Nghiên cứu điều chế natri risedronat - Phần 1: Điều chế acid 3 - pyridylacetic hydroclorid

Nghien CLFU - Ky thuat<br /> subthpllnerve Blume (Oleaceae) was developed 389 tr, 16-19.<br /> and validated for the LOD (2 ng). LOQ (10 ng) on 2. Nguyen Thi Hdng Huong, Nguyen Khic Quynh<br /> columm. precision (intraday RSD < 2.1% and Cir. Tnnh Van Quy, Christian Zidorn. Markus<br /> interday RSD < 1.95 %), accuracy (recovery > Ganzera, Hermann Stuppner. (2008), JA NPR, 11,<br /> p.1035-1038.<br /> 97.05 %). Nicotiflonn content was 1.92 - 4.4 mg.g'\<br /> 3. Nguyen Thi H6ng Huong. Hoang Thai Phugng<br /> Tai lieu tham khao Cac. Nguyin Khic Quynh Cu. Trinh Van Quy. Tap<br /> 1, Nguyen Thi Hong Huong. Nguyen Ktiac cbi Kiem nghiem thuoc, (2008), 3, tr, 10-15.<br /> Quynti Cu. Trjnfi Van Quy, Markus Ganzera, 4. Maceij Stobiecki. Phytochemistry. (2000), 54, p,<br /> Hermann Stuppner . Tap chi Dwgc hoc, (2008), 237-256.<br /> <br /> <br /> <br /> <br /> Nghien cuu dieu che natri risedronat<br /> Phan 1- Dieu che acid 3-pyridylacetic hydroclorid<br /> ':, Tru'O'ng Phu'o'ng, Nguyen Anh Duy, Nguyen Anh Tuan<br /> • ' Dai lioc Y-Dirac TP. Ho Chi Minh<br /> <br /> Dat van de Tdi uu hda quy trinh tdng hpp d quy md<br /> Risedronat, mdt thudc tn loang xuang dang phdng thi nghiem,<br /> dugc sir dung phd bidn d Viet Nam cung nhu Nguyen lieu<br /> tren thd gidi'' ^', Cd nhidu phuang phap didu chd Aeid nicotinic (An Op) tinh khidt hda hpc,<br /> nsedronat tren thd gidi, Tuy nhien. t i t ca cae Ethanol tuyet ddi, H2SO4 dd, NH3 dd, ethyl<br /> phuang phap didu ehd ddu sir dung nguyen lieu acetat, natri kim loai, NaOH. acid acetic, diethyl<br /> dau la aeid 3-pyridylaeetie hydroelorid'^^l Hien ether, morpholin, Na2S04 khan. HCI dd. tinh<br /> nay. trong nudc v i n chua cd ea sd nao san xuit<br /> khidt hda hpe (Trung Qude).<br /> dugc va cung ehua cd nghien eiru nao vd ehit<br /> Luu huynh (Viet Nam) tinh khidt ky thuat,<br /> nay, Trong chuang trinh nghien ciru tao nhirng<br /> Phu'O'ng phap nghien cu'u<br /> ngudn nguyen lieu cho cdng nghiep Dugc ma d<br /> day ia nguyen lieu thudc trj loang xuang chiing - Dua vao cac tai lieu da ed tren thd gidi vd<br /> tdi chil y tdi cae d i n chit biphosphonat, trong dd nghien ciru tdng hgp aeid 3-pyridylaeetie<br /> cd nsedronat. Qui trinh didu chd risedronat chia hydroelond, ehpn phuang phap kha thi va<br /> lam nhidu giai dean trong dd giai dean didu ehe nguyen lieu thieh hgp dd ap dung vao didu kien<br /> acid 3-pyhdylacetic hydroelond ehidm ty le ldn cu the d phdng thi nghiem,<br /> nhit '^•'''. Trong bai nay ehiing tdi xin trinh bay - Tidn hanh khao sat eac bude eiia quy trinh.<br /> nhirng ket qua nghien ciru tdng hgp acid 3- theo ddi phan ung bing SKLM va dua tren eae<br /> pyndyfacetic hydroclorid. ehit ehuin da cd,<br /> Doi tu'O'ng, nguyen lieu va phu'O'ng - Chpn eae thdng sd phan ir'ng c i n tdi uu hda<br /> phap va thidt kd eae thi nghiem tdi uu hda bac 1 kidu<br /> Ddi tu'O'ng tirng phin, dua tren tinh toan thdng ke dd xay<br /> Tdng hgp ethyl nicetinat tir aeid nieetinie va dung phupng trinh hdi quy thuc nghiem, kidm tra<br /> ethanol, y nghla eac he so hdi quy, tien ddn vijng cue trj<br /> Tdng hap 3-acetylpyhdin tir ethyl nieotinat va bing phuang phap Box-Willson dd ehdn ra didu<br /> ethyl acetat, kien tdi uu nhit cho quy trinh didu chd,<br /> Tdng hpp 4-(3-pyridylthipaeetyl)morpholin tir' - Tidn hanh didu chd theo quy trinh da tdi uu<br /> 3-acetylpyridin, luu huynh, morpholin, hda va kidm nghiem san phim, san phim trung<br /> Tdng hgp acid 3-pyridylacetie hydroclorid tir gian bing eac phuang phap: S i c ky Idp mdng,<br /> 4-(3-pyridylthipacetyl)mprphplin, UV, IR, 'H-NMR,'^C-NMR,<br /> <br /> <br /> T.\P CHi DUOC HOC - 3/2011 (SO 419 N.AM 51) 31<br />  Nghien CLFU - Ky thuat<br /> Ket qua va ban luan<br /> Didu chd ethyl nieotinat tip acid nicotinic va ethanol<br /> 0<br /> H2SO4<br /> ^OH + H.C^OH ^ = ^ H,0<br /> <br /> <br /> Day la phan irng ester hda eiia acid hii'u ca Xi3 = X11.X12 la he thirc sinh. vi eae thi nghiem<br /> (acid nicotinic) va alcol bac 1 (ethanol) theo ca phan irng dugc thidt kd theo kidu tii'ng phin.<br /> ehd ai nhan. aeid sulfuric cd vai trd xiic tae tao Phuang trinh hdi quy thuc nghiem: yi (%) =<br /> earboeation, 68,9 + 3,41xii + 1,59xi2- 1,14Xi3<br /> Bd tri ma tran thi nghiem kidu tirng phin vdi Thuc hien 5 thi nghiem lap d didu kien ca<br /> eae ydu td ed dinh: ban (Xioi) kidm tra y nghTa eae he sd bu<br /> - Lugng acid nieetinie tham gia phan irng la Bang 3: Cae thi nghiem lap cua phan wng<br /> 99g (0,8 mpl), tdng hqp ethyl nieotinat<br /> - Nhiet dp cd djnh la nhiet do dun hdi luu 2 3 4 5<br /> Ni 1<br /> each thiiy,<br /> yi (ml) 74 77 76 77 76<br /> Cae ydu td anh hudng ddn hieu suit phan<br /> irng duge khao sat la: lugng ethanol, lugng yi (%) 67.31 70.04 69.13 70.04 69.13<br /> aeid sulfuric va thdi gian phan irng.<br /> Bang 1: Cae ydu td khao sat cua phan wng !(>'„ -y„r<br /> tdng hqp ethyl nieotinat s~. = - ,24<br /> N.-]<br /> Ky<br /> Yeu to Xioi Xii XHM ^1im<br /> hieu<br /> Lugng ethanol 0.248 • 0,498<br /> X11 350 50 400 300<br /> tuyet 6d\ (ml)<br /> Lugng acid<br /> X12 140 20 160 120<br /> sulfuric (ml)<br /> • T.\H 1 = 6,85<br /> Thgi gian phan 5.<br /> Xl3 10 2 12 8<br /> irng (h)<br /> Xio,: dieu kien ea ban<br /> TTNhV. = L ^ = 3,19<br /> X11M = XiiMax: niue eao nhat; Xnm = X, muc<br /> thip nhit.<br /> AXii la kheang bidn ddi giua hai mirc<br /> T 2.28<br /> 2<br /> s.<br /> Tra bang Student: (f=Ni-1=^4), T (0,05;4) = 2,776<br /> Ma hda cac bidn:<br /> Nhu vay, TJN bii > T(0,05;4), TjNbiz ><br /> X11 ~* X11 => X11M = + 1 Xl1m - -1<br /> T(0,05;4), TT T(0,05;4),<br /> X12 ~* X12 => Xi2M - + 1 Xl2m - - 1<br /> Tire la: bn va bi2 cd y nghla, bi3 khdng ed y<br /> X i 3 - • Xi3 => Xi3M = + 1 Xl3m - -1<br /> nghla, vdi dp tin cay a = 95%<br /> Bang 2: Ma tran bd tri thl nghiem va kdt qua<br /> cua phan irng tdng hqp ethyl nieotinat DP dd: yi (%) = 68,9 + 3,41xii + 1,59xi2<br /> Thi<br /> Tidn ddn vung ciec trj bing phu'ang phap<br /> Xio X11 X12 X13 - X11.X12 yi(ml) yir/o) Box-Willson<br /> nghiem<br /> 1 + + + + 80 72.77 Xac dinh budc nhay: S = C x bi, x x^<br /> 2 + + - - 79 71,86 S11 = C X 3,41 X 50 = 170,5C; Si2= C x 1,59<br /> 3 + - + - 75 68,22 X 20 = 31,80<br /> 4 + - - + 69 62,76 Chpn C = 0,15 ^ Sii« 25 ml, S12 - 5 ml, bd<br /> bl, 68,9 3.41 1.59 -1.14 tri eac thi nghiem va thu duge kdt qua:<br /> <br /> <br /> 32 TAP CHi DUOC H O C - 3 / 2 0 1 1 (SO 419 NAM I)<br />  Nghien CLFU - Ky thuat<br /> Bang 4: Bd tri thi nghiem tidn ddn ewe tn cua Ket luan: Didu kien tdi uu eho phan i^ng<br /> phan wng tdng hqp ethyl nieotinat ester hoa giira acid nicotinic va ethanol vdi eae<br /> Thi Xu Xl2 X13 ydu td cd djnh ban d i u la: thdi gian phan irng<br /> yi (ml) yU"/")<br /> nghiem Xm*Su X2M^Sl2 Xl3m 8h, 475ml ethanol tuyet ddi, 175ml aeid sulfuhe<br /> 5 425 165 8 78 70,95 dam dae.<br /> 6 450 170 8 82 74,59 Didu chd 3-acetylpyridin tiy ethyl nieotinat<br /> 7 475 175 8 84 76,41 Bw&c 1: Phan irng ngwng tu Clalsen giira<br /> 8 500 180 8 80 72.77 ethyl nieotinat va ethyl acetat<br /> O O<br /> <br /> H.C ^ONa<br /> <br /> <br /> San phim eua phan irng ngung tu Claisen la san pham 3-acetylpyridin.<br /> keto ester va ethanol. Ethanol dd dang phan Do dd, muc tieu ciia bude 1 la ehpn duge ty<br /> irng vdi natri kim loai tao aleolat eho mdi trudng le ethyl nieotinat, natri kim loai va thdi gian dd<br /> kidm manh, mdt mat tao xiie tac thiic day phan phan irng hdt nguyen lieu ethyl nieotinat.<br /> irng xay ra theo chidu thuan, mat khae thiiy Kdt qua khao sat ty le ethyl nieotinat va xiic<br /> phan d i n chit keto ester tao thanh keto acid, tac natn<br /> din chit nay dac biet kem bdn trong didu kien Cae ydu td ed djnh:<br /> nhiet dp va bj decarboxy hda mot phin thanh 3- - Lugng ethyl nieotinat tham gia phan irng la<br /> acetylpyridin '^'. Nen san phim thu duge d bude 55g (0,36 mol),<br /> 1 cd ca 4-(3-pyridyl)-3-oxo-propionyl aeetat va - Thdi gian phan irng la 5h,<br /> 3-acetylpyhdin. Day ddu la nhii'ng san pham - Nhiet dp phan irng la nhiet dp dun hdi luu<br /> mong mudn nen chiing tdi nghien eiru tdng hgp each thiiy,<br /> in situ bing each tidp tuc thuy phan djeh phan Cae ydu td anh hudng duge khao sat: ty le<br /> irng thu duge d bude 1 bing H2SO4 20% dd thu ethyl aeetat va natri kim loai.<br /> <br /> Bang 5: Cac thl nghiem khao sat ty le ethyl nieotinat va natri cho phan wng ngwng tu Claisen<br /> Thi Ethyl aeetat Natri<br /> nghiem Ty le mol so v&i ethyl nieotinat Khoi Iwang (g) Ty le mol so v&i ethyl nieotinat Khoi Iwong (g)<br /> 1 2 1 64,05 1: 1 23<br /> 2 3 1 96,06 1: 1 23<br /> 3 2 1 64.05 1,5: 1 34.5<br /> 4 3 1 96,06 1,5: 1 34,5<br /> 5 2 1 64,05 2: 1 46<br /> 6 3 1 96,06 2; 1 46<br /> <br /> San pham thu dugc tir cac phan irng nay phan irng cd do sanh vifa phai, thich hgp eho<br /> dugc pha leang trpng methanol rdi ehim tren viec tinh ehd tidp theo.<br /> ciing mpt ban SKLM, he dung mdi khai tridn: n- Kdt qua khao sat thbi gian phan irng<br /> hexan - CHCI3 - CH3OH (7:2:1), phat hien: soi Dun hdi luu hdn hgp gdm 96.06 g ethyl<br /> UV254nm, aeetat, 46 g Na va 55 g ethyl nieotinat (ty le<br /> Nhan xet: Bit d i u d t'y- le ethyl acetat: natri : ethyl aeetat: natri: ethyl nieotinat = 3: 2: 1) trong<br /> ethyl nicetinat = 2: 2: 1, ethyl nieotinat da phan lOh, mdi gid thu djeh phan irng 1 l i n va ehim<br /> ung hdt, tuy nhien hdn hpp sau phan irng ee thd cae vdt san pham theo thdi gian tren eiing mdt<br /> chit dae quanh, tinh ehd khd khan nen ehiing tdi ban SKLM.<br /> chpn ty le ethyl acetat: natri : ethyl nieotinat = 3: Nhan xet: B i t d i u tii' 3h dich phan irng da<br /> 2: 1. a ty le nay, hdn hgp sau phan irng da hdt vdt nguyen lieu ethyl nieotinat, nen ehiing tdi<br /> hoan toan hdt nguyen lieu ethyl nicetinat va dieh ehpn thdi gian phan irng la 3h,<br /> <br /> <br /> TAP CHI DUQC HOC-3/2011 (SO 419 NAM 51) 33<br />  Nghien CLFU - Ky thuat<br /> Ket luan: Didu kien che phan irng ngung tu ethyl nieotinat = 3 : 2 : 1 .<br /> Claisen vdi cae ydu td ed djnh ban d i u la: thdi Bu'dc 2: Phan irng thiiy phn dan chit -keto<br /> gian phan irng 3h. ty le mei ethyl acetat: natri: ester tao 3-aeetyl pyridin<br /> O O O<br /> <br /> t"C CH,<br /> H2S04 (C2H5)2S04 CO.<br /> <br /> N<br /> Ket qua khao sat thai gian phan irng tdi ehpn thdi gian tdi uu cho phan irng nay la<br /> Oun hdi luu each thuy hdn hgp gdm 70g san 2h.<br /> phim thu duge sau phan irng ngung tu (tir' 55g Kit qua khao sat Iwg'ng H2SO4 20%<br /> ethyl nieotinat ban diu) va 300 ml dung dieh Tidn hanh cae phan irng vdi thdi gian ed<br /> H2SO4 20% treng 5 h. mdi 30 phiit liy dieh phan djnh la 2h, thay ddi ty le mol giti'a ethyl nieotinat<br /> irng 1 l i n va c h i m cac vdt san phim thee thdi va H2SQ4 20%. Kdt qua thu duge nhu sau:<br /> gian tren eung mdt ban SKLM, Bang 7: Kdt qua khao sat Iwqng H2S04<br /> Nhan xet: Sau l b djeh phan irng da hdt vdt 20% phan irng tdng hqp 3-acetyl pyridin<br /> nguyen lieu, San pham thu duge ed vdt eua tap Ty le mol ethyl<br /> 1:2 1:3 1:4<br /> va ndu tidp tuc keo dai phan irng thi vdt tap v i n nieotinat: H2SO4 20%<br /> edn, Tuy nhien nhirng tap phu nay de dang bj Lugng dd H2SO4 20%<br /> 200 300 400<br /> loai di treng qua trinh tinh ehd. Vi vay ehiing tdi (ml) tugng irng<br /> ehi tidp tuc thuc bien phan irng khao sat d Ih, Hieu suat (%) 73,19 86,23 59.48<br /> 2h. 3h. thu san pham, tinh va so sanh bleu suit. Nhan xet: Ty le ethyl nieotinat: H2SO4 = 1 : 3<br /> Bang 6: Kdt qua khao sat thbi gian phan irng la tdi uu eho phan irng thuy phan tao 3-<br /> tdng hqp 3-acetyl pyridin acetylpyridin.<br /> Th&i gian Kdt luan: Didu kien tdi uu eho phan irng thuy<br /> Ih 2h 3h<br /> phan irng phan tdng hgp 3-acetylpyhdin vdi eae ydu td ed<br /> Hieu suat (%) 66,37 86.23 84.02 djnh ban dau la: thdi gian phan irng 2h, ty le mol<br /> Nhan xet: Q thdi gian 2h hieu suat phan irng ethyl nieotinat: aeid sulfuric = 1 : 3 .<br /> kha cao. neu tiep tuc keo dai thdi gian phan Oidu chd 4-(3-pyridyIthioacetyl) morpholin<br /> -irng, hieu suit cd xu hudng giam, vi vay chiing tiF 3-acetyl pyridin, morpholin va lu'u huynh<br /> O<br /> <br /> t"C<br /> CH,<br /> NH H.O<br /> <br /> <br /> Day la phan irng Willgerodt-Kindler, la phan - Lugng 3-aeetylpyridin phan irng la 36g (0,3<br /> irng ngung tu morpholin va luu huynh vdi d i n mol).<br /> ehit ceton dj vdng la 3-acetylpyridin, va chuydn - Nhiet dp ed dinh la nhiet dp dun hdi luu<br /> vj dd tae 4-(3-pyridylthioacetyl) morpholin. each thuy.<br /> Bd tri ma tran thi nghiem kidu tirng p h i n vdi Cac ydu td anh hudng dugc khao sat: ty le<br /> cac yeu td ed dinh: morphplin, ty le luu huynh va thdi gian phan irng.<br /> Bang 8: Cac ydu td khao sat cita phan irng Willgerodt-Kindler<br /> Yeu to Ky hieu X30i Xii XsiM ^3im<br /> Ty le mol so vdi 1,3: 1 1,5: 1 1.1: 1<br /> 3-acetyl pyridin<br /> X31<br /> Khoi lugng (g) 34 5 39 29<br /> Ty ie mol so vcri 1.3: 1 1,5: 1 1.1: 1<br /> 3-acetyl pyridin<br /> X32<br /> Khoi lugng (g) 12.48 1,92 14.40 10.56<br /> Thdi gian phan irng (h) X33 10 2 12 8<br /> <br /> <br /> 34 TAP CHi DUOC HOC-3/2011 (SO 419 NAM 51)<br />  Nghien CLFU - Ky thuat<br /> Ma hoa cac bien va b6 tri thi nghiem: Tien den vijng cwc tri bang phwang phap<br /> Bang 9: Ma tran bd tn thi nghiem va kdt qua Box-Willson<br /> eua phan wng Willgerodt-Kindler Budc nhay: S31 = C x 1,97 x 5 = 9,85C; S33 =<br /> Thi C X 1,26 x 2 = 2,52C<br /> X30 X31 X32 X33= X31.X32 ystg) y3(%)<br /> nghiem Chpn C = 0,4 => S31 = 4 g, S33 = 1 h, Bd tri<br /> 1 + + + + 26 38.99 cae thi nghiem va thu dupe kdt qua:<br /> 2 + - + 21,7 32.54 Bang 10: Bd tri thl nghiem tidn ddn cwc tri<br /> 3 + + - 23,95 35.91 ciia phan irng Willgerodt-Kindler<br /> 4 + - + 23 34,49 Thi X31 X32 X33<br /> y3(g) yi (%)<br /> nghiem X31M+S31 X32M X33M*S33<br /> bs, 35.48 1.97 0,28 1,26<br /> 5 43g 14.4g 13h 26,51 39,75<br /> Phuang trinh hdi quy thue nghiem: y3 (%) =<br /> 6 47g 14.4g 14 h 28,88 43,31<br /> 35.48 + 1.97X31 + 0.28x32 + 1,26x33<br /> 7 51g 14,4g 15 h 25.63 38,43<br /> Thuc hien 5 thi nghiem d didu kien ca ban<br /> Ket luan: Dieu kien tdi uu eho phan irng<br /> (X301) dd kidm tra y nghla cua he sd b3j,<br /> Willgerodt-Kindler tdng hgp 4-(3-pyridyl<br /> Ket qua: bsi va b33 cd y nghTa. b32 khdng cd y<br /> thioacetyl) morpholin vdi cae ydu td ed dinh ban<br /> nghTa. vdi dp tin cay a = 95%<br /> d i u la: thdi gian phan irng 14h, 47g morpholin.<br /> Do dd: y3 (%) = 35.48 + 1,97x3, + 1.26x33 14.4g luu huynh,<br /> Tdng hop acid 3-pyridylacetic hydroclorid tiK 4-(3-pyridylthioacetyl) morpholin<br /> <br /> O COOH<br /> HCI + 2 H.O H.S HN O<br /> N N HCI<br /> Day la phan irng thuy phan 4-(3- Ma hda cac bidn va bd tri thi nghiem.<br /> pyhdylthioacetyl) morpholin dd tao acid hii'u ca Bang 12: Ma tran bd tri thi nghiem va kdt<br /> tuang irng la acid 3-pyhdylacetic, acid nay thu qua phan irng didu chd aeid 3-pyridylacetic<br /> dugc dudi dang hydroclorid, hydroclorid<br /> Bd tri ma tran thi nghiem kidu tivng phin Thi<br /> X40i X41 X42 y4(g) y4(%)<br /> vdi cac yeu to dwcvc djnh: nghiem<br /> 1 + + + 7.25 83.53<br /> - Lugng 4-(3-pyridylthioacetyl) morpholin<br /> 2 + - - 6,25 72<br /> phan ii'ng la 11,12g (0,05mol),<br /> 3 + + - 6,84 78.8<br /> - Nhiet dp ed djnh la nhiet dp dun hdi luu<br /> 4 + - + 6.64 76.5<br /> each thiiy,<br /> b4, 77,71 3.46 2.3<br /> Cac ydu td anh hudng ddn hieu suit phan<br /> Phuang trinh hdi quy thue nghiem: y4 (%) =<br /> ii'ng dugc khao sat: ty le HCl va thdi gian phan<br /> 77,71 + 3,46X41 + 2,3x42<br /> irng.<br /> Thue hien 5 thi nghiem d didu kien ea ban<br /> Bang 11: Cac ydu td khao sat phan wng didu<br /> (X40i) dd kidm tra y nghla eae he sd b4i.<br /> ehd acid 3-pyndylacetie hydroclorid<br /> Kdt qua: b4i va b42 ed y nghTa, vdi dp tin cay<br /> Ky a = 95%<br /> Yeu to X40i X4i X4iM X4ir<br /> hieu<br /> Do dd: y4 (%) = 77,71 + 3,46x41 + 2,8X42<br /> Ty le mol so voi 4- Tien den viing cwc tri bang phwang phap<br /> dd (3-pyhdylthioacetyl) Box-Willson<br /> HCI morpholin 4: 1 5: 1 3: 1<br /> Budc nhay: S41 = C x 3,46 x 15 = 51,9C; S42<br /> 10%<br /> The tich (ml) 62 15 77 47 = C x2,3 X 1 =2,3C<br /> Chpn C = 0,4 ^ S41 = 20 ml, S42 ~ Ih. Bd tri<br /> Thoi gian phan irng (h) X42 5 1 6 4<br /> eac thi nghiem va thu dugc kdt qua (bang 13):<br /> <br /> <br /> TAP CHl DUOC HOC-3/2011 (SO 419 NAM 51) 35<br />  Nghien CLFU - Ky thuat<br /> Bang 13: Sd tn thl nghiem tidn ddn owe tri - Trong mdt binh e i u 1000 ml. cho vao hdn<br /> cua phan wng didu chd acid 3-pyridyl acetic hgp gdm 36 g 3-aeetylpyridin (0,3 mol) va 47 g<br /> hydroelond morpholin (0,54 mol). L i p sinh han va dun hdi<br /> X41 X32 y4(g) luu. Trong liic khuiy trdn, them tu" tb 14,4 g luu<br /> Thi nghiem y4 (%)<br /> X3IM* S4I X33M'^S42 huynh (0,45 mol) vao binh. Dun hdi luu trong 14<br /> 5 97 ml 7h 7.09 82,0 b. Gan liy phin djeh phia tren, lam lanh, xuit<br /> 6 117ml 8h 7,27 84.1 hien tinh the, Idc qua phdu Buchner thu tinh thd,<br /> 7<br /> Rira phin c i n cdn lai 3 l i n vdi nudc, mdi lin<br /> 137 ml 9h 7,04 81,1<br /> 200 ml nudc. Hoa tan trong nude ndng, tiy<br /> Ket luan: Dieu kien tci uu eho phan irng<br /> mau bing lugng than boat, Ipe ndng. Lam lanh<br /> didu ehd aeid 3-pyhdylaeetie hydroclorid vdi eae<br /> djeh lpc xuit hien tinh the, Ipe qua phdu<br /> ydu td ed dinh ban d i u nhu sau: thdi gian phan<br /> Buchner thu tinh thd, s i y khd dugc san phim<br /> irngSb, 117mldd HCI 10%.<br /> tinh khidL Hieu s u i t 43,31%,<br /> Tien hanh didu chd acid 3-pyridylacetic<br /> - Trong mdt binh e i u 1000 ml, eho vao hdn<br /> hydroclorid<br /> hgp gdm 36 g 4-(3-pyridylthioacetyl) morpholin<br /> -Trong mdt binh c i u dung tich 1000 ml,<br /> (0,05 mol) va 117 ml HCI 10% (0,38 mol). Lip<br /> cho vao hdn hgp gdm 99 g aeid nicotinic (0.8<br /> sinh ban va dun hdi luu each thiiy trong 8h. Lpc<br /> mol) va 475 ml ethanol tuyet ddi (mol). them tu'<br /> hdn hgp sau phan irng, ed djeh lpc ddn thd ehit<br /> tir 175 ml aeid sulfuhe dam dae (3.2 mol). L i p<br /> dac sanh (cdn khoang 1/3 thd tieh). Them vao 50<br /> sinh ban va dun hdi luu each thiiy trong 8 h,<br /> ml ethanol tuyet ddi, dun ndng. hoa tan. lam lanh,<br /> Cho tir tw dung dich amoniae 25% vao eho den<br /> xuit hien tinh the, gan bd dich cdn thu tinh the,<br /> khi pH = 7, Dung binh ling gan thu liy Idp tren<br /> Tinh thd dugc rira nhidu l i n vdi aceton rdi hoa<br /> rdi rira hai lin vdi nudc. mdi l i n 100 ml, Nudc<br /> tan trong 200 ml hdn hgp aeeton: ethanol = 1:2.<br /> rira va ldp dudi dugc ehidt 4 lin vdi diethyl<br /> dun ndng. t i y mau bing than boat, loc ndng.<br /> ether, mdi lin 50 ml, Cd quay djeh ehidt ether<br /> Lam lanh dich lpe xuit hien tinh the, gan bd phin<br /> loai dung mdi thu duge ethyl nieotinat tinh khidt.<br /> djch thu liy tinh thd, s i y khd. Hieu suit 84,1 %.<br /> Hieu suit 76.41%,<br /> Kidm nghiem 3-pyridylacetic hydroclorid<br /> - Trong mpt binh cdu dung tieh 1000 ml. ehe<br /> - Cam quan: Bdt mjn mau tring nga, hiit i m<br /> vao hdn hgp gdm 55 g ethyl nieotinat (0.36 mol);<br /> manh d didu kien thudng.<br /> 96.06 g ethyl aeetat (1,09 mol) va 46 g nath (0,72<br /> mol). L i p sinh ban va dun hdi luu each thuy trong - t° ndng ehay = 162°C phii hgp vdi t° ndng<br /> ehay treng tai lieu tham khao va ehat ehuan.<br /> 3 h, Trung boa hdn hgp bing aeid acetic 50%<br /> ddn pH = 7, Diing binh ling gan thu liy Idp tren - Kdt qua tren SKLM: San pham sau tinh chd<br /> rdi rira hai lin vdi nudc. mdi lin 200 ml. Nude ehl eho 1 vdt ed Rf triing vdi Rf ciia ehit chuin<br /> rira va ldp dudi duge ehidt 4 lan vdi diethyl va khac vdi vet nguyen lieu.<br /> ether, mdi lin 50 ml, Cd quay djeh ehidt ether loai - Kdt qua do phd tir ngoai UV-VIS: eho phd<br /> dung mdi thu dugc 70 g hdn hgp gdm 1-(3- ed hinh dang va eac peak tuang tu phd dd cua<br /> pyridyl)-1-oxeethyl propanoat va 3-aeetyl pyhdin, acid 3-pyridylacetie hydroclorid chuan,<br /> - Cho 70 g san phim trung gian thu duge d - Kdt qua do phd hdng ngoai IR: Phd IR ciia<br /> tren vao binh e i u 1000 ml, them vao 300 ml ehit tdng hgp cd hinh dang va eae peak tuang tu<br /> H2SO4 20%, L i p sinh han va dun hdi luu each phd dd ciia acid 3-pyridylacetie hydroclorid ehuin.<br /> thuy treng 2h, Trung hoa hdn hpp bing NaOH TiJ- nhuag kdt qua kidm nghiem cd the khing<br /> 30% eho ddn pH = 7. Dimg binh ling gan thu dinh san phim tdng hgp la acid 3-pyridylacetic<br /> liy Idp tren rdi rira bing 50 ml ethanol tuyet ddi hydroclorid va da tinh khidt.<br /> de loai mudi Na2S04 bao hoa, lpe qua phdu K§t luan<br /> Buchner, thu liy djeh Ipc. Ldp dudi duge ehidt 4 Tii' nhii'ng nguyen lieu re tidn, dd kidm d Viet<br /> l i n vdi elerpfprm, mdi lin 50 ml. Tay mau djeh Nam nhu aeid nicotinic, ethanol, morpholin...<br /> chidt cloroform bing than boat, Ipe qua phdu ehiing tdi da tdng hgp duge aeid 3-pyridylaeetie<br /> Buchner thu liy dieh. Cd quay djch Ipc loai hydroclorid mdt nguyen lieu c i n thidt cho tdng hgp<br /> ethanol va cloroform thu duge 3-aeetylpyridin, natri nsedronat mdt thude chdng loang xuang phd<br /> Hieu suit 86.23%. bidn. Qui trinh didu chd 3-pyridylaeetie hydr :lorid<br /> <br /> 36 TAPCHl DUOC HOC-3/2011 (SO 419 N ;i)<br />  Nghien CLFU - Ky thuat<br /> da dugc tdi uu hda vi thd dn djnh, dan gian phu xugng - Nguyen nhan, chan doan, dieu tri va phong<br /> hgp vdi didu kien Viet Nam, ngua. NXB Y bgc Tp. HCM, (2007).<br /> 3. Tavhare M. Ankush et al. Novel process for<br /> Summary<br /> preparing risedronic acid US Pafenf 0121066 (2010).<br /> 3-pyridylacetic hydrochloride acid, an<br /> 4. Lorenzo De Ferra; Stefano Turchetta:<br /> important material for synthesis of PietroMassardo. Preparation of bisphosptionic acid,<br /> antiosteomalacia drug sodium risedronat, was USpatent 0288509 (2005).<br /> synthesized from comonly and cheaply avaible 5. Balasubramaniam; Ravisanka. Improved<br /> materials such as nicotinic aeid, ethanol, process for the preparation of risedronate sodium<br /> morpholin.... The synthetic process was hemipentahydrate. WO patent 034580 (2009)<br /> successfully optimized for stability, simplicity to 6. Yun Gen Tu, Zheng Yong Weng. De Chuan<br /> Weng, Ren Yu Xu. Xia Yin, Wei Yi Hua, A method of<br /> be suitable for domestic praration. preparation of 3-pyridylacetic acid hydrochlorid.<br /> Tai lieu tham khao Ch/nese Patent 03112631.6 (2003).<br /> 1, Sean C Sweetman, Martindale the complete 7. Zhao, Y. W. Tang, L. Q. Meng, Z. L. Wang. D.<br /> drug reference. Pharmaceutical Press, 36th edition F, Synthesis of 3-pyridine acetic acid hydrochloride,<br /> (2009), pp,1103-1104 Chinese Joumal Of Pharmaceuticals, (2002), vol. 33;<br /> 2. Nguyen Van Tuan, Nguyin Dinh Nguyen. Loang Part 9. p, 427,<br /> <br /> <br /> <br /> r<br /> <br /> Phan lap va xac dinh cau true quercitrin va<br /> afzelin tir cay tam gm - Taxillus chinensis<br /> r<br /> <br /> (DC) Dans. - song tren cay gao Vu Xuan Giang', Pham Thanh Ky', Phan Van Kiem^<br /> Trirang Dgi hgc Dirge Ha Ngi<br /> ^ Vien Hoa hgc cdc hgp chdt thien nhien<br /> <br /> Oat van de Nguyen lieu va phu'cyng phap<br /> Tim giri cd nhidu loai va la nhirng eay nhd nghien cicu<br /> sdng ky sinh tren nhidu cay chu khac nhau, T i m Nguyen lieu<br /> giri sdng tren cay dau (Tang ky sinh) duge ghi T i m giri sdng tren eay gao dugc thu hai vao<br /> trong Dugc Didn Viet Nam - 4 ''' cd tae dung bd thang 7-2007 tai Phii Thg. M i u nghien eiru da<br /> can than, manh gan xuang, thdng kinh lae, an dugc GS.TSKH Nguyen NghTa Thin - Khoa<br /> thai, Chil tri: dau lung, nhirc xuang khdp, dau sinh hdc Oai hpe qudc gia Ha Ndi djnh ten khoa<br /> thin kinh n'goai bien, phu nir ddng thai, it sii'a hpc la: Taxillus chinensis (DC) Dans -<br /> sau khi de, Treng Tii' didn eay thude eiia Vd Van Lpranthaeeae.<br /> Phu'O'ng phap nghien cu'u<br /> Chi '^' ghi: canh. la leai Taxillus chinensis (DC)<br /> - s i e ky ldp mdng: Diing ban mdng silicagel<br /> Dans, cd avicularin va quercetin. De gdp phin<br /> GF254 (Merck) da trang s i n . Khai trien trong he<br /> tim hidu thanh phin hda hpc trong loai t i m giri<br /> dung mdi: Toluen - Ethylacetat - acid formic -<br /> sdng tren eay gao, chiing tdi da tidn hanh ehidt<br /> H 2 0 [ 6 : 5 : 1,5: 1]<br /> xuit va phan lap cac hgp chit treng eay, Bai<br /> Quan sat ban s i e ky dudi den tir ngoai d<br /> bao nay thdng bao kdt qua phan lap va xac djnh bude sdng 254nm va 365nm. phun hien mau<br /> ciu triie hda hpc 2 flavpnpid: Quercitrin va bing aeid H2SO410% trong ethanol (TT) rdi s i y<br /> afzelin. ndng eho hien mau.<br /> <br /> <br /> T.APCHI DUOC HOC-3/2011 (S6419NA1V151) 37<br />