CN104744377A - Preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein - Google Patents
Preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein Download PDFInfo
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- CN104744377A CN104744377A CN201510075229.6A CN201510075229A CN104744377A CN 104744377 A CN104744377 A CN 104744377A CN 201510075229 A CN201510075229 A CN 201510075229A CN 104744377 A CN104744377 A CN 104744377A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- ZPOOWKOQKFRKJB-AATRIKPKSA-N n-[4-(4-fluorophenyl)-5-[(e)-3-oxoprop-1-enyl]-6-propan-2-ylpyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\C=O ZPOOWKOQKFRKJB-AATRIKPKSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- 150000002118 epoxides Chemical class 0.000 claims abstract description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011593 sulfur Substances 0.000 claims abstract description 11
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 230000002829 reductive effect Effects 0.000 claims abstract description 9
- 239000002585 base Substances 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical group [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000010931 gold Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052737 gold Inorganic materials 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 4
- WOCOTUDOVSLFOB-UHFFFAOYSA-N n-[4-(4-fluorophenyl)-5-formyl-6-propan-2-ylpyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1C=O WOCOTUDOVSLFOB-UHFFFAOYSA-N 0.000 abstract 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 abstract 1
- 229960000672 rosuvastatin Drugs 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000004821 distillation Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000012790 confirmation Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- -1 sec.-propyl Chemical group 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 239000011943 nanocatalyst Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RHIAGXPBZHFBGN-UHFFFAOYSA-N 2-(dimethyl-$l^{4}-sulfanylidene)acetonitrile Chemical compound CS(C)=CC#N RHIAGXPBZHFBGN-UHFFFAOYSA-N 0.000 description 2
- ZPYFGZYCBFUTNN-UHFFFAOYSA-N COC(=O)[S+](C)C Chemical compound COC(=O)[S+](C)C ZPYFGZYCBFUTNN-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein which can be used as a rosuvastatin intermediate. The preparation method comprises the following steps: reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl-formaldehyde with a sulfur ylide reagent under an alkaline condition to generate an epoxide shown in the formula III; then, reducing in the presence of a metal catalyst to generate a compound shown in the formula II; and finally reacting the compound shown in the formula II to generate the target product. The preparation method is simple in process and low in cost; no expensive catalyst is used; the generation of byproducts is reduced effectively so that the post-treatment becomes simple and easy to operate; in addition, the reaction yield is improved greatly; and therefore, the preparation method is quite suitable for large-scale industrial production.
Description
Technical field
The invention belongs to organic chemical synthesis field, be specifically related to a kind of preparation method of (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(the N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal that can be used as rosuvastain calcium intermediate.
Background technology
(E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal is the important intermediate of synthesizing clinical blood lipid-lowering medicine rosuvastain calcium.For this intermediate, in prior art, disclose multiple synthetic method.Such as:
Chinese patent CN100351240A discloses the preparation method utilizing witting to react, and reaction formula is as follows:
Preparation process as follows is disclosed in Chinese patent CN200710024034:
Following synthetic route is disclosed in international patent application WO2006100689A1:
Disclose a kind of method that the Vilsmeier of utilization reagent carries out reacting in international application WO2010038124A1, reaction formula is as follows:
Also a kind of synthesis technique is disclosed in international application WO2011154015A1:
But, there is the problems such as such as cost is high, by product is many, aftertreatment is loaded down with trivial details, yield is low more or less in these techniques, be unfavorable for the technical transform of large-scale industrial production.
Summary of the invention
The invention provides the preparation method of one (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal.The method simple process, cost is lower, can reduce the generation of by product, such that aftertreatment is simple, easy handling, and reaction yield improves greatly, more applicable large-scale industrial production.
Technical scheme of the present invention is specific as follows.
A kind of preparation method of (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal, comprises the following steps:
A) 4-(4-fluorophenyl)-6-sec.-propyl-2-(the N-methyl-N-methanesulfonamide base) pyrimidine-5-base-formaldehyde shown in formula IV and sulfur ylide reagent react in the basic conditions and generate the epoxide shown in formula III, then under metal catalyst effect, reduce production II compound, reaction formula is as follows:
B) the compound reaction production I shown in formula II, i.e. (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal, reaction formula is as follows:
Wherein, R be selected from-CN,
wherein, R
1and R
2h, alkyl or substituted alkyl independently of one another, acyl group or substituted acyl, aralkyl or substituted aralkyl or both be connected to each other to form ring as alkylidene group or sub-aralkyl; R
3for C
1-C
4alkyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl.
In the preparation process in accordance with the present invention, described sulfur ylide reagent is preferably
wherein R ' and R " be selected from alkyl, cycloalkyl, aryl, substituted aryl independently of one another.
Step a) in, sulfur ylide reagent is dissolved in organic solvent, with alkali mixing 10-60 minute, then adds formula IV compound reaction 2-10 hour, obtain the epoxide of formula III, under metal catalyst effect, then reduce production II compound.
Described organic solvent is selected from the ether solvents such as tetrahydrofuran (THF), or the aprotic solvent such as methylene dichloride, toluene, DMF, DMSO.Described alkali is selected from n-Butyl Lithium, tert-butyl lithium, LDA, potassium tert.-butoxide, sodium tert-butoxide, alkali alcoholate, alkali-metal oxyhydroxide and carbonate etc.Described metal catalyst is selected from gold (Au).
Preferably, described sulfur ylide reagent and the mol ratio of alkali are 1:1-3; Described sulfur ylide reagent and the mol ratio of formula IV compound are 1-3:1; The mol ratio of described metal catalyst and formula III compound is 0.01-0.1:1.
As mentioned above, in the structural formula of formula II compound, R can be selected from-CN,
according to the kind of R, step b) in by the reaction of formula II converting compounds accepted way of doing sth I also difference to some extent.
When R gets-CN, (E)-N-(5-vinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-the base)-N-methylmethanesulfonamide shown in formula II is obtained by reacting formula I with reductive agent in organic solvent.Described reductive agent is selected from diisobutyl aluminium hydride or red aluminium.Described organic solvent is selected from toluene, dimethylbenzene, tetrahydrofuran (THF) etc.
When R gets
and R
1and R
2when being selected from alkyl independently of one another, (E)-N-(5-(3,3-dialkoxy third-1-thiazolinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-base)-N-methylmethanesulfonamide shown in formula II is hydrolyzed production I in acid condition.
When R gets
time, (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] acrylate shown in formula II generates (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] vinylcarbinol under reductive agent effect, then under oxygenant effect, is oxidized production I.Preferably, described reductive agent is selected from DIBAL-H, tetrahydrochysene lithium aluminium, lithium borohydride etc.Described oxygenant is selected from pyridinium chlorochromate (PCC), DESSMARTIN oxygenant, 2,2,6,6-tetramethyl piperidines-oxyradical (TEMPO) etc.
Relative to prior art, disclosed by the invention for the preparation of the formula I i.e. method simple process of (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal, cost is low, avoid and adopt expensive catalyzer, effectively can reduce the generation of by product, make that aftertreatment is simple, easy handling, and reaction yield improves greatly, more applicable large-scale industrial production.
Embodiment
Below in conjunction with specific embodiment to be described in further details the present invention, but limiting the scope of the invention should not be understood as.
Embodiment 1
Dimethyl sulphide (8.8mL) and bromoacetonitrile (8.4mL) are dissolved in 100mL anhydrous tetrahydro furan, stirring at room temperature reaction is spent the night, add sodium ethylate (8.2g) process after completion of the reaction, filter, filtrate decompression distillation obtains dimethyl cyanomethylene sulfur ylide reagent.
By above-mentioned dimethyl cyanomethylene sulfur ylide dispensing reagents in tetrahydrofuran (THF) (170mL), add Anhydrous potassium carbonate (18.2g), stirring at room temperature mixing 1h, then formula IV compound (35.1g) is added, be heated to back flow reaction 3h, TLC display reacts completely, solids removed by filtration salt, filtrate is concentrated except desolventizing, obtains the epoxide shown in intermediate and formula III.
Epoxide shown in formula III is dissolved in toluene (200mL), adds nano catalyst 1.57g and 2mL water, pass into carbon monoxide in autoclave to 6000-7000tor, be heated to 100 DEG C of reaction 5h.Gold recovering catalyzer after cooling, concentrates solvent and obtains formula II compound 32.5g, yield 87%.
By proton nmr spectra and electrospray ionization mass spectrometry, structure and the molecular weight of the epoxide shown in formula III and formula II compound obtain confirmation, and characterization result is as follows.
(1) epoxide shown in formula III
1H NMR(400MHz,CDCl
3):δ7.03-7.46(4H,s,Ar-H),3.92(1H,d,-OCH-CN),3.8(1H,d,-OCHAr),3.12(1H,m,-CHMe
2),2.84(3H,s,-SO
2CH
3),2.47(3H,s,-NCH
3),1.29(6H,d,-C(CH
3)
2).
MS(ESI)m/z：(M+H)＝391.1
(2) formula II compound
1H NMR(400MHz,CDCl
3):δ7.03-7.46(4H,m,-C
6H
4),7.38(1H,s,-CH＝CH-),5.88(1H,s,-CH＝CH-),3.12(1H,m),2.84(3H,s,-SO
2CH
3),2.47(3H,s),1.29(6H,d).
MS(ESI)m/z：(M+H)＝375.1.
Embodiment 2
Dimethyl sulphide (8.8mL) and methyl bromoacetate (11.2mL) are dissolved in 100mL anhydrous tetrahydro furan, stirring at room temperature reaction is spent the night, add sodium hydride (2.8g) process after completion of the reaction, filter, filtrate decompression distillation obtains dimethyl methoxycarbonyl sulfonium methylide ylide reagent.
By above-mentioned dimethyl methoxycarbonyl sulfonium methylide ylide dispensing reagents in tetrahydrofuran (THF) (150mL), add dehydrated alcohol sodium (8.2g), stirring at room temperature mixing 1h, then formula IV compound (35.1g) is added, be heated to back flow reaction 4h, TLC display reacts completely, solids removed by filtration salt, filtrate is concentrated except desolventizing, obtains the epoxide shown in intermediate and formula III.
Epoxide shown in formula III is dissolved in toluene (180mL), adds nano catalyst 1.26g and 2mL water, pass into carbon monoxide in autoclave to 6000-7000tor, be heated to 100 DEG C of reaction 5h.Gold recovering catalyzer after cooling, concentrates solvent and obtains formula II compound 33.5g, yield 89.6%.
By proton nmr spectra and electrospray ionization mass spectrometry, structure and the molecular weight of the epoxide shown in formula III and formula II compound obtain confirmation, and characterization result is as follows.
(1) epoxide shown in formula III
1H NMR(400MHz,CDCl
3):δ7.03-7.46(4H,s,Ar-H),4.45(1H,d,-OCHAr),3.75(1H,d,-OCHCOOMe),3.67(3H,s,-COOCH
3),3.12(1H,m,-CHMe
2),2.84(3H,s,-SO
2CH
3),2.47(3H,s,-NCH
3),1.29(6H,d,-C(CH
3)
2).
MS(ESI)m/z：(M+H)＝424.1
(2) formula II compound
1H NMR(400MHz,CDCl
3):δ.7.64(1H,s,CH＝),7.03-7.46(4H,m,-C
6H
4),6.39(1H,s,CH＝),3.76(3H,s,-OCH
3),3.12(1H,m),2.84(3H,s,-SO
2CH
3),2.47(3H,s),1.29(6H,d,-CH
3).
MS(ESI)m/z：(M+H)＝408.1.
Embodiment 3
Diphenyl sulfide (20.1mL) and bromo-acetaldehyde diethyl acetal (18.0mL) are dissolved in 100mL anhydrous tetrahydro furan, stirring at room temperature reaction is spent the night, add sodium ethylate (8.2g) process after completion of the reaction, filter, filtrate decompression distillation obtains phenylbenzene ethylal sulfonium methylide ylide reagent.
By above-mentioned phenylbenzene ethylal sulfonium methylide ylide dispensing reagents in tetrahydrofuran (THF) (150mL), add dehydrated alcohol sodium (8.2g), stirring at room temperature mixing 1h, add formula IV compound (35.1g), be heated to back flow reaction 4h, TLC display reacts completely, solids removed by filtration salt, filtrate is concentrated except desolventizing, obtains the epoxide shown in intermediate and formula III.
Epoxide shown in formula III is dissolved in toluene (150mL), adds nano catalyst 0.99g and 2.2mL water, pass into carbon monoxide in autoclave to 6000-7000tor, be heated to 100 DEG C of reaction 5h.Gold recovering catalyzer after cooling, concentrates solvent and obtains formula II compound 38.7g, yield 85.8%.
By proton nmr spectra and electrospray ionization mass spectrometry, structure and the molecular weight of the epoxide shown in formula III and formula II compound obtain confirmation, and characterization result is as follows.
(1) epoxide shown in formula III
1H NMR(400MHz,CDCl
3):δ7.03-7.46(4H,s,Ar-H),4.51(1H,d,-CH(OEt)),3.81(1H,d,-OCHAr),3.56(1H,d,-OCH-),3.41(4H,t,-OCH
2-),3.12(1H,m,-CHAr),2.84(3H,s,-SO
2CH
3),2.47(3H,s,-NCH
3),1.29(6H,d,-C(CH
3)
2),1.11(6H,t,-C(OCH
2CH
3)
2).
MS(ESI)m/z：(M+H)＝468.1.
(2) formula II compound
1H NMR(400MHz,CDCl
3):δ7.03-7.46(4H,m,-C
6H
4),6.62(1H,s,CH＝),6.25(1H,s,CH＝),4.88(1H,s,-CH),3.41(4H,q,-OCH
2CH
3),3.12(1H,m),2.84(3H,s,-SO
2CH
3),2.47(3H,s),1.29(6H,d,-CH
3),1.11(6H,t,-OCH
2CH
3).
MS(ESI)m/z：(M+H)＝452.2.
Embodiment 4
30g formula II compound i.e. (E)-N-(5-vinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-base)-N-methylmethanesulfonamide is dissolved in 280mL dry toluene, be cooled to-10 DEG C, stir the toluene solution 38mL of the diisobutyl aluminium hydride of lower dropping 40%, dropwise rear reaction 1 hour, drip 16mL dehydrated alcohol, then dilute hydrochloric acid process is added, separatory, the 1M salt acid elution of organic phase 200mL once, neutrality is washed again with saturated sodium bicarbonate, anhydrous sodium sulfate drying, underpressure distillation, resistates hexane-sherwood oil crystallization, obtain having the off-white color solid 26.3g of structure shown in formula I, fusing point about 93 DEG C, yield is 87%.
Product structure and molecular weight thereof are confirmed respectively by proton nmr spectra and electrospray ionization mass spectrometry, and characterization result is as follows.
1H NMR(400MHz,CDCl
3):δ9.58(1H,-CHO),7.57(2H,dd,Ar-H),7.52(1H,d,-CH＝CHCHO),7.12(2H,t,Ar-H),6.18(1H,dd,＝CHCHO),3.57(3H,s,-SO
2CH3),3.5(3H,s,-NCH
3),3.33-3.4(1H,m,-CH(CH
3)
2),1.29(6H,d,-CH(CH
3)
2).
MS(ESI)m/z：(M+H)＝378.1.
Embodiment 5
Formula II compound i.e. (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] methyl acrylate 37g is dissolved in 185mL toluene, be cooled to-5 DEG C, DIBAL-H (the toluene solution of 20% is dripped wherein under stirring, 159.3mL), dropwise rear reaction 1 hour, then 50mL acetic acid is dripped, then 200mL water and 300mL ethyl acetate is added, separatory, aqueous phase 300mL extraction into ethyl acetate, merge organic phase, organic phase uses 500mL saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous magnesium sulfate drying, filter, filtrate decompression distillation obtains (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] vinylcarbinol, stand-by.
Chromium trioxide 49.15g is mixed with 200mL methylene dichloride, be cooled to 0 DEG C, dropwise add 77.74g pyridine, add rear stirring and within 10 minutes, make pyridinium chlorochromate (PCC) oxygenant, stand-by, the dichloromethane solution 200mL of (E) obtained above-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] vinylcarbinol is dripped wherein, add rear stirring reaction 2-3 hour, add 100g silica gel and stir 15 minutes, reacting liquid filtering, filter cake 200mL washed with dichloromethane twice, organic phase merges, use the sodium hydroxide solution of 2.5% of 300mL successively, the hydrochloric acid soln of 2.5%, saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate decompression distillation obtains having the off-white color solid 23.3g of structure shown in formula I, yield is 75.5%.
By proton nmr spectra and electrospray ionization mass spectrometry, (E) structure of-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] vinylcarbinol and product and molecular weight obtain confirmation, and characterization result is as follows.
(1) (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] vinylcarbinol
1H NMR(400MHz,CDCl
3):δ7.03-7.46(4H,s,Ar-H),6.62(1H,d,-CH＝CH-),6.25(1H,d,-CH＝CH-),4.20(2H,d,-CH
2OH),3.12(1H,m,-CH-),2.84(3H,s,-SO
2CH
3),2.47(3H,s,-NCH
3),2.0(1H,s,-OH),1.29(6H,d,-C(CH
3)
2).
MS(ESI)m/z：(M+H)＝380.1.
(2) formula I
1H NMR(400MHz,CDCl
3):δ9.58(1H,-CHO),7.57(2H,dd,Ar-H),7.52(1H,d,-CH＝CHCHO),7.12(2H,t,Ar-H),6.18(1H,dd,＝CHCHO),3.57(3H,s,-SO
2CH3),3.5(3H,s,-NCH
3),3.33-3.4(1H,m,-CH(CH
3)
2),1.29(6H,d,-CH(CH
3)2)。
MS(ESI)m/z：(M+H)＝378.1.
Embodiment 6
By formula II compound i.e. (E)-N-(5-(3,3-dimethoxy third-1-thiazolinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-base)-N-methylmethanesulfonamide 4.23g is dissolved in 50mL tetrahydrofuran (THF), be cooled to 10 DEG C, slowly add the aqueous hydrochloric acid 80mL of 10% wherein, stirring reaction 2 hours, reaction solution is extracted with ethyl acetate, organic phase uses saturated sodium bicarbonate solution, saturated common salt water washing successively, anhydrous magnesium sulfate drying, filters.Filtrate decompression distillation obtains oily matter, and gained oily matter silica column purification obtains the compound 3.5g shown in formula I, and yield is 92.8%.
Product structure and molecular weight thereof are confirmed respectively by proton nmr spectra and electrospray ionization mass spectrometry, and characterization result is as follows.
1H NMR(400MHz,CDCl
3):δ9.58(1H,-CHO),7.57(2H,dd,Ar-H),7.52(1H,d,-CH＝CHCHO),7.12(2H,t,Ar-H),6.18(1H,dd,＝CHCHO),3.57(3H,s,-SO
2CH3),3.5(3H,s,-NCH
3),3.33-3.4(1H,m,-CH(CH
3)
2),1.29(6H,d,-CH(CH
3)2)。
MS(ESI)m/z：(M+H)＝378.1.
Finally be necessary described herein, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted the present invention.Although with reference to preferred embodiment to invention has been detailed description; those of ordinary skill in the art is to be understood that; can modify to the technical scheme of invention or equivalent replacement, and not depart from the spirit and scope of technical solution of the present invention, it all should be encompassed in protection scope of the present invention.
Claims (10)
1., such as formula a preparation method for (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(the N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal shown in I, comprise the following steps:
A) 4-(4-fluorophenyl)-6-sec.-propyl-2-(the N-methyl-N-methanesulfonamide base) pyrimidine-5-base-formaldehyde shown in formula IV and sulfur ylide reagent react in the basic conditions and generate the epoxide shown in formula III, then under metal catalyst effect, reduce production II compound, reaction formula is as follows:
B) the compound reaction production I shown in formula II, i.e. (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] propenal, reaction formula is as follows:
Wherein, R be selected from-CN,
wherein R
1and R
2h, alkyl or substituted alkyl independently of one another, acyl group or substituted acyl, aralkyl or substituted aralkyl or both be connected to each other to form ring as alkylidene group or sub-aralkyl, R
3for C
1-C
4alkyl.
2. preparation method according to claim 1, is characterized in that: described sulfur ylide reagent is
wherein R ' and R " be selected from alkyl, cycloalkyl, aryl, substituted aryl independently of one another.
3. preparation method according to claim 1 and 2, it is characterized in that: step a) in, first sulfur ylide reagent is dissolved in organic solvent, with alkali mixing 10-60 minute, then formula IV compound reaction 2-10 hour is added, obtain the epoxide of formula III, under metal catalyst effect, then reduce production II compound.
4. preparation method according to claim 3, is characterized in that: described organic solvent is selected from ether solvent or aprotic solvent; Described alkali is selected from n-Butyl Lithium, tert-butyl lithium, LDA, potassium tert.-butoxide, sodium tert-butoxide, alkali alcoholate, alkali-metal oxyhydroxide and carbonate; Described metal catalyst is selected from gold (Au).
5. preparation method according to claim 3, is characterized in that: described sulfur ylide reagent and the mol ratio of alkali are 1:1-3; Described sulfur ylide reagent and the mol ratio of formula IV compound are 1-3:1; The mol ratio of described metal catalyst and formula III compound is 0.01-0.1:1.
6. preparation method according to claim 1, is characterized in that: R is-CN; In step b) in, (E)-N-(5-vinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-the base)-N-methylmethanesulfonamide shown in formula II is obtained by reacting formula I with reductive agent in organic solvent.
7. preparation method according to claim 6, is characterized in that: described reductive agent is selected from diisobutyl aluminium hydride or red aluminium; Described organic solvent is selected from toluene, dimethylbenzene, tetrahydrofuran (THF) etc.
8. preparation method according to claim 1, is characterized in that: R is selected from
wherein R
1and R
2be selected from alkyl independently of one another; In step b) in, (E)-N-(5-(3,3-dialkoxy third-1-thiazolinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-base)-N-methylmethanesulfonamide shown in formula II is hydrolyzed production I in acid condition.
9. preparation method according to claim 1, is characterized in that: R is selected from
in step b) in, (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] acrylate shown in formula II generates (E)-3-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base) pyrimidine-5-base] vinylcarbinol under reductive agent effect, then under oxygenant effect, is oxidized production I.
10. preparation method according to claim 9, is characterized in that: described reductive agent is selected from DIBAL-H, tetrahydrochysene lithium aluminium, lithium borohydride etc.; Described oxygenant is selected from pyridinium chlorochromate (PCC), DESSMARTIN oxygenant, 2,2,6,6-tetramethyl piperidines-oxyradical (TEMPO) etc.
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