CN101497589A - 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 synthetic method that relates to a kind of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, also relate to its intermediate 4-isobutoxy-1, the synthetic method of 3-benzene dinitrile and 3-cyano-4-isobutoxy benzene thioformamide.
Background technology
Gout (gout) be long-term purine metabolic disturbance and (or) uric acid excretion reduces caused one group of heterogeneity, metabolic disease.Gout is the human second largest metabolism class disease that is only second to diabetes.The clinical characters of gout is acute arthritis, uratoma deposition, uratoma 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.
Using medicine to reduce uric acid concentration in the blood is one of common method of taking place of prevention gout, and this class 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 side effects, use the back patient heating, allergic rash, stomachache, diarrhoea, white corpuscle and thrombopenia can be arranged, even side effects such as liver dysfunction are arranged, limit 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, then with the cyclization of 2-chloroacetyl acetacetic ester, the isobutane bromide hydrocarbonylation, hydrogen reducing, diazotization, cyano groupization, hydrolysis reaction makes 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, 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 intermediate 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 industrialization 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 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, the different reaction sequence of being, 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 to be solved in the present invention 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 through iodo, carry out alkylation reaction with isobutane bromide again and make 3-iodo-4-isobutoxy cyanobenzene, carry out cyaniding with cuprous cyanide then and make intermediate 4-isobutoxy-1, the 3-benzene dinitrile, again with Sodium sulfhydrate, the anhydrous chlorides of rase reactive magnesium makes key intermediate 3-cyano-4-isobutoxy phenyl thioformamide, at last again by cyclization, hydrolysis reaction makes 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid.Whole technological process comprises the steps:
(1) the 3-iodo-4-hydroxy-phenylformonitrile shown in the preparation formula II:
Add potassiumiodide 16.7～100g, iodine 21～128g, water 86～516ml and 14～86ml strong aqua in three-necked bottle, 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, DMF100～500ml 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 standby.
(3) the 4-isobutoxy-1 shown in the preparation formula IV, the 3-benzene dinitrile:
In above-mentioned filtrate, 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, dehydrated alcohol recrystallization.
(4) the 3-cyano-4-isobutoxy phenyl thioformamide shown in the preparation formula V:
Add 4-isobutoxy-1 in round-bottomed flask, 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-shown in the preparation formula VI (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester:
In round-bottomed flask, add 3-cyano-4-isobutoxy phenyl thioformamide 7.2～44.9g, 2-chloroacetyl acetacetic ester 15.1～94.7g, dehydrated 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, dehydrated 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, dehydrated alcohol recrystallization with 10% dilute hydrochloric acid.
Its synthetic route is expressed as follows:
The invention has the advantages that: 2-(3-cyano-4-isobutoxy phenyl)-more existing technology of 4-methyl-5-thiazole formic acid synthesis technique that the present invention is designed, 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 transfers pH1 with concentrated hydrochloric acid under ice bath, 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: ethyl 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 filtrate, add cuprous cyanide 11.0g, back flow reaction 7h.Reaction is finished, suction filtration, and underpressure distillation is poured in the water then to 1/5 of filtrate, stirs.Suction filtration, drying, chloroform extraction, after the distillation of gained filtrate decompression, drying is used the dehydrated 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, dehydrated 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, tetrahydrofuran (THF) 35ml, dehydrated alcohol 35ml and 1M sodium hydroxide solution 25ml, stopped reaction after stirring 2.5h under 50 ℃.Transfer plI1 with 10% dilute hydrochloric acid, the suction filtration drying, the dehydrated 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 transfers pH1 with concentrated hydrochloric acid under ice bath, 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 filtrate, add cuprous cyanide 23.5g, back flow reaction 7h.Reaction is finished, suction filtration, and underpressure distillation is poured in the water then to 1/5 of filtrate, stirs.Suction filtration, drying, chloroform extraction, after the distillation of gained filtrate decompression, drying is used the dehydrated 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, dehydrated 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, tetrahydrofuran (THF) 65ml, dehydrated alcohol 65ml and 1M sodium hydroxide solution 50ml, stopped reaction behind 50 ℃ of following stirring reaction 3.0h.Transfer pH1 with 10% dilute hydrochloric acid, suction filtration, drying, the dehydrated 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 transfers pH1 with concentrated hydrochloric acid under ice bath, 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, DMF 500ml, PEG400 10ml, 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 filtrate, add cuprous cyanide 60.9g, back flow reaction 7h.Reaction is finished, suction filtration, and underpressure distillation is poured in the water then to 1/5 of filtrate, stirs.Suction filtration, drying, chloroform extraction, after the distillation of gained filtrate decompression, drying is used the dehydrated 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, dehydrated 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, tetrahydrofuran (THF) 210ml, dehydrated alcohol 210ml and 1M sodium hydroxide solution 175ml, stopped reaction behind 50 ℃ of following stirring reaction 4h.Transfer pH1 with 10% dilute hydrochloric acid, suction filtration, drying, the dehydrated alcohol recrystallization gets white solid 22.9g, yield: 58.0%.mp：205～206℃。
Claims (4)
1, the synthetic method of a kind of 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 intermediate 4-isobutoxy-1 through iodo, hydrocarbonylation, cyanogenation, the 3-benzene dinitrile, make key intermediate 3-cyano-4-isobutoxy phenyl thioformamide with Sodium sulfhydrate, anhydrous chlorides of rase reactive magnesium again, and then make 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid by cyclization and hydrolysis reaction.
2, the synthetic 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 synthetic 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 3-cyano-4-isobutoxy phenyl thioformamide synthetic is to be raw material with the 4-hydroxy-phenylformonitrile, get 3-iodo-4-hydroxy-phenylformonitrile, carry out hydrocarbonylation with isobutane bromide and get 3-iodo-4-isobutoxy cyanobenzene, make 4-isobutoxy-1 with cuprous cyanide reaction again through iodo, the 3-benzene dinitrile makes with Sodium sulfhydrate, anhydrous chlorides of rase reactive magnesium at last again.
4, the synthetic 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:
Add potassiumiodide 16.7～100g, iodine 21～128g, water 86～516ml and 14～86ml strong aqua in three-necked bottle, 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 standby;
(3) the 4-isobutoxy-1 shown in the preparation formula IV, the 3-benzene dinitrile:
Add cuprous cyanide 11.0～60.9g in above-mentioned filtrate, 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, dehydrated alcohol recrystallization;
(4) the 3-cyano-4-isobutoxy phenyl thioformamide shown in the preparation formula V:
Add 4-isobutoxy-1 in round-bottomed flask, 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-shown in the preparation formula VI (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester:
In round-bottomed flask, add 3-cyano-4-isobutoxy phenyl thioformamide 7.2～44.9g, 2-chloroacetyl acetacetic ester 15.1～94.7g, dehydrated 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, dehydrated 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% dilute hydrochloric acid, suction filtration, drying, dehydrated alcohol recrystallization.
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