CN1462748A - Preparation of 3-(formamide)-7-(methylsulfonyl amine)-6-(phenoxy)-4H-1-(benzopyran)-4-ketone - Google Patents
Preparation of 3-(formamide)-7-(methylsulfonyl amine)-6-(phenoxy)-4H-1-(benzopyran)-4-ketone Download PDFInfo
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Abstract
A process for preparing 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy) -4H-1-(benzopyran)-4-one as an anti-inflammatory from 3-phenoxy-4-methylsulfonylamine-6- methoxyacetophenone includes demethylation, cyclization, catalytic hydrogenation, bromination, vinylog and amination.
Description
Technical field
The present invention relates to a kind of method for preparing antiphlogiston 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone from 3-phenoxy group-4-Toluidrin-6-methoxyacetophenone.
Background technology
3-(methane amide)-7-(Toluidrin)-6-phenoxy group-4H-1-chromene-4-ketone (code name: T-614, English name: Iguratimod, Chinese medicine name: Ailamode) be a kind of newtype drug for the treatment of osteoarthritis and rheumatoid arthritis, it can not only selectivity suppress cyclooxygenase COX-II, and can regulate the T-cell, has the autoimmunization regulating effect, determined curative effect, side effect is little, and onset is rapid, and effective to the patient of other medicines inefficacy.Clinical test results shows: T-614 can significantly reduce inflammatory reaction, can suppress the generation of inflammatory cytokine, tumour necrosis factor and lymphocyte and immunoglobulin (Ig).3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-(chromene)-4-ketone will be the novel specific new drug of a treatment of arthritis.The further investigation of this compound has been become the heat subject of domestic and international pharmaceutical industry.Japan is carrying out III phase clinical study at present, and II phase clinical study is being carried out in South Africa, and Britain is in that to carry out the I phase clinical, and China and Korea S also are in preclinical study at present.Patent US4954518 disclose 3-(methane amide)-7-(Toluidrin)-6-phenoxy group-4H-1-chromene-4-ketone synthetic method; it is a starting raw material with 4-phenoxy group-3-nitrophenols, is reduced into ammonia, amino methylsulfonylization, phenol through the nitro iron powder and becomes ether, PPA cyclization, bromo, fork alkene to become seven steps reaction such as amine and formylation and synthesize.This method such as suitability for industrialized production, also there are the following problems: raw material 4-phenoxy group-3 nitrophenols can't be buied from the market; Phenol becomes the ether reaction yield low, and needs column chromatographic isolation and purification; PPA pass ring productive rate is low, and aftertreatment is numerous and diverse; Bromo-reaction is made raw material with bromine, and toxicity should not be synthesized greatly in a large number.
Summary of the invention
In order to overcome the problems referred to above, the invention provides the method that a kind of 3-Toluidrin-4-phenoxy group-6-acetyl phenol is feedstock production 3-(methane amide)-7-(Toluidrin)-6-phenoxy group-4H-1-chromene-4-ketone.
The present invention is a kind of to prepare the method for 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone from 3-phenoxy group-4-Toluidrin-6-methoxyacetophenone, and 3-phenoxy group-4-Toluidrin-6-methoxyacetophenone has
Structural formula, 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone has
Structural formula makes by following reaction respectively:
The present invention is a raw material with 3-phenoxy group-4-Toluidrin-6-methoxyacetophenone (compound 1); make 2-ethanoyl-4-phenoxy group-5-Toluidrin phenol (compound 2) through demethylation; compound 2 cyclization under the effect of oxygenant generates 3-Toluidrin-4-phenoxy group benzopyrone (compound 3); compound 3 makes 3-Toluidrin-4-phenoxy group benzo 2 through catalytic hydrogenation; 3-dihydro pyrone (compound 4); compound 4 generates 3-(bromine)-7-(Toluidrin)-6-(phenoxy group)-4H-1-benzo 2 through bromo; 3-dihydropyrane-4-ketone (compound 5); compound 5 makes 3-(amido)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone (compound 6) through the vinylogy amination; compound 6 generates 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone (T-614) through formylation, thereby has realized synthesizing of T-614.
Method of the present invention can be represented with following reaction formula:
, can realize by following step respectively from compound 1 synthetic 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone (T-614) with method of the present invention.
In polar solvent, compound 1, NaX and AlCl
3-10-30 ℃ reaction 0.2-10h, recommendation response time 1-5h, reaction is finished, and adds 1% Sulfothiorine, filters, and filtrate adds water and obtains compound 2; Compound 2 cyclization under the effect of oxygenant generates 3-Toluidrin-4-phenoxy group benzopyrone (compound 3); Compound 3 in polar solvent with catalyzer, ammonium salt in 0-30 ℃ of reaction 0.5-24h, recommend catalyzer, ammonium salt to be respectively Pd/C and ammonium formiate, reaction is finished, drain compound 4; Compound 4 obtains compound 5 with brominated reagent at 0-100 ℃ of reaction 0.5-12h in organic solvent, the recommendation brominated reagent is CuBr
2Nitrogenize reagent is in 25-100 ℃ of reaction 1-9h in polar solvent with repeatedly for compound 5, and reaction is finished, and drains to obtain compound 6; Compound 6 gets white cotton-shaped T-614 in 10-95 ℃ of reaction 0.5-24h with the formic acid acetic anhydride in polar solvent.
Organic solvent that the present invention is used or polar solvent are one or more in the middle of chloroform, methylene dichloride, ethyl acetate, methyl alcohol, ethanol, tetrahydrofuran (THF), the second cyanogen.
Document (Chem.Pharm.Bull.48 (1), 2000, p131-139) in the synthetic F6.4 route of report, the hydrogenation condition under the hydrogen condition of an atmospheric pressure, adds Pd-C for product is dissolved in the acetate, reacts 1 hour under 40-45 ℃ of temperature.This reaction is had relatively high expectations to production unit, and certain danger is arranged in process of production for compressive reaction.Therefore, we improve its technology, reaction conditions changed into product is dissolved in tetrahydrofuran (THF): in the solution of methyl alcohol=4: 1, at room temperature add Pd-C and ammonium formiate, make to be reflected under room temperature, the non-pressurized condition and carry out, both reduced the requirement of reaction pair production unit, provide cost savings, improved the security in the reaction process again, made it more be applicable to industrialized production.
Document (Chem.Pharm.Bull.48 (1), 2000, p131-139) bromo-reaction in the synthetic F6.4 route of report is that raw material is dissolved in the chloroform, at 25-30 ℃ of dropping liquid bromine slowly, after dripping, reaction is 1 hour under this temperature.We find that in process of the test there are some problems in this reaction, at first be this reaction selection be the liquid bromine, the liquid bromine has volatility, and toxicity is big, easily health is caused damage in operating process.Secondly, the liquid feeding bromine reacts, and the by product of reaction is too many, and productive rate is low.Therefore, behind our the process repeated screening test conditions, adopt cupric bromide to replace the liquid bromine, so both avoided of the infringement of liquid bromine, reduced the production of by-products of reaction again, make productive rate bring up to 85% by 65% to health.
In the ammoxidation, the temperature of reaction of bibliographical information is 70-75 ℃ in existing technology.Easily blast because of sodium azide is heated, the low more then security of temperature of reaction is high more.Therefore, we pass through the repeated screening temperature of reaction from improving the angle of reaction safety, temperature of reaction is changed at 45-50 ℃ reacted 3 hours down, react completely.Make that like this danger reduces greatly in the production process.
Embodiment
The preparation of embodiment 1:2-ethanoyl-4-phenoxy group-5-methylsulfonyl amido phenol (compound 2)
54L acetonitrile, the anhydrous AlCl of 3.0kg
3Add in the reactor with 3.7kg compound 1; add the 1.9kg sodium iodide down at 0-5 ℃; at room temperature reaction 3h; reaction is finished, and adds 1% Sulfothiorine under the frozen water cooling, filters; filtrate adds elutriation and goes out solid; filter, vacuum-drying promptly gets 2-ethanoyl-4-phenoxy group-5-Toluidrin phenol (compound 2), productive rate: 86%.
1H?NMR(300MHz，CDCl
3)δ：2.45(3H，s)，3.10(3H，s)，6.94-7.40(m，10)，12.44(1H，s)；
EI-Ms(m/z，int.％)：321(M
+，100)，242(21.54)，306(20.60)，199(18.80)，322(18.34)，144(16.65)，200(16.33)，43(15.33).IR(υ
KBr max)：3254，1634，1600，1569，1504，1493，1430，1409cm
-1.
The preparation of embodiment 2:7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone (compound 3)
23.05Kg is suspended in triethyl orthoformate with compound, at room temperature adds perchloric acid 2.5L, reaction 1-24h, reaction is finished, and filters poach 1-3h, drain compound 7-(Toluidrin)-6-phenoxy group-4H-1-cumarone-4-ketone (compound 3), productive rate: 85%.
1H?NMR(300MHz，CDCl
3)δ：3.18(3H，s)，6.28(1H，d)，7.05(2H，d)，7.26-7.27(2H，m)，7.44(2H，m)，7.57(1H，s)，7.77(1H，s)，7.83(1H，d).
EI-Ms(m/z，int.％)：3?31(M
+，100)，251(95.56)，332(20.10)，252(18.23)，168(16.15)，154(15.28)，149(15.07)，196(13.66).IR(υ
KBr max)：3027，1625，1594，1567，1473，1444，1325，1305cm
-1.
The preparation of embodiment 3:7-(Toluidrin)-6-(phenoxy group)-4H-1-(benzo-2,3 dihydro furan)-4-ketone (compound 4)
2.72kg the mixing solutions of compound 3,30L tetrahydrofuran (THF) and methyl alcohol adds in the reactor, stirs compound 3 is all dissolved, at N
2Protection joins 0.79kg palladium carbon in the reactor after fully wetting with ethanol down, at room temperature adds the 13.44kg ammonium formiate then in batches, and reaction 2-3h filters, and concentrates, and is drying to obtain compound 4, productive rate: 90%.
1H?NMR(300MHz，CDCl
3)δ：2.75(2H，t)，3.13(3H，s)，4.52(2H，t)，6.97-7.37(m，7H)；
EI-Ms(m/z，int.％)：333(M
+，100)，254(72.42)，198(43.58)，144(23.82)，170(21.56)，77(19.16)，334(16.6).
IR(υ
KBr max)：3254，1674，1618，1578，1497，1450，1394，1322，1270，1219，1166，1140。
The preparation of embodiment 4:3-(bromine)-7-(Toluidrin)-6-(phenoxy group)-4H-1-(cumarone)-4-ketone (compound 5)
3.9kg cupric bromide, 30L ethyl acetate and 30L chloroform dissolved compound 4 drop into reactor, reaction 4h filters, and adds 1% hypo solution in the filtrate, separates organic layer, washing, anhydrous Na
2SO
4Drying is filtered, and concentrates and promptly gets compound 5, productive rate 76%.
1H?NMR(300MHz，CDCl
3)δ：3.15(3H，s)，4.15-4.61(2H，m)，6.97-7.47(m，7H)；
EI-Ms(m/z，int.％)：305(100)，411(M
+，78.08)，413(76.64)，77(52.09)，225(47.45)，55(38.35)，198(37.95)，57(6.58).
The preparation of embodiment 5:3-(methane amide)-7-(phenolic hydroxyl group)-6-phenolic hydroxyl group-4H-1-cumarone-4-ketone (T-614)
3.10kg compound 5 dissolves in 20L N, dinethylformamide under agitation adds the 1.05kg sodium azide, in 65 ℃ of reaction 2-3h, filters, and concentrates.Enriched material filters the methylene dichloride insolubles again with methylene dichloride dissolving, methylene dichloride solution 1..With the formic acid aceticanhydride add solution 1. in, reaction 2-4h filters, solid washes with water, and 45-50 ℃ of vacuum-drying, promptly gets compound T-614, productive rate: 75%.
1H?NMR(400MHz，DMSO-d
6)δ：3.22(3H，s)，7.14(2H，d)，7.25(1H，t)，7.32(1H，s)，7.47(2H，t)，7.69(1H，s)，8.30(1H，d)，9.28(1H，s)，9.88(1H，s)，10.16(1H，s)；
13C?NMR(400MHz，DMSO-d
6)δ：40.6(CH
3SO
2)，108.8(C-5)，110.9(C-8)，117.6(C-4a)，119.6(C-2’)，123.2(C-3)，124.6(C-4’)，130.2(C-3’)，135.3(C-7)，145.7(C-2)，151.4(C-6)，155.5(C-8a)，160.4(-CHO)，169.7(C-4)；
EI-Ms(m/z，int.％)：346(100)，267(20.17)，347(19.54)，240(14.19)，374(M
+，13.94)，77(8.14)，154(7.22)，348(7.21).
IR(υ
KBr max)：3341，3278，1686，1623，1608，1536，1491，1468，1339，1263，1209，1153cm
-1.
HREI-Ms：C
17H
14N
2O
6S：374.06225.
T-614 (C
17H
14N
2O
6S) ultimate analysis, calculated value: C, 54.54; H, 3.77; N, 7.48; S, 8.56.
Measured value: C, 54.47; H, 3.70; N, 7.39; S, 8.70.
Claims (2)
1, the preparation method of a kind of 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone, raw material 3-phenoxy group-4-Toluidrin-6-methoxyacetophenone has
Structural formula, 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone has
Structural formula is characterized in that making by following reaction respectively:
A, in polar solvent, 3-phenoxy group-4-Toluidrin-6-methoxyacetophenone is that (mol ratio is 1: 1-2: 1-4), making 2-ethanoyl-4-phenoxy group-5-Toluidrin phenol at-10-30 ℃ of reaction a 0.2-10h is compound 2 for compound 1, sodium halide and Lewis acid;
B, in organic solvent, (mol ratio is 1: 1-30: Toluidrin-4-phenoxy group benzopyrone is a compound 3 1-4) to obtain a 3-at-10-50 ℃ of reaction a 10min-24h, and described oxygenant is a perchloric acid for 2-ethanoyl-4-phenoxy group-5-Toluidrin phenol, carboxylic acid triethyl and oxygenant;
C, in polar solvent, (mol ratio is 1: 1-2: 1-4) for 3-Toluidrin-4-phenoxy group benzopyrone, catalyzer and ammonium salt, make 3-Toluidrin-4-phenoxy group benzo 2 at 0-60 ℃ of reaction 0.5-24h, the 3-dihydro pyrone is a compound 4,3-Toluidrin-4-phenoxy group benzopyrone is 1 with the catalyst weight ratio: 0.01-0.7,3-Toluidrin-4-phenoxy group benzopyrone and ammonium salt mol ratio are 1: 1-50, described catalyzer are PtO
2, Pd/C, Riney Ni;
D, in organic solvent, 3-Toluidrin-4-phenoxy group benzo 2,3-dihydro pyrone and bromide reagent, generate 3-(bromine)-7-(Toluidrin)-6-(phenoxy group)-4H-1-benzo 2 at 0-100 ℃ of reaction 0.5-12h, 3-dihydropyrane-4-ketone is compound 5,3-Toluidrin-4-phenoxy group benzo 2,3-dihydro pyrone and bromide reagent mol ratio are 1: 0.5-3, described bromide reagent are Br
2, CuBr
2
E, in organic solvent, 3-(bromine)-7-(Toluidrin)-6-(phenoxy group)-4H-1-benzo 2, (mol ratio is 1: 1-3), making 3-(amido)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone at 25-100 ℃ of reaction 0.5-13h is compound 6 for 3-dihydropyrane-4-ketone and sodium azide;
F, in polar solvent, (mol ratio is 1: 1-3) at 10-95 ℃ of reaction 0.5-24h, making 3-(methane amide)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone is T-614 for 3-(amido)-7-(Toluidrin)-6-(phenoxy group)-4H-1-chromene-4-ketone and formic acid acetic anhydride;
Method of the present invention can be represented with above-mentioned reaction formula.
2, method according to claim 1 is characterized in that described organic solvent or polar solvent are one or more in the middle of chloroform, methylene dichloride, ethyl acetate, methyl alcohol, ethanol, tetrahydrofuran (THF), the second cyanogen.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102516252A (en) * | 2011-12-23 | 2012-06-27 | 四川滇虹医药开发有限公司 | Preparation method of Nedocromil sodium |
| CN101597272B (en) * | 2008-06-05 | 2012-07-04 | 杨喜鸿 | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof |
| CN106986797A (en) * | 2017-04-24 | 2017-07-28 | 常州佳德医药科技有限公司 | N (2 (4 acetyl phenoxy group) 5 methoxyphenyls) Methanesulfomide and preparation method thereof |
| CN107021891A (en) * | 2017-04-24 | 2017-08-08 | 常州佳德医药科技有限公司 | A kind of preparation method of Ailamode intermediate |
| CN108586408A (en) * | 2018-04-09 | 2018-09-28 | 扬子江药业集团有限公司 | A kind of preparation method of the Ailamode intermediate of high yield and high-purity |
| CN113527148A (en) * | 2021-05-26 | 2021-10-22 | 佳尔科生物科技南通有限公司 | Preparation method of N- [4- (2-formamidoacetyl) -5-hydroxy-2-phenoxyphenyl ] methanesulfonamide |
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2003
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101597272B (en) * | 2008-06-05 | 2012-07-04 | 杨喜鸿 | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof |
| CN102516252A (en) * | 2011-12-23 | 2012-06-27 | 四川滇虹医药开发有限公司 | Preparation method of Nedocromil sodium |
| CN106986797A (en) * | 2017-04-24 | 2017-07-28 | 常州佳德医药科技有限公司 | N (2 (4 acetyl phenoxy group) 5 methoxyphenyls) Methanesulfomide and preparation method thereof |
| CN107021891A (en) * | 2017-04-24 | 2017-08-08 | 常州佳德医药科技有限公司 | A kind of preparation method of Ailamode intermediate |
| CN106986797B (en) * | 2017-04-24 | 2018-09-28 | 常州佳德医药科技有限公司 | N- (2- (4- acetyl phenoxy group) -5- methoxyphenyls) Methanesulfomide and preparation method thereof |
| CN108586408A (en) * | 2018-04-09 | 2018-09-28 | 扬子江药业集团有限公司 | A kind of preparation method of the Ailamode intermediate of high yield and high-purity |
| CN108586408B (en) * | 2018-04-09 | 2022-01-18 | 扬子江药业集团有限公司 | Preparation method of high-yield and high-purity Iguratimod intermediate |
| CN113527148A (en) * | 2021-05-26 | 2021-10-22 | 佳尔科生物科技南通有限公司 | Preparation method of N- [4- (2-formamidoacetyl) -5-hydroxy-2-phenoxyphenyl ] methanesulfonamide |
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