来氟米特的合成

0D100%010μ000% Chinese Journal of Pharmaceuticals 2001 ,32(2)●49.100ND%i ↓TAOAtaeA: 1001 -8255(2001 )02- 0049-03A- -uAx i0μA≌T3∈EOW"E%'，1o 6”， A个-a'， AxA+94UI， TuEeOE!(1. 001UgENSO∈TεcOirNDWεEi ,ETec 200031; 2. A￥$ExEu °x0@Oμ0DIPOδET1u EwNDWE Ei, 16- E0A￥E% 215315)@0但:0w0A@Ox uAμA0OδOOEa005￥个≌RδE40_ AT, E69T、》- 2γ960Wa20个Y 3 2》-0Ae , E@%aμAμ% 68%μA 5-/%x>u- 4-01口BoNxEa,W~AE>- 、in~eo0e 10Ey -0)/x >uth2.-" 0| μAμi6A~ -(Ax 10 , ANk2yEOAE 60. 8%，xUE0AE 41%。20x+wota,-0| .+2011E0。10%U"E: A-UAx10; Aa -c∈DO10wNUNx; 9[3E0D [%4 -0Aa2A: R971+. 1TATx reETAe:AA-uAx 10 (leflunomide, 1)μA》- NgAu个目5-14x >u-EC 1"1000Ex如E0OEaμA∈uTr°3EA~ ie3EμAC , ECN-(qOEy -0%x >u+12>U)-4-0i口BONx 62。., OE μA1uμ0O》. ,°πxl%6AOU_ AEEO: Oa μAjU -p00Tr。AT%4YTATx[23Hoechest Marion Roussel 1《1 94阳;1 0x+0A, OD iEA0-φ01 PBADIμA;10Ex个ETED。EG%ABODAaOBOOOERT;1Nx x+0A, ECOAOUOTAE00, OTo0yE8AE 1a .9μA10xC。Aa -cEe D010)WUNx (RA )μA°01o i0Dgo0 ,0+ 0≈EuAix+OATA1x+"μA[2≈5]1 μA≌°3EA- 1B0+00日3 16([41)。1: HzC~ ^CHC(OE) Hc^ottoNHOHHsc^ 02 0^个 CH3HC/HOACSOCh.HO50a CH3| NH2OHI:6 CFysCHz_ HC(OE1)3、CH3HzC CH3Ac2OHo^ CH3CF、II:H2CNH28[%41 1 μA0+O@°Y3EA_TBA-IBI91m 0D,0-AT 79[ 8 DEA1DDOEt。, TIoCOq06￥、'x60 .0-I4xEaEyv006￥1≌0-AT，0DWa2u11 3 2> -0Ae,Ey -U%x >it/° -(6)V0，0916, Eox+个@ENExO- ATδμ￥°AμAμmEOAF 6&%1A 5-1xi1_0i ]0%(xEa(4),4 34-AE中国煤化工，1< 6。T0ACNj0nA.Iβ 1 ,w"00w0AAXxμAμA00ol0OEa0O°γ3∈3E压- 1, A1i2hEOAE60.TY HCN MH G .t2u1rEU。00o00aE0, ,aE0EU :2000 10-0806￥%- EA2%.0|9ζ3∈5 μAEOAET 51%(TAIx[0]: EOx+oBWile :EoW" E%( 1962) ,AD ,20Ei ,0+0 °0EAOOTr>- NSw∞°≈E1=AE 44% ), xUE0AETβ 41%。00ND能ε。土%4j-[3JON0D2EOAA-TB I °3∈1 μA+" uA, 000fTel:021序芳数据41500Ea006￥0A 4 μAEOAEO>0D 27. 2%;μ< 5 20D -0AoE-mail :sshen@ toppharma. com00 100%6010μ000% Chinese Journal of Pharmaceuticals 2001 ,32(2)i》~ ,01600 0E-0e 6 E6°963∈1,EOAE .B T95. 4% .4(127 g, 1.0 mol)、/4xlh(300 ml)40Ee .0|Fi,(4%4TAO> 0D 60. 8%,iEAOOEAj2> 0》Nu),x0EOAE个e60 50~55 Cμ14OAE》NCi(142.8g, 1.2 mol),>026%。A:0%3 h,TLC 412a1P0-AT96 i201 >0A+。A- E63yE￥)4xEμ4EOE士, ,00 ,0昨2 0A 4 iEOOZEEjO> 1g[3E。μuAμ%t块, -.0A6, Eδ%- 78~79C/1. 87 kPa μAAo -0, μATpE<4 6,00 Fr1yo0oWawg/%oODD i》- ,IE0=AE 5μA~;作。0U0°1a 5(109 g, 75%), 9-Ai 98. 5%(Eo IaE.2T- 0| EC0u_ δ°ζ3E1y3iμA( TA 1x[6]: bp 78 ~ 79C/1. 87 kPa)。 'HNMR10%40。+0De i0OENTEaδC° . μAμ1%0EUq唯, .0: TAE2>A0(CDCl3):8(ppm)2. 73(3H, s, CH3), 8. 56 (1H, s,1《, B, -n0EYOx E的sE 3 μA0i11 1a 3-/4x >心- 4-0i口β0%4xCH=N)。Ea006￥(9),9 iE 1-Nu -CEuE@a、AE 0- 0| ,μA 3-/4x》uA- -(Ax 10(1)-4-0i口B0%xδZAE (10)。5 0e 10 2>0x i"1y -0A6μA 12-”heu 6(161 g, 1. 0 mol)、Ey00.(167 ml)9[AE-0Ae ,0+400100211 1 μA iE。10 uA'HNMR(CD-V4x ie( 1000 ml)40Ee-' 0! REi , 0Atu0j 00u 0~5CμClz)但:δ(ppm)2.24(3H,s,CH3),9. 05(1H,s,CH405(162 g, 1. 11 mol),3.E￥tu0i ,25~30C.-010%=C)。3 h,TLC Wi 2a1P0- AT。4OE间( 1000 ml), .0360>01a,CHs09>uTa%- E@T (200 ml)、t￥9E3NTE@T° (200 ml)96,IpEBAOEaAE。EOT 。146N1 A" E60AO%4 1/3 a>y ,40Ee∈E- 01AN(500 ml),AaE” 0A 10C 00TA, 1yAE ,μA -OE- 1,0000C2H,OCI-0Ea 0￥00)%a%65 , μA°xEu6as -0AO 1(219g, 81%),91(mp 166~ 167C(TATx[4]:mp 166. 5C, EOAE 78%)。EμNe2i -0'HNMR (CDCl3):8(ppm) 2. 65(3H, s, CH3), 7.48(2H, d, ArH)，7.58 (2H, d, ArH)，7. 60 (1H,HNMR 0A GEMINI- 2000(300 MHz)Di E -A120n0C2a9" ;MSs, CH=N), 8.37 (1H, s, ArNH)。 MS(EI):m/z0A MAT-95 DTOExoc2aT。270(M + ),200,161,145,110(心-a) ,83, 68,43。2 00N6NCV4x >u006200Ea006￥(2)00δ900Ea006￥(65 g, 0. 5 mol)、0-%4x Eay005￥(111 g, 0.75 mol)9i'x6U(153 g, 1.5 mol) iq[Ee."21j4TATx:[1] Bertolini G，Aquino M, Biffi M, et al. Leflunomide, an im-0| Ei0D, >0A-045 h,TLC V师2a1p0-AT96 i£01 >OA+。munorestoring drug for the therapy of autoimmune disorders，146N10688 62i -.0μi -D个Y , 6U -0A6E0%- 140~ 150C/especially rheumatoid arthritis [J]. Transplant Proc, 1996. 281. 87 kPa μuAAo -0, μAu-EE《O°ia 2(79 g, 85%)(TA: 3074-3078.Yx[6] :bp 140~ 150C/1.87 kPa,EOAE 63%)。[2] Hirth KP, Schwartz DP, Mann E, et al. Treatment of platelet5-/4x>u- 4 _0i口B0/4xEa(4)derived growth factor related disorders such as cancers usinginhibitors of platelet derived growth receptor [P]. WO:2(93 g, 0. 5 mol)9仆800 74(100 ml)iq[Ee-"9519169, 1995- 07-20; US: 5700822, 1997-11-23. (CA 1996,0|Ei,00 10~ 15CμT4ONTEaoC°-(38.3 g, 0. 55124: 21813m)mol)、00EaAE(45. 1 g, 0. 55 mol )106A6E@(150 ml)[3] .1 1.0Aμ0E9 ，白U如,uE. A- -.0Ax i0uA°TE[J]. 010%6010μA>iq10°,i0OFμT40EUE,0/41 h μ1+T,0U00 10~00004,2000730(12): 455.15C-" 0!04 8 h,TLC V4i 2a1p0- AT96A" E3yE$0”%4。4] Kammerer FJ, Schleyerbach R. Isoxazole derivatives[P]. DE:2854439, 1980-07-03. (CA 1980, 93 : 239392m)VOEeA"NTEa(160g, 1. 58 mol)、tu00Ea(60g，1. 0[5] Fossa P, Menozzi G, Schenone P, et al. 5- Substituted 4- isox-mol), >0A+ 5 h, )46N1 A-~EoOA .0|Ei 0D20Aδ0% 1/2 uAazolecarboxamides with platelet antiaggregating and other ac-E印0°Ai。AaE' 0A 10C00TA, 1yAE，μA OE- 4,0000%-tivities[]1. Earmacn.1991 .46(6) : 789- 802.@(100 ml)00a %4S，μA°xE0- 40iβo0%x 0EAE(5)101 : 230507d)0D 100%6010μ000% Chinese Journal of Pharmaceuticals 2001.32(2)●51●Synthesis of LeflunomideSHEN Jing- Shan'，WANG Bin2，LI Jian-Feng'，LEI Li-Jun'，JI Ru-Yun'*(1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031;2. Development Dept. ，Kunshan Double- Crane Pharm. Co. Ltd. ，Kunshan 215315)中国煤化工ABSTRACT:Leflunomide，a new drug for treating rlMHC N M H Gsynthesized from ethylacetoacetate and triethyl orthoformate by condensation, cyclization, hydrolysis and chlorination to obtain5- methyl-4- isoxazolecarboxylic acid chloride which reacted with 4-trifluoromethylaniline to give the desiredproduct in an overall yield of 41%.Key苏呐数据eflunomide ; rheumatoid arthritis; synthesis