CN102079731A - Method for synthesizing 2-(3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole formic acid - Google Patents
Method for synthesizing 2-(3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole formic acid Download PDFInfo
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims abstract description 22
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 235000019253 formic acid Nutrition 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title abstract 2
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000018044 dehydration Effects 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 28
- -1 phenyl aldehyde Chemical class 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000010189 synthetic method Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 14
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 150000003556 thioamides Chemical class 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 5
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012336 iodinating agent Substances 0.000 claims description 4
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 3
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 2
- 229910019093 NaOCl Inorganic materials 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003354 benzotriazolyl group Chemical class N1N=NC2=C1C=CC=C2* 0.000 claims description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexediene Natural products C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- VGYYSIDKAKXZEE-UHFFFAOYSA-L hydroxylammonium sulfate Chemical compound O[NH3+].O[NH3+].[O-]S([O-])(=O)=O VGYYSIDKAKXZEE-UHFFFAOYSA-L 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- 229920001083 polybutene Polymers 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000007333 cyanation reaction Methods 0.000 abstract 1
- 238000006266 etherification reaction Methods 0.000 abstract 1
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000006146 oximation reaction Methods 0.000 abstract 1
- 238000005980 thioamidation reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QBNJPSHRAWSBDW-UHFFFAOYSA-N 2-methylpropane;hydrobromide Chemical compound Br.CC(C)C QBNJPSHRAWSBDW-UHFFFAOYSA-N 0.000 description 1
- YTHJCZRFJGXPTL-UHFFFAOYSA-N 4-hydroxy-3-nitrobenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1[N+]([O-])=O YTHJCZRFJGXPTL-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- AWZDEJYHQQWKRO-UHFFFAOYSA-N formonitrile;phenol Chemical compound N#C.OC1=CC=CC=C1 AWZDEJYHQQWKRO-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- FBYRYEFDOMKFEE-UHFFFAOYSA-N n-hydroxybenzenecarbothioamide Chemical compound ON=C(S)C1=CC=CC=C1 FBYRYEFDOMKFEE-UHFFFAOYSA-N 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000003407 synthetizing effect Effects 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a method for synthesizing 2-(3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole formic acid, which is prepared by using cheap and readily available p-hydroxybenzaldehyde as a starting material and by etherification, halogenations, oximation, dehydration, thioamidation, cyclization, cyanation and hydrolysis. In the method, the reaction conditions at all steps are mild, expensive agent is not used, dangerous operation such as catalytic hydrogenation is avoided, the yield of each step is high, side reactions and byproducts are avoided, the repeatability is high, the intermediates of the reactions in the previous 4 steps are not required to be separated or purified, the operation is simple and the cost is low; and the method is suitable for industrial production.
Description
Technical field
The present invention relates to the chemosynthesis novel method of a kind of 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid.
Background technology
2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid (I) is a kind of non-purine class XOD selective depressant, the hyperuricemia that is used for the treatment of the gout patient, get permission listing in a plurality of countries such as Europe, the U.S. at present, its chemical structural formula is as follows:
EP0513379A1 discloses a kind of synthetic method of above-mentioned formula I compound, and its reaction formula is as follows:
This method is a starting raw material with 4-hydroxyl-3-nitrobenzaldehyde, uses expensive thioacetamide and expensive palladium/carbon in the building-up process, has certain potential safety hazard in carrying out the catalytic hydrogenation process.
JP06329647 discloses the another kind of synthetic method of above-mentioned formula I compound, and reaction formula is as follows:
This method is starting material with what be not easy to obtain to the hydroxyl thiobenzamide, and first synthetizing thiazolium ring finally get target product again, but cost is higher.
JP10139770 discloses another synthetic method of above-mentioned formula I compound, and reaction formula is as follows:
This method is a starting material with para hydroxybenzene formonitrile HCN cheap and easy to get, and reaction scheme is short, and reaction conditions gentleness, but when carrying out bromo-reaction, condition is wayward, tends to obtain two more bromo by products is for the purifying of the finished product brings difficulty.
Masaichi Hasegawa (Heterocycles, 1998,47 (2): 857～864) reported the most succinct synthetic method of formula I compound, only 5 steps, reaction formula is as follows:
Though this method synthetic route is short, first step reaction impurities is more, and it is said 80% that yield does not reach, only 20%, and in the 3rd step, thioacetamide is not high to the selectivity of two cyano group, and impurity in products is more, and yield is low.
Summary of the invention
Technical problem to be solved by this invention provides the new synthetic method of a kind of 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid, with p-Hydroxybenzaldehyde cheap and easy to get is starting material, makes through etherificate, halo, one-tenth oxime, dehydration, thioamidesization, cyclization, cyaniding, hydrolysis.The present invention respectively goes on foot the reaction conditions gentleness, does not use expensive reagent, risky operation such as no catalytic hydrogenation, and each goes on foot the yield height, and no side reaction generation and by product produce, and good reproducibility, and each intermediate of the preceding 4 steps reaction of the present invention need not separation and purification.The present invention is simple to operate, and is with low cost, is suitable for industrialized production.
In order to achieve the above object, the present invention realizes by the following technical solutions:
The synthetic method of a kind of 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid, reaction formula is as follows:
Specifically may further comprise the steps:
(1) preparation 4-(2-methyl propoxy-) phenyl aldehyde (III):
P-Hydroxybenzaldehyde (II) and halo Trimethylmethane react under the alkaline condition, room temperature～155 ℃ in water or organic solvent, and wherein organic solvent is selected from acetone, acetonitrile, ethyl acetate, toluene or N, dinethylformamide; Catalyzer is selected from NaI or KI, or does not select; Alkaline matter is selected from K
2CO
3, Na
2CO
3, NaHCO
3, NaOH or KOH, preferred K
2CO
3
(2) preparation 3-halo-4-(2-methyl propoxy-) phenyl aldehyde (IV):
4-(2-methyl propoxy-) phenyl aldehyde (III) reacts under-10～50 ℃ with the halo agent in organic solvent, and wherein organic solvent is selected from acetone, acetonitrile, ethyl acetate, Glacial acetic acid, methylene dichloride, chloroform or tetracol phenixin; The halo agent is selected from chlorizating agent, bromizating agent or iodinating agent; Catalyzer is selected from sulfuric acid or chlorsulfonic acid, or does not select.
Described chlorizating agent is selected from Cl
2, NaOCl, t-BuOCl, N-chloro polybutene imide, 1-chlorinated benzotriazole or cyanuric chloride, described bromizating agent is selected from Br
2, NBS, bromine close dioxane or tetrabromo cyclohexadiene ketone, described iodinating agent is I
2Or ICl.
The preferred bromizating agent Br of described halo agent
2
(3) preparation 3-halo-4-(2-methyl propoxy-) benzaldoxime (V):
3-halo-4-(2-methyl propoxy-) phenyl aldehyde (IV) reacts down in-10～50 ℃ with aqueous hydroxylamine in organic solvent, and wherein organic solvent is selected from methyl alcohol, ethanol or Virahol; Aqueous hydroxylamine is generated with alkali substance reaction at low temperatures by the aqueous solution of the inorganic acid salt of azanol, and the inorganic acid salt of azanol is selected from oxammonium hydrochloride, oxammonium sulfate or hydroxylamine nitriate, and alkaline matter is selected from K
2CO
3, Na
2CO
3, NaHCO
3, NaOH, KOH, triethylamine or pyridine.
(4) preparation 3-halo-4-(2-methyl propoxy-) cyanobenzene (VI):
3-halo-4-(2-methyl propoxy-) benzaldoxime (V) reacts down at-10～50 ℃ with dewatering agent in organic solvent, carries out intramolecular dehydration, and wherein organic solvent is selected from acetone, acetonitrile or ethyl acetate; Dewatering agent is selected from SOCl
2Or P
2O
5
(5) preparation 3-halo-4-(2-methyl propoxy-) benzene first thioamides (VII):
3-halo-4-(2-methyl propoxy-) cyanobenzene (VI) is following and ammonium sulfide effect at alkaline condition (as triethylamine).
(6) preparation 2-(3-halo-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester (VIII):
3-halo-4-(2-methyl propoxy-) benzene first thioamides (VII) is reflected at 40～120 ℃ of reacting by heating in the organic solvent with 2-halo methyl aceto acetate, and wherein organic solvent is selected from methyl alcohol, ethanol, Virahol, acetone or acetonitrile.
(7) preparation 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester (IX):
Under nitrogen protection, in high boiling organic solvent, 70～160 ℃ of reactions down, wherein high boiling organic solvent is DMF or DMSO with formula VIII compound and cuprous cyanide.
(8) preparation 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid (I):
With 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester (IX) under alkaline condition, hydrolysis in containing the organic solvent of water, organic solvent is selected from methyl alcohol, ethanol, Virahol, acetone or acetonitrile; 20～110 ℃ of temperature of reaction; Alkaline condition is K
2CO
3, Na
2CO
3, NaOH or KOH.
Wherein, among the above-mentioned preparation method, each intermediate compound III, IV, V, VI need not separation and purification promptly can be used for next step reaction.
Synthetic route of the present invention respectively goes on foot the reaction conditions gentleness, does not use expensive reagent, risky operation such as no catalytic hydrogenation, and each goes on foot the yield height, and no side reaction generation and by product produce, good reproducibility, and simple to operate, with low cost, be suitable for industrialized production.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is described in further detail.
Embodiment 1
Preparation 4-(2-methyl propoxy-) phenyl aldehyde (III)
With p-Hydroxybenzaldehyde (II) (300g, 2.46mol), salt of wormwood (373g, 2.70mol), DMF (1L), isobutane bromide (558ml, 4.92mol) mix, reflux stirs, and TLC follows the tracks of reaction process, after question response finishes, cooling, it is an amount of to add entry, dichloromethane extraction, water, 1.2M hydrochloric acid, saturated common salt water washing respectively then, anhydrous sodium sulfate drying, the dichloromethane solution of formula III compound.
Embodiment 2
Preparation 3-bromo-4-(2-methyl propoxy-) phenyl aldehyde (IV)
The dichloromethane solution of the formula III compound that the last step was obtained is put in the ice bath and is cooled off, stir following slowly dropping liquid bromine (226ml, 4.426mol) be dissolved in the solution of methylene dichloride (100ml), after waiting to finish, remove ice bath, stirring at room, TLC follows the tracks of reaction process, needs 6h approximately, after finishing, slowly drip saturated sodium sulfite liquid and eliminate excessive bromine, separatory, dichloromethane layer are washed anhydrous sodium sulfate drying with saturated sodium sulfite liquid, saturated sodium bicarbonate liquid, water, saturated sodium-chloride liquid respectively, decompression and solvent recovery gets formula IV compound to the greatest extent.
1H-NMR (BRUKER AVANCE DRX-500, CDCl
3Be solvent, TMS is interior mark): δ (ppm) 1.090～1.104 (d, J=7Hz, 6H), 2.176～2.230 (m, 1H), 3.878～3.8892 (d, J=7Hz, 2H), 6.964～6.980 (d, J=8Hz, 1H), 7.784～7.806 (dd, J=2Hz, J=9Hz, 1H), 8.082～8.086 (d, J=2Hz, 1H), 9.840 (s, 1H).
Embodiment 3
Preparation 3-bromo-4-(2-methyl propoxy-) benzaldoxime (V)
With sodium hydroxide (127.87g, 3.197mol) water (150ml) dissolving, with oxammonium hydrochloride (222.17g, 3.197mol) water (150ml) dissolving, then with both very long mixing, with mixed solution under water-bath refrigerative situation on very long the splashing in the reaction solution of the ethanol (700ml) of step gained formula IV compound, after dripping off, stirring at normal temperature 2h.Reclaim under reduced pressure is to doing, and it is an amount of to add water, and with EA extraction, saturated common salt water washing, anhydrous sodium sulfate drying is spin-dried for, and gets solid type V compound.
Embodiment 4
Preparation 3-bromo-4-(2-methyl propoxy-) cyanobenzene (VI)
At room temperature, with SOCl
2(144ml, acetonitrile 1.97mol) (50ml) solution splash in acetonitrile (1.45L) solution of formula V compound, and interior temperature control is at 40 ℃ below the degree, and after dripping, restir 1h finishes under the room temperature, be spin-dried for, formula VI compound.
1H-NMR (BRUKER AVANCE DRX-500, CDCl
3Be solvent, TMS is interior mark): δ (ppm) 1.085～1.097 (d, J=6Hz, 6H), 2.153～2.207 (m, 1H), 3.833～3.846 (d, J=6.4Hz, 2H), 6.886～6.903 (d, J=8.6Hz, 1H), 7.549～7.570 (dd, J=2Hz, J=8.6Hz, 1H), 7.811～7.821 (d, J=2Hz, 1H).
Embodiment 5
Preparation 3-bromo-4-(2-methyl propoxy-) benzene first thioamides (VII)
In DMF (860ml), (20% (w/v), 861.5ml 2.534mol), are warmed up to 50 ℃, and TLC follows the tracks of reaction process, needs 4h approximately to add the triethylamine (352ml) and the ammonium sulfide aqueous solution then with the formula VI compound dissolution of gained of last step.Cool off, slowly add an amount of purified water under stirring, filter, with the purified water washing, the dry formula VII compound crude product that gets weighs 303.2 grams, yield 83.0%.Above-mentioned crude product gets 234.9g with ethyl acetate-sherwood oil mixed solvent recrystallization.
1H-NMR (BRUKER AVANCE DRX-500, CDCl
3Be solvent, TMS is interior mark): δ (ppm) 1.080～1.094 (d, J=7Hz, 6H), 2.174～2.200 (m, 1H), 3.842～3.856 (d, J=7Hz, 2H), 6.852～6.870 (d, J=9Hz, 2H), 7.878～7.900 (dd, J=2Hz, J=9Hz, 1H), 8.112～8.116 (d, J=2Hz, 1H)
Embodiment 6
Preparation 2-(3-bromo-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester (VIII)
With formula VII compound (520.1g, 1.805mol), (299ml 2.167mol) mixes, and reflux stirs for ethanol (2L), a-chloroacetyl acetacetic ester, TLC follows the tracks of reaction process, needs 4h to finish cooling crystallization approximately, filter, get formula VIII compound crude product 628.9g, yield 87.5%.
1H-NMR (BRUKER AVANCE DRX-500, CDCl
3Be solvent, TMS is interior mark): δ (ppm) 1.111～1.125 (d, J=6.5Hz, 6H), 1.401～1.431 (t, J=7.0Hz, 3H), 2.202～2.228 (m, 1H), 2.793 (s, 3H), 3.868～3.881 (d, J=6.5Hz, 2H), 4.358～4.401 (q, J=7.0Hz, 2H), 6.921～6.938 (d, J=8.5Hz, 1H), 7.869～7.886 (d, J=8.5Hz, 1H), 8.214 (s, 1H)
Embodiment 7
Preparation 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester (IX)
With formula VIII compound (283g, 0.71mol), CuCN (128g, 1.429mol), DMF (1.2L) mixes, logical nitrogen, reflux stirs, and TLC follows the tracks of reaction process, needs the 3h reaction to finish approximately, cooling, reaction solution is slowly joined in an amount of water, and the limit edged stirs, and filters, the gained filter cake is joined in the methylene dichloride, stir, filter, filtrate is successively with ammoniacal liquor, purified water, saturated common salt washing, anhydrous sodium sulfate drying, decompression and solvent recovery is to most, and gained solid 95% ethyl alcohol recrystallization gets the pure product of formula IX compound, heavy 195.7g, yield 80%.
1H-NMR (BRUKER AVANCE DRX-500, DMSO are solvent, and TMS is interior mark): δ (ppm) 1.014～1.028 (d, J=7Hz, 6H), 1.294～1.322 (t, J=7Hz, 3H), 2.080～2.108 (m, 1H), 2.682 (s, 3H), 4.008～4.020 (d, J=6Hz, 2H), 4.282～4.324 (q, J=7Hz, 2H), 7.376～7394 (d, J=9Hz, 1H), 8.238～8.260 (dd, J=2Hz, J=9Hz, 1H), 8.318～8.320 (d, J=1Hz, 1H).
Embodiment 8
Preparation 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid (I)
With formula IX compound (327.1g, 0.950mol), (41.84g 1.046mol) mixes for ethanol (1L), THF (0.5L), purified water (1L), sodium hydroxide, reflux stirs, and TLC follows the tracks of reaction process, must the 1h reaction finish approximately, cooling, reclaim under reduced pressure is to the greatest extent, dripping hydrochloric acid, filter solid, be washed to neutrality, with 95% alcohol recrystallization, get the pure product of formula I compound, Mp201-202 ℃.
1H-NMR (BRUKER AVANCE DRX-500, CDCl
3Be solvent, TMS is interior mark): δ (ppm) 1.090～1.104 (d, J=7Hz, 6H), 2.200～2.226 (m, 1H), 2.796 (s, 3H), 3.902～3.916 (d, J=7Hz, 2H), 7.020～7.038 (d, J=9Hz, 1H), 8.094～8.116 (dd, J=2Hz, J=9Hz, 1H), 8.196～8.202 (d, J=3Hz, 1H).
Should be noted that at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can make amendment or be equal to replacement the technical scheme of invention, and not breaking away from the spirit and scope of technical solution of the present invention, it all should be encompassed in the claim scope of the present invention.
Claims (15)
1. the synthetic method of a 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid, reaction formula is as follows:
Specifically may further comprise the steps:
(1) preparation formula III compound 4-(2-methyl propoxy-) phenyl aldehyde:
Formula II compound p-Hydroxybenzaldehyde and halo Trimethylmethane are in water or organic solvent, and room temperature under the alkaline condition～155 ℃ react;
(2) preparation formula IV compound 3-halo-4-(2-methyl propoxy-) phenyl aldehyde:
The formula III compound reacts under-10～50 ℃ with the halo agent in organic solvent;
(3) preparation formula V compound 3-halo-4-(2-methyl propoxy-) benzaldoxime:
Formula IV compound reacts down in-10～50 ℃ with aqueous hydroxylamine in organic solvent;
(4) preparation formula VI compound 3-halo-4-(2-methyl propoxy-) cyanobenzene:
Formula V compound reacts down at-10～50 ℃ with dewatering agent in organic solvent, carries out intramolecular dehydration;
(5) preparation formula VII compound 3-halo-4-(2-methyl propoxy-) benzene first thioamides:
Formula VI compound 3-halo-4-(2-methyl propoxy-) cyanobenzene under alkaline condition with the ammonium sulfide effect;
(6) preparation formula VIII compound 2-(3-halo-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester:
Formula VII compound and 2-halo methyl aceto acetate are reflected at 40～120 ℃ of reacting by heating in the organic solvent;
(7) preparation formula IX compound 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid ethyl ester:
Under nitrogen protection, with formula VIII compound and cuprous cyanide in organic solvent, 70～160 ℃ of reactions down;
(8) preparation I compound 2-(3-cyano group-4-(2-methyl propoxy-) phenyl)-4-methyl-5-thiazole formic acid:
With formula IX compound under alkaline condition, hydrolysis in containing the organic solvent of water.
2. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (1) is selected from acetone, acetonitrile, ethyl acetate, toluene or N, dinethylformamide; Catalyzer is selected from NaI or KI, or does not select; Alkaline matter is K
2CO
3, Na
2CO
3, NaHCO
3, NaOH or KOH.
3. synthetic method according to claim 2 is characterized in that, the preferred K of described alkaline matter
2CO
3
4. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (2) is selected from acetone, acetonitrile, ethyl acetate, Glacial acetic acid, methylene dichloride, chloroform or tetracol phenixin; The halo agent is selected from chlorizating agent, bromizating agent or iodinating agent; Catalyzer is selected from sulfuric acid or chlorsulfonic acid, or does not select.
5. synthetic method according to claim 4 is characterized in that, described chlorizating agent is Cl
2, NaOCl, t-BuOCl, N-chloro polybutene imide, 1-chlorinated benzotriazole or cyanuric chloride, described bromizating agent is Br
2, NBS, bromine close dioxane or tetrabromo cyclohexadiene ketone, described iodinating agent is I
2Or ICl.
6. synthetic method according to claim 4 is characterized in that, the preferred Br of described halo agent
2
7. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (3) is selected from methyl alcohol, ethanol or Virahol; Aqueous hydroxylamine is generated with alkali substance reaction at low temperatures by the aqueous solution of the inorganic acid salt of azanol.
8. according to claim 1 or 7 described synthetic methods, it is characterized in that described alkaline matter is selected from K
2CO
3, Na
2CO
3, NaHCO
3, NaOH, KOH, triethylamine or pyridine.
9. synthetic method according to claim 7 is characterized in that, the inorganic acid salt of described azanol is oxammonium hydrochloride, oxammonium sulfate or hydroxylamine nitriate.
10. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (4) is selected from acetone, acetonitrile or ethyl acetate; Dewatering agent is selected from SOCl
2Or P
2O
5
11. synthetic method according to claim 1 is characterized in that, the alkaline matter in the described step (5) is a triethylamine.
12. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (6) is selected from methyl alcohol, ethanol, Virahol, acetone or acetonitrile.
13. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (7) is DMF or DMSO.
14. synthetic method according to claim 1 is characterized in that, the organic solvent in the described step (8) is selected from methyl alcohol, ethanol, Virahol, acetone or acetonitrile; 20～110 ℃ of temperature of reaction; Alkaline matter is K
2CO
3, Na
2CO
3, NaOH or KOH.
15. synthetic method according to claim 1 is characterized in that, described intermediate compound III, IV, V, VI need not promptly can be used for next step reaction by purifying.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105452228A (en) * | 2013-08-07 | 2016-03-30 | 法尔玛赞公司 | A novel process for the preparation of febuxostat |
-
2009
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105452228A (en) * | 2013-08-07 | 2016-03-30 | 法尔玛赞公司 | A novel process for the preparation of febuxostat |
| CN105452228B (en) * | 2013-08-07 | 2018-10-09 | 法尔玛赞公司 | Prepare the novel method of Febuxostat |
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Assignee: Shanghai Qicheng Chemical Industry Science & Tech Development Co., Ltd. Assignor: Shanghai Hechen Pharma Engineering Co., Ltd. Contract record no.: 2011310000246 Denomination of invention: Synthesis method of 2- (3- cyano -4- (2- methyl methoxy) phenyl) -4- methyl -5- thiazole formic acid License type: Exclusive License Open date: 20110601 Record date: 20111206 |
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