CN102285937B - Method for synthesizing febuxostat - Google Patents
Method for synthesizing febuxostat Download PDFInfo
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Abstract
The invention provides a method for synthesizing febuxostat. The method comprises the following steps of: (a) performing aromatic ring substitution reaction on a compound of a formula I to obtain a compound of a formula II; (b) performing halogen-metal exchange reaction on the compound of the formula II to obtain a compound of a formula III; (c) performing coupling reaction on the compound of the formula III and the compound of a formula VI under the action of a metal catalyst to obtain a compound of a formula IV; and (d) performing hydrolysis reaction on the compound of the formula IV to obtain the compound of a formula V, namely febuxostat, wherein X is I or Br; M is selected from boric acid ester or SnBu3; and R is H or an alkyl group. In the method, a convergent synthesis strategy is adopted, and a carbon-carbon bond is formed by applying metal catalyzed aromatic ring coupling reaction in a key step, so that a system in which a benzene ring is coupled with a thiazole ring is established. The method has the advantages of simple and short steps, high yield and low environmental pollution and can be suitable for industrial production.
Description
Technical field
the present invention relates to the pharmaceutical chemistry field, relate more specifically to a kind of anti-gout drugs Febuxostat-2-[3-cyano group-4-(2-methyl propoxy-) phenyl]-synthetic method of 4-methyl-5 thiazol formic-acid.
Background technology
gout claims again hyperuricemia, is the disease that the purine metabolism obstacle causes, along with the raising of people's living standard, its sickness rate is more and more higher, and united state classifies one of large chronic disease of 21 centurys 20 as.But not Bu Suotan is a kind of selectivity XOD/xanthine dehydrogenase inhibitor of new high efficiency, can effectively reduce the uric acid level in the goat patient body, obviously improve the symptom of patient with gout.At present, adopt traditional structure synthetizing thiazolium method through the synthetic method of the Febuxostat of report is most of, synthetic route long (generally more than six steps) usually, and wherein in related molecule the conversion of functional group very loaded down with trivial details; Secondly, the starting raw material of multiple synthetic route is expensive, even in some step, need to use severe toxicity, corrodibility and the stronger chemical reagent of contaminative such as sodium cyanide, trifluoroacetic acid, urotropine, hydrogen sulfide, thiophosphoric anhydride, operator and environment are had to larger disadvantageous effect.In addition, some reaction needed is used diazotization reaction, in the operation of extensive reaction, should not control, and this makes suitability for industrialized production more difficult.And the total recovery of the synthetic method of existing bibliographical information is lower, generally lower than 30%, this also makes it be not suitable for suitability for industrialized production.
in traditional synthetic method, in molecule, build and while introducing cyano group: JP06345724, EP0513379A1, WO9209279, CN101386604 disclose in raw material by existing two substituting groups on phenyl ring, connect cyano group it is positioned; JP10139770 discloses in intermediate by the existing leavings group on phenyl ring, and it is carried out to substitution reaction; WO9209279 carries out diazotization reaction to the amino on phenyl ring in raw material or intermediate; This several method all will adopt the prussiates such as hypertoxic potassium cyanide, sodium cyanide, and the security of technique is very low, and the destructiveness of environment is very large.
when building ring closure reaction generation thiazole ring, to the cyano group in raw material or intermediate, utilize sulfo-reagent to change into thioamides: US20050075503, US2005027128 disclose to use and passed into hydrogen sulfide pressurization preparation in solution, react very dangerous, corrodibility is strong, environmental disruption is large, is unfavorable for amplifying producing; CN101391988 discloses one pot reaction synthetizing thiazolium ring, avoid using hydrogen sulfide, but raw materials cost is higher; CN101412699 discloses use HCl/DMF system synthetizing thiazolium ring, avoids using gas-operated, and yield is higher, but reaction time is very long, and aftertreatment is loaded down with trivial details.When the acid amides on raw material or intermediate phenyl ring is changed into to thioamides, JP06293746 discloses and has used hypertoxic thiophosphoric anhydride, is unfavorable for scale production.
while on the phenyl ring of the intermediate after building thiazole ring, introducing aldehyde radical: JP11060552, JP1045733 disclose the use polyphosphoric acid and have made solvent, produce polymerization in reaction process and become sticky thickly, are unfavorable for stirring and yield is low, and impurity is more, is unfavorable for producing; CN101412699 discloses the use trifluoroacetic acid and has made solvent, and yield significantly improves, but the trifluoroacetic acid Costco Wholesale is high, be difficult to reclaim and corrodibility very strong, security is low; CN102002017 discloses use mixing acid and has made solvent, but acid pollution does not still improve.
on traditional structure thiazole ring method, need to repeatedly carry out functional group's conversion, change loaded down with trivial details, increased reactions steps, for example, more than generally needing six steps,, just be synthesized to final compound through nine step reactions in Chinese Medicine magazine [2009,40 (1): 1-5].
Summary of the invention
for overcoming the problems referred to above of the prior art, the invention provides a kind of novel synthesis of Febuxostat of applicable suitability for industrialized production, the method step is brief, total recovery is high, and less on the impact of operator and environment.
the technical solution used in the present invention is: the invention provides a kind of synthetic method of Febuxostat, comprise the following steps:
(a) make formula
the substitution reaction of compound generation aromatic nucleus obtain formula
compound;
(b) make the formula of gained in step (a)
compound obtain formula through halogen-metal exchange reaction
compound;
(c) make the formula of gained in step (b)
compound and formula
compound linked reaction occurs under the effect of metal catalyst obtains formula
compound;
(d) make the formula of gained in step (c)
compound obtain formula through hydrolysis reaction
the compound Febuxostat;
wherein X is I, Br;
m is selected from boric acid ester or SnBu
3
;
r is H or alkyl.
further, in step (a), formula
the condition that exists at alkali of compound under, with 2-methyl isophthalic acid-propyl alcohol generation aromatic nucleus substitution reaction, obtain formula in aprotic solvent
compound.
further, above-mentioned alkali is selected from sodium, potassium, liquefied ammonia, sodium hydrogen, lithium diisopropylamine, LHMDS, sodium hexamethyldisilazide; Above-mentioned aprotic solvent is selected from DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, ether, methyl tertiary butyl ether, dioxane, toluene, tetrahydrofuran (THF), methyl-sulphoxide or its arbitrary combination.
again further, in step (b), formula
compound and metal exchange reagent carry out halogen-metal exchange reaction obtain formula in aprotic solvent
compound.
preferably, formula
compound carry out halogen-metal exchange reaction, can be under the protection of nitrogen under-78-100 ℃, carry out 1-20 hour.
further, in step (b), aprotic solvent is DMSO, dioxane, toluene, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone or its arbitrary combination.
further, in step (c), under the condition that linked reaction exists at alkali, in aprotic solvent, carry out.
further, in step (c), alkali is selected from sodium carbonate, salt of wormwood, sodium acetate, potassium acetate, lithium hydroxide, hydrated barta, sodium hydroxide, triethylamine, cesium fluoride, Potassium monofluoride, tetra-n-butyl Neutral ammonium fluoride, tetrabutylammonium chloride, cesium carbonate, salt of wormwood, alkoxyl group negative ion or its arbitrary combination; Aprotic solvent is selected from dioxane, toluene, acetonitrile, DMF, methyl-sulphoxide, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethylamine, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or its arbitrary combination.
preferably, in step (c), metal catalyst can be that palladium catalyst (0 valency or II valency) or other can play the metal catalyst of suitable catalytic effect, for example, four triphenyl phosphorus palladiums, palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, two (tricyclohexyl phosphine) palladium, two (tri-butyl phosphine) palladium, two (bis-Ya Benzyl benzylacetones) palladium, two (triphenyl is seen) dichloride, three (dibenzalacetone) two palladiums, two (tricyclohexyl phosphine) palladium chloride, (1, the 5-cyclooctadiene) palladium chloride, two (1, two (diphenylphosphine) ethane of 2-) palladium, two (tri-o-tolyl phosphine) palladium chloride, 1, two (diphenylphosphine butane) palladium chlorides of 4-, 1, two (diphenylphosphine) propane of 3-) palladium chloride, 1, 2-bis-(diphenylphosphino) ethane palladium chloride, palladium carbon, cupric iodide or Nickel Chloride etc.
again further, in step (d), formula
the compound reaction that is hydrolyzed in the mixing solutions of methyl alcohol and tetrahydrofuran (THF) under alkaline condition, the alkali used is sodium hydroxide, potassium hydroxide or lithium hydroxide.
compared with prior art, the present invention has following advantages: avoid using the strong acid make solvent, reduced the dangerous of reaction and to the corrosion of equipment; Avoid using gas to participate in reaction, reduced the triviality of operation, improved the security of reaction; Avoid using the hypertoxicity materials such as prussiate and non-oxidation two sulphur, safe; Avoided traditional structure thiazole ring method, adopted the aromatic ring coupling of palladium catalysis to introduce thiazole ring, synthesis step is short, only needs 4 steps can synthesize final compound Febuxostat, and total recovery can reach more than 40%.
Embodiment
below in conjunction with specific embodiment, the present invention is described in further detail.
example: Febuxostat-2-[3-cyano group-4-(2-methyl propoxy-) phenyl]-4-methyl-5 thiazol formic-acid synthetic
synthesizing of the iodo-2-isobutoxy of 5-cyanophenyl
2-methyl isophthalic acid-propyl alcohol (2.8 mL, 30.2 mmol) is dissolved in 50 mL DMF, is chilled to 0 ℃, add NaH(1.21 g, 30.2 mmol), stir 30 minutes, add fluoro-5 ioxynil of 2-(5.0 g, 20.2 mmol), rise to room temperature, stirring is spent the night.Add water (100 mL), ethyl acetate (100 mL) extracts three times, saturated nacl aqueous solution for organic phase (150 mL) washs 2 times, anhydrous sodium sulfate drying, filter, concentrated, silicagel column purifying (sherwood oil: ethyl acetate=20:1 wash-out), the concentrated weak yellow liquid (5.78 g, 95% yield) that obtains.
1
H-NMR（d-DMSO,?400?MHz）：1.00(d,?6H,?J=6.8),?2.05(m,?1H),3.90(d,?2H,?J=6.8),?7.06(d,?1H,?J=8.8),?7.93(dd,?1H),?8.04(d,?1H,?J=2.4)。
synthesizing of 3-cyano-4-isobutoxy phenylo boric acid pinacol ester
under nitrogen protection, to the iodo-2-isobutoxy of above-mentioned synthetic 5-cyanophenyl (4.9 g, 16 mmol), connection pinacol borate (8.3 g, 32 mmol), potassium acetate (4.8 g, 49 mmol) and DMSO(150 mL) mixed solution in add PdCl
2
(dppf) (1.32 g, 1.6 mmol), be heated to 80 ℃, and stirring is spent the night.Add water (300 mL), by ethyl acetate (150 mL), extract four times, after merging organic phase, with the saturated nacl aqueous solution washing once, anhydrous sodium sulfate drying, filter, filtrate is concentrated, the silicagel column purifying (sherwood oil: ethyl acetate=20:1 wash-out), the concentrated colourless liquid (3.53g, 72% yield) that obtains.
1
H-NMR（d-DMSO,400?MHz）：1.00(d,?6H,?J=6.8),?1.28(s,?12H),?2.05(m,?1H),?3.94(d,?2H,?J=6.4),?7.25(d,?1H,?J=8.4),?7.84(d,?1H,?J=1.2),?7.88(dd,?1H)。
synthesizing of 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate
under nitrogen protection; to above-mentioned synthetic 3-cyano-4-isobutoxy phenylo boric acid pinacol ester (2.8g; 9.3 mmol), the bromo-4-methylthiazol of 2-ethyl formate (3.0 g; 12 mmol), 2N sodium carbonate solution (18.5 mL; 37 mmol) and add four triphenyl phosphorus palladium (1.08 g in the mixed solution of dioxane (200 mL); 0.93 mmol), gained solution is heated to 80 ℃, stirring is spent the night.Reaction solution is concentrated into dry, silicagel column purifying (sherwood oil: ethyl acetate=20:1 and 10:1 wash-out), the concentrated white solid (2.4g, 75% yield) that obtains.
1
H-NMR（d-DMSO,?400?MHz）：1.02(d,?6H,?J=6.8),?1.30(t,?3H),?2.09(m,?1H),?2.68(s,?3H),?4.01(d,?2H,?J=6.4),?4.30(dd,?2H),?7.38(d,?1H,?J=8.8),?8.25(dd,?1H),?8.32(d,?1H,?J=2.4)。
synthesizing of 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid (Febuxostat)
by above-mentioned synthetic 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate (100 mg, 0.29 mmol) be dissolved in the mixed solution of methyl alcohol and tetrahydrofuran (THF), add 1N NaOH(0.6 mL, 0.58 mmol), be heated to 70 ℃, stir 3 hours.Mixed solution is concentrated into dry, add water (10 mL), methylene dichloride (20 mL) extracts three times, organic phase is abandoned it, and water, extracts three times with methylene dichloride (20 mL) to 1-2 with 1N salt acid for adjusting pH value, the organic phase anhydrous sodium sulfate drying, filter the concentrated white solid (85 mg, 93% yield) that obtains.
1
H-NMR（d-DMSO,400MHz）：1.02(d,?6H,?J=6.8),?2.09(m,?1H),?2.66(s,?3H),?4.01(d,?2H,?J=6.4),?7.37(d,?1H,?J=8.8),?8.22(dd,?1H),?8.28(d,?1H,?J=2),?13.40(s,?1H)。
Claims (6)
1. the synthetic method of a Febuxostat, is characterized in that, comprises the following steps:
(a) make the compound generation aromatic nucleus substitution reaction of formula I obtain the compound of formula II;
(b) make the compound of the described formula II of gained in step (a) obtain the compound of formula III through halogen-metal exchange reaction;
(c) make the compound of the described formula III of gained in step (b) and the compound of formula VI that the compound that linked reaction obtains formula IV occur under the effect of metal catalyst;
(d) make the compound of the described formula IV of gained in step (c) obtain the compound Febuxostat of formula V through hydrolysis reaction;
Wherein X is I, Br;
M is selected from boric acid ester or SnBu
3;
R is H or alkyl;
In step (a), under the condition that the compound of described formula I exists at alkali, in aprotic solvent, with 2-methyl isophthalic acid-propyl alcohol generation aromatic nucleus substitution reaction, obtain the compound of described formula II;
In step (b), the compound of described formula II and metal exchange reagent carry out the compound that halogen-metal exchange reaction obtains described formula III in aprotic solvent; Described halogen-metal exchange reaction carries out 1-20 hour under the protection of nitrogen under-78-100 ℃;
In step (c), under the condition that described linked reaction exists at alkali, in aprotic solvent, carry out.
2. the synthetic method of Febuxostat according to claim 1, it is characterized in that: in step (a), described alkali is selected from sodium hydrogen; Described aprotic solvent is selected from DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, ether, methyl tertiary butyl ether, dioxane, toluene, tetrahydrofuran (THF), methyl-sulphoxide or its arbitrary combination.
3. the synthetic method of Febuxostat according to claim 1, it is characterized in that: in step (b), described aprotic solvent is methyl-sulphoxide, dioxane, toluene, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone or its arbitrary combination.
4. the synthetic method of Febuxostat according to claim 1, it is characterized in that: in step (c), described alkali is selected from sodium carbonate; Described aprotic solvent is selected from dioxane, toluene, acetonitrile, DMF, methyl-sulphoxide, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethylamine, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or its arbitrary combination.
5. the synthetic method of Febuxostat according to claim 1 is characterized in that: in step (c), described metal catalyst is (0) valency or (II) valency palladium catalyst, palladium carbon, cupric iodide or Nickel Chloride.
6. the synthetic method of Febuxostat according to claim 1, it is characterized in that: in step (d), the reaction that is hydrolyzed in the mixing solutions of methyl alcohol and tetrahydrofuran (THF) under alkaline condition of the compound of described formula IV, the alkali used is sodium hydroxide, potassium hydroxide or lithium hydroxide.
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| CN103910694B (en) * | 2012-12-29 | 2016-08-24 | 广东东阳光药业有限公司 | A kind of preparation method of 2-aryl nitrile thiazole |
| CN104130170A (en) * | 2014-08-11 | 2014-11-05 | 济南大学 | Synthesis method of 4-Hydroxythiobenzamide |
| CN109293597B (en) * | 2018-10-29 | 2022-05-10 | 安徽省庆云医药股份有限公司 | Preparation method of febuxostat |
| CN110878064A (en) * | 2019-11-06 | 2020-03-13 | 武汉光谷亚太医药研究院有限公司 | High-yield synthesis method of certain specific impurity of febuxostat |
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| JP2012096999A (en) * | 2009-02-27 | 2012-05-24 | Nagoya Univ | Method of manufacturing phenyl substitution heterocyclic derivative by coupling process using nickel catalyst |
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