CN101497589B - Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate - Google Patents
Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and relates to a method for synthesizing 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid. The method comprises that: 4-hydroxyl cyanobenzene is used as a raw material, and subjected to iodination, hydrocarbylation and cyanation to obtain an intermediate of 4-isobutoxy-1,3-benzene dinitrile, the intermediate reacts with sodium bisulfide and anhydrous magnesium chloride to obtain a key intermediate of 3-cyano-4-isobutoxy phenyl thioformamide, and the 3-cyano group-4-isobutoxy phenyl thioformamide is subjected to cyclization and hydrolysis reaction to obtain the 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid. The method has the advantages of easily obtained materials, simple and convenient operation, high yield, low cost and suitability for industrialized production.
Description
Technical field
The invention belongs to medical technical field; The compound method that relates to a kind of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid; Also relate to its midbody 4-isobutoxy-1, the compound method of 3-benzene dinitrile and 3-cyano-4-isobutoxy benzene thioformamide.
Background technology
Gout (gout) be long-term purine metabolic disturbance with (or) uric acid excretion reduces caused one group of heterogeneous, metabolic disease.Gout is the human second largest metabolism class disease that is only second to mellitus.The clinical characters of gout is acute arthritis, uratoma deposition, uratoma property chronic arthritis and the joint deformity of hyperuricemia, outbreak repeatedly, involves kidney and causes chronic interstitial nephritis and urinary stone disease etc.Chang Bingfa cardiovascular and cerebrovascular diseases and threat to life.The prerequisite of gout morbidity is a hyperuricemia, when hyperuricemia is meant 37 ℃ in the serum uric acid content male sex surpass 70mg/L; The women surpasses 60mg/L.Uric acid can be deposited in the tissue when surpassing this concentration, causes gout Histological change.5%～12% hyperuricemia patient is finally developed into gout.
Hesperian gout sickness rate is higher, and Europe is 0.13～0.37%, and the sickness rate of Zelanian Moari family adult man is up to 10%.But China people are along with growth in the living standard in recent years, and the sickness rate of gout is also rising year by year.At present, China's gout morbidity reaches 0.84% general crowd, and 1,200 ten thousand people are arranged approximately; Wherein 95% is the male patient; Men and women's ratio is about 20: 1.China hyperuricemia person has 1.2 hundred million (account for total population 10%) approximately; The age male sex occurred frequently is 50～59 years old, and the women is after climacteric.
Making medicament reduce uric acid concentration in the blood is one of domestic method of taking place of prevention gout, and this type medicine comprises can block uricosuric eccritic that uriniferous tubules chamber film absorbs uric acid and xanthine oxidase inhibitor etc.But the uricosuric medicine is forbidden in the renal tubal dysfunction patient, and the patient of tool normal renal function then can cause the urine alkalization with this type of medicine; Zyloric is the xanthine oxidase inhibitor of the listing sixties in last century; Though use so far always; But it has a lot of spinoffs; Using the back patient can have heating, allergic rash, stomachache, diarrhoea, white corpuscle and thrombopenia, even spinoff such as liver dysfunction is arranged, and limits its clinical application.The 3-cyano-4-isobutoxy phenyl)-the 4-methyl-5-thiazole formic acid is by the xanthine oxidase inhibitor of efficient, the highly selective of Japanese Teijin company exploitation, has the good market development and application prospect.At present; Bibliographical information about 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid synthetic following several method is arranged: method 1 is a raw material with 3-nitro-4-hydroxy benzaldehyde; Through oximate-cyaniding, make 3-nitro-4-hydroxy-phenylformonitrile, react with thioacetamide again; Generate important intermediate 3-nitro-4-hydroxy phenyl thioformamide; Make 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with the cyclization of 2-chloroacetyl acetacetic ester, isobutane bromide hydrocarbonylation, hydrogen reducing, diazotization, cyanic acidization, hydrolysis reaction then, the raw material of this method is not easy to obtain, synthesis step is longer, (JP 1993500083) not easy to operate; Method 2 is a raw material with the 4-nitrobenzonitrile; In DMSO, make important intermediate 4-isobutoxy 1 with KCN generation cyaniding, hydroxylation, isobutane bromide alkylation reaction; The 3-benzene dinitrile; And then make target compound 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with thioacetamide, the cyclization of 2-chloroacetyl acetacetic ester, hydrolysis; The midbody 4-isobutoxy-1 of this method gained, 3-benzene dinitrile and 3-cyano-4-isobutoxy phenyl thioformamide all will pass through column chromatography purification, are not suitable for industriallization and use (JP1994345724); Method 3 is a raw material with 4-hydroxy phenyl thioformamide; Generate 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester with 2-ethyl bromoacetoacetate generation ring-closure reaction, make target compound 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid through formylation, hydrocarbonylation, oximate-cyaniding, hydrolysis reaction; Method 4 is the same with route 3; All be to be raw material, generate 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester, the different reaction sequence of being with 2-ethyl bromoacetoacetate generation ring-closure reaction with 4-hydroxy phenyl thioformamide; Be first oximate, cyaniding; Hydrocarbonylation again, hydrolysis, the starting raw material 4-hydroxy phenyl thioformamide of above-mentioned two kinds of methods be not easy to obtain, cost an arm and a leg (JP 1994329647, and JP 1998045733).
Summary of the invention:
The technical problem that the present invention will solve is exactly that existing 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid synthesis technique is not suitable for problems such as suitability for industrialized production, production cost height, poor stability and raw material are not easy to obtain.
For solving the problems of the technologies described above; The present invention adopts following technical scheme: with the 4-hydroxy-phenylformonitrile is raw material; Make 3-iodo-4-hydroxy-phenylformonitrile, carry out alkylation reaction with isobutane bromide again and make 3-iodo-4-isobutoxy cyanobenzene, carry out cyaniding with cuprous cyanide then and make midbody 4-isobutoxy-1 through iodo; The 3-benzene dinitrile; Make key intermediate 3-cyano-4-isobutoxy phenyl thioformamide with Sodium sulfhydrate, anhydrous chlorides of rase reactive magnesium again, make 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid through cyclization, hydrolysis reaction more at last.Whole technological process comprises the steps:
(1) the 3-iodo-4-hydroxy-phenylformonitrile shown in the preparation formula II:
In three-necked bottle, add potassiumiodide 16.7～100g, iodine 21～128g, water 86～516ml and 14～86ml strong aqua, stirring at room adds 4-hydroxy-phenylformonitrile 10～60g again, and room temperature continues reaction 6～10h..Reaction solution is reduced pH1 at ice bath, leaves standstill 4h, suction filtration, washing, the dry product that gets.
(2) the 3-iodo-4-isobutoxy cyanobenzene shown in the preparation formula III:
In round-bottomed flask, add 3-iodo-4-hydroxy-phenylformonitrile 18.8～116g, Anhydrous potassium carbonate 15.9～98.0g, DMF 100～500ml stirs, and adds the PEG400 of isobutane bromide 26.1～160.1g and catalytic amount again, reacts 4～8h down in 50～80 ℃.50～80 ℃ of following underpressure distillation 0.5～2h, suction filtration, filter cake is washed with DMF, and merging filtrate is subsequent use.
(3) the 4-isobutoxy-1 shown in the preparation formula IV, the 3-benzene dinitrile:
In above-mentioned filtrating, add cuprous cyanide 11.0～60.9g, stir, react 3～7h down in 100～150 ℃.Cold slightly, suction filtration, pressure reducing and steaming solvent 4/5 is poured water 300～1000ml in residue, stir suction filtration, washing, drying, chloroform extraction, absolute ethyl alcohol recrystallization.
(4) the 3-cyano-4-isobutoxy phenyl thioformamide shown in the preparation formula V:
In round-bottomed flask, add 4-isobutoxy-1,3-benzene dinitrile 9.5～54.9g, Magnesium Chloride Anhydrous 5.8～26.1g and DMF50～260ml stir, and reaction 25min adds Sodium sulfhydrate 10.4～58.4g again under 25～60 ℃, continue reaction 2～6h.Reaction solution is poured among water 100～1000ml, leaves standstill 2h, suction filtration, washing, drying, anhydrous methanol recrystallization.
(5) 2-(3-the cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester shown in the preparation formula VI:
In round-bottomed flask, add 3-cyano-4-isobutoxy phenyl thioformamide 7.2～44.9g, 2-chloroacetyl acetacetic ester 15.1～94.7g, absolute ethyl alcohol 50～270ml, back flow reaction 2～4h.Cooling, suction filtration, drying.
(6) 2-shown in the preparation formula (I) (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid:
In round-bottomed flask, add 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester 7.2～42.9g, THF15～250ml, absolute ethyl alcohol 20～250ml and 1mol/l aqueous sodium hydroxide solution 25～175ml; Stir, in 50 ℃ of reaction 2.5～4h.Reaction is finished, and transfers pH1, suction filtration, drying, absolute ethyl alcohol recrystallization with 10% Hydrogen chloride.
Its synthetic route is represented as follows:
The invention has the advantages that: the 2-that the present invention designed (3-the cyano-4-isobutoxy phenyl)-more existing technology of 4-methyl-5-thiazole formic acid synthesis technique; Have raw material be easy to get, easy and simple to handle, yield is higher, cost is lower, the three wastes are less, safe, product purity is higher (HPLC purity >=99.9%) characteristics, relatively is fit to industrial production.
Embodiment
The present invention wants synthetic 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and 4-isobutoxy-1, and 3-benzene dinitrile and 3-cyano-4-isobutoxy phenyl thioformamide can follow these steps to carry out:
Embodiment 1
1) 3-iodo-4-hydroxy-phenylformonitrile
In the three-necked bottle of 250ml, add potassiumiodide 16.7g, iodine 21.3g, water 86ml, strong aqua 14ml, mechanical stirring under the room temperature is waited to dissolve the back and is added 4-hydroxy-phenylformonitrile 10.0g, reacts 7h under the room temperature.Reaction is finished, and under ice bath, transfers pH1 with concentrated hydrochloric acid, leave standstill 1h after, suction filtration, washing, drying, khaki color solid 18.8g, yield: 91.5%.ESI-MS m/z:268 [M+Na]
+, 244 [M-H]
-2) 3-iodo-4-isobutoxy cyanobenzene
In the round-bottomed flask of 250ml; Add 3-iodo-4-hydroxy-phenylformonitrile 18.8g, Anhydrous potassium carbonate 15.9g, DMF100ml, PEG4003ml; After stirring 15min under 60 ℃, add isobutane bromide 26.1g again, continue reaction; Elevated temperature to 80 ℃ behind the 6h, underpressure distillation 1～2h (steaming clean excessive isobutane bromide).Suction filtration, with DMF filter wash cake, merging filtrate directly carries out next step, and yield calculates by 100%.Get portioned product, column chromatography purification (eluent: sherwood oil: ETHYLE ACETATE=50: 1),
1H-NMR (300MHz, CDCl
3) δ: 8.00 (d, 1H, J=2Hz, Ar-H), 7.58 (dd, 1H, J=2, J=8.6Hz, Ar-H), 6.79 (d, 1H, J=8.6Hz, Ar-H), 3.83 (d, 2H, J=6.3Hz, C
H 2 CH (CH
3)
2), 2.17 (m, 1H, CH
2C
H(CH
3)
2), 1.09 (d, 6H, J=6.8Hz, CH
2CH (C
H 3 )
2).
3) 4-isobutoxy-1, the 3-benzene dinitrile
In above-mentioned filtrating, add cuprous cyanide 11.0g, back flow reaction 7h.Reaction is finished, suction filtration, and underpressure distillation is poured in the water to 1/5 of filtrating then, stirs.Suction filtration, drying, chloroform extraction, after the distillation of gained filtrate decompression, drying is used the absolute ethyl alcohol recrystallization again.Get bluish yellow look solid 9.45g, yield: 61.4%.mp：122～126℃。
4) 3-cyano-4-isobutoxy phenyl thioformamide
In the round-bottomed flask of 50ml, add 4-isobutoxy-1,3-benzene dinitrile 9.45g, Magnesium Chloride Anhydrous 5.8g, DMF50ml add Sodium sulfhydrate 10.4g, reaction 6h again after 45 ℃ stirring is waited to dissolve down.Reaction is finished, reaction solution poured in the water, and suction filtration, the washing filter cake, drying, the anhydrous methanol recrystallization gets bluish yellow look solid matter 7.2g, yield 65.0%.mp：125～126℃。
1H-NMR(300MHz，CDCl
3)δ：8.16(dd，1H，J＝2.5Hz，J＝9Hz，Ar-H)，8.10(d，1H，J＝2.5Hz，Ar-H)，7.61(s，1H，NH
2)，7.24(s，1H，NH
2)，6.96(d，1H，J＝9Hz，Ar-H)，3.89(d，2H，J＝6.5Hz，C
H 2 CH(CH
3)
2)，2.19(m，1H，CH
2C
H(CH
3)
2)，1.08(d，6H，J＝6.7Hz，CH
2CH(C
H 3 )
2)。5) 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester
In the round-bottomed flask of 100ml, add 3-cyano-4-isobutoxy benzene thioformamide 7.2g, 2-chloroacetyl acetacetic ester 15.1g, absolute ethyl alcohol 50ml, stirring and refluxing reaction 2.5h.Reaction is finished, and is cooled to room temperature, suction filtration, and drying gets pale solid material 7.2g, yield: 68.0%.mp：174～175℃。
1H-NMR(300MHz，DMSO-d6)δ：8.31(d，1H，J＝2.3Hz，，Ar-H)，8.24(dd，1H，J＝2.3Hz，J＝9Hz，Ar-H)，7.38(d，1H，J＝9Hz，Ar-H)，4.30(q，2H，OC
H 2 CH
3)，4.01(d，2H，J＝6.5Hz，C
H 2 CH(CH
3)
2)，2.68(s，3H，C
H 3 )，2.09(m，1H，CH
2C
H(CH
3)
2)，1.30(t，3H，OCH
2C
H 3 )，1.02(d，6H，J＝6.7Hz，CH
2CH(C
H 3 )
2)。
6) 2-(3-cyano-4-isobutoxy phenyl)--4-methyl-5-thiazole formic acid
In the round-bottomed flask of 100ml, add 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid ethyl ester 7.2g, THF 35ml, absolute ethyl alcohol 35ml and 1M sodium hydroxide solution 25ml, stopped reaction after stirring 2.5h under 50 ℃.Transfer pH1 with 10% Hydrogen chloride, suction filtration is dry, and the absolute ethyl alcohol recrystallization gets white solid 3.96g, yield: 60.0%.mp：205～206℃。
1H-NMR(600MHz，DMSO-d6)δ：13.39(s，1H，COOH)，8.25(d，1H，J＝2.3Hz，，Ar-H)，8.20(dd，1H，J＝2.3Hz，J＝9Hz，Ar-H)，7.35(d，1H，J＝9Hz，Ar-H)，4.00(d，2H，J＝6.5Hz，C
H 2 CH(CH
3)
2)，2.66(s，3H，C
H 3 )，2.09(m，1H，CH
2C
H(CH
3)
2)，1.02(d，6H，J＝6.7Hz，CH
2CH(C
H 3 )
2)；
13C-NRM(600MHz，DMSO-d6)δ：166.27，162.92，162.12，159.12，133.10，131.59，125.41，122.94，115.46，113.92，101.60，75.18，27.68，18.80，17.12；FT-IR(KBr)：v＝3428.4，2962.3，2875.4，2228.6，1679.2，1605.4，1511.6，1427.5，1386.3，1371.7，1296.0，1169.9，1116.5，912.3cm
-1；HRMS：m/z?Calcd?for?C
16H
15N
2O
3S315.0809[M-H]，found?315.0799。
Embodiment 2
1) 3-iodo-4-hydroxy-phenylformonitrile
In the three-necked bottle of 250ml, add potassiumiodide 33.5g, iodine 43.7g, water 172ml, strong aqua 28ml, mechanical stirring under the room temperature is waited to dissolve the back and is added 4-hydroxy-phenylformonitrile 20.0g, reacts 7h under the room temperature.Reaction is finished, and under ice bath, transfers pH1 with concentrated hydrochloric acid, leave standstill 1h after, suction filtration, washing, drying, khaki color solid 40.0g, yield: 97.1%.
2) 3-iodo-4-isobutoxy cyanobenzene
In the round-bottomed flask of 250ml; Add 3-iodo-4-hydroxy-phenylformonitrile 40.0g, Anhydrous potassium carbonate 33.7g, DMF200ml, PEG4006ml, after stirring 15min under 60 ℃, add isobutane bromide 55.5g again; Continue reaction, elevated temperature to 80 ℃ behind the 6h, underpressure distillation 1～2h (steaming clean excessive isobutane bromide).Suction filtration, with DMF filter wash cake, merging filtrate directly carries out next step, and yield calculates by 100%.
3) 4-isobutoxy-1, the 3-benzene dinitrile
In above-mentioned filtrating, add cuprous cyanide 23.5g, back flow reaction 7h.Reaction is finished, suction filtration, and underpressure distillation is poured in the water to 1/5 of filtrating then, stirs.Suction filtration, drying, chloroform extraction, after the distillation of gained filtrate decompression, drying is used the absolute ethyl alcohol recrystallization again.Get bluish yellow look solid 18.0g, yield: 55.0%.mp：125～128℃。
4) 3-cyano-4-isobutoxy phenyl thioformamide
In the round-bottomed flask of 250ml, add 4-isobutoxy-1,3-benzene dinitrile 18.0g, Magnesium Chloride Anhydrous 9.5g, DMF100ml add Sodium sulfhydrate 19.1g, reaction 6h again after 45 ℃ stirring is waited to dissolve down.Reaction is finished, reaction solution poured in the water, and suction filtration, the washing filter cake, drying, the anhydrous methanol recrystallization gets bluish yellow look solid matter 12.6g, yield 60.0%.mp：123～125℃。
5) 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid ethyl ester
In the round-bottomed flask of 250ml, add 3-cyano-4-isobutoxy benzene thioformamide 12.6g, 2-chloroacetyl acetacetic ester 26.6g, absolute ethyl alcohol 80ml, stirring and refluxing reaction 2.5h.Reaction is finished, and is cooled to room temperature, suction filtration, and drying gets pale solid material 13.3g, yield: 72.0%.mp：174.5～175.0℃。
6) 2-(3-cyano-4-isobutoxy) phenyl--4-methyl-5-thiazole formic acid
In the round-bottomed flask of 250ml, add 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid ethyl ester 13.3g, THF 65ml, absolute ethyl alcohol 65ml and 1M sodium hydroxide solution 50ml, stopped reaction behind 50 ℃ of following stirring reaction 3.0h.Transfer pH1 with 10% Hydrogen chloride, suction filtration, drying, the absolute ethyl alcohol recrystallization gets white solid 6.59g, yield: 54.0%.mp：205～206℃。
Embodiment 3
1) 3-iodo-4-hydroxy-phenylformonitrile
In the three-necked bottle of 1000ml, add potassiumiodide 100g, iodine 128g, water 516ml, strong aqua 86ml, mechanical stirring under the room temperature is waited to dissolve the back and is added 4-hydroxy-phenylformonitrile 60.0g, reacts 7h under the room temperature.Reaction is finished, and under ice bath, transfers pH1 with concentrated hydrochloric acid, leave standstill 1h after, suction filtration, washing, drying, khaki color solid 116.0g, yield: 94.3%.
2) 3-iodo-4-isobutoxy cyanobenzene
In the round-bottomed flask of 1000ml; Add 3-iodo-4-hydroxy-phenylformonitrile 116.0g, Anhydrous potassium carbonate 98.0g, DMF500ml, PEG40010ml; After stirring 15min under 60 ℃; Add isobutane bromide 160.1g again and continue reaction, elevated temperature to 80 ℃ behind the 6h, underpressure distillation 1～2h (steaming clean excessive isobutane bromide).Suction filtration, with DMF filter wash cake, merging filtrate directly carries out next step, and yield calculates by 100%.
3) 4-isobutoxy-1, the 3-benzene dinitrile
In above-mentioned filtrating, add cuprous cyanide 60.9g, back flow reaction 7h.Reaction is finished, suction filtration, and underpressure distillation is poured in the water to 1/5 of filtrating then, stirs.Suction filtration, drying, chloroform extraction, after the distillation of gained filtrate decompression, drying is used the absolute ethyl alcohol recrystallization again.Get bluish yellow look solid 54.9g, yield: 58.0%.mp：126～129℃。
4) 3-cyano-4-isobutoxy phenyl thioformamide
In the round-bottomed flask of 500ml, add 4-isobutoxy-1,3-benzene dinitrile 54.9g, Magnesium Chloride Anhydrous 26.1g, DMF260ml add Sodium sulfhydrate 58.4g, reaction 3h again after 45 ℃ stirring is waited to dissolve down.Reaction is finished, reaction solution poured in the water, and suction filtration, the washing filter cake, drying, the anhydrous methanol recrystallization gets bluish yellow look solid matter 44.9g, yield 70.0%.mp：127～128℃。
5) 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid ethyl ester
In the round-bottomed flask of 500ml, add 3-cyano-4-isobutoxy benzene thioformamide 44.9g, 2-chloroacetyl acetacetic ester 94.7g, absolute ethyl alcohol 270ml, stirring and refluxing reaction 2.5h.Reaction is finished, and is cooled to room temperature, suction filtration, and drying gets pale solid material 42.9g, yield: 65.0%.mp：174.0～175.0℃。
6) 2-(3-cyano-4-isobutoxy) phenyl--4-methyl-5-thiazole formic acid
In the round-bottomed flask of 500ml, add 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid ethyl ester 42.9g, THF 210ml, absolute ethyl alcohol 210ml and 1M sodium hydroxide solution 175ml, stopped reaction behind 50 ℃ of following stirring reaction 4h.Transfer pH1 with 10% Hydrogen chloride, suction filtration, drying, the absolute ethyl alcohol recrystallization gets white solid 22.9g, yield: 58.0%.mp：205～206℃。
Claims (3)
1. the compound method of a 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid; It is characterized in that: with the 4-hydroxy-phenylformonitrile is raw material; Make midbody 4-isobutoxy-1 through iodo, hydrocarbonylation, cyanogenation; The 3-benzene dinitrile makes key intermediate 3-cyano-4-isobutoxy phenyl thioformamide with Sodium sulfhydrate, anhydrous chlorides of rase reactive magnesium again, and then makes 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid through cyclization and hydrolysis reaction.
2. the compound method of a kind of 2-according to claim 1 (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid; It is characterized in that: described 4-isobutoxy-1; 3-benzene dinitrile synthetic is to be raw material with the 4-hydroxy-phenylformonitrile, gets 3-iodo-4-hydroxy-phenylformonitrile, carries out hydrocarbonylation with isobutane bromide and get 3-iodo-4-isobutoxy cyanobenzene, carry out cyanogenation with cuprous cyanide again and make through iodo.
3. the compound method of 2-according to claim 1 (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid is characterized in that comprising the steps:
(1) the 3-iodo-4-hydroxy-phenylformonitrile shown in the preparation formula II:
In three-necked bottle, add potassiumiodide 16.7～100g, iodine 21～128g, water 86～516mL and 14～86mL strong aqua, stirring at room adds 4-hydroxy-phenylformonitrile 10～60g again; Room temperature continues reaction 6～10h, and reaction solution is reduced pH1 at ice bath, leaves standstill 4h; Suction filtration, washing, the dry product that gets;
(2) the 3-iodo-4-isobutoxy cyanobenzene shown in the preparation formula III:
In round-bottomed flask, add 3-iodo-4-hydroxy-phenylformonitrile 18.8～116g, Anhydrous potassium carbonate 15.9～98.0g, DMF100～500mL; Stir, add the PEG400 of isobutane bromide 26.1～160.1g and catalytic amount again, react 4～8h down in 50～80 ℃; 50～80 ℃ of following underpressure distillation 0.5～2h; Suction filtration, filter cake is washed with DMF, and merging filtrate is subsequent use;
(3) the 4-isobutoxy-1 shown in the preparation formula IV, the 3-benzene dinitrile:
In above-mentioned filtrating, add cuprous cyanide 11.0～60.9g, stir, reaction 3～7h is cold slightly under 100～150 ℃, suction filtration; Pressure reducing and steaming solvent 4/5 is poured water 300～1000mL in residue, stir suction filtration; Washing, drying, chloroform extraction, absolute ethyl alcohol recrystallization;
(4) the 3-cyano-4-isobutoxy phenyl thioformamide shown in the preparation formula V:
In round-bottomed flask, add 4-isobutoxy-1,3-benzene dinitrile 9.5～54.9g, Magnesium Chloride Anhydrous 5.8～26.1g and DMF50～260mL stir, and reaction 25min adds Sodium sulfhydrate 10.4～58.4g again under 25～60 ℃, continue reaction 2～6h; Reaction solution is poured among water 100～1000mL, leaves standstill 2h, suction filtration, washing, drying, anhydrous methanol recrystallization;
(5) 2-(3-the cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole first shown in the preparation formula VI
Acetoacetic ester:
In round-bottomed flask, add 3-cyano-4-isobutoxy phenyl thioformamide 7.2～44.9g, 2-chloroacetyl acetacetic ester 15.1～94.7g, absolute ethyl alcohol 50～270mL, back flow reaction 2～4h, cooling, suction filtration, drying;
(6) 2-(3-the cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid shown in the preparation formula I:
In round-bottomed flask, add 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester 7.2～42.9g, THF15～250mL, absolute ethyl alcohol 20～250mL and 1mol/L aqueous sodium hydroxide solution 25～175mL; Stir, in 50 ℃ of reaction 2.5～4h, reaction is finished; Transfer pH1 with 10% Hydrogen chloride; Suction filtration, drying, absolute ethyl alcohol recrystallization.
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| CN102276550B (en) * | 2010-06-10 | 2015-08-19 | 浙江九洲药业股份有限公司 | The synthetic method of 2-aryl nitrile thiazole derivative and intermediate thereof |
| CN101863854A (en) * | 2010-06-29 | 2010-10-20 | 沈阳药科大学 | Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid |
| CN102295619B (en) * | 2011-07-07 | 2013-09-18 | 石药集团欧意药业有限公司 | Febuxostat compound, preparation method and pharmaceutical composition thereof |
| CN102285937B (en) * | 2011-09-14 | 2013-06-19 | 安润医药科技（苏州）有限公司 | Method for synthesizing febuxostat |
| CN102964313B (en) * | 2012-11-27 | 2015-04-29 | 周广连 | Synthetic method of febuxostat |
| CN103333134B (en) * | 2013-03-01 | 2016-02-24 | 沈阳药科大学 | 2-(3-cyano group-4-alkoxyl group) phenyl-4-substituted thiazole-5-formic acid compound, composition and method of making the same and purposes |
| CN103739547B (en) * | 2014-01-03 | 2015-09-02 | 沈阳药科大学 | The synthetic method of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid |
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| JP特开平10-139770A 1998.05.26 |
| 武瑊等.抗痛风药物febuxostat的合成.《中国药物化学杂志》.2008,第18卷(第4期),259-262. * |
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