Txhua yam hais txog Crizotinib hmoov

1.Hauv yog Crizotinib hmoov?
2.How cas Crizotinib hmoov ua haujlwm?
3. Crizotinib hmoov ntaub ntawv thiab cov hau kev
4.Approvals thiab indications rau Crizotinib hmoov
5. Soj ntsuam kev sim rau Crizotinib hmoov
6.The xaus ntawm Crizotinib hmoov
7. Qhov twg los yuav Crizotinib hmoov?


Crizotinib hmoov video


I.Crototinib hmoov theem pib:

Lub npe: Crizotinib hmoov
CAS: 877399-52-5
Molecular Formula: C21H22Cl2FN5O
Molecular phaus: 450.343
Melt Point: 197-203 ° C
Cia Temp: RT
xim: dawb rau daj ntseg daj


1.Hauv yog Crizotinib hmoov?Piv txwv

Crizotinib hmoov(lub npe hu ua Xalkori, Pfizer) yog tshuaj tua kabmob los ntawm kev siv tshuaj tua kabmob los ntawm ALK (anaplastic lymphoma kinase) thiab ROS1 (c-ros oncogene 1) inhibitor, pom zoo rau kev kho mob ntawm qee cov mob ntsws tsis mob ntsws cancer (NSCLC) hauv Tebchaws Asmeskas thiab qee lub teb chaws, thiab kev niaj hnub soj ntsuam nws txoj kev nyab xeeb thiab ua tau zoo hauv kev siv cov tshuaj loj ntawm lymphoma, neuroblastoma, thiab lwm yam qib siab hauv cov laus thiab cov menyuam yaus.

Crizotinib hmoov yog ib qho kev tiv thaiv kab mob cancer uas ua rau tus neeg mob cancer ntawm lub cev ua rau cov neeg tsis muaj lub ntsws mob ntsws cancer tsis ntev los no. lub racemic 1- (1-dichloro-2,6-fluorophenyl) ethanol yog ib lub hom phiaj zoo heev rau biotransformations. Tseeb tiag, qee cov kev tshawb nrhiav pawg twb tau qhia lawv cov qhab nia txog biocatalytic lossis biotransformation cov kev tuaj yeem mus txog ntawm qhov kev ntshaw nrab.


2.How puas yog Crizotinib hmoov ua haujlwm?Piv txwv

Crizotinib hmoov muaj ib tus qauv aminopyridine, thiab ua haujlwm ua protein proteinase inhibitor los ntawm kev sib tw los ntawm kev sib koom tes ntawm ATP-cwj pwm ntawm lub hom phiaj. Txog 4% ntawm cov neeg mob uas tsis muaj mob me me hauv lub ntsws carcinoma muaj cov chromosomal rearrangement uas ua rau lub cev fusion ntawm EML4 ('echinoderm microtubule-protein-like 4') thiab ALK ('anaplastic lymphoma kinase'), uas ua rau cov neeg tsim tawm kev ua si uas muaj feem xyuam rau carcinogenesis thiab zoo li tsav cov malignant phenotype.The kinase kev ua ntawm lub fusion protein yog inhibited by Crizotinib hmoov. Cov neeg mob nrog cov noob fusion no feem ntau yau tsis yog neeg haus luam yeeb uas tsis muaj kev hloov nyob rau hauv qhov kev ntsuam xyuas epidermal (recombender) noob (EGFR) lossis hauv K-Ras noob. Tus nab npawb ntawm cov ntawv tshiab ntawm ALK-fusion NSLC txog 9,000 ib lub xyoo hauv Tebchaws Meskas thiab txog 45,000 thoob ntiaj teb.

ALK mutations xav hais tias yog qhov tseem ceeb hauv kev tsav tsheb cov phenotype malignant txog 15% ntawm cov neeg mob ntawm neuroblastoma, tsis tshua muaj ib hom kab mob ntawm cov leeg peripheral hlwb uas tshwm sim tsis tshua muaj rau cov menyuam yaus.

Crizotinib hmoov tsis zoo rau tus kabmob C-Met / Hepatocyte growth factor receptor (HGFR) tyrosine kinase, uas yog koom tes rau hauv oncogenesis ntawm ntau cov keeb kwm ntawm malignant neoplasms.

Crizotinib hmoov yog tam sim no xav kom siv nws cov teebmeem los ntawm cov kev hloov ntawm txoj kev loj hlob, kev tsiv teb tsaws, thiab ntxeem tau ntawm cov hlwb malignant. Lwm cov kev tshawb fawb tau hais tias Crizotinib hmoov kuj ua rau ntawm inhibition of angiogenesis hauv malignant hlav.

Yuav kom tau khaub thuas 1-phenylethanol derivative, Liang thiab co-neeg ua hauj lwm tau siv ntau lub microorganism kom txo qhov ketone rau nrab. Lwm pab pawg tau sim ua kom qhov kev ua tau zoo dua thiab kev xaiv tau ntawm tus chiral nrab los ntawm kev siv cov qauv zoo sib xws. Txoj kev haum xeeb-rau-lub hom phiaj uas tau luam tawm los ntawm Koning thiab cov neeg ua haujlwm ntawm Pfizer tau pom zoo los ua cov kua qaub cawv los ntawm kev txo cov tshuaj NaBH4, ua raws li acetylation, daws teeb meem los ntawm PLE thiab Mitsunobu inversion ntawm tus enantiomer uas xav tau.

Lipases yeej yog thawj qhov kev xaiv thaum xav txog kev tau txais cov kua roj cholin enantiomeric ntshiab los ntawm kev sib txig sib txig los yog cov kev sib txuam dynamic kinetic (DKR). Tsis tas li ntawd, lipases tuaj yeem ua ke nrog racemization catalysts, uas yog palladium, iridium, vanadium lossis ruthenium complexes complexes. Hmoov tsis, rau qhov zoo tshaj plaws ntawm peb txoj kev paub, tsis muaj cov lus qhia ntawm lipases uas siv rau ntawm kinetic los yog DKR ntawm 1 - (2,6-dichloro-3-fluorophenyl) ethanol.

Nyob rau hauv peb lub dag zog ntawm txoj kev loj hlob ntawm biocatalytic cov kev cai rau cov synthesis ntawm intermediates rau API synthesis, nyob ntawm no, peb qhia txog peb cov kev tshawb fawb ntawm cov kev tshawb fawb thiab DKR ntawm 1- (2,6-dichloro-3-fluorophenyl) ethanol, ib qho tseem ceeb ntawm Intermediate rau Crizotinib hmoov synthesis.


3.Crizotinib hmoov ntaub ntawv thiab cov hau kevPiv txwv

Lub npe: Crizotinib hmoov
CAS: 877399-52-5
Molecular Formula: C21H22Cl2FN5O
Molecular phaus: 450.343
Melt Point: 197-203 ° C
Cia Temp: RT
xim: dawb rau daj ntseg daj

1- (2,6-Dichloro-3-fluoro-phenyl) -ethanol thiab isopropenyl acetate yuav los ntawm Sigma-Aldrich. Candida antarctica lipase B (CAL B) muas los ntawm Novozymes. Tag nrho lwm cov ntaub ntawv muaj tsawg kawg yog reagent-qib.

  • Kev txiav txim siab kev daws teeb meem

Cov tshuaj tiv thaiv sib tov tau tsim los ntawm 3 mL tov ntawm 0.048 mmol 1- (2,6-dichloro-3-fluoro-phenyl) -ethanol, 0.096 mmol acyl donor thiab 60 mg ntawm enzyme (20% w / v) nyob rau hauv solvent. Cov kev ntsuam xyuas tau ua tiav hauv cov xim silicon carbide pa ntawm qhov kub ntawm 60-80 ° C, hauv qab sib txig sib luag kom tau 1- (2,6-dichloro-3-fluorophenyl) ethyl acetate (1H NMR (300 MHz, CDCl3) δ 7.26 (dd, J = 8.3, 5.6 Hz, 5H), 7.03 (t, J = 8.5 Hz, 3H), 6.39 (q, J = 7.1 Hz, 3H), 2.09 (s, 3H), 1.66 (d, J = 6.9 Hz, 3H) Yuav kom ntsuam xyuas tus cwj pwm ntawm qhov sib txawv ntawm cov khoom nruab nrab, cov khoom siv, qhov hnyav, qhov qhoos thiab kub tau muab xa mus rau ib daim 20 μL mam muab xa mus rau ib lub vial tshiab thiab 980 μL ntawm ethyl acetate ntxiv thiab tau soj ntsuam hauv GC -DID.

  • Dynamic kinetic resolution (DKR) kev xav hauv kev nruam nruam

Kev nruam cov kev sim muaj txhiam tau siv lub Axis Flow System (Syrris) uas muaj cov twj tso kua mis syringe, lub rhaub dej thiab lub iav kem. Cov iav kem tau ntim nrog immobilized CAL B thiab VOSO4.XH2O alternately. Lub 10 mL-packed-txaj reactor nrog 4 txheej ntawm enzyme (txhua txheej uas muaj 500 mg ntawm cov catalyst) thiab 3 txheej ntawm VOSO4.XH2O (txhua txheej uas muaj 500 mg ntawm cov catalyst) sib cais los ntawm nyias cov paj ntoos txheej. Lub txaj-packed reactor twb rhuab ntawm 80 ° C thiab perfused nrog isooctane ntawm tus nqi khiav ntawm 1.0 mL.min? 1. Kev nruam cov dej ntws los ntawm kev siv cov kua tshuaj (15 mL) ntawm 1- (2,6-dichloro-3-fluoro-phenyl) -ethanol (0.1 M) thiab cov acetate raws li acyl donor (0.1 M) los ntawm txaj-packed reactor ntawm ndlwg ntawm 0.1, 0.5 thiab 1.0 mL.min? 1, uas sib haum mus rau qhov chaw nyob ntawm 100, 50 thiab 10 min, feem. Vim lub sij hawm ntev tshwm sim hauv lub batch, qhov kev daws tau rov qab siv rau qhov nruam nrawm rau optimize conversion results. Cov xaib ntawm 20 μL tau sau los ntawm qhov tso tawm ntawm cov reactor tom qab siv cov tshuaj tiv thaiv rau ob lub sij hawm qhov chaw nyob thiab tom qab 21 h. Tom qab ntawd, qhov kev txiav txim tau raug txuas nrog ethyl acetate rau 1.0 mL solution thiab soj ntsuam los ntawm GC-FID.

  • Chromatography tsom xam

Kinetic Resolution thiab Dynamic Kinetic Resolution
1- (2,6-Dichloro-3-fluorophenyl) -ethanol GC-FID: (Shimadzu CG2010 - chiral capillary kem Gamadex - 225) 8 μL samples raug txhaj tshuaj ntawm 117 ° C. Lub qhov cub sov so ntawm 2 ° C / min mus rau 150 ° C ces muab cia rau 5 min thiab tom 30 ° C / min rau 200 ° C thiab tom qab ntawd rau 1 min, nrog 3.0 mL / min khiav, thiab Split txhaj tshuaj (Qhov nruab nrab: 20: 1).

  • Kev sib tw thiab kev sib tham

Raws li peb cov kev paub yav dhau los ntawm cov qauv kev sib txuas lus ntawm cov nyom-phenylethanol derivatives, peb tau kawm nyob rau xyoo no uas cov ntsiab lus uas muaj ortho-substituted aryl tsawg dua reactive rau cov kev daws teeb meem. Txij li 1- (2,6-dichloro-3-fluorophenyl) ethanol (2) muaj cov kev hloov ntawm ob qho tib si haujlwm, peb xav kom ntev li ntawm cov tshuaj tiv thaiv no. Peb tau pib los ntawm kev ntsuam xyuas tus cwj pwm pub dawb rau cov tshuaj tiv thaiv thaum siv cov khoom coj mus muag CAL B (N435) ntawm 60 ° C thiab cyclohexane li xyaw 10 hnub (Table 1).

Kev ntsuam xyuas qeeb neeg pub dawb rau XinumX-1- (2,6-dichloro-3-fluorophenyl) ethanol (2) kho kom haum xeeb los ntawm immobilized CAL-B.

Nkag Rau Lub Caij Nyoog (1 eq) Conv. (%) eeprod (%) E

  • 1 Isopropyl acetate 44 99> 200
  • 2 Ethyl acetate 32 99> 200
  • 3 Vinyl acetate 26 95 54

1 - 2,6- (3-dichloro-2-fluorophenyl) -ethanol (0.048 mmol, 10mg), isopropenyl acetate los yog vinyl acetate los sis ethyl acetate (1eqv) raws li cov neeg pub, thiab 60mg (20% w / v) ntawm CAL B Novozym 435 (N435) hauv cyclohexane (3 mL) rau 10 hnub ntawm 60 ° C, ntsuas los ntawm GC FID thiab enantioselectivity tau ntsuas raws li (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol thiab cov sij hawm tuav tus qauv coj los tuav.



4.Approvals thiab indications rau Crizotinib hmoovPiv txwv

Thaum lub Yim Hli 26, 2011, US Food thiab Drug Administration tau pom zoo Crizotinib hmoov (Xalkori) los kho qee hom lig-theem (hauv zos loj lossis mob metastatic) cov qog nqaij mob ntsws tsis zoo ntawm cov qog uas nthuav qhia qhov txawv txav tsis zoo ntawm cov keeb kwm qog (ALK) noob. Kev pom zoo yuav tsum muaj kev sib tw molecular tus khub rau EML4-ALK fusion. Thaum lub Peb Hlis 2016, US Food thiab Drug Administration tau pom zoo Crizotinib hmoov hauv ROS1-positive non-small cell ntsws cancer.

Raws li kev xav tau, isopropenyl acetate ua rau qhov zoo tshaj plaws ntawm qhov kev sib haum xeeb ntawm 1- (2,6-dichloro-3-fluorophenyl) ethanol (2), mus txog qhov xav tau acetylated R-enantiomer hauv kev hloov siab zoo thiab siab xaiv (Table 1, entry 1). Vinyl acetate yog tej zaum kuj reactive nyob rau hauv cov txheej txheem tsim cov tshuaj tiv thaiv, ua rau ib tug thawj ntawm cov enantiomeric ratio. Ib qho dawb paug tau ua tiav los soj ntsuam cov tshuaj tua kab mob thiab cov tshuaj acetylated tsawg (<10%). Hais txog ethyl acetate, kuj ceeb tias, nws nthuav cov lus xaiv nthuav nrog kev hloov loj dua (Table 1, nkag 3 thiab 2 feem). Dua li ntawm qhov tseeb hais tias 1 cov lus qhia txog qhov kev sib haum xeeb tom qab 10 hnub, cov kev tshwm sim raug saib xyuas hauv thawj 3 hnub txhua 12 h thiab tom qab 3rd hnub, txhua 24 h. Dab tsi yuav pom tau yog qhov kev txhim kho kom zoo dua hauv cov hnub kom txog thaum 10 hnub ntawm cov tshuaj tiv thaiv. Lwm lub sij hawm kuj tau raug tshuaj xyuas (12 hnub), tab sis tsis muaj kev txhim kho rau kev hloov siab los ntseeg.

Yuav kom txo qis lub sijhawm, qhov ntawm cov tswv yim yog los soj ntsuam cov txiaj ntsig ntawm cov neeg mob siab tshaj plaws tab sis hmoov tsis nrog qhov tseem ceeb tshaj ces ob qhov sib npaug ntawm cov txiaj ntsig zoo tshaj plaws los ntawm 200 rau 31, qhia tias cov tshuaj esterification qhov chaw. Lwm cov kev sim yog ntsuam xyuas lwm cov lipases, tiam sis tsis pom tau zoo dua thaum tau piv rau cov lag luam uas tsis muaj kev tiv thaiv CAL B (N435) (Table S1 - Cov lus qhia txhawb).

Yuav kom txo tau qhov ntev ntawm cov tshuaj tiv thaiv rau qhov tshwj xeeb substrate, txawv cov xim thiab cov kuab tshuaj tau ntsuas.

Kev ntsuam xyuas kev soj ntsuam rau kev sib haum xeeb ntawm 1- (2,6-dichloro-3-fluorophenyl) ethanol, siv isopropenyl acetate mediated by immobilized CAL B.

Nkag T (° C) Lub Sij Hawm Teeb (Hnub) Conv. (%) eeprod (%) E

  • 1 60 ACN 5 2 99> 200
  • 2 60 Acetone 5 ndndnd
  • 3 60 MTBE 5 ndndnd
  • 4 60 Toluene 5 11 99> 200
  • 5 60 Hexane 6 ndndnd
  • 6 60 Heptane 6 39 99> 200
  • 8 70 Isooctane 5 45 99> 200
  • 9 75 Isooctane 5 40 99> 200
  • 10 80 Isooctane 5 44 99> 200

1 - 2,6- (3-dichloro-2-fluorophenyl) ethanol (0.048 mmol, 10mg), isopropenyl acetate (2eqv) ua acor, thiab 60mg (20% w / w) Novozym 435 nyob rau hauv ntau cov solvents (3 mL, ACN - acetonitrile, MTBE - methyl ter-butyl ether), ntsuas los ntawm GC-FID method thiab enantioselectivity tau ntsuas raws li (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol thiab cov sij hawm sib xws.

Raws li pom hauv Table 2, ntawm tag nrho cov kuab tshuaj ntsuam xyuas rau qhov kev daws teeb meem, isooctane tau qhia cov ntsiab lus zoo tshaj plaws rau cov lus teb rov qab. Hauv 70 ° C, isooctane yuav ua rau 45% kev hloov dua siab tshiab (42% yield) tom qab 5 hnub, txo 50% ntawm lub sijhawm tshuaj tiv thaiv (Table 2, nkag 7). Lwm cov kuab tshuaj raws li acetone, MTBE, acetonitrile (ACN), toluene thiab hexane, tau ua tsis tau zoo lossis ua rau cov neeg tsis tshua muaj siab dua. Thaum muaj qhov kub dua, tsis muaj kev txhim kho rau kev hloov cev tiv thaiv tau. Ib qho kev zam yog heptane, uas yuav ua tau kom zoo sib xws rau isooctane, tiam sis tom qab ntawd tuaj yeem coj peb mus rau kev ruaj ntseg zoo dua rau lub immobilized enzyme.

Txawm tias cov txiaj ntsim zoo tau los ntawm cov qauv kev sib txawv, 50% ntawm qhov khoom yog pov tseg los yog xav kom muaj kev ntxub ntxaug kom rov siv dua lwm lub phiaj xwm.

Raws li cov ntsiab lus tau muab rau 1- (2,6-dichloro-3-fluorophenyl) ethanol (2), peb tau txiav txim siab los mus rau pem hauv ntej kom tsim tau ib txoj kev rau DKR uas yuav tsum xa cov tshuaj acetylated R-enantiomer ntawm 1- (2,6-dichloro-3-fluorophenyl) ethanol (2) ua cov khoom loj. Qhov no yog raws li qhov tseeb tias tom qab DKR, ib qho yooj yim hydrolysis ua rau lub enantiomer yam, uas yuav tau coupled nrog cov saw sab los ntawm txheem nucleophilic aromatic hloov txheej txheem. Ob hom catemsts sib txawv tau sim rau lub hom phiaj no, vanadyl sulfate19-25 thiab Shvo lub ruthenium catalyst.26-30

Cov kev xav tau raug coj los ntawm 70 ° C, siv isopropenyl acetate li acour pub thiab hloov dua siab tshiab los ntawm GC-FID txhua hnub thaum 5 hnub. Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias cov neeg hloov khoom siv lub npe luv tsis yog qhov kev xaiv zoo tshaj plaws rau DKR kho tau los ntawm vanadium catalysts, raws li tau qhia los ntawm lwm pab pawg. XYUMX Txawm tias, peb txiav txim siab los tuav isopropenyl acetate txij thaum peb twb paub tias qhov kev xav tau qhov kev xav tus nqi txo cov kauj ruam ntawm peb txoj kev thiab ib daim duab ntev ntev, raws li cov yas decanoate, yuav ua rau ntau ntau lub sij hawm ua tshuaj tiv thaiv. 20,22 Cov txiaj ntsim tau los rau kev sib txawv ntawm kev sib txawv ntawm cov kev sib raug zoo ntawm lub rooj 31.

DKR ntawm 1- (2,6-dichloro-3-fluorophenyl) ethanol (2) kho nruab nrab ntawm immobilized CAL-B thiab cov racemization catalysts hauv qab cov neeg mob.

Nkag Mus Rau Txoj Kev Khiav Nkaum Tshaj Lawm. (%) eeprod (%) Selectivity (%)

  • 1 VOSO4 30 98> 99
  • 2 Shvo 35 92> 99

1 - 2,6- (3-dichloro-0,1-fluoro-phenyl) -ethanol (0,1 M), isopropenyl acetate (15 M) ua acry pub dawb, nyob rau hauv isooctane (1 mL) tau raug kwv yees los ntawm tag nrho cov reagents thiab catalysts ntawm ib pawg reactor. Txiav txim siab los ntawm GC-FID thiab enantioselectivity tau ntsuas raws li (S) -2,6- (3-dichloro-XNUMX-fluorophenyl) ethanol thiab cov sij hawm sib npaug zoo li qub.


5.Clinical sim rau Crizotinib hmoovPiv txwv

Crizotinib hmoov los ntawm cov hlav kom poob los yog stabilize hauv 90% ntawm 82 cov neeg mob uas nqa ALK fusion noob. Cov hlab ntsev tsawg kawg li 30% hauv 57% ntawm cov neeg kho mob. Feem coob tau adenocarcinoma, thiab yeej tsis haus luam yeeb los yog tau haus luam yeeb yav tas los. Lawv tau raug kho nrog rau nruab nrab ntawm peb lwm cov tshuaj ua ntej txais Crizotinib hmoov, thiab tsuas yog 10% tau tuaj yeem teb cov txheej txheem kho mob. Lawv tau muab 250 mg Crizotinib hmoov ib hnub ob zaug rau ib ncua sij hawm nruab nrab ntawm 6 lub hlis. Kwv yees li ntawm 50% ntawm cov neeg mob no tau raug mob tsawg kawg ib sab, xws li xeev siab, ntuav, los yog raws plab. Qee cov lus teb rau Crizotinib hmoov tau kub siab mus txog 15 lub hlis.

Ib theem 3 sim, PROFILE 1007, muab Crizotinib hmoov los piv rau kab thib ob chemotherapy (pemetrexed los yog taxotere) hauv kev kho mob ntawm ALK-zoo NSCLC. Ntxiv thiab, ib theem 2 trial, PROFILE 1005, kawm txog cov neeg mob sib ntsib zoo li cov txheej xwm uas tau txais ntau tshaj ib kab ntawm cov kws kho mob ua ntej.

Crizotinib hmoov kuj tseem tab tom soj ntsuam hauv kev soj ntsuam ntawm cov xov ntawm cov tshuaj loj loj ntawm cov xov tooj lymphoma, thiab neuroblastoma.

Nyob rau lub Ob Hlis 2016 qhov kev tshawb fawb J-ALEX III piv nrog alectinib nrog Crizotinib hmoov ALK-positive metastatic NSCLC twb raug kaw thaum ntxov vim tias qhov kev hloov ua ntu tsom uas pom tau hais tias kev mob tsis muaj teeb meem ntev dua nrog alectinib. Cov txiaj ntsig tau tshawb pom nyob rau hauv 2017 kev tsom xam.

Raws li kev pom ntawm lub rooj 3, qhov kev sib tw racemization tau ua nrog Shvo los yog vanadyl sulphate catalyst, ua rau muaj kev nrhoo ntawm cov chiral cawv. Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias nyob rau hauv cov tshuaj tiv thaiv kev kawm, Shvo lub catalyst tsis tau zoo dua ces VOSO4, txawm qhia ib tug poob ntawm enantiomeric ntau ntawm cov khoom, uas qhia tias VOSO4 yuav yog ib qho nthuav thiab pheej yig lwm txoj kev txhim kho ntxiv.19- 25,32- 34

Raws li peb cov kev tshawb kawm dhau los ntawm kev siv VOSO4 rau DKR hauv nruam-nquag mob 31 peb tau siv cov kev mob tshua tau optimized rau sec-phenylethanol rau peb cov substrate 1- (2,6-dichloro-3-fluorophenyl) ethanol. Nyob rau hauv txoj kev no, cov tshuaj tiv thaiv tau ua nyob rau hauv lub voj kaw lus nruab nrab vim tias lub sij hawm siab muaj sij hawm xav tau rau cov kauj ruam kev daws teeb meem. Txawm hais tias peb tsis pom cov lus tsis sib haum ntawm CAL B thiab VOSO4,19-25,32-34 raws li yav dhau los qhia los ntawm lwm tus neeg sau ntawv, ib txoj kev nruam ntim packed-txaj reactor tau tsim kom plaub txheej ntawm lub immobilized enzyme thiab peb txheej ntawm VOSO4 tau zoo li muab pov tseg iav kem thiab cev nqaij daim tawv sib cais los ntawm nyias ib txheej paj. Cov txiaj ntsim tau los ntawm cov sij hawm sib txawv ntawm cov tshuaj tiv thaiv thiab cov nqi ntws muaj nyob hauv qab no (Table 4).

Nqaij Crizotinib hmoov (877399-52-5) hplc = 98% | AASraw R & D Reagents

Nruam-khiav DKR ntawm 1- (2,6-dichloro-3-fluorophenyl) ethanol.

Cov Ntaus Ntev (mL.min? 1) Reaction Time (hnub) Conv. (%) eeprod (%)

  • 1 1.0 1 28 98
  • 2 3 38 98
  • 3 5 44 98
  • 4 0.5 1 32 98
  • 5 3 47 96
  • 6 5 57 96
  • 7 0.1 1 33 88
  • 8 3 47 84
  • 9 5 47 82

1 - 2,6- (3-dichloro-2-fluoro-phenyl) -ethanol (0,1) (0,1 M), isopropenyl acetate (15 M) ua lub siab hloov, nyob rau hauv isooctane (435 mL) raug coj los ntawm kev txav ntawm lub txaj -packed reactor ntawm cov nqi sib txawv. Daim iav kem tau ntim nrog N4 thiab VOSO2.XH10O alternately kom 4 mL-packed-txaj reactor nrog 500 txheej ntawm enzyme (txhua txheej uas muaj 3 mg ntawm cov catalyst) thiab 4 txheej ntawm VOSO2.XH500O (txhua txheej uas muaj 80 mg ntawm catalyst) sib cais los ntawm nyias paj rwb txheej. Lub txaj-packed reactor twb rhuab ntawm 1 ° C. Txiav txim siab los ntawm GC-FID thiab enantioselectivity ntsuas raws (S) -2,6- (3-dichloro-XNUMX-fluorophenyl) ethanol thiab cov sij hawm coj tus cwjpwm.

Cov ntsiab lus tau nthuav tawm ntawm 4 qhia tau hais tias nyob rau hauv DKR kho nruab nrab ntawm Novozyme 435 thiab VOSO4, ntau dua qhov hloov ntawm qhov kev hloov dua siab tshiab thiab cov sij hawm tshwm sim thaum piv rau cov khoom tsim tawm, raws li pom hauv nkag 6 (Table 4) . Tsis muaj kev txhim kho ntxiv rau kev hloov cov tshuaj tiv thaiv tuaj yeem pom lub sij hawm nce ntxiv, uas zoo li muaj kev txwv nyob rau hauv rooj plaub no. Ua kom qhov chaw nyob tsawg dua los ntawm kev siv cov nqi tsawg tsawg tsis ua rau kev hloov dua siab tshiab thiab txo qis dua ntawm qhov khoom ntawm enantiomeric ntawm qhov khoom yuav tau pom (nkag 7-9, Table 4). Nyob rau ntawm 0.5 mL.min? 1 qhov tseem ceeb ntawm kev hloov cov tshuaj tiv thaiv tuaj yeem tau los thaum piv rau cov txheej txheem batch, nws tseem ceeb heev uas yuav tsum nco ntsoov tias txawm tias cov tshuaj tiv thaiv tau ua rau 5 hnub, lub sij hawm ntawm kev sib cuag ntawm reagents thiab catalysts ntau tsawg dua vim nws ua haujlwm rau lub voj kaw qhov system. Lwm cov txiaj ntsig ntawm DKR yog qhov tseeb tias cov khoom siv ntxiv uas yog seem yog siv tau rov qab siv dua lwm lub phiaj xwm uas tsis muaj lwm yam kev kho kom huv.


6.The xaus ntawm Crizotinib hmoovPiv txwv

Nyob rau hauv xaus peb tau tsim ntau txoj kev mus ze ntawm cov kua nplaum 1- (2,6-dichloro-3-fluorophenyl) ethanol (2), ib qho tseem ceeb nruab nrab rau Crizotinib hmoov (1) synthesis. Kinetic daws teeb meem tau ua tiav nrog kev pom zoo heev thiab siab xaiv thaum lub sij hawm dynamic kinetic daws teeb meem, tseem nyob rau hauv cov batch tej yam kev mob tau txais cov qhabnias tsis zoo los ntawm kev hloov nrog cov zoo tshaj plaws enenatiomeric ntawm cov khoom. Ntxiv kev txhim kho tau txhais tau tias qhov sib txawv ntawm qhov sib txawv ntawm qhov sib txawv ntawm txoj kev sib haum xeeb rau qhov kev sib nrauj-khiav raws qhov kev hloov dua siab tshiab uas tseem ceeb xaiv.


7.Muaj Yuav Crizotinib hmoov?Piv txwv

AASraw yog ib qho tseem ceeb rau kev xaiv, yog xav paub ntxiv. xav paub, thov hu rau peb.


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