ((benzyloxy) methyl)-1,3-two
Figure 2006800126056_208
(17.46g adds palladium hydroxide (20wt.%Pd (based on dry weight)/carbon, wet (maximum amount of water 50%)) and (1.7g) and with mixture at room temperature stirred in nitrogen atmosphere 46 hours alkane in ethyl acetate 53.2mmol) (200ml) solution.Reaction vessel with nitrogen purge and by removing by filter catalyzer, is washed with ethyl acetate then.Filtrate concentrating obtained title compound (7.67g, 97.3% yield), be white solid.
1H?NMR(400MHz，DMSO-d 6)δ?ppm；1.58(2H，quint，J＝6Hz)，3.47(4H，d，J＝6Hz)，3.80(4H，t，J＝6Hz)，4.43(2H，t，J＝6Hz)。
(76c) (9-methyl isophthalic acid, 5,8,10-four oxaspiros [5.5] undecane-9-yl) methyl acetate
[formula 307]
Figure S2006800126056D01972
With above step (76b) obtain 1,3-two
Figure 2006800126056_209
Alkane-2,2-two basic dimethanols (4g, 27mmol), methyl acetoacetate (4.4ml, 40.8mmol), (4.6ml, 27.7mmol) (160mg, mixture 0.843mmol) at room temperature stirred 4.5 hours triethyl orthoformate with the tosic acid monohydrate.In mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.With organic layer water and salt brine solution washed twice, with anhydrous sodium sulfate drying and concentrated.To obtain crude product by silica gel chromatography (silica gel, eluting solvent: heptane/ethyl acetate=1/0-4/1-1/1 gradient).Required fraction concentrated obtain title compound (1.60g, 24.1% yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.39(3H，s)，1.53-1.63(2H，m)，2.72(2H，s)，3.56(3H，s)，3.70-3.86(8H，m)。
(76d) 2-(9-methyl isophthalic acid, 5,8,10-four oxaspiros [5.5] undecane-9-yl) ethanol
[formula 308]
(the 9-methyl isophthalic acid that obtains to step (76c), 5,8,10-four oxaspiros [5.5] undecane-9-yl) methyl acetate (1.6g, 6.5mmol) THF (20ml) solution in add down lithium aluminum hydride in 0 ℃ (300mg 7.9mmol) and with mixture stirred 1 hour to room temperature at 0 ℃.After adding entry (0.3ml), 2N aqueous sodium hydroxide solution (0.3ml) and water (0.9ml) termination reaction successively, to wherein adding anhydrous sodium sulphate and diatomite.Mixture is filtered by glass fibre.Throw out is washed and concentrates with ethyl acetate.The resistates that forms is passed through silica gel chromatography (silica gel, eluting solvent: heptane/ethyl acetate=3/1-1/4 gradient).Required fraction concentrated obtain title compound (950mg, 67.0% yield), be water white oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.24(3H，s)，1.53-1.63(2H，m)，1.78(2H，t，J＝7Hz)，3.43(2H，dt，J＝6，7Hz)，3.67-3.85(8H，m)，4.30(1H，t，J＝6Hz)。
(76e) 2-(((4-(2-(9-methyl isophthalic acid, 5,8,10-four oxaspiros [5.5] undecane-9-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 309]
Figure S2006800126056D01982
Repeat the identical method of step (5d) to (5h) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step) with embodiment 5,2-(the 9-methyl isophthalic acid that utilizes above step (76d) to obtain, 5,8,10-four oxaspiros [5.5] undecane-9-yl) ethanol makes title compound (228mg, 11.4% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.28(3H，s)，1.53-1.64(2H，m)，2.02(2H，t，J＝7Hz)，3.68-4.00(10H，m)，4.46(1H，d，J＝12Hz)，4.54(1H，d，J＝12Hz)，6.72-6.90(4H，m)，7.36-7.47(2H，m)，8.32(1H，d，J＝6Hz)。
(embodiment 77) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_210
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-6,7-dihydro-1H-[1.4] dioxine [2.3-f] benzoglyoxaline sodium salt also
[formula 310]
Figure S2006800126056D01991
Repeat and the identical method of above step (5f) to (5h) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step), utilize that step (12b) obtains (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_211
Alkane-5-yl) methoxyl group)-3-picoline-2-yl) methyl alcohol and 6,7-dihydro-1H-[1.4] dioxine also [2 ' .3 ': 4.5] benzo [d] imidazoles-2-mercaptan obtain title compound (137mg, 25.8% total recovery), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.35(3H，s)，2.03-2.14(1H，m)，2.16(3H，s)，3.70-3.82(2H，m)，3.92-4.02(2H，m)，4.09(2H，d，J＝7Hz)，4.14(4H，s)，4.32(1H，d，J＝13Hz)，4.75(1H，d，J＝13?Hz)，6.83(2H，s)，6.92(1H，d，J＝6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 78) 6-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_212
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-5H-[1.3] dioxole [4,5-f] benzoglyoxaline sodium salt also
[formula 311]
Figure S2006800126056D02001
(78a) 5,6-dinitrobenzene-1,3-benzo dioxole
[formula 312]
Figure S2006800126056D02002
With 5-nitro-1,3-benzo dioxole (10g, 59.8mmol), tetramethyl-ammonium nitrate (10.6g, 77.7mmol) and the mixture of methylene dichloride (100ml) ice cooling under stir, then below 7 ℃ to wherein drip trifluoromethanesulfanhydride anhydride (13.1ml, 77.7mmol).Mixture is at room temperature stirred 30 minutes and reflux to spend the night.Reaction mixture stirred under the cooling of ice and to wherein add tetramethyl-ammonium nitrate (4.07g, 29.9mmol) and trifluoromethanesulfanhydride anhydride (5.03ml, 29.9mmol).The mixture that forms was stirred 6 hours down at 50 ℃.Reaction mixture is cooled to room temperature and adds saturated sodium bicarbonate aqueous solution and ice.Mixture is stirred and organic layer is taken out.With the water layer ethyl acetate extraction.Organic layer is merged,, pass through filtered through silica gel then with sodium sulfate, dried over mgso.Filtrate concentrating obtained title compound (7.4g, 58.3%), be yellow solid.
1H?NMR(400MHz，CDCl 3)δppm；6.27(2H，s)，7.31(2H，s)。
(78b) 1,3-benzo dioxole-5,6-diamines
[formula 313]
Figure S2006800126056D02003
With above step (78a) obtain 5,6-dinitrobenzene-1,3-benzo dioxole (7.4g, 34.9mmol) and 10% palladium carbon (contain 50% water, 1.09g), the mixture of methyl alcohol (200ml) and tetrahydrofuran (THF) (50ml) stirred 3 days in nitrogen atmosphere.Make the mixture (6.48g) that contains title compound with the reaction mixture filtration and with filtrate concentrating, be yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；4.10(4H，brs)，5.67(2H，s)，6.23(2H，s)。
(78c) 5H-[1,3] dioxole [4,5-f] benzoglyoxaline-6-mercaptan also
[formula 314]
Figure S2006800126056D02011
Contain 1 with what above step (78b) obtained, 3-benzo dioxole-5, the mixture of 6-diamines (6.48g) is dissolved in methyl alcohol (100ml).In mixture, add dithiocarbonic anhydride (30ml) and mixture was at room temperature stirred 1 day.With the reaction mixture concentrating under reduced pressure.In solid residue, add ethyl acetate and filter.Solid is washed by adding tetrahydrofuran (THF), ethyl acetate and dilute hydrochloric acid, then insolubles is collected by filtering, drying under reduced pressure obtained title compound (3.8g in 2 hours under room temperature in moisture eliminator, 56.1%, with 5,6-dinitrobenzene-1,3-benzo dioxole meter), be brown solid.
1H?NMR(400MHz，DMSO-d 6)δppm；5.99(2H，s)，6.74(2H，s)，12.36(2H，brs)。
(78d) 6-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_213
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-5H-[1,3] dioxole [4,5-f] benzoglyoxaline sodium salt also
[formula 315]
Figure S2006800126056D02012
Repeat the identical method of step (5f) to (5h) with embodiment 5, utilize that above step (12b) obtains (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_214
Alkane-5-yl) methoxyl group)-3-picoline-2-yl) 5H-[1 that obtains of methyl alcohol and above step (78c), 3] dioxole also [4,5-f] benzoglyoxaline-6-mercaptan obtain title compound (347mg, 51.9% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.34(3H，s)，2.03-2.13(1H，m)，2.16(3H，s)，3.71-3.81(2H，m)，3.93-4.02(2H，m)，4.09(2H，d，J＝7Hz)，4.30(1H，d，J＝13Hz)，4.80(1H，d，J＝13Hz)，5.82(2H，s)，6.89(2H，s)，6.92(1H，d，J＝6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 79) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_215
Alkane-5-yl) sulfinyl methyl pyridine-2-yl methoxyl group))))-6,7-dihydro-1H-[1,4] dioxine [2,3-f] benzoglyoxaline sodium salt also
[formula 316]
Figure S2006800126056D02021
(79a) 4-((2,2-dimethyl-1,3-two
Figure 2006800126056_216
Alkane-5-yl) methoxyl group)-and N, N-di-isopropyl pyridine-2-carboxamide
[formula 317]
Figure S2006800126056D02022
The 4-chloro-N that will obtain according to the mode identical with step (92a), N-di-isopropyl pyridine-2-carboxamide (5g, 20.8mmol), according to the mode identical with step (11a) obtain (2,2-dimethyl-1,3-two
Figure 2006800126056_217
Alkane-5-yl) methyl alcohol (3.34g, 22.8mmol), potassium hydroxide (2.57g, 45.8mmol) and the mixture of toluene (50ml) with the equipment reflux 7 hours that is equipped with the Dean-Stark device and at room temperature stirred 3 days.With reaction mixture water and saturated brine solution washing, with dried over mgso and filtration.Filtrate decompression is concentrated and resistates is dissolved in toluene-heptane-ethyl acetate, carry out NH silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=2/1 → 1/1) then.The fraction that will contain required product concentrates and with the solid residue heptane wash, collects by filtration then and obtain title compound (5.39g, 73.9%), is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.09(6H，d，J＝7Hz)，1.23(3H，s)，1.36(3H，s)，1.43(6H，d，J＝6Hz)，2.02-2.10(1H，m)，3.51-3.65(2H，m)，3.74(2H，dd，J＝6，12Hz)，3.98(2H，dd，J＝4，12Hz)，4.16(2H，d，J＝7Hz)，6.95-7.00(2H，m)，8.33(1H，d，J＝6Hz)。
(79b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_218
Alkane-5-yl) sulfinyl methyl pyridine-2-yl methoxyl group))))-6,7-dihydro-1H-[1,4] dioxine [2,3-f] benzoglyoxaline sodium salt also
[formula 318]
Figure S2006800126056D02031
Repeat with step (92d) with (5f) to the identical method of (5h) (in the oxidation step that utilizes 3-chlorine peroxybenzoic acid, not carrying out reppd step), utilize the 4-that step (79a) obtains ((2,2-dimethyl-1,3-two
Figure 2006800126056_219
Alkane-5-yl) methoxyl group)-N, N-di-isopropyl pyridine-2-carboxamide and 6,7-dihydro-1H-[1,4] dioxine also [2 ', 3 ': 4,5] benzo [d] imidazoles-2-mercaptan obtains title compound (373m, 40.8% total recovery), is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.30(3H，s)，1.33(3H，s)，1.82-1.95(1H，m)，3.53-3.73(3H，m)，3.79-3.91(3H，m)，4.14(4H，s)，4.38(1H，d，J＝12Hz)，4.54(1H，d，J＝12Hz)，6.55-6.63(1H，m)，6.74-6.86(1H，m)，6.83(2H，s)，8.28(1H，d，J＝6Hz)。
(embodiment 80) 2-(((4-(1,4-dioxo spiro [4.4] ninth of the ten Heavenly Stems-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 319]
Figure S2006800126056D02041
(80a) 1,4-dioxo spiro [4.4] ninth of the ten Heavenly Stems-6-methyl-formiate
[formula 320]
Figure S2006800126056D02042
The reflux exchanger that is equipped with the Dean-Stark water separator is connected to contains 2-cyclopentanone methyl-formiate (2ml, 16.2mmol), ethylene glycol (994 μ l, 17.8mmol), (139mg is 0.73mmol) and on the round-bottomed flask of benzene (30ml) for the tosic acid monohydrate.Mixture heating up was refluxed 2 hours.In reaction mixture, add triethylamine (0.22ml) and mixture is concentrated, by silica gel chromatography (eluting solvent: ethyl acetate/heptane=1/9,1/1) obtain title compound (2.12g, yield 70.3%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.59-1.72(1H，m)，1.77-1.98(4H，m)，2.06-2.18(1H，m)，2.93(1H，t，J＝8Hz)，3.70(3H，s)，3.86-4.06(4H，m)。
(80b) 1,4-dioxo spiro [4.4] ninth of the ten Heavenly Stems-6-base methyl alcohol
[formula 321]
Figure S2006800126056D02043
To lithium aluminum hydride (630mg, in diethyl ether 16.6mmol) (30ml) suspension 0 ℃ of method that adds down by above step (80a) obtain 1,4-dioxo spiro [4.4] nonane-6-methyl-formiate (3.1g, 16.6mmol).Mixture was at room temperature stirred 3 hours.Water (0.6ml), 5N aqueous sodium hydroxide solution (0.6ml) and water (1.8ml) joined in the mixture and with mixture under 0 ℃ successively filter.After joining water in the filtrate, organic layer is separated.With water layer ethyl acetate extraction 3 times.With the extraction liquid dried over sodium sulfate that forms, concentrating under reduced pressure also passes through silica gel chromatography (eluting solvent: ethyl acetate/heptane=1/4,1/1) obtain title compound (1.9g, yield 72.4%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.51-1.92(6H，m)，2.11-2.18(1H，m)，2.53-2.69(1H，br)，3.58-3.73(2H，m)，3.88-4.02(4H，m)。
(80c) 2-(((4-(1,4-dioxo spiro [4.4] ninth of the ten Heavenly Stems-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 322]
Figure S2006800126056D02051
Repeat the identical method of step (14a) to (14e) with embodiment 14, utilize that above step (80b) obtains 1,4-dioxo spiro [4.4] ninth of the ten Heavenly Stems-basic methyl alcohol of 6-makes title compound (383mg, the total recovery of 5 steps: 14.6%), be light yellow solid.Note, in the process identical, replace ethanol as solvent with methyl alcohol with step (14c).
1H?NMR(400MHz，DMSO-d 6)δppm；1.42-1.80(5H，m)，1.86-2.01(1H，m)，2.15(3H，d，J＝7Hz)，2.28-2.41(1H，m)，3.70-3.93(5H，m)，4.02-4.13(1H，m)，4.38(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.79-6.87(2H，m)，6.89(1H，dd，J＝2，6Hz)，7.37-7.46(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 81) 2-(((4-((3,3-dimethyl-1,5-dioxo spiro [5.5] undecane-9-yl) oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 323]
Figure S2006800126056D02061
(81a) 3,3-dimethyl-1,5-dioxo spiro [5.5] undecane-9-alcohol
[formula 324]
Figure S2006800126056D02062
(748mg adds 1 down at 0 ℃ in tetrahydrofuran (THF) 19.7mmol) (40ml) suspension, 4-cyclohexanedione list-2,2-dimethyl trimethylene ketal (3.9g, tetrahydrofuran solution 19.7mmol) to lithium aluminum hydride.Mixture was at room temperature stirred 3 hours.After under 0 ℃, joining water (0.7ml), 5N aqueous sodium hydroxide solution (0.7ml) and water (2.1ml) in the mixture successively, with the mixture dried over sodium sulfate, filter, concentrating under reduced pressure also passes through silica gel chromatography (eluting solvent: ethyl acetate/heptane=1/2,1/1,2/1) obtains title compound (3.6g, yield: 91.2%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；0.97(6H，s)，1.51-1.60(4H，m)，1.74-1.86(2H，m)，2.04-2.14(2H，m)，3.50(4H，d，J＝4Hz)，3.74-3.84(1H，m)。
(81b) 2-(((4-((3,3-dimethyl-1,5-dioxo spiro [5.5] undecane-9-yl) oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 325]
Figure S2006800126056D02071
Repeat the identical method of step (14a) to (14e) with embodiment 14, utilize that above step (81a) obtains 3,3-dimethyl-1,5-dioxo spiro [5.5] undecane-9-alcohol obtains title compound (275mg, the total recovery of 5 steps: 3.3%), be white solid.Note, in the process identical, behind the adding diacetyl oxide, add 10 equivalent triethylamines to react with respect to pyridine 1-oxide derivative with step (14b).In the process identical, replace ethanol as solvent with tetrahydrofuran (THF) with step (14c).
1H?NMR(400MHz，DMSO-d 6)δppm；0.90(6H，s)，1.62-1.94(8H，m)，2.18(3H，s)，3.45(4H，d，J＝6Hz)，4.35(1H，d，J＝13Hz)，4.70-4.78(1H，br)，4.81(1H，d，J＝13Hz)，6.81-6.88(2H，m)，6.97(1H，d，J＝6Hz)，7.39-7.46(2H，m)，8.23(1H，d，J＝6Hz)。
(embodiment 82) 2-(((4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 326]
Figure S2006800126056D02072
(82a) 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-base methyl alcohol
[formula 327]
Figure S2006800126056D02073
The reflux exchanger that is equipped with the Dean-Stark water separator is connected to contains 4-pimelinketone ethyl formate (5ml, 31.4mmol), ethylene glycol (1.93ml, 34.5mmol), (200mg is 1.05mmol) and on the round-bottomed flask of benzene (30ml) for the tosic acid monohydrate.Mixture heating up was refluxed 3 hours.(181 μ l 1.3mmol) and with mixture concentrate to add triethylamine in reaction mixture.The tetrahydrofuran solution of crude product is joined lithium aluminum hydride under 0 ℃ (1.31g is in tetrahydrofuran (THF) 34.5mmol) (30ml) suspension.After mixture at room temperature stirred 7 hours, water (1.3ml), 5N aqueous sodium hydroxide solution (1.3ml) and water (3.9ml) are joined in the mixture under 0 ℃ successively.After dried over sodium sulfate, mixture is filtered.Filtrate decompression is concentrated and obtain title compound (4.6g, yield: 85.1%), be water white oil by silica gel chromatography (eluting solvent: ethyl acetate/heptane=1/2,1/1,2/1).
1H?NMR(400MHz，CDCl 3)δ?ppm；1.20-1.33(3H，m)，1.48-1.61(2H，m)，1.74-1.82(4H，m)，3.49(2H，t，J＝6Hz)，3.92-3.96(4H，m)。
(82b) 2-(((4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 328]
Figure S2006800126056D02081
Repeat and the step (14a) to (14b) of embodiment 14 and the identical method of step (7d) to (7f) of embodiment 7, utilize that above step (82a) obtains 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-base methyl alcohol obtains title compound (115mg, the total recovery of 5 steps: 7.3%), be white solid.Note, in the process identical, behind the adding diacetyl oxide, add 2 equivalent triethylamines to react with respect to pyridine 1-oxide derivative with step (14b).
1H?NMR(400MHz，DMSO-d 6)δppm；1.23-1.55(4H，m)，1.65-1.89(5H，m)，2.19(3H，s)，3.81-3.95(6H，m)，4.36(1H，d，J＝13Hz)，4.83(1H，d，J＝13Hz)，6.79-6.88(2H，m)，6.90(1H，d，J＝6Hz)，7.38-7.46(2H，m)，8.24(1H，d，J＝6Hz)。
(embodiment 83) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 329]
Figure S2006800126056D02091
(83a) 4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-N, N-di-isopropyl pyridine-2-carboxamide
[formula 330]
Figure S2006800126056D02092
Repeat the identical method of step (92c) with embodiment 92, utilize with the identical method of step (9a) to (9e) of embodiment 9 obtain 5, the 4-chloro-N that the method for the step (92a) of the pure and mild embodiment 92 of 9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-obtains, N-di-isopropyl pyridine-2-carboxamide obtains title compound (1.69g, yield 97%), be water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.12-1.31(6H，d，J＝6Hz)，1.74-1.82(2H，m)，2.24-2.34(4H，m)，3.45-3.63(1H，m)，3.72-3.87(1H，m)，3.90(2H，dd，J＝5，12Hz)，4.05-4.15(2H，m)，4.36-4.44(1H，m)，6.88(1H，dd，J＝2，6Hz)，6.95(1H，d，J＝2Hz)，8.40(1H，d，J＝6Hz)。
(because and H 2The peak of O is overlapping at 1.4-1.7 ppm place, so lack 6 H)
(83b) (4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base) pyridine-2-yl) methyl alcohol
[formula 331]
Figure S2006800126056D02101
The 4-(5 that obtains to step (83a), 9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-N, N-di-isopropyl pyridine-2-carboxamide (1.69g, 4.85mmol) tetrahydrofuran (THF) (60ml) solution in add down lithium aluminum hydride (552mg at-6 to-5 ℃, 14.5mmol), then mixture was at room temperature stirred 1 hour.Water (0.55ml), 5N aqueous sodium hydroxide solution (0.55ml) and water (1.65ml) are joined in the mixture successively.After dried over sodium sulfate, obtain title compound (560mg, yield 45.9%) with the mixture concentrating under reduced pressure and by silica gel chromatography (eluting solvent: heptane, ethyl acetate/heptane=1/1, ethyl acetate), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.65(2H，quint，J＝8Hz)，2.14(2H，t，J＝8Hz)，2.23(2H，t，J＝8Hz)，3.77(2H，dd，J＝3，13Hz)，3.99-4.06(2H，m)，4.44-4.49(3H，m)，6.82(1H，dd，J＝2，6Hz)，6.96(1H，d，J＝2Hz)，8.25(1H，d，J＝6Hz)。
(83c) 2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 332]
Figure S2006800126056D02102
Repeat the identical method of step (9h) to (9j) with embodiment 9, utilize that above step (83b) obtains (4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base) pyridine-2-yl) methyl alcohol obtains title compound (100mg, the total recovery of 3 steps: 50%), be white solid.Note, in the process identical, join 2-mercaptobenzimidazole in the reaction mixture and at room temperature stirred 25 hours with step (9h), then with respect to alcohol to wherein adding 3 Equivalent Hydrogen potassium oxides.Mixture was at room temperature reacted 6 hours.
1H?NMR(400MHz，DMSO-d 6)δppm；1.56-1.70(2H，m)，2.04-2.24(4H，m)，3.44-3.53(1H，m)，3.60-3.72(2H，m)，3.80(1H，dd，J＝2，13Hz)，3.96(1H，t，J＝2Hz)，4.41(1H，d，J＝12Hz)，4.57(1H，d，J＝12Hz)，6.55(1H，d，J＝3Hz)，6.81-6.91(3H，m)，7.40-7.48(2H，m)，8.31(1H，d，J＝6Hz)。
(embodiment 84) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-5-fluoro-1H-benzoglyoxaline sodium salt
[formula 333]
Figure S2006800126056D02111
(84a) phenylformic acid 2,2-diethoxy ethyl ester
[formula 334]
Figure S2006800126056D02112
To the hydroxy-acetaldehyde diethyl acetal (19.8g, in pyridine 148mmol) (30ml) solution in-20 to 30 ℃ drip down Benzoyl chloride (51.7ml, 444mmol).Mixture was at room temperature stirred 167 hours 50 minutes.After joining the first alcohol and water in the mixture, use ethyl acetate extraction.The organic layer that merges is washed with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and saturated brine solution.Behind anhydrous magnesium sulfate drying, with the mixture concentrating under reduced pressure and by silica gel chromatography (eluting solvent: heptane, ethyl acetate/heptane=1/9).And then obtain title compound (34g, yield: 96.4%), be light green oil by silica gel chromatography (eluting solvent: heptane, ethyl acetate/heptane=1/100,1/30,1/10).
1H?NMR(400MHz，CDCl 3)δppm；1.24(6H，t，J＝7Hz)，3.58-3.68(2H，m)，3.72-3.82(2H，m)，4.34(2H，d，J＝6Hz)，4.83(1H，t，J＝6Hz)，7.42-7.48(2H，m)，7.54-7.60(1H，m)，8.02-8.09(2H，m)。
(84b) phenylformic acid 5,7-dioxo spiro [2.5] suffering-6-base methyl esters
[formula 335]
Figure S2006800126056D02121
The reflux exchanger that is equipped with the Dean-Stark water separator is connected to contains the phenylformic acid 2 that above step (84a) obtains, 2-diethoxy ethyl ester (33g, 139mmol), 1,1-two (hydroxymethyl) cyclopropane (15.6g, 153mmol), (2.64g is 13.9mmol) and in the round-bottomed flask of toluene (100ml) for the tosic acid monohydrate.Mixture heating up was refluxed 2 hours and be cooled to room temperature.In reaction mixture, add triethylamine (10ml), ethyl acetate (100ml) and silica gel (50g).Mixture concentrated and by silica gel chromatography (eluting solvent: ethyl acetate/heptane=1/30,1/10) obtain title compound (25.5g, yield 73.9%), be light yellow oil.
1H?NMR(400MHz，CDCl 3)δppm；0.32-0.39(2H，m)，0.68-0.76(2H，m)，3.29(2H，d，J＝12Hz)，4.16(2H，d，J＝12Hz)，4.41(2H，d，J＝5Hz)，4.98(1H，t，J＝5Hz)，7.40-7.46(2H，m)，7.52-7.58(1H，m)，8.04-8.09(2H，m)。
(84c) 5,7-dioxo spiro [2.5] suffering-6-base methyl alcohol
[formula 336]
To the phenylformic acid 5 that above step (84b) obtains, 7-dioxo spiro [2.5] suffering-6-base methyl esters (25.1g, 101mmol) and in the mixture of methyl alcohol (150ml) under 0 to 4 ℃ internal temperature adding 2N aqueous sodium hydroxide solution (55.6ml, 111mmol).After mixture at room temperature stirred 3 hours, saturated aqueous ammonium chloride is joined in the mixture to regulate pH to about 9.The mixture concentrating under reduced pressure is fallen small amount of methanol.Join ethyl acetate in the resistates and isolate organic layer.With the water layer ethyl acetate extraction, in the water layer that obtains, add sodium-chlor then.With the mixture ethyl acetate extraction, then organic layer is merged, wash with saturated brine solution.With the organic layer anhydrous magnesium sulfate drying, obtain title compound (10g, yield: 68.6%), be water white oil by distillation except that desolvating then.
1H?NMR(400MHz，CDCl 3)δppm；0.33-0.37(2H，m)，0.68-0.72(2H，m)，1.87(1H，t，J＝6Hz)，3.28(2H，d，J＝11Hz)，3.68(2H，dd，J＝4，6Hz)，4.16(2H，d，J＝11Hz)，4.73(1H，t，J＝4Hz)。
(84d) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-5-fluoro-1H-benzoglyoxaline sodium salt
[formula 337]
Figure S2006800126056D02131
Repeat and the step (79a) of embodiment 79, the step (92d) of embodiment 92, the step (5f) of embodiment 5 and the identical method of step (9i) to (9j) of embodiment 9, utilize that above step (84c) obtains 5,7-dioxo spiro [2.5] suffering-6-base methyl alcohol obtains title compound (298 mg, the total recovery of 5 steps: 14.1%), be white solid.Note, in the process identical, replace methyl alcohol with ethanol with step (92d).In the process identical with step (5f), the 5-fluoro-1 H-benzimidazolyl-2 radicals-mercaptan that obtains with the step (52a) of embodiment 52 replaces 2-mercaptobenzimidazole.
1H?NMR(400MHz，DMSO-d 6)δppm；0.33(2H，dd，J＝7，8Hz)，0.59(2H，dd，J＝7，8Hz)，3.24(2H，d，J＝12Hz)，3.92-4.04(2H，m)，4.09(2H，d，J＝12Hz)，4.43(1H，d，J＝12Hz)，4.50(1H，d，J＝12Hz)，4.94(1H，t，J＝4Hz)，6.64-6.78(1H，m)，6.80-6.98(2H，m)，7.16(1H，dd，J＝2，10Hz)，7.42(1H，d，J＝5，8Hz)，8.37(1H，d，J＝6Hz)。
(embodiment 85) 2-(((4-(6,8-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 338]
(85a) tetramethylene-1,1-two basic dimethanols
[formula 339]
Figure S2006800126056D02142
With 1, (4.97g, tetrahydrofuran (THF) 24.8mmol) (50ml) solution cools off under the cooling of ice 1-tetramethylene dicarboxylate.In solution, add lithium aluminum hydride (1.6g, 42.2mmol).Reaction mixture was stirred 10 minutes down at 0 ℃, at room temperature continue then to stir 15 minutes.Come termination reaction by in reaction mixture, adding diethyl ether-water.The solution that will contain the mineral compound that is settled out steams solvent with anhydrous magnesium sulfate drying and decompression and obtains title compound (2.88g, 100%), is water white oil.
1H?NMR(400MHz，CDCl 3)δppm；1.77-1.82(4H，m)，1.90-1.96(2H，m)，2.38(2H，brs)，3.75(4H，s)。
(85b) 7-((benzyloxy) methyl)-6,8-dioxo spiro [3.5] nonane
[formula 340]
The tetramethylene-1 that above step (85a) is obtained, 1-one basic dimethanol (2.88g, 24.8mmol), benzyloxy acetaldehyde (3.72g, 24.8mmol), tosic acid monohydrate (214mg, 1.13mmol) and the mixture heating up of toluene (70ml) refluxed 1 hour, remove by the Dean-Stark device simultaneously and anhydrate.Reaction mixture is cooled to room temperature and to wherein adding triethylamine (3ml), steams then and desolventize.Resistates is passed through silica gel chromatography (silica gel: 200g, eluting solvent: ethyl acetate/heptane=1/50 → 1/9) obtain title compound (3.8g, yield: 48.7%), be white solid.
1H?NMR(400MHz，CDCl 3)δppm；1.54(2H，t，J＝8Hz)，1.90(2H，quint，J＝8Hz)，2.10(2H，t，J＝8Hz)，3.49(2H，d，J＝4Hz)，3.52(2H，d，J＝11Hz)，4.00(2H，d，J＝11Hz)，4.57(2H，s)，4.67(1H，t，J＝4Hz)，7.25-7.33(5H，m)。
(85c) 6,8-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base methyl alcohol
[formula 341]
Figure S2006800126056D02151
With the 7-((benzyloxy) methyl)-6 that above step (85b) obtains, and 8-dioxo spiro [3.5] nonane (3.8g, 15.3mmol), the mixture of 20% palladium hydroxide (800mg) and ethyl acetate (70ml) stirs in nitrogen atmosphere and spend the night.With reaction vessel with nitrogen purge and by removing by filter catalyzer.Filtrate concentrating obtained title compound (2.0g, yield: 82.6%), be white solid.
1H?NMR(400MHz，CDCl 3)δppm；1.56(2H，t，J＝8Hz)，1.83(1H，t，J＝4Hz)，1.92(2H，quint，J＝8Hz)，2.10(2H，t，J＝8Hz)，3.54(2H，d，J＝11Hz)，3.60(2H，t，J＝5Hz)，4.02(2H，d，J＝11Hz)，4.56(1H，t，J＝4Hz)。
(85d) 2-(((4-(6,8-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 342]
Figure S2006800126056D02152
Repeat with step (62c) with (8d) to (8g) identical method, the alcohol that utilizes above step (85c) to obtain obtains title compound (198mg, total recovery 13.6%), is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.51(2H，t，J＝8Hz)，1.85(2H，quint，J＝8Hz)，1.98(2H，t，J＝8Hz)，2.16(3H，s)，3.54(2H，d，J＝10Hz)，3.97(2H，d，J＝10Hz)，4.01(2H，d，J＝4Hz)，4.38(1H，d，J＝13Hz)，4.76(1H，d，J＝13Hz)，4.86(1H，t，J＝4Hz)，6.83-6.85(2H，m)，6.92(1H，d?J＝6Hz)，7.41-7.43(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 86) 2-(((4-(2-(5,5-dimethyl-1,3-two
Figure 2006800126056_220
Alkane-2-yl) oxyethyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 343]
Figure S2006800126056D02161
Repeat the identical method of step (1c) to (1g) with embodiment 1, utilize 5,5-dimethyl-1,3-two
Figure 2006800126056_221
(1.00g, (138mg 0.31mmol), is beige solid to alkane-2-ethanol 6.24mmol) to obtain title compound.
1H?NMR(400MHz，DMSO-d 6)δppm；0.68(3H，s)，1.09(3H，s)，1.96-2.07(2H，m)，2.16(3H，s)，3.41(2H，d，J＝11Hz)，3.53(2H，d，J＝11Hz)，4.10(2H，t，J＝6Hz)，4.38(1H，d，J＝13Hz)，4.65(1H，t，J＝5Hz)，4.74(1H，d，J＝13Hz)，6.79-6.88(2H，m)，6.90(1H，d，J＝6Hz)，7.38-7.47(2H，m)，8.25(1H，d，J＝6Hz)。
(embodiment 87) 2-(((4-(1,3-dioxolane-4-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 344]
Figure S2006800126056D02162
Repeat the identical method of step (1c) to (1g) with embodiment 1, (1.76ml, (87mg 0.22mmol), is beige solid 20.3mmol) to obtain title compound to utilize Sericosol N.
1H?NMR(400MHz，DMSO-d 6)δppm；2.18(3H，s)，3.68-3.74(1H，m)，4.01(1H，t，J＝8Hz)，4.06-4.17(2H，m)，4.33-4.43(2H，m)，4.78(1H，d，J＝13Hz)，4.85(1H，s)，4.94(1H，s)，6.78-6.88(2H，m)，6.93(1H，d，J＝6Hz)，7.36-7.46(2H，m)，8.26(1H，d，J＝6Hz)。
(embodiment 88) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_222
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 345]
Below be described in the another kind of synthetic method of the synthetic that carries out among the embodiment 20.
(88a) 2-(((4-((and 2,2-dimethyl-1,3-two Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 346]
Figure S2006800126056D02172
With 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_224
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) sulfenyl methyl))-1H-benzoglyoxaline (500mg, 1.21mmol), zirconium iso-propoxide (IV) Virahol mixture (295mg, 0.76mmol) and N, N, N ', N '-(-)-tetramethyl--(D)-(396mg, toluene 1.94mmol) (4ml) solution stirred 1 hour down at 40 ℃ in nitrogen atmosphere tartramide.After solution is cooled to room temperature, add N, (91 μ l 0.52mmol), drip cumene hydroperoxide (content is by 80% for 243 μ l, 1.32mmol) and mixture were at room temperature stirred 22 hours the N-diisopropyl ethyl amine then in mixture.After adding saturated sodium bicarbonate aqueous solution and saturated aqueous sodium thiosulfate, with the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 30g, eluting solvent: ethyl acetate, ethyl acetate/methanol 7: 3,1; 1 gradient).The fraction that will contain title compound is collected with ethyl acetate and concentrated title compound (328mg, the yield: 63%), be colourless foam of obtaining.
HPLC
(condition) post: CHIRALPAK IA (by Daicel Chemical Industries, Ltd. produces) (0.46cm
Figure 2006800126056_225
* 25cm)
Eluent: hexane/ethanol=3/2 (v/v), flow velocity: 0.5ml/min detects: UV (254nm).
(analytical results)
Retention time: 17.5 minutes, enantiomeric excess: 99%ee.
(88b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_226
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 347]
Repeat the method identical and obtain title compound (299mg, yield: 88%), be white solid to form sodium salt with embodiment 20b.
HPLC
(condition) post: CHIRALPAK IA (by Daicel Chemical Industries, Ltd. produces) (0.46cm
Figure 2006800126056_227
* 25cm)
Eluent: hexane/ethanol=3/2 (v/v), flow velocity: 0.5ml/min detects: UV (254nm).
(analytical results)
Retention time: 18.0 minutes, enantiomeric excess: 99%ee.
Specific rotation: α D 22.4=+78.51 (c=0.5, EtOH).
(embodiment 89) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_228
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 348]
Figure S2006800126056D02191
Below be described in the another kind of synthetic method of the synthetic that carries out among the embodiment 20.
(89a) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_229
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 349]
With 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_230
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) sulfenyl methyl))-1H-benzoglyoxaline (500mg, 1.21mmol) and N, N, N ', N '-(-)-tetramethyl--(D)-(396mg, 1.94mmol) mixture in toluene (4ml) is by heating dissolving in 10 minutes in nitrogen atmosphere under 40 ℃ for tartramide.(315 μ L 0.78mmol) join in the mixture and continue under identical temperature and stirred 1 hour with four butanols hafniums.After reaction mixture is cooled to room temperature, add N, (90 μ l 0.52mmol), drip cumene hydroperoxide (content is by 80% for 267 μ l, 1.46mmol) and mixture were at room temperature stirred 22 hours the N-diisopropyl ethyl amine then in mixture.After adding saturated sodium bicarbonate aqueous solution and saturated aqueous sodium thiosulfate, with the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel: 30g, eluting solvent: ethyl acetate, ethyl acetate/methanol 7: 3,1; 1 gradient).The fraction that will contain title compound is collected with ethyl acetate and concentrated title compound (206mg, the yield: 40%), be colourless foam of obtaining.
HPLC
(condition) post: CHIRALPAK IA (by Daicel Chemical Industries, Ltd. produces) (0.46cm
Figure 2006800126056_231
* 25cm)
Eluent: hexane/ethanol=3/2 (v/v), flow velocity: 0.5ml/min detects: UV (254nm).
(analytical results)
Retention time: 17.2 minutes, enantiomeric excess: 90%ee.
(89b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_232
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 350]
Figure S2006800126056D02201
Repeat the method identical and obtain title compound (182mg, yield: 84%), be white solid to form sodium salt with embodiment 20b.
HPLC
(condition) post: CHIRALPAK IA (by Daicel Chemical Industries, Ltd. produces) (0.46cm
Figure 2006800126056_233
* 25cm)
Eluent: hexane/ethanol=3/2 (v/v), flow velocity: 0.5ml/min detects: UV (254nm).
(analytical results)
Retention time: 18.1 minutes, enantiomeric excess: 89%ee.
(embodiment 90) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_234
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 351]
Figure S2006800126056D02211
Below be described in the another kind of synthetic method of the synthetic that carries out among the embodiment 20a.
In flask, add (S)-(-)-2-(3; 5-two-tertiary butyl salicylidene amino)-3; 3-dimethyl-1-butanols (115mg, 0.35mmol), the vanadyl Acetyl Acetone (64mg, 0.24mmol) and acetonitrile (0.8mL) and mixture at room temperature stirred 30 minutes.With mixture join the 2-that in another flask, makes (((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_235
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-(500mg in methylene dichloride 1.21mmol) (3mL) solution, at room temperature stirred the mixture that forms 30 minutes the 1H-benzoglyoxaline.In 20 hours, be divided into 15 times (each 10 μ l) by amount and add aqueous hydrogen peroxide solution (150 μ l) and mixture is continued stirring 24 hours solution.After adding 1N aqueous sodium hydroxide solution (3mL) and mixture being stirred 48 hours, saturated sodium bicarbonate aqueous solution and saturated aqueous sodium thiosulfate are joined in the mixture, then with the mixture ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.Resistates is passed through silica gel chromatography (NH silica gel 30g, eluting solvent: ethyl acetate, ethyl acetate/methanol 7: 3,1; 1 gradient).The fraction that will contain title compound is collected with ethyl acetate and concentrated title compound (76mg, the yield: 15%), be colourless foam of obtaining.
HPLC
(condition) post: CHIRALPAK IA (by Daicel Chemical Industries, Ltd. produces) (0.46cm * 25cm)
Eluent: hexane/ethanol=3/2 (v/v), flow velocity: 0.5ml/min detects: UV (254nm).
(analytical results)
Retention time: 19.9 minutes, enantiomeric excess: 45%ee.
The sodium salt of the optically active isomer of (embodiment 91) 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline
[formula 352]
Figure S2006800126056D02221
Preparation 2-(((3-methyl-4-(1; 5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) sulfinyl methyl pyridine-2-yl)))-sodium salt (racemic modification) of 1H-benzoglyoxaline (192mg) ethanolic soln and separate (post: CHIRALCEL OD-H 2cm by HPLC
Figure 2006800126056_237
* 25cm (by Daicel ChemicalIndustries, Ltd. produces), moving phase: ethanol/normal hexane=3/2, flow velocity: 3.0ml/min detects wavelength: 254nm).Obtain immediately 1N aqueous sodium hydroxide solution (1ml) being joined in each fraction after the fraction.Collect the fraction that contains the short and long optically active isomer of retention time respectively, separate with saturated aqueous ammonium chloride with ethyl acetate then.With the organic layer anhydrous sodium sulfate drying of each fraction, concentrate and carry out component distillation with diethyl ether.
The resistates of the optically active isomer that retention time is short carries out separating drying and concentration operation with above-described identical HPLC fraction.The resistates that obtains is passed through silica gel chromatography (NH silica gel 20g, eluting solvent: methylene dichloride, methylene chloride=10/1).Carry out then separating with above-described identical HPLC fraction, drying concentrates and makes the free form (20mg) of the short optically active isomer of retention time with the component distillation of diethyl ether, is colorless solid.
The resistates of the optically active isomer that retention time is long carries out separating with above-described identical HPLC fraction, and drying concentrates and makes the free form (14mg) of the long optically active isomer of retention time with the component distillation of diethyl ether, is colorless solid.
All free optically active isomers are changed into sodium salt according to the mode identical with the step (11i) of embodiment 11 make the sodium salt (18mg) of the short optically active isomer of retention time and the sodium salt (14mg) of the optically active isomer that retention time is grown, both are colorless solid.
1H NMR (400MHz, DMSO-d 6); About the sodium salt of these two kinds of optically active isomers, obtained the identical chart of sodium salt (racemic modification) with 2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline.
HPLC
(condition) post: CHIRALPAK OD-H (by Daicel Chemical Industries, Ltd. produces) (0.46cm
Figure 2006800126056_238
* 25cm)
Eluent: hexane/ethanol=4/1 (v/v), flow velocity: 0.5ml/min detects: UV:(280nm).
(analytical results)
Sodium salt about the short optically active isomer of retention time
Retention time: 36 minutes, enantiomeric excess:＞98.0%ee.
Specific rotation: α D 25.5=+107.73 (c=0.32, EtOH).
Sodium salt about the long optically active isomer of retention time
Retention time: 44 minutes, enantiomeric excess:＞98.0%ee.
Specific rotation: α D 25.0=-115.85 (c=0.19, EtOH).
(embodiment 92) 2-(((4-((2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-and 3-ethylpyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 353]
Figure S2006800126056D02231
(92a) 4-chloro-N, N-di-isopropyl pyridine-2-carboxamide
[formula 354]
(60ml 823mmol) dilutes with toluene (100ml) and is heated to 45 ℃ with thionyl chloride.Add N in mixture, (16ml 207mmol) and with the mixture that forms stirred 1 hour under identical condition dinethylformamide.(25g 203mmol) and with the mixture that forms stirred 1 hour 20 minutes down at 80 ℃ to add pyridine carboxylic acid in mixture.Reaction mixture concentrated and (185ml 807mmol) and after acetonitrile (500ml) joins in the resistates, at room temperature stirred mixture 21 hours 30 minutes with diisopropylamine.After reaction mixture concentrated, with resistates with ethyl acetate and water sepn.Organic layer is washed with saturated brine solution, use anhydrous magnesium sulfate drying, filter and concentrate.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (31.1g, yield: 63.6%), be the light brown solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.11(6H，d，J＝7Hz)，1.43(6H，d，J＝6Hz)，3.54-3.66(2H，m)，7.56-7.62(2H，m)，8.51-8.56(1H，m)。
(92b) 4-chloro-3-ethyl-N, N-di-isopropyl pyridine-2-carboxamide
[formula 355]
To diisopropylamine (1.35g, 13.3mmol) tetrahydrofuran (THF) (anhydrous) (50ml) under the cooling of ice, in nitrogen atmosphere, drip n-Butyl Lithium (1.6M hexane solution in the solution, 6.75ml, 10.8mmol) and with the mixture that forms under identical condition, stirred 30 minutes.After reaction mixture being cooled to-70 ℃, with the 4-chloro-N that above step (92a) obtains, (2g, tetrahydrofuran solution 8.31mmol) join in the mixture and with the mixture that forms and stirred 1.5 hours down at-70 ℃ N-di-isopropyl pyridine-2-carboxamide.(798 μ l 10mmol) and with the mixture that forms stirred 3 hours down at-70 ℃ to 0 ℃ to add iodoethane in reaction mixture.In reaction mixture, add saturated aqueous ammonium chloride and use ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.With resistates by silica gel chromatography (eluting solvent: heptane/ethyl acetate) obtain title compound (1.9g, yield: 85.1%), be light yellow solid.
1H?NMR(400MHz，CDCl 3)δppm；1.15(6H，d，J＝7Hz)，1.25(3H，t，J＝7Hz)，1.58(6H，d，J＝7Hz)，2.70-2.84(2H，m)，3.42-3.60(2H，m)，7.26(1H，d，J＝6Hz)，8.28(1H，d，J＝6Hz)。
(92c) 4-((2,2-dimethyl-1,3-two
Figure 2006800126056_240
Alkane-5-yl) methoxyl group)-and 3-ethyl-N, N-di-isopropyl pyridine-2-carboxamide
[formula 356]
Figure S2006800126056D02251
The 4-chloro-3-ethyl-N that obtains to above step (92b), N-di-isopropyl pyridine-2-carboxamide (1g, 3.72mmol) dimethyl sulfoxide (DMSO) (20ml) solution under room temperature, add the oil solution (content is by 55% for 195mg, 4.46mmol) of oily sodium hydride.Add in mixture that embodiment (11a) obtains (2,2-dimethyl-1,3-two
Figure 2006800126056_241
Alkane-5-yl) (598mg 4.09mmol) and with mixture at room temperature stirred 16.5 hours methyl alcohol.Ethyl acetate is joined in the reaction mixture.Mixture is washed 2 times with saturated brine solution.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate.Resistates is obtained title compound (520mg, yield: 36.9%), be light yellow solid with the diethyl ether washing.
1H?NMR(400MHz，CDCl 3)δppm；1.10-1.22(9H，m)，1.44(3H，s)，1.49(3H，s)，1.58(6H，d，J＝7Hz)，2.14-2.22(1H，m)，2.55-2.66(2H，m)，3.46-3.60(2H，m)，3.86-3.98(2H，m)，4.10-4.26(4H，m)，6.77(1H，d，J＝6Hz)，8.32(1H，d，J＝6Hz)。
(92d) (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_242
Alkane-5-yl) methoxyl group)-and 3-ethylpyridine-2-yl) methyl alcohol [formula 357]
The 4-that obtains to above step (92c) ((2,2-dimethyl-1,3-two
Figure 2006800126056_243
Alkane-5-yl) methoxyl group)-3-ethyl-N, N-di-isopropyl pyridine-2-carboxamide (520mg, 1.37mmol) tetrahydrofuran (THF) (10ml) solution under the cooling of ice, add lithium aluminum hydride (156mg 4.11mmol) and with mixture stirred 1 hour under the cooling of ice.In reaction mixture, add entry (0.2ml), 2N aqueous sodium hydroxide solution (0.2ml) and water (0.6ml) successively.Then mixture is reduced pressure by diatomite filtration and from filtrate and steam solvent.(51.8mg 1.37mmol) and with mixture at room temperature stirred 1 hour to add sodium borohydride in methyl alcohol (20ml) solution of resistates.Saturated brine solution is joined in the reaction mixture.With the mixture ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate crude product (456mg, the yield: 118%), be light yellow solid that obtains title compound.
1H?NMR(400MHz，CDCl 3)δppm；1.09(3H，t，J＝7Hz)，1.43(3H，s)，1.49(3H，s)，2.14-2.22(1H，m)，2.52(2H，q，J＝7Hz)，3.90(2H，dd，J＝5，12Hz)，4.08-4.22(4H，m)，4.71(2H，s)，6.76(1H，d，J＝6Hz)，8.31(1H，d，J＝6Hz)。
(92e) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_244
Alkane-5-yl) methoxyl group)-and 3-ethylpyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline sodium salt
[formula 358]
Figure S2006800126056D02261
Repeat and the step (6d) of embodiment 6, (6e) and (6f) identical method, utilize that above step (92d) obtains (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_245
Alkane-5-yl) methoxyl group)-and 3-ethylpyridine-2-yl) methyl alcohol obtains title compound (159mg, total recovery: 25%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δ?ppm；1.07(3H，t，J＝7Hz)，1.33(3H，s)，1.35(3H，s)，2.06-2.16(1H，m)，2.62-2.82(2H，m)，3.78(2H，dd，J＝6，12Hz)，3.98(2H，dd，J＝4，12Hz)，4.09(2H，d，J＝10Hz)，4.36(1H，d，J＝13Hz)，4.77(1H，d，J＝13Hz)，6.80-6.98(2H，m)，6.93(1H，d，J＝6Hz)，7.38-7.48(2H，m)，8.28(1H，d，J＝6Hz)。
(embodiment 93) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_246
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-6,7-dihydro-1H-[1,4] dioxine [2,3-f] benzoglyoxaline sodium salt also
[formula 359]
Figure S2006800126056D02271
Repeat and the identical method of step (5f) to (5h), utilize (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_247
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl alcohol (its can by will obtain according to the mode identical with embodiment 96 (5) (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_248
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl alcohol monohydrate and toluene carry out component distillation and obtain) and 6,7-dihydro-1H-[1,4] dioxine also [2 ', 3 ': 4,5] benzo [d] imidazoles-2-mercaptan makes title compound (395mg, 61.7% total recovery), is white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.32(3H，s)，1.35(3H，s)，2.00-2.13(1H，m)，2.18(6H，s)，3.69-3.86(4H，m)，3.91-4.03(2H，m)，4.14(4H，s)，4.31(1H，d，J＝12Hz)，4.70(1H，d，J＝12Hz)，6.82(2H，s)，8.19(1H，s)。
(embodiment 94) 2-(((3-methyl-4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-6,7-dihydro-1H-[1,4] dioxine [2,3-f] benzoglyoxaline sodium salt also
[formula 360]
Figure S2006800126056D02272
Repeat and the identical method of step (5d) to (5h), utilize 2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) ethanol and embodiment (73b) obtain 6,7-dihydro-1H-[1,4] dioxine also [2 ', 3 ': 4,5] benzo [d] imidazoles-2-mercaptan obtains title compound (110mg, content: 93.5%, 9.2% total recovery), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.39(3H，s)，2.05-2.23(5H，m)，3.56-3.72(4H，m)，3.75-3.93(4H，m)，4.02-4.22(6H，m)，4.31(1H，d，J＝13Hz)，4.75(1H，d，J＝13Hz)，6.82(2H，s)，6.88(1H，d，J＝5Hz)，8.24(1H，d，J＝5Hz)。
(embodiment 95) 2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-6,7-dihydro-1H-[1,4] dioxine [2,3-f] benzoglyoxaline sodium salt also
[formula 361]
Figure S2006800126056D02281
Repeat and the identical method of step (5f) to (5h), utilize that embodiment (2d) obtains (4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-and 3-picoline-2-yl) methyl alcohol and 6,7-dihydro-1H-[1,4] dioxine also [2 ', 3 ': 4,5] benzo [d] imidazoles-2-mercaptan obtains title compound (364mg, 55.6% total recovery), be the baby pink solid.
1H?NMR(400MHz，DMSO-d 6)δppm；0.26-0.40(2H，m)，0.50-0.66(2H，m)，2.16(3H，s)，3.26(2H，d，J＝12Hz)，4.09(2H，d，J＝4Hz)，4.12(2H，d，J＝12Hz)，4.15(4H，s)，4.33(1H，d，J＝13Hz)，4.76(1H，d，J＝13Hz)，5.02(1H，t，J＝4Hz)，6.83(2H，s)，6.94(1H，d，J＝6Hz)，8.26(1H，d，J＝6Hz)。
(embodiment 96) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_249
Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 362]
Figure S2006800126056D02282
(1) with 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_250
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-optically active isomer of 1H-benzoglyoxaline (retention time is short) (429mg; 1mmol) be dissolved in ethanol (0.85ml) and to wherein add the 1N aqueous sodium hydroxide solution (1ml, 1mmol).With the mixture concentrating under reduced pressure and after wherein adding ethanol (0.85ml), with the mixture concentrating under reduced pressure.Add tetrahydrofuran (THF) (0.85ml), add t-butyl methyl ether (8ml) then so that mixture becomes muddy (white opacity).Mixture at room temperature after the standing over night, is obtained title compound (191mg, yield 42%) (lot A) with the throw out that produces by filtering to collect, be white solid.
(2) with 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_251
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-optically active isomer of 1H-benzoglyoxaline (retention time is short) (490mg; 1.14mmol; enantiomeric excess: 98%ee) be dissolved in ethanol (0.98ml) and to wherein add the 1N aqueous sodium hydroxide solution (1.14ml, 1.14mmol).With the mixture concentrating under reduced pressure and after wherein adding ethanol (0.98ml), with the mixture concentrating under reduced pressure.Should operate and repeat 2 times.After adding ethyl acetate (6ml), the title compound that step (1) (lot A) is obtained joins in the mixture as crystal seed.With the mixture concentrating under reduced pressure.After adding ethyl acetate (8ml), the title compound that step (1) (lot A) is obtained joins in the mixture as crystal seed, and mixture was at room temperature left standstill 1 hour 13 minutes.After adding ethyl acetate (2ml) in the mixture, with mixture standing over night at room temperature.The throw out that produces is obtained title compound (309mg, yield 60%) (lot B) by filtering to collect, be white crystals.
(3) to 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_252
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-optically active isomer of 1H-benzoglyoxaline (retention time is short) (4g; 9.31mmol) ethanol (8ml) solution in add the 1N aqueous sodium hydroxide solution (9.31mmol, 9.31mmol).After stirring 2 hours under the identical condition, decompression steams solvent with mixture.Join in the resistates ethanol (8ml) and underpressure distillation.After repeating this operation 2 times, (80ml) joins in the resistates with ethyl acetate, adds title compound (lot B) that step (2) obtains as crystal seed and with the mixture that forms standing over night at room temperature.After continuing standing over night under 4 ℃, the throw out that produces is obtained title compound by the filtration collection, and (1.1g, yield: 25.9%) (lot C) is light yellow crystallization.A part of solvent that decompression steams gained filtrate.After the crystallization that forms at room temperature left standstill 2 hours, obtain title compound (2.5g, yield: 59.5%) (lot D) is light yellow crystallization by filtering to collect.
(4) to 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_253
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-optically active isomer of 1H-benzoglyoxaline (retention time is short) (200mg; 0.466mmol; enantiomeric excess: under room temperature, add 1N aqueous sodium hydroxide solution (466 μ l in ethanol 77.1%ee) (10ml) solution; 0.466mmol), then with the mixture concentrating under reduced pressure.After adding ethanol (10ml), with the mixture concentrating under reduced pressure.Should operate and repeat 2 times.In resistates, add ethyl acetate (40ml) and the suspension that forms is dissolved in ethanol.With the mixture concentrating under reduced pressure and be dissolved in ethyl acetate (4ml) and ethanol (2ml).Add title compound (lot D) that step (3) obtains then as crystal seed and with the mixture concentrating under reduced pressure.Resistates is dissolved in 2-propyl alcohol (0.4ml) and ethyl acetate (4ml), adds title compound (lot D) that step (3) obtains then as crystal seed.After at room temperature leaving standstill, with the mixture concentrating under reduced pressure.After the mixture that forms is dissolved in ethanol (0.2ml) and ethyl acetate (3ml), under agitation under room temperature, add title compound (lot D) that step (3) obtains as crystal seed.In about 10 minutes, throw out begins to form.Continue stir about after 10 minutes, the throw out that produces is obtained title compound (44mg, yield 21%) (lot E) by filtering to collect, be white crystals.
(5) with 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_254
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-optically active isomer of 1H-benzoglyoxaline (retention time is short) (340mg; 0.792mmol; enantiomeric excess; 47%ee) at room temperature be dissolved in ethanol (4.5ml) and to wherein drip the 1N aqueous sodium hydroxide solution (792 μ L, 0.792mmol).With mixture at 40 ℃ of following concentrating under reduced pressure.After adding ethanol (0.9ml), with the mixture concentrating under reduced pressure.Should operate and repeat 2 times with azeotropic removal of water.After joining ethyl acetate in the mixture, mixture is at room temperature stirred, obtain title compound (lot F) (230mg, yield 64.3%), be light yellow solid by filtering to collect and wash (4.5ml) with ethyl acetate.Filtrate is carried out identical operations obtain title compound (lot G) (47mg, yield: 13.1%), be light yellow solid.
HPLC
(condition) post: CHIRALPAK AD-H (by Daicel Chemical Industries, Ltd. produces) (0.46cm
Figure 2006800126056_255
* 25cm)
Eluent: hexane/ethanol=1/1 (v/v), flow velocity: 0.6ml/min detects: UV 254nm).
(analytical results)
Lot B: retention time: 16.7 minutes, enantiomeric excess: 100%ee;
Lot C: retention time: 17.2 minutes, enantiomeric excess: 100%ee;
Lot D: retention time: 16.8 minutes, enantiomeric excess: 100%ee;
Lot E: retention time: 18.0 minutes, enantiomeric excess: 100%ee;
Lot F: retention time: 17.1 minutes, enantiomeric excess: 39%ee;
Lot G: retention time: 17.1 minutes, enantiomeric excess: 62%ee.
(embodiment 97) 2-(((4-((2,2-dimethyl-1,3-two Alkane-5-yl) sulfinyl methyl methoxyl group)-3,5-lutidine-2-yl)))-sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
(1) 2,3,5-trimethylpyridine 1-oxide compound
[formula 363]
Figure S2006800126056D02311
To acetate (1.43kg added 2,3 in 23.83mol) in 15 minutes, the 5-trimethylpyridine (1.43kg, 11.80mol).After 15 minutes, (1.38kg's Dropwise 35 % superoxol in 30 minutes 14.2mol), spends the night mixture stirring under 90 ℃ to 95 ℃.In reaction mixture, add S-WAT (220g).Reaction mixture is poured in the mixture of yellow soda ash (2.5kg) and water (12L) and with mixture with chloroform extraction (3.0L * 4).The organic layer that obtains is concentrated into crystalline deposit separates out.In this throw out, add normal hexane (2.5L).The mixture that forms stirred under the cooling of ice spend the night.The crystallization filtration that forms is obtained required compound (1.53kg).
(2) 2,3,5-trimethylammonium-4-nitropyridine 1-oxide compound
[formula 364]
To 98% sulfuric acid (4.93kg adds 2,3 in 49.3mol), 5-trimethylpyridine 1-oxide compound (1.38kg, 10.1mol).In 50 minutes, after wherein dripping 97% nitric acid (1.44kg), mixture was heated 4 hours down at 85 ℃.Reaction mixture is poured in the mixture of bicarbonate of ammonia (10.6kg) and water (9.0L).With mixture ethyl acetate extraction (3.0L * 3).The organic layer that obtains concentrated and vacuum-drying is spent the night and obtained required product (1.50kg).
(3) the 4-chloro-2,3,5-trimethylpyridine 1-oxide compound
[formula 365]
Figure S2006800126056D02321
To 2,3, (850g adds entry (400g) and 36% concentrated hydrochloric acid (1.69kg) in 4.67mol) and with mixture heating up to 70 ℃ to 5-trimethylammonium-4-nitropyridine 1-oxide compound.Add N in mixture, dinethylformamide (115mL) is then with the mixture heating up to 100 that forms ℃.The reaction finish after, with reaction mixture be cooled to 20 ℃ and pour salt of wormwood (1.40kg) into and the mixture of water (7L) in.Mixture with chloroform extraction (1.0L * 3), is also concentrated organic layer with dried over sodium sulfate.The crude product that obtains was stirred 2 hours in the mixture of Di Iso Propyl Ether (500mL) and normal hexane (1.0L), carry out suction filtration then.The wet product vacuum-drying that obtains spent the night obtain required product (666.4g).
(4) 4-(2,2-dimethyl-1,3-two
Figure 2006800126056_257
Alkane-5-ylmethoxy)-2,3,5-trimethylpyridine 1-oxide compound
[formula 366]
Figure S2006800126056D02322
With 4-chloro-2,3,5-trimethylpyridine 1-oxide compound (840g), (2,2-dimethyl-1,3-two
Figure 2006800126056_258
Alkane-5-yl) mixture heating up of methyl alcohol (688g) and toluene (2.52L) refluxes, and removes moisture simultaneously.When continuing azeotropic dehydration, in 3 hours 45 minutes, join potassium hydroxide (0.58kg) in the reaction mixture and continued azeotropic dehydration 2.5 hours.Mixture is cooled to 30 ℃ or lower, ethyl acetate (2.5L) and 17% salt brine solution (3.5L) is joined in the mixture, then with the mixture standing over night.Ethyl acetate layer is separated, with water layer ethyl acetate extraction (1.0L * 3).Ethyl acetate layer is merged, obtain required product (1.20kg) by diatomite filtration and concentrating under reduced pressure.
(5) (4-(2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group-3,5-lutidine-2-yl) the methyl alcohol monohydrate
[formula 367]
To 50 ℃ to 60 ℃ down the 4-of heating (2,2-dimethyl-1,3-two
Figure 2006800126056_260
Alkane-5-yl) methoxyl group-2,3 dripped diacetyl oxide (1.10kg) in the mixture of 5-trimethylpyridine N-oxide compound (1.20kg) and sodium acetate (0.18kg) in 1.5 hours.0.5 after hour, mixture 80 ℃ of down heating 4.5 hours, is cooled to internal temperature and is below 30 ℃ or lower then, leave standstill and concentrating under reduced pressure.The resistates that obtains is dissolved in methyl alcohol (1.0L), solution was joined in the mixture of 48% aqueous sodium hydroxide solution (0.71kg) and icy water (2.85L) 1 hour.After at room temperature stirring 5 hours 45 minutes, with the mixture concentrating under reduced pressure.In the spissated resistates of institute, add entry (3.0L) and mixture is extracted (2.3L * 4) with toluene.Toluene layer is merged water (1.2L) washing.The organic layer that obtains is also concentrated by diatomite filtration.In the resistates of gained, under room temperature, add Di Iso Propyl Ether (1.15L) and add hot water (45 ℃, 74mL).After having confirmed crystalline deposit, mixture was stirred 1 hour down at 25 ℃.After pouring heptane (3.6L) into, the mixture stirring is spent the night.Mixture is continued to stir 5 hours under the cooling of ice, filter then and obtain yellow crystal.In resulting yellow crystal, add Di Iso Propyl Ether (3.5L) and mixture is descended dissolving at 50 ℃.After removing by filter insolubles, mixture is cooled off gradually, 5 ℃ of following standing over night.The crystallization that obtains is filtered and wash, obtain required product (0.69kg) after air-dry with heptane (0.5L).
(6) 2-(((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_261
Alkane-5-yl) methoxyl group-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 368]
To (4-(2,2-dimethyl-1,3-two
Figure 2006800126056_262
Alkane-5-yl) methoxyl group-3,5-lutidine-2-yl) add toluene in the methyl alcohol monohydrate (690g) to carry out azeotropic dehydration (2.1L * 5,1.75L * 1).In the enriched product that obtains, add toluene (393mL) make (4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_263
Alkane-5-yl) toluene solution (921g) of methyl alcohol methoxyl group-3,5-lutidine-2-yl).
To (4-(2,2-dimethyl-1,3-two
Figure 2006800126056_264
Alkane-5-yl) methoxyl group-3,5-lutidine-2-yl) methyl alcohol (845.7g, content: 61.7%, the amount: 521.8g, 1.855mol) toluene solution in nitrogen atmosphere, add successively tetrahydrofuran (THF) (2609mL), toluene (669mL) and triethylamine (375.3g, 3.709mol).Mixture is stirred, simultaneously with dry ice/ethanol cooling.Back 30 minutes of cooling beginning, in 42 minutes, drip methylsulfonyl chloride (254.9g, 2.226mol).After being added dropwise to complete, mixture is stirred under the ice bath cooling.After about 1.5 hours, (334.28g, tetrahydrofuran (THF) 2.226mol) (3653mL) solution poured in 2 minutes in the mixture and with mixture stir about 18 hours at room temperature with 2-mercaptobenzimidazole.In reaction mixture, pour toluene (3653mL) into and add 20%w/w aqueous sodium hydroxide solution (1852.4g) and H 2O (2322mL).Extract and separate with this kind mode.Organic layer is washed 2 times with 20%w/w aqueous ammonium chloride solution (4174g), and further use H 2O (4174ml) washing.
The organic layer concentrating under reduced pressure (40 ℃) that obtains is obtained brown oil matter (2.40kg contains toluene 1446mL, and tetrahydrofuran (THF) 168mL calculates from the 1H-NMR wave spectrum).
The brown oil of gained is transferred in the crystallisation vessel, at room temperature stirred with toluene (119mL) washing and with mixture.Pour t-butyl methyl ether (134mL) after 10 minutes into and mixture is continued stirring at room temperature.Add t-butyl methyl ether (127mL) after 20 minutes and mixture is continued stirring at room temperature.In 20 minutes, add t-butyl methyl ether (266mL) after 30 minutes and mixture is continued stirring at room temperature.After 1 minute, begin to continue to drip t-butyl methyl ether (522mL).After 8 minutes, confirm to form crystalline deposit.After 1 hour 20 minutes, stop dripping.After the mixture that forms at room temperature stirred 40 minutes, in 1 hour 17 minutes, drip heptane (2348mL) and mixture at room temperature stirred and spend the night.
Drip heptane after about 15.5 hours, suction filtration is carried out in the crystallization that precipitation is separated out, with toluene/t-butyl methyl ether/heptane (587mL/391mL/587mL) flushing and vacuum-drying.Resulting wet crystallization air-dry (50 ℃) is obtained required product.
Yield: 619.0g, content: 96.5%, amount: 597.3g, yield: 77.8% (in amount), HPLC purity: 98.0%
＜HPLC analysis condition (reaction is checked, the mensuration of HPLC purity and quantitative) 〉
Post: YMC-Pack Pro C18 AS-302 (5 μ m, 4.6mm * 150mm I.D.)
Eluent: A solution (MeCN/20mM AcONH4 aq.=100/900 (v/v)), B solution (MeCN/20mM AcONH4 aq.=800/200 (v/v))
Flow velocity: 1.0mL/min
Detect: UV 254nm
Furnace temperature: 25 ℃
Sample temperature: 25 ℃
Gradient condition (time/the B strength of solution): 0.01 minute/0% → 25 minute/100% → 30 minute/100% → 30.01 minute/0% → 40 minute/stop
RT=18.4 minute
(7) 2-(((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_265
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-the thick sodium salt of the optically active isomer (retention time is short) of 1H-benzoglyoxaline
[formula 369]
The used 2-of the present invention (((4-(2,2-dimethyl-1,3-two
Figure 2006800126056_266
Alkane-5-yl) sulfenyl methyl methoxyl group-3,5-lutidine-2-yl)))-and 1H-benzoglyoxaline, benzene, L-(+)-diethyl tartrate and N, the water content of N-diisopropyl ethyl amine is measured (total amount: 0.885g) by Karl Fischer technology.
In nitrogen atmosphere, add successively 2-(((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_267
Alkane-5-yl) sulfenyl methyl methoxyl group-3,5-lutidine-2-yl)))-and the 1H-benzoglyoxaline (580.3g, content: 96.5%, amount: 560.0g, 1.354mol), toluene (3864mL) and H 2(2.81g 0.156mol) and with mixture stirs O, simultaneously 60 ℃ of heating down.After 6 minutes, (122.9g 0.596mol) joins in the formed suspension and the wash reagent bottle with toluene (560 mL) with L-(+)-diethyl tartrate.After 30 minutes, confirm to dissolve.After 8 minutes, (77.0g 0.271mol) and with reagent bottle washs with toluene (56mL) to add titanium tetraisopropylate (IV).The mixture that forms is stirred, under identical temperature, heated about 1 hour simultaneously.Mixture is cooled to 8 ℃ and add N, and the toluene of N-diisopropyl ethyl amine (280mL) solution (56.01g, 0.742mol), washing reagent bottle then.After 10 minutes, in 47 minutes, drip cumene hydroperoxide (259.2g, toluene solution 1.422mol) (840mL) and with mixture 8 ℃ of following stir abouts 18.5 hours.Pour refrigerative 30%w/w sodium thiosulfate solution (2240g) into and mixture was stirred 12 minutes, then water layer is abandoned.In organic layer, pour 4%w/w aqueous sodium hydroxide solution (2240g) into and mixture is stirred, leave standstill then.With water layer separate the 2-obtain with the aqueous sodium hydroxide solution extraction (((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_268
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-and the aqueous solution of the optically active isomer (retention time is short) of 1H-benzoglyoxaline, be pale brown look suspension.In toluene (7840mL), pour into 2-with aqueous sodium hydroxide solution extraction (((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_269
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-solution (2.98kg) of the optically active isomer (retention time is short) of 1H-benzoglyoxaline and mixture stirred.Under agitation in mixture, add 20%w/w acetic acid aqueous solution (400mL), the 8%NaOH aqueous solution (50mL) and 20%w/w acetic acid aqueous solution (8mL) successively and with pH regulator to 8.64.Mixture is left standstill and separate, then water layer is abandoned.With organic layer with 5%w/w salt brine solution (2240g) washing, separate obtain 2-(((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_270
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-(its content: 567.7g 1.322mol), is brown yellow solution for the toluene extraction solution (7.31kg) of the optically active isomer (retention time is short) of 1H-benzoglyoxaline.
(245.6g, methanol solution 1.286mol) at room temperature stir simultaneously to add 28.3% sodium methylate in the toluene extraction solution that obtains in 1 minute.In this solution, in 3 minutes, drip t-butyl methyl ether (1120mL) subsequently and mixture is at room temperature stirred.After 6 minutes, the affirmation crystalline deposit is separated out.Mixture was continued stir about 30 minutes.In addition, dripping t-butyl methyl ether (7840mL) in 2 hours 40 minutes also at room temperature continues to stir to spend the night.
Drip t-butyl methyl ether after about 13 hours, suction filtration is carried out in the crystallization that precipitation is separated out, wash also vacuum-drying 15 minutes with toluene/t-butyl methyl ether (1047mL/1193mL).The wet crystallization drying under reduced pressure (40 ℃) of gained is obtained required product.
Yield: 546.8g, content: 101.7%, amount: 546.8g (content is by 100%), yield: 90.9% (in amount), HPLC purity: 98.2%, enantiomeric excess: 100%ee
＜HPLC analysis condition (reaction is checked, the mensuration of HPLC purity and quantitative) 〉
Post: YMC-Pack Pro C18 AS-302 (5 μ m, 4.6mm * 150mm I.D.)
Eluent: A solution (MeCN/20mM AcONH4 aq.=100/900 (v/v)), B solution (MeCN/20mM AcONH4 aq.=800/200 (v/v))
Flow velocity: 1.0mL/min
Detect: UV 254 nm
Furnace temperature: 25 ℃
Sample temperature: 25 ℃
Gradient condition (time/the B strength of solution): 0.01 minute/0% → 25 minute/100% → 30 minute/100% → 30.01 minute/0% → 40 minute/stop
RT＝14.1min
＜HPLC analysis condition (enantiomeric excess) 〉
Post: DAICEL CHIRALPAK IA (4.6mm * 250mm I.D.)
Eluent: EtOH/MTBE=150/850 (v/v)
Flow velocity: 1.0mL/min
Detect: UV 284nm
Furnace temperature: 25 ℃
Sample temperature: 25 ℃
(8) 2-(((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_271
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-the pure sodium salt of 1H-benzoglyoxaline optically active isomer (retention time is short)
[formula 370]
Figure S2006800126056D02381
To 2-(((4-(and 2,2-dimethyl-1,3-two
Figure 2006800126056_272
Alkane-5-yl) sulfinyl methyl methoxyl group-3,5-lutidine-2-yl)))-(536.8g adds ethanol (1074mL) in 1.189mol) for the thick optically active isomer (retention time is short) of 1H-benzoglyoxaline sodium.Thick isomer at room temperature is dissolved in ethanol.In this solution, pour t-butyl methyl ether (1074mL) into.Gained solution is carried out suction filtration by Hyflo Super-Cel bed (107.4g uses the washing of ethanol/t-butyl methyl ether (1074mL/1074mL) and t-butyl methyl ether (537mL) successively), use ethanol/t-butyl methyl ether (215mL/215mL) flushing then.
The filtrate that obtains transferred in the crystallisation vessel and with ethanol/t-butyl methyl ether (54mL/54mL) washing to shift fully, begin then at room temperature to stir.In 6 minutes, drip t-butyl methyl ether (1610mL) then and mixture is continued stirring at room temperature.In 2 minutes, drip t-butyl methyl ether (268mL) after 11 minutes and mixture is continued stirring.After 1 minute, the affirmation crystalline deposit is separated out.Mixture is continued to stir 31 minutes and dripped t-butyl methyl ether (268mL) in 9 minutes.After mixture at room temperature stirred 8 minutes, in 1 hour 10 minutes, add t-butyl methyl ether (8589mL) and mixture is continued at room temperature to stir.
The dropping of finishing t-butyl methyl ether is carried out suction filtration with the crystallization that precipitation is separated out after about 22 hours under spraying nitrogen gas, use the washing of ethanol/t-butyl methyl ether (107mL/966mL) and t-butyl methyl ether (1074mL) successively, vacuum-drying 8 minutes.In resulting wet crystallization (584.54g), crystallization (531.10g) drying under reduced pressure (50 ℃) that will wet obtains required product.
Yield: 419.6g, HPLC purity: 99.4%
＜HPLC analysis condition (mensuration of HPLC purity and quantitative) 〉
Post: the YMC-Pack Pro C18 A second month in a season 302 (5 μ m, 4.6mm * 150mm I.D.)
Eluent: A solution (MeCN/20mM AcONH4 aq.=100/900 (v/v)), B solution (MeCN/20mM AcONH4 aq.=800/200 (v/v))
Flow velocity: 1.0mL/min
Detect: UV 254nm
Furnace temperature: 25 ℃
Sample temperature: 25 ℃
Gradient condition (time/the B strength of solution): 0.01 minute/0% → 25 minute/100% → 30 minute/100% → 30.01 minute/0% → 40 minute/stop
RT＝14.1min。
(preparation embodiment 1) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_273
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 371]
Figure S2006800126056D02391
(1a) (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_274
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) the methylmethanesulfonate ester
[formula 372]
Will (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_275
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl alcohol (water content is in 7.28% for 2.5g, 8.35mmol) is dissolved in toluene and mixture is carried out azeotropic dehydration 2 times.Resistates is dissolved in tetrahydrofuran (THF) (30ml).(2.33ml 16.7mmol) and with mixture stirs under the cooling of ice in nitrogen atmosphere to add triethylamine in solution.Be lower than at internal temperature in 2 minutes, drip under 11.5 ℃ the condition methylsulfonyl chloride (0.766ml, 10mmol).Reaction mixture was stirred 13 minutes under identical condition, wash with the ethyl acetate dilution and with saturated sodium bicarbonate aqueous solution and saturated brine solution.Organic layer is also passed through filtered through silica gel with dried over mgso, filtrate decompression is concentrated obtain title compound (2.8g, 93.3%), be the light orange solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.37(3H，s)，2.07-2.15(1H，m)，2.23(3H，s)，2.26(3H，s)，3.22(3H，s)，3.81(2H，dd，J＝6，12Hz)，3.89(2H，d，J＝7Hz)，4.02(2H，dd，J＝4，12Hz)，5.29(2H，s)，8.24(1H，s)。
(1b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_276
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 373]
Figure S2006800126056D02401
To (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_277
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methylmethanesulfonate ester (500mg, 1.39mmol), 2-mercaptobenzimidazole (209mg, 1.39mmol) and the mixture of tetrahydrofuran (THF) (5ml) in add triethylamine (0.387ml 2.78mmol) and with mixture at room temperature stirred 14 hours 25 minutes.With the reaction mixture concentrating under reduced pressure, with toluene with the 0.1N aqueous sodium hydroxide solution joins in the resistates and by removing by filter insolubles.Organic layer is taken out, water layer is extracted with toluene once more.Organic layer is merged, with the saturated brine solution washing, with dried over sodium sulfate and filtration.Filtrate decompression is concentrated.Resistates is dissolved in normal heptane/ethyl acetate (1/1) and carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1 → 0/1) obtain title compound (549mg, 95.5%), be colourless thick oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.16(1H，m)，2.20(3H，s)，2.28(3H，s)，3.80(2H，dd，J＝6，12Hz)，3.86(2H，d，J＝7Hz)，4.01(2H，dd，J＝4，12Hz)，4.68(2H，s)，7.08-7.14(2H，m)，7.38-7.50(2H，m)，8.17?(1H，s)。
(preparation embodiment 2) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_278
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 374]
Figure S2006800126056D02411
(2a) (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_279
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl 4-toluene sulfonic acide ester
[formula 375]
Figure S2006800126056D02412
To (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_280
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) (738mg, (313mg 7.84mmol) and with mixture at room temperature stirred 35 minutes methyl alcohol to add powdered sodium hydroxide in tetrahydrofuran (THF) 2.61mmol) (30ml) solution.Mixture continue was stirred 10 minutes under the cooling of ice, in 1 minute, slowly add then Tosyl chloride (1.09g, 5.74mmol).Reaction mixture at room temperature stirred 17 hours 40 minutes and with the tetrahydrofuran (THF) dilution, then by removing by filter insolubles.In filtrate, add silica gel and mixture is concentrated, carry out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1) obtain title compound (1.00g, 88%), be white solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.37(3H，s)，2.03-2.11(1H，m)，2.07(3H，s)，2.18(3H，s)，2.41(3H，s)，3.76-3.81(4H，m)，4.00(2H，dd，J＝4，12Hz)，5.13(2H，s)，7.42(2H，d，J＝8Hz)，7.73(2H，d，J＝8Hz)，8.14(1H，s)。
(2b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_281
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 376]
Figure S2006800126056D02421
To (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_282
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl 4-toluene sulfonic acide ester (457mg, 1.05mmol), 2-mercaptobenzimidazole (158mg, 1.05mmol) and the mixture of tetrahydrofuran (THF) (5ml) in add triethylamine (0.293ml 2.1mmol) and with mixture at room temperature stirred 15 hours 30 minutes.In reaction mixture, add toluene and dilute sodium hydroxide aqueous solution and organic layer is taken out.Water layer is extracted with toluene once more.Organic layer is merged, with the saturated brine solution washing, with dried over sodium sulfate and filtration.Filtrate decompression is concentrated.Resistates is dissolved in normal heptane/ethyl acetate (1/1) and carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1 → 0/1) obtain title compound (419mg, 96.5%), be colourless thick oil.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.16(1H，m)，2.20(3H，s)，2.28(3H，s)，3.80(2H，dd，J＝6，12Hz)，3.86(2H，d，J＝7Hz)，4.01(2H，dd，J＝4，12Hz)，4.68(2H，s)，7.08-7.14(2H，m)，7.38-7.50(2H，m)，8.17(1H，s)。
(preparation embodiment 3) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_283
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 377]
Figure S2006800126056D02422
(3a) 2-(chloromethyl)-(4-((2,2-dimethyl-1,3-two
Figure 2006800126056_284
Alkane-5-yl) methoxyl group)-3, the 5-lutidine
[formula 378]
Figure S2006800126056D02431
To (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_285
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) (800mg, (0.397ml 2.85mmol) and with mixture stirs under the cooling of ice in nitrogen atmosphere methyl alcohol to add triethylamine in toluene 2.85mmol) (16ml) solution.(0.208ml 2.85mmol) and with mixture at room temperature stirred 20 minutes to be lower than under 7.7 ℃ the internal temperature thionyl chloride in 2 minutes.Reaction mixture is washed with the ethyl acetate dilution and with saturated sodium bicarbonate aqueous solution and salt brine solution under the cooling of ice.With organic layer with dried over sodium sulfate and use filtered through silica gel.Filtrate decompression concentrated obtain title compound (0.837g, 98%), be light brown oily material.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.37(3H，s)，2.05-2.16(1H，m)，2.21(3H，s)，2.28(3H，s)，3.81(2H，dd，J＝6，12Hz)，3.88(2H，d，J＝7Hz)，4.01(2H，dd，J＝4，12Hz)，4.76(2H，s)，8.19(1H，s)。
(3b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_286
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-1 H-benzoglyoxaline
[formula 379]
Figure S2006800126056D02432
To 2-(chloromethyl)-(4-((2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-3,5-lutidine (837mg, 2.79mmol), 2-mercaptobenzimidazole (419mg, 2.79mmol) and sodium hydroxide (223mg adds methyl alcohol (20ml) and mixture was at room temperature stirred 12 hours 55 minutes in mixture 5.58mmol).With the reaction mixture concentrating under reduced pressure.Toluene and 0.1N aqueous sodium hydroxide solution are joined in the resistates,, then organic layer is taken out by removing by filter insolubles.Water layer is extracted with toluene once more.Organic layer is merged, with the saturated brine solution washing, with dried over sodium sulfate and filtration.Filtrate decompression is concentrated.Resistates is dissolved in normal heptane/ethyl acetate (1/1) and carries out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1 → 0/1) obtain title compound (980mg, 84.9%), be white foam.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.16(1H，m)，2.20(3H，s)，2.28(3H，s)，3.81(2H，dd，J＝6，12Hz)，3.86(2H，d，J＝7Hz)，4.01(2H，dd，J＝4，12Hz)，4.68(2H，s)，7.08-7.14(2H，m)，7.38-7.50(2H，m)，8.17(1H，s)。
(preparation embodiment 4) 2-(((4-((2,2-dimethyl-1,3-two
Figure 2006800126056_288
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 380]
Figure S2006800126056D02441
(4a) (4-((2,2-dimethyl-1,3-two Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) the methyl acetic acid ester
[formula 381]
Figure S2006800126056D02442
With 4-((2,2-dimethyl-1,3-two
Figure 2006800126056_290
Alkane-5-yl) methoxyl group)-2,3, (10.5g 37.4mmol) is dissolved in diacetyl oxide (100mL) and solution stirred 1.5 hours down at 85 ℃ to 5-trimethylpyridine 1-oxide compound.After reaction mixture concentrated, with resistates by silica gel chromatography (eluting solvent: normal heptane/ethyl acetate=1/1 → 0/1), required fraction concentrated obtain title compound (6.1g, 50.4%), be light yellow solid.
1H?NMR(400MHz，DMSO-d 6)δppm；1.31(3H，s)，1.35(3H，s)，2.04(3H，s)，2.05-2.13(1H，m)，2.17(3H，s)，2.19(3H，s)，3.79(2H，dd，J＝6，12Hz)，3.85(2H，d，J＝7Hz)，4.00(2H，dd，J＝4，12Hz)，5.09(2H，s)，8.17(1H，s)。
(4b) 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_291
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfenyl)-the 1H-benzoglyoxaline
[formula 382]
Figure S2006800126056D02451
To potassium tert.-butoxide (262mg, 2.33mmol) and 2-mercaptobenzimidazole (349mg, add in dimethyl sulfoxide (DMSO) 2.33mmol) (10ml) solution (4-((2,2-dimethyl-1,3-two
Figure 2006800126056_292
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) (500mg 1.55mmol) and with mixture was stirring 3 hours 10 minutes down at 150 ℃ in nitrogen atmosphere the methyl acetic acid ester.After being cooled to room temperature, reaction mixture with dilution with toluene and with dilute sodium hydroxide aqueous solution and saturated brine solution washing, is also filtered with dried over sodium sulfate.Filtrate decompression is concentrated.Resistates is carried out silica gel column chromatography (eluting solvent: normal heptane/ethyl acetate=1/1) obtain title compound (441mg, 68.8%), be white foam 2 times.
1H?NMR(400MHz，DMSO-d 6)δppm；1.33(3H，s)，1.36(3H，s)，2.05-2.16(1H，m)，2.20(3H，s)，2.28(3H，s)，3.80(2H，dd，J＝6，12Hz)，3.86(2H，d，J＝7Hz)，4.01(2H，dd，J＝4，12Hz)，4.68(2H，s)，7.08-7.14(2H，m)，7.38-7.50(2H，m)，8.17(1H，s)。
(EXPERIMENTAL EXAMPLE 1) is to the inhibition effect of the gastric acid secretion of the dog that suffers from chronic gastric fistula
(1) method
Utilization suffers from the towser (body weight: about 14 to 19kg) of chronic gastric fistula, and the compound of embodiment is studied to the inhibition effect of gastric acid secretion with to the persistence of the effect of gastric acid secretion.Test was carried out 2 days.First day, with histamine (50 or 75 μ g/kg/h) intravenously successive administration 3 hours.In histamine administration process, gastric juice of collection in per 20 minutes.Beginning histamine administration is after 1 hour, stays conduit to carry out administration with the volume of 0.1ml/kg by ID putting the testing compound (compound for preparing among the embodiment) that is suspended in or be dissolved in 0.5% methocel solution.Check the inhibition effect of testing compound in 2 hours after administration to gastric acid secretion.Second day (that is, using testing compound after 24 hours) continued intravenous administration 2 hours with histamine.In histamine administration process, collected gastric juice in per 20 minutes once and check persistence to the inhibition effect of gastric acid secretion.After measuring the amount of gastric juice, use the titration of 0.04mol/l sodium hydroxide solution to pH7.0 in the sample of 0.5ml gastric juice.Measure the acid concentration of gastric juice thus.The volume of hydrochloric acid in gastric juice output (secretory volume) by gastric juice multiply by acid concentration and calculates.The inhibition effect of gastric acid secretion is estimated based on the inhibiting rate (%) first day gastric acid secretion.Inhibition effect (%) to gastric acid secretion obtains according to following equation.When the number of animal is 2 or more for a long time, obtain mean value.
Inhibition effect (%)=(A-B)/A * 100 to gastric acid secretion
[A]: played after the administration 1 hour 20 minutes hydrochloric acid in gastric juice output (secretory volume) after the beginning histamine administration in 40 minutes.
[B]: played after the administration 2 hours 20 minutes hydrochloric acid in gastric juice output after the testing compound administration in 1 hour 40 minutes.
Based on second day inhibiting rate (%), the persistence of the inhibition effect of gastric acid secretion is estimated gastric acid secretion.Persistence (%) to the inhibition effect of gastric acid secretion obtains according to following equation:
Persistence (%)=(C-D)/C * 100 to the inhibition effect of gastric acid secretion.
[C]: the total amount of the hydrochloric acid in gastric juice output that begins from the histamine administration (at first day, to the administration 1 hour).
[D]: the total amount of the hydrochloric acid in gastric juice output that begins from the histamine administration (at second day, to the administration 1 hour).
(2) result
[table 1]
Compound Dosage (mg/kg, i.d.) The animal number Inhibition effect (%) to gastric acid secretion Persistence (%) to the inhibition effect of gastric acid secretion
Embodiment 1 0.4 2 94 76
Embodiment 1 0.8 2 100 90
Embodiment 2 0.2 3 83 52
Embodiment 2 0.4 3 100 90
Embodiment 2 0.8 2 100 96
Embodiment 3 0.8 1 100 86
Embodiment 4 0.8 1 100 93
Embodiment 5 0.8 2 100 89
Embodiment 5 0.4 2 54 61
[table 2]
Compound Dosage (mg/kg, i.d.) The animal number Inhibition effect (%) to gastric acid secretion Persistence (%) to the inhibition effect of gastric acid secretion
Embodiment 6 0.8 1 100 89
Embodiment 7 0.8 1 99 90
Embodiment 8 0.8 1 100 88
Embodiment 9 0.8 2 100 90
Embodiment 10 0.8 2 98 90
Embodiment 10 1.6 1 100 87
Embodiment 11 0.4 3 79 65
Embodiment 11 0.8 3 100 89
Embodiment 12 0.8 1 100 86
Embodiment 13 0.8 2 100 74
Embodiment 19 0.4 4 13 -4
Embodiment 19 0.8 4 82 56
Embodiment 20 0.1 4 8 6
Embodiment 20 0.2 4 65 46
Embodiment 20 0.4 10 97 77
Embodiment 20 0.8 8 100 89
Embodiment 21 1.6 1 100 94
Embodiment 22 1.6 1 100 97
Embodiment 23 1.6 1 100 92
Embodiment 24 1.6 1 88 80
Embodiment 26 1.6 1 100 80
Embodiment 27 1.6 1 100 92
Embodiment 28 1.6 1 94 77
Embodiment 29 1.6 1 100 87
Embodiment 30 1.6 1 100 95
Embodiment 30 0.8 1 100 63
Embodiment 31 1.6 1 100 97
Embodiment 32 1.6 1 100 83
Embodiment 33 1.6 1 100 84
Embodiment 34 1.6 1 100 78
Embodiment 36 1.6 1 100 90
Embodiment 39 1.6 1 100 86
[table 3]
Compound Dosage (mg/kg, i.d.) The animal number Inhibition effect (%) to gastric acid secretion Persistence (%) to the inhibition effect of gastric acid secretion
Embodiment 40 1.6 1 100 92
Embodiment 40 0.8 1 99 66
Embodiment 41 1.6 1 100 85
Embodiment 42 0.8 1 60 72
Embodiment 46 0.8 1 100 95
Embodiment 47 1.6 1 100 87
Embodiment 50 0.8 1 79 80
Embodiment 51 1.6 1 100 83
Embodiment 52 1.6 1 100 87
Embodiment 53 0.8 1 99 87
Embodiment 55 0.8 1 83 75
Embodiment 56 0.8 1 84 74
Embodiment 57 0.8 2 98 83
Embodiment 58 0.8 2 95 77
Embodiment 59 0.8 1 89 77
Embodiment 60 0.8 1 89 74
Embodiment 61 1.6 2 100 90
Embodiment 64 0.8 2 100 78
Embodiment 65 1.6 1 100 91
Embodiment 66 1.6 1 100 79
Embodiment 67 1.6 1 100 83
Embodiment 69 1.6 1 100 78
Embodiment 70 1.6 1 100 77
Embodiment 70 1.6 1 100 64
Embodiment 73 0.8 1 100 94
Embodiment 75 0.8 1 85 75
Embodiment 81 0.8 1 96 70
Embodiment 83 0.8 1 71 94
Embodiment 85 0.8 1 100 86
Embodiment 86 0.8 1 100 75
Embodiment 87 0.8 1 100 92
(example of formulations 1) capsule
With 30.0g 2-(((4-((and 2,2-dimethyl-1,3-two
Figure 2006800126056_293
Alkane-5-yl) methoxyl group)-3; 5-lutidine-2-yl) sulfinyl methyl))-1H-benzoglyoxaline sodium salt (below be called " compd A "), 8.1g ethyl cellulose (trade(brand)name: Etcel; produce by Dow Chemical Co.) and 16.2g hydroxypropylcellulose (trade(brand)name: HPC-L is by Shin-Etsu Chemical Co.Ltd. production) be dissolved in the 489g dehydrated alcohol.(trade(brand)name: Multiplex Pawlek) is coated to the 500.1g nuclear substance with this solution, and on the Nonpareil 108 (trade(brand)name is produced by Freund Corporation), drying makes particle then to utilize Wurster-type fluidized-bed coated particle machine.
Then 48.6g ethyl cellulose (trade(brand)name: Etcel, Dow Chemical Co.) and 291.9g hydroxypropylcellulose (trade(brand)name: HPC-L, Shin-Etsu Chemical Co.Ltd.) are dissolved in dehydrated alcohol (6860g).In addition, 136.8g Magnesium Stearate (being produced by Marin Klot) is dispersed in this solution to make coating solution.The above particle that makes (554.4g) is applied with coating solution, dry then to make the coated particle in middle layer.
In addition; with 460.2g hydroxypropyl methylcellulose phthalate (trade(brand)name: HP-55S; Shin-Etsu Chemical Co.Ltd.) and the direactive glyceride of 45.3g diacetylization (trade(brand)name: Mybassett, by Quest International produce) be dissolved in 80% aqueous ethanolic solution (11045g).In addition, 42.3g talcum (trade(brand)name: Talc, by Matsumura Industry produce) and 24.3g titanium oxide (trade(brand)name: titanium oxide (IV), by Merck production) are dispersed in the above ethanolic soln that obtains.The coated particle (1031.7g) in middle layer is applied with this dispersion soln, and drying makes full of enteric coated granules then.
In this full of enteric coated granules (1603.8g), add 15.0g light anhydrous silicic acid (trade(brand)name: AEROSIL-200 (Japanese Pharmacopoeia), produce by Nippon Aerosil) and 15.0g talcum (trade(brand)name, Hi-filler#17, produce by Matsumura Industry) and with they usefulness container type mixing tank (trade(brand)names: 2/5L container type mixing tank, produce by Toyo Packing) the mixed compd A (Compound A) that gets, it is packed into capsule with the capsular amount of 1mg/.
(example of formulations 2) capsule
Make capsule according to following prescription according to the mode identical with example of formulations 1.(Compound A) is packed into capsule with the capsular amount of 10mg/ with compd A.
[table 4]
Composition
Nonpareil?108 ?465.0
Main component stratification compound A ethyl cellulose HPC-L ?500.0?135.0?270.0
Middle layer ethyl cellulose HPC-L Magnesium Stearate ?40.0?240.0?112.5
Outer HP-55SMybassett talcum titanium oxide ?380.0?37.5?35.0?20.0
The AEROSIL-200 talcum ?30.0?30.0
Unit: g
Nonpareil 103 (trade(brand)name, Freund Corporation)
[industrial applicibility]
The compounds of this invention gastric acid inhibitory secretion efficiently, the gastric acid inhibitory secretion of persistence ground are safe, have suitable physical and chemical stability, so useful as drug, in particular as with the curative drug or the preventive medicine of sour diseases associated or symptom.

Claims (42)

1. the compound or its salt shown in the following formula (1)
[formula 1]
Figure FSB00000543838400011
Wherein
R 1And R 3Can represent hydrogen atom or C identical or different and separately 1-C 6Alkyl;
R 2It is the group shown in the following formula (2)
[formula 2]
Figure FSB00000543838400012
W wherein 2Expression hydrogen atom, C 1-C 6Alkyl or halogen atom, condition are W 2On phenyl ring, occur 1 to 3 time, and can be identical or different; N1 represents 1 to 5; N2 represents 1 to 4; N3 represents 1 to 6,
Described group randomly has 1 to 4 group that is selected from the A1 group, and described A1 group is by halogen atom, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Haloalkyl, C 1-C 6Alkoxy C 1-C 6Alkyl and hydroxyl are formed;
R 4, R 5, R 6And R 7Can represent hydrogen atom, hydroxyl, halogen atom, C identical or different and separately 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group or C 1-C 6Halogenated alkoxy; And
W 1Expression singly-bound or have the straight or branched alkylidene group of 1 to 8 carbon atom.
2. the described compound or its salt of claim 1, wherein R 1Be hydrogen atom or methyl.
3. the described compound or its salt of claim 1, wherein R 1It is methyl.
4. the described compound or its salt of any one in the claim 1 to 3, wherein R 2It is the group shown in the following formula (3)
[formula 3]
Figure FSB00000543838400031
W wherein 2Expression hydrogen atom, C 1-C 6Alkyl or halogen atom, condition are W 2On phenyl ring, occur 1 to 3 time, and can be identical or different; N1 represents 1 to 5; N2 represents 1 to 4; N3 represents 1 to 6,
Described group randomly has 1 or 2 group that is selected from the A2 group, and described A2 group is made up of fluorine atom, methyl, ethyl, propyl group, methoxyl group and single methyl fluoride.
5. the described compound or its salt of any one in the claim 1 to 3, wherein R 2Be the group shown in the following formula (4):
[formula 4]
6. the compound or its salt shown in any one in the claim 1 to 3, wherein R2 is the group shown in the following formula (5)
[formula 5]
Figure FSB00000543838400042
7. the described compound or its salt of any one in the claim 1 to 3, wherein R 3Be hydrogen atom or methyl.
8. the described compound or its salt of any one in the claim 1 to 3, wherein R 3It is methyl.
9. the described compound or its salt of any one in the claim 1 to 3, wherein R 4Be hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom.
10. the described compound or its salt of any one in the claim 1 to 3, wherein R 4Be hydrogen atom, methyl or fluorine atom.
11. the described compound or its salt of any one in the claim 1 to 3, wherein R 4It is hydrogen atom.
12. the described compound or its salt of any one in the claim 1 to 3, wherein R 5Be hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom.
13. the described compound or its salt of any one in the claim 1 to 3, wherein R 5Be hydrogen atom, methyl or fluorine atom.
14. the described compound or its salt of any one in the claim 1 to 3, wherein R 5It is hydrogen atom.
15. the described compound or its salt of any one in the claim 1 to 3, wherein R 6Be hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom.
16. the described compound or its salt of any one in the claim 1 to 3, wherein R 6Be hydrogen atom, methyl, methoxyl group or fluorine atom.
17. the described compound or its salt of any one in the claim 1 to 3, wherein R 6It is hydrogen atom.
18. the described compound or its salt of any one in the claim 1 to 3, wherein R 7Be hydrogen atom, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group or fluorine atom.
19. the described compound or its salt of any one in the claim 1 to 3, wherein R 7Be hydrogen atom, methyl or fluorine atom.
20. the described compound or its salt of any one in the claim 1 to 3, wherein R 7It is hydrogen atom.
21. the described compound or its salt of any one in the claim 1 to 3, wherein W 1Be singly-bound, methylene radical or ethylidene.
22. the described compound or its salt of any one in the claim 1 to 3, wherein W 1It is methylene radical.
23. the described compound or its salt of any one in the claim 1 to 3, wherein W 2When occurring, be hydrogen atom at every turn.
24. the described compound or its salt of any one in the claim 1 to 3, wherein n1 is 1 to 3.
25. the described compound or its salt of any one in the claim 1 to 3, wherein n1 is 1 or 2.
26. the described compound or its salt of any one in the claim 1 to 3, wherein n2 is 1 or 2.
27. the described compound or its salt of any one in the claim 1 to 3, wherein n3 is 1 to 4.
28. the described compound or its salt of any one in the claim 1 to 3, wherein n3 is 1 or 2.
29. the described compound or its salt of claim 1, wherein this compound is a kind of following compound that is selected from:
2-(((4-((5,5-dimethyl-1,3-two
Figure FSB00000543838400061
Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline,
2-(((4-(5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((4-((2,2-dimethyl-1,3-two
Figure FSB00000543838400062
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline,
2-(((3-methyl-4-(2-(8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((4-(2-(8-ethyl-1,4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) oxyethyl group)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((4-(1,3-dioxolane-4-ylmethoxy)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((4-((2,2-two (methyl fluoride)-1,3-two
Figure FSB00000543838400071
Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline,
2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-base oxygen base)-3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
(((((2-methoxyl group-1,3-two for 4-for 2- Alkane-5-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline,
2-(((3-methyl-4-((8-methyl isophthalic acid, 4,7,9-four oxaspiros [4.5] last of the ten Heavenly stems-8-yl) methoxyl group) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline,
2-(((4-(5,9-dioxo spiro [3.5] ninth of the ten Heavenly Stems-7-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline and
2-(((4-((5,5-two fluoro-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-the 1H-benzoglyoxaline.
30.2-(((4-((5,5-dimethyl-1,3-two Alkane-2-yl) methoxyl group)-and 3-picoline-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline or its salt.
(31.2-(((5,7-dioxo spiro [2.5] suffering-6-ylmethoxy)-3-picoline-2-is poor for 4-) methyl) sulfinyl)-1H-benzoglyoxaline or its salt.
(32.2-((3-methyl-4-(1,5,9-trioxa spiral shell [5.5] undecane-3-ylmethoxy) pyridine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline or its salt.
33.2-(((4-((2,2-dimethyl-1,3-two
Figure FSB00000543838400075
Alkane-5-yl) methoxyl group)-3,5-lutidine-2-yl) methyl) sulfinyl)-1H-benzoglyoxaline or its salt.
34. comprise the medicine of any one the described compound or its salt in the claim 1 to 33.
35. comprise the gastric acid secretion inhibitor of any one the described compound or its salt in the claim 1 to 33.
36. be used for therapeutical agent or preventive with sour diseases associated or symptom, it comprises any one the described compound or its salt in the claim 1 to 33.
37. described therapeutical agent of claim 36 or preventive wherein are ulcer, gastritis, gastrorrhagia, gastrointestinal hemorrhage, peptide ulceration, hemorrhagic ulcer, hyperchlorhydria, maldigestion, gastroparesis, senile ulcer, intractable ulcer, acute gastric mucosal lesion, pyrosis, bruxism, stomachache, stomach sense of heaviness, the vomitings brought out of gastroesophageal reflux disease, throat paresthesia, Barrett esophagus, NSAID-, feel sick or hyposiagonarthritis with sour diseases associated or symptom.
38. described therapeutical agent of claim 36 or preventive are stomach ulcer, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux disease, Zollinger-Ellison syndrome or acute gastric mucosal lesion with sour diseases associated or symptom wherein.
39. described therapeutical agent of claim 36 or preventive are stress ulcers with sour diseases associated or symptom wherein.
40. described therapeutical agent of claim 36 or preventive are gastroesophageal reflux diseases with sour diseases associated or symptom wherein.
41. described therapeutical agent of claim 36 or preventive are stomach ulcer or duodenal ulcer with sour diseases associated wherein.
42. the assisting sterilisation agent of Hp in the antagonism stomach, it comprises any one the described compound or its salt in the claim 1 to 33, and described assisting sterilisation agent is meant and is controlled at the Working environment that is difficult to the sterilant that plays a role under the acidic conditions so that make sterilant produce the material of rendeing a service.
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