Yonke into ngeCrizotinib powder

1.Iphi i-Crizotinib powder?
2.I-powzotinib powder isebenza njani?
3. I-Crizotinib powder Izinto zokusebenza kunye neendlela
4.Izicelo kunye nezibonakaliso zeCrizotinib powder
5. Uvavanyo lwezonyango kwiCrizotinib powder
6.Ukupheliswa kweCrizotinib powder
7. Kuphi Ukuthenga i-Crizotinib powder?


Crizotinib powder ividiyo


I.Crizotinib powder Abalinganiswa basisiseko:

igama: Crizotinib powder
CAS: 877399-52-5
I-molecular Formula: C21H22Cl2FN5O
Isisindo somzimba: 450.343
Melt Point: 197-203 ° C
Isitoreji sokugcina: RT
umbala: i-white-powder-yellow yellow powder


1.Iphi i-Crizotinib powder?aasraw

Crizotinib powder(igama lezorhwebo Xalkori, Pfizer) liyi-anti-cancer (drug-lymphoma kinase) kunye ne-ROS1 (c-ros oncogene 1) inhibitor, evunyelwe unyango lwe-cell non-small lung carcinoma (NSCLC) e-US kunye namanye amazwe, kunye nokuvavanywa kweemvavanyo zeklinikhi ukhuseleko kunye nokusebenza kwazo kwiplastiki enkulu i-lymphoma, i-neuroblastoma, kunye nezinye izicubu ezinzulu eziphambili kubantu abadala kunye nabantwana.

I-Crizotinib powder yinkampani yokulwa nomhlaza eyenza i-iplasma i-lymphoma kinase inhibitor kwaye isandul 'ukuvunyelwa kunyango lwe-cell cell non-lung carcinoma. Uhlalutyo lokubuyiswa kwelo molecule lucacile ngokucacileyo kwiibhloko ezimbini ezibalulekileyo, njengoko kuchazwe kwi-Scheme 1, I-1- (2,6-dichloro-3-fluorophenyl) i-ethanol ithagethi enomdla kakhulu kwi-biotransformations. Enyanisweni, amanye amaqela ophando sele sele echaze iziphumo zawo kwiindlela zokuhamba nge-biocatalytic okanye i-biotransformation zokufikelela kwi-middle intermediate.


2.Kwenzeka njani I-Crizotinib powder isebenza?aasraw

I-crizotinib powder inesakhiwo se-aminopyridine, kwaye isebenza njengeprotein kinase inhibitor ngokuzibophezela ngokubambisana ngaphakathi kwe-ATP-ebophezelayo ipokethi ye-target kinases. Mayelana ne-4% yezigulane ezingenanto encinci ye-cell lung carcinoma ene-chromosomal rearrangement eyenza i-gene fusion phakathi kwe-EML4 ('i-echinoderm microtubule-eneprotheni efana ne-4') kunye ne-ALK ('i-amaplastic lymphoma kinase'), eyenza i-kinase umsebenzi owenza i-carcinogenesis kwaye ibonakala iqhuba i-phenotype ebulalayo. Umsebenzi we-kinase weprotheni ye-fusion uyinqandwe yi-Crizotinib powder. Izigulane ezine-fusion fusion zifana nabancinci abangabhimiyo abangenalo utshintsho kwi-epidermal ukukhula kwegciwane le-receptor (EGFR) okanye kwi-gene-K-Ras. Amanani amatsha amatsha e-ALK-fusion NSLC malunga ne-9,000 ngonyaka e-US kunye ne-45,000 ehlabathini lonke.

Iinguqulelo ze-ALK zicingelwa ukuba zibalulekile ekuqhubeni i-phenotype enobungozi malunga ne-15% yamatyala e-neuroblastoma, uhlobo olunqabileyo lwe-peripheral yomdlavuza womnyoba olwenzeka cishe phantse kubantwana abancinci.

I-Crizotinib powder inhibisa i-c-Met / i-Hepatocyte yokukhula kwe-factor receptor (HGFR) i-tyrosine kinase, echaphazelekayo kwi-oncogenesis yezinye iindidi ze-histological ze-neoplasms ezimbi.

I-crizotinib powder okwangoku kucatshangelwe ukuba iphumeze imiphumo yayo ngokumodyuli yokukhula, ukufuduka kunye nokuhlasela kweeseli ezibi. Olunye uphando lubonisa ukuba iCrizotinib powder iyakwenza kwakhona ngokuthintela i-angiogenesis kwiimvumi ezimbi.

Ukuze uthole i-chiral 1-phenylthanol derivative, i-Liang kunye nabasebenzi basebenzisane basebenzise amancinci amancinci amaninzi ukwenzela ukunciphisa ngokuphumelelayo i-ketone ephakathi. Amanye amaqela azame ukwandisa ukusebenza kunye nokukhetha kwi-chiral ephakathi ngokusebenzisa iindlela ezifanayo. Umzila owenzela ukulungelelanisa owenziwe nguConing kunye nabasebenzi be-Pfizer bavelisa isicwangciso sokuvelisa utywala oludityanisiweyo ngokunciphisa ukuphuculwa kweNBHNUMX, kulandelwa yi-acetylation, isisombululo esisombululo nge-PLE kunye neMitsunobu ukuguquguquka kwi-enantiometer efunekayo.

I-Lipases yisoloko iyona ndlela yokuqala xa ucinga ngokufumana i-chiral alcohols ecocekileyo kakhulu enonomeric enezigqibo ezinzulu okanye i-kkinetic solution (DKR). Ukongezelela, iifases zingabandakanywa kunye neengcambu zokuhlengahlengisa, okuyi-palladium, i-iridium, i-vanadium okanye i-ruthenium complexes complexes. Ngelishwa, ukufumana ulwazi olusemandleni ethu, akukho ziphumo zeepasase ezisetyenziswe kwi-kinetic okanye kwi-DKR ye-1- (2,6-dichloro-3-fluorophenyl) ethanol.

Kwimizamo yethu eqhubekayo ekuphuhlisweni kweprotocols ze-biocatalytic zokuququzelelwa kweziphambili ze-API synthesis, apha, sichaza izifundo zethu kwi-kinetic ne-DKR ye-1- (2,6-dichloro-3-fluorophenyl) ethanol, obalulekileyo phakathi kweCrizotinib powder ukuhlanganisa.


3.Crizotinib powder Izinto zokwakha kunye neendlelaaasraw

igama: Crizotinib powder
CAS: 877399-52-5
I-molecular Formula: C21H22Cl2FN5O
Isisindo somzimba: 450.343
Melt Point: 197-203 ° C
Isitoreji sokugcina: RT
umbala: i-white-powder-yellow yellow powder

1- (2,6-Dichloro-3-fluoro-phenyl) -ethanol kunye ne-acetate ye-isopropenyl ethengiwe kwi-Sigma-Aldrich. Candida antarctica lipase B (I-CAL B) ithengwe kuNovozymes. Zonke ezinye izinto zenziwa ubuncinci bakala.

  • Impendulo yeCinetic

Umxube wokusabela wenziwa ngumxube we-3 mL we-0.048 mmol 1- (2,6-dichloro-3-fluoro-phenyl) -ethanol, 0.096 mmol acyl kunye ne-60 mg ye-enzyme (20% w / v) kwi-solvent. Ukusabela zeemvavanyo yayidlalwa lesilicon iipleyiti khabhayithi kwiqondo lobushushu of 60-80 ° C, phantsi ibangele magnetic ukufumana 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, I-3H) Ukuze ikhusele impembelelo yamacandelo asebenzayo ahlukeneyo, ama-enzyme, i-solvent, i-acyl nomnikeli kunye nobushushu bavandlakanywe. I-aliquot ye-20 ihanjiswe kwi-vial entsha kwaye i-980 μL ye-acetate ye-ethyl yongezwa kwaye yahlaziywa kwi-GC -FID.

  • Isisombululo se-Dynamic kinetic (DKR) ekuqhubeni okuqhubekayo

Uvavanyo oluqhubekayo lwaluqhutyelwa ngokusebenzisa i-Asia Flow System (i-Syrris) eyayiquka ipompo yesirinji, i-heater kunye neklasi yeglasi. Ikholomu yeglasi yayigcwele i-CAL B engenakunqandwa kunye neVOSO4.XH2O ngokunye. I-10 i-reactor-beded bedbar ne-4 izitha ze-enzyme (uluhlu ngalunye oluqukethe i-500 mg ye-catalyst) kunye neendlela ze-3 ze-VOSO4.XH2O (uluhlu ngalunye oluqukethe i-500 mg ye-catalyst) ehlukaniswe ngamacwecwe amaconti amancinci atholakala. I-reactor-packed reactor yafuthelwa kwi-80 ° C kwaye yaqhutyiswa nge-isooctane kwisantya sokuhamba kwe-1.0 mL.min? 1. reactions flow Continuous bathwalwa ngaphandle afakwe isisombululo isooctane (15 ml) of 1- (2,6-dichloro-3-fluoro-phenyl) -ethanol (0.1 M) kunye IVinyl acetate njengoko acyl zomzimba (0.1 M) ngokusebenzisa kwebhedi-ezise- i-reactor inqanaba le-0.1, i-0.5 ne-1.0 mL.min? i-1, ehambelana namaxesha okuhlala kwe-100, i-50 kunye ne-10 min, ngokulandelanayo. Ngenxa yexesha elide lokuphendula kwi-batch, isisombululo saphinda senziwa kwakhona kwi-flow flow ukuze kulungiswe iziphumo zokuguqulwa. Ii-aliquots ze-20 μL zaqokelelwa kwimveliso ye-reactor emva kokupompa isisombululo sempendulo ngokuphindwe kabini ixesha lokuhlala nangemva kwe21 h. Emva koko, i-aliquots yahlanjululwa nge-ethyl acetate kwi-1.0 mL isisombululo kwaye yahlaziywa yi-GC-FID.

  • Uhlalutyo lweChromatography

Isisombululo seKinetic kunye nesisombululo seDynamic Kinetic
I-1- (2,6-Dichloro-3-fluorophenyl) -ethanol GC-FID: (Shimadzu CG2010 - ikholam ye-caprary capade Gamadex - 225) Iisampuli ze-8 μL zafakwa kwi-117 ° C. I-oven yatshiswa ku-2 ° C / min ukuya kwi-150 ° C kwaye igcinwa nge-5 min kunye ne-30 ° C / min ukuya kwi-200 ° C ize igcinwe nge-1 min, kunye nokuhamba kwe-3.0 mL / min, kunye ne-Injection split mode (Ukulinganisa: 20: 1).

  • Iziphumo kunye neengxoxo

Ngokusekelwe kwimeko yethu yangaphambili kwiinqununu ze-kinetic ze-phenylethanol derivatives, esiye safunda kule minyaka i-ortho-substituted aryl alcohols ayisebenzisekanga kakhulu kwisisombululo sekinetic. Ekubeni i-1- (2,6-dichloro-3-fluorophenyl) ethanol (i-2) iqulethe indawo endaweni zombini i-ortho isikhundla, sasilindele ixesha elide lokusabela kule nguqulelo. Siye saqala ngokuphonononga impembelelo yomnikeli we-acyl kwimiphumo yokusabela xa usebenzisa i-CAL B (N435) engenakucatshulwa kwezoshishino kwi-60 ° C kunye ne-cyclohexane njengesixazululo seentsuku ze-10 (iThebhile 1).

I-Acyl yokuvavanya i-kinetic isisombululo se-1- (2,6-dichloro-3-fluorophenyl) ethanol (i-2) idibaniswa yi-CAL-B engenakunyuswa.

Ukungena kwe-Acyl Umnikeli (1 eq) Conv. (%) eeprod (%) E

  • 1 I-acetate ye-Isopropenyl 44 99> 200
  • 2 i-acetate ye-ethyl 32 99> 200
  • 3 i-acetate ye-Vinyl 26 95 54

Izimo zokuphendula: 1- (2,6-dichloro-3-fluorophenyl) -ethanol (2) (0.048 mmol, 10mg), i-acetate ye-isopropenyl okanye i-acetate ye-vinyl okanye i-acetate ye-ethyl (1eqv) njenge-acyl donor, kunye ne-60mg (20% w / v) of Cal B Novozym 435 (N435) e cyclohexane (3 ml) iintsuku 10 kwi 60 ° C, kulinganiswa GC-Fid indlela kunye enantioselectivity lalibalwa ngokusekelwe (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol kunye nezihlandlo zokulinda ester ezifanayo.



4.Izicelo kunye nezibonakaliso zeCrizotinib powderaasraw

Ngo-Agasti 26, i-2011, i-US Food and Drug Administration ivunyelwe i-Crizotinib powder (Xalkori) ukunyanga i-lateral-stage (iindawo ezisekuhlaleni okanye ezenziwe ngamatriki) ezingekho ezincinci zamanqamzana emiphunga e-pulmenti ezichaza i-gene kliniki ye-lymphoma kinase (ALK) engavamile. Ukuvunyelwa kufuneke umlingane wokuhlola i-molecular for the fusion EML4-ALK. Ngo-Matshi i-2016, i-US Food and Drug Administration ivunyiwe i-Crizotinib powder kwi-ROS1-positive engenomncinci wesifo somhlaza wamaphaphu.

Njengoko kulindelekile, isopropenyl acetate kukhokelela kwiziphumo best ukusonjululwa entshukumo of 1- (2,6-dichloro-3-fluorophenyl) ethanol (2), bafike kwi ezinqwenelekayo acetylated R-enantiomer in ngokuguqulwa elungileyo kunye selectivity ophezulu (Table 1, ungeno 1). I-acetate ye-vinyl mhlawumbi iphinde iphumelele phantsi kweemeko zokusabela ezenziwe, ezikhokelela ekunciphiseni komlinganiselo we-enantiomeric. Uvavanyo olungenanto luyenziwe ukwenzela ukuvavanya ukungapheli komzimba kunye nexabiso elincinci le-alcoety acetylated (<10%). Ngokubhekiselele kwi-acetate ye-ethyl, ngokumangalisa, ibonisa ukhetho oluthambileyo kunye nokuguqulwa okucwangcisiweyo (Itafile 1, i-3 kunye ne-2 ngokulandelanayo). Nangona iTheyibhile 1 iveza iziphumo zesisombululo sekinetic emva kweentsuku ze-10, iimpendulo zajongwa kwimihla yokuqala ye-3 yonke i-12 h nangemva kwe3rd ngosuku, yonke i-24 h. Yintoni enokubonwa nguphuculo lokuguqulwa kwimihla ukuya kwiintsuku ze-10 zokuphendula. Ixesha lokusabela ngokuqhubekayo liye lavanywa (iintsuku ze-12) kodwa akukho phuculo lokuguqulwa kwagqitywa.

Ukuze uzame ukunciphisa ixesha lokuphendula, esinye sezicwangciso kukuhlalutya umphumo wamazinga aphezulu e-acyl donor kodwa ngelanga ngamanani aphakamileyo kwaye ixabiso elilinganayo le-enantiomeric lehlile ukusuka> 200 ukuya kwi-31, ebonisa ukuba i-chemical esterification ithatha indawo. Enye inzame ukukhangela ezinye iipilases kodwa akukho miphumo engcono efunyenweyo xa kuthelekiswa ne-CAL B engenakulinganiswa (N435) (Ithebula iS1 - Ulwazi oluxhasayo).

Ukuze uzame ukunciphisa ixesha elide lokuphendula elifunyenweyo kule substrate ethile, amaqondo okushisa kunye nama-solvents ahlukeneyo ahlolwe.

I-solvent yokujonga i-kinetic isisombululo se-1- (2,6-dichloro-3-fluorophenyl) i-ethanol, usebenzisa i-acetate ye-isopropeny edibeneyo yi-CAL B.

Ukungena T (° C) Ixesha lokuSombulula (iintsuku) iConv. (%) eeprod (%) E

  • 1 60 ACN 5 2 99> 200
  • 2 60 I-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

Izimo zokuphendula: 1- (2,6-dichloro-3-fluorophenyl) ethanol (2) (0.048 mmol, 10mg), i-acetate ye-isopropenyl (2eqv) njenge-acyl donor, kunye ne-60mg (20% w / w) i-Novozym 435 kwi-solvents ehlukeneyo (3 i-ACN - i-acetonitrile, i-MTBE - i-methyl ter-butyl ether), ilinganiselwe indlela ye-GC-FID kwaye i-enantioselectivity ilinganiswe ngokusekelwe kwi- (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol kunye nezihlandlo ezigcinwayo zokugcinwa kwe-ester.

Njengoko kuphawuliwe kwiThebhile 2, phakathi kwazo zonke iisombululo ezivandlakanywe kwisisombululo esifanelekileyo, i-isooctane inikeze iziphumo ezifanelekileyo ngokuphathelele ixesha lokuphendula. Ngaphantsi kweemeko ezifundwayo, kwi-70 ° C, i-isooctane inokukhokelela kwi-45% yokuguqulwa (i-42% isivuno) emva kweentsuku ze-5, ukucutha kwe-50% ngexesha lokusabela (Itafile 2, ukungena kwi-7). Ezinye i-acetone, i-MTBE, i-acetonitrile (ACN), i-toluene kunye ne-hexane, ayiphumelelanga okanye iholele ekuguquleni okukhulu. Emazingeni aphezulu aphezulu, akukho phuculo lokuguqulwa komphendulelo lungabonwa. I-exception yi-heptane, engakhokelela kwiziphumo ezifanayo kwi-isooctane, kodwa kamva kunokusikhokelela ekuzinzileyo kwe-enzyme engenakulinganiswa.

Nangona iziphumo ezilungileyo zifumaneke phantsi kweemeko zesisombululo se-kinetic, i-50% yalo mveliso yinkcitho okanye kufuneka ihlaziywe ukuze iphinde isetyenziswe kwakhona kwelinye iqela.

Ngokusekelwe kwiziphumo ezifunyenweyo kwi-1- (2,6-dichloro-3-fluorophenyl) ethanol (i-2), sinqume ukuqhubela phambili ukwenzela ukuphuhlisa indlela ye-DKR ekufuneka ihambise i-enantiomeri ye-R ene-acetylated. 1- (2,6-dichloro-3-fluorophenyl) i-ethanol (i-2) njengemveliso ephambili. Esi sicwangciso sisekelwe kwinto yokuba emva kweDKR, i-hydrolysis elula ikhokelela kwi-enantiomeri efunwayo, enokuthi idibaniswe kunye nekholeji ecaleni kwindlela yokumisa inxalenye ye-nucleophilic aromatic. Izixhobo ezihlukeneyo zokuhlengahlengiswa kwezihlomelo ziye zavanywa kule njongo, i-vanadyl sulfate19-25 kunye ne-Shvo ye-ruthenium catalyst.26-30

Izimpendulo zenziwa kwi-70 ° C, usebenzisa i-acetate ye-isopropenyl njenge-acyl umniki kunye nokuguqulwa okuhlaziywa yi-GC-FID imihla ngemihla kwii-5 iintsuku. Kubalulekile ukuqaphela ukuba abaxhasi be-acyl abancinci abayiyo ikhethelo elikhethekileyo kwi-DKR edibaniswa ngabantwana be-vanadium catalysts, njengoko sele zichazwe ngamanye amaqela.20,22 Nangona kunjalo, sinqume ukugcina i-acetate ye-isopropenyl njengoko sele sisazi ukuba isisombululo sekinetic sifanele sibe Isilinganiselo sokunciphisa inkqubo yethu kunye nomxhasi omdala we-acyl donor, njenge-vinyl decanoate, inokunyusa ngakumbi ixesha lokuphendula.31 Iziphumo ezifunyenweyo kwisisombululo se-kinetic ziguqulelwe kwiTable 3.

I-DKR ye-1- (i-2,6-dichloro-3-fluorophenyl) i-ethanol (i-2) idibanisiswe yi-CAL-B engenakulinganiswa kunye neendawo zokuxhaswa kwezinto ezihlukeneyo phantsi kweemeko zeetch.

Ukungena Ukuhluthwa kweCatalyst Conv. (%) eeprod (%) Ukukhethwa (%)

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

iimeko Reaction: 1- (2,6-dichloro-3-fluoro-phenyl) -ethanol (0,1 M), isopropenyl acetate (0,1 M) njengoko acyl yeminikelo, isooctane (15 ml) bathwalwa ngokuxuba zonke wezenzi kunye ehlanganisa kwi ibhetshi reactor. Ukuchongwa ngu-GC-FID kunye ne-enantioselectivity yayilinganiswa ngokusekelwe kwi (S) -1- (2,6-dichloro-3-fluorophenyl) i-ethanol kunye nexesha eligcinwayo lokugcinwa kwe-ester.


Izilingo ze-5.Clinical zeCrizotinib powderaasraw

I-Crizotinib powder yabangela ukuba izidumbu zihlaziye okanye zizinze kwi-90% yezigulane ze-82 ezithwala i-ALK fusion gene. Izidumbu zenza i-30% kwi-57% yabantu baphathwe. Uninzi lwaba ne-adenocarcinoma, kwaye aluzange lubheke okanye lwaluye lwaba tshi. Baye baphathwa ngononophelo lwezinye izidakamizwa ezintathu ngaphambi kokufumana i-Crizotinib powder, kwaye kuphela i-10% kulindeleke ukuba iphendule kwindlela yokwenza unyango oluqhelekileyo. Banikwa 250 mg Crizotinib powder kabini imihla ngemihla ngexesha eliphakathi kweenyanga ezintandathu. Ngokumalunga ne-50% yezi zi gulane zabuhlungu ubuncinane omnye umphumo wecala, njenge-nasusea, ukuhlanza, okanye urhudo. Ezinye iimpendulo kwiCrizotinib powder ziye zadlulela kwiinyanga ze-15.

Icandelo le-3, Icandelo le-1007, lifanisa i-Crizotinib powder ukuya kumgangatho wesibini we-chemotherapy (i-pemetrexed okanye i-taxotere) ekwonyango kwe-NSCLC ye-ALK-positive. Ukongeza, isilingo se-2, I-PROFILE 1005, izigulane zihlola iziganeko ezifanayo eziye zafumana ngaphezulu kweyure enye ye-chemotherapy yangaphambili.

I-Crizotinib powder iphinda ivivinywe kwizilingo zeclini ye-eplasm ehamba phambili e-cell-cell lymphoma kunye ne-neuroblastoma.

NgoFebruwari 2016 uvavanyo lwe-J-ALEX lwesigaba III luqhathanisa i-electinib kunye ne-Crizotinib powder I-NSCLC ye-ALK-positi yapheliswa kusasa kuba uhlalutyo lwesikhashana lubonise ukuba ukusinda okungahambanga-nkululeko kwakuninzi kunye ne-electinib. Ezi ziphumo ziqinisekisiwe kuhlalutyo lwe-2017.

Njengoko kunokubonwa kwiThebhile 3, inkqubo yokwenza i-racemization protocol eyenziwa ngo-Shvo okanye i-vanadyl sulphate catalyst, ikhokelela ekuguquleni ngokulinganisela kwi-chiral alcohol. Kubalulekile ukuba uqaphele ukuba phantsi kweemeko zokuphendula, i-catalyst ye-Shvo ayizange yenze ngcono kangcono ke i-VOSO4, ize ibonise ukwehla kokugqithiseleyo kwemveliso yemveliso, kubonisa ukuba i-VOSO4 ingaba yindlela ekhangayo kunye nexabiso elincinci yokuphucula phambili.19-25,32- 34

Ukulandela izifundo zethu zakutshanje malunga nokusetyenziswa kwe-VOSO4 kwi-DKR phantsi kweemeko eziqhubekayo zokuhamba kwe-31 sisebenzise iimpendulo eziye zacwangciswa ngokusesikweni kwe-phenylethanol kwi-substrate yethu 1- (2,6-dichloro-3-fluorophenyl) ethanol. Ngale ndlela, impendulo yenziwa kwindlela yovalo evaliweyo ngenxa yexesha eliphezulu lokuphendula elifunekayo kwisinyathelo sokwenza isigqibo sekinetic. Nangona asizange sigcine ukungahambelani phakathi kwe-CAL B kunye ne-VOSO4,19-25,32-34 njengoko kwakunikwe kwangaphambili ngabanye ababhali, i-reactor ye-bed-bed reactor eqhubekayo idibeneyo ukwenzela ukuba iziqalo ezine ze-enzyme engenakulinganiswa kunye neendwangu ezintathu ze-VOSO4 zahlulwa ngaphandle iklasi yeglasi kunye nokuhlukana ngokwasemzimbeni ngumgca ongciniweyo wekotoni. Iziphumo ezifumaneka phantsi kwexesha lokusabela ezahlukeneyo kunye neentlawulo zokuhamba ziya kuboniswa ngezantsi (Itheyibhile 4).

I-Crizotinib powder (Rax-877399-52) hplc =5% | Ukurhoxisa iR & D Reagents

I-DKR eqhubekayo ye-1- (2,6-dichloro-3-fluorophenyl) ethanol.

Inani lokungena kwi-Entry (mL.min? 1) Ixesha lokuphendula (iintsuku) iConv. (%) 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

Iimeko: I-1- (2,6-dichloro-3-fluoro-phenyl) -ethanol (2) (0,1 M), i-acetate ye-isopropenyl (0,1 M) njenge-acyl donor, kwi-isooctane (i-15 mL) yenziwa ngokupompoza embhedeni i-reactor ekhutshwe kwiizinga ezahlukeneyo zokuhamba. Ikholamu yeglasi yayigcwele i-N435 kunye ne-VOSO4.XH2O engenakucala ukuze i-10 i-mL-packed-bed beder ne-4 izitha ze-enzyme (uluhlu ngalunye oluqukethe i-500 mg ye-catalyst) kunye neendlela ze-3 ze-VOSO4.XH2O (uluhlu ngalunye oluqukethe i-500 mg we-catalyst) ehlukaniswe ngamacwecwe amathonti amancinci. I-reactor-packed reactor yatshiswa kwi-80 ° C. Ukuchongwa ngu-GC-FID kunye ne-enantioselectivity esilinganiselwe ngokusekelwe kwi- (S) -1- (2,6-dichloro-3-fluorophenyl) i-ethanol kunye nezihlandlo ezigcinwayo zokugcinwa kwe-ester.

Iziphumo eziboniswe kwiTable 4 zibonisa ukuba phantsi kweemeko eziqhubekayo zokuhamba kweDKR elamkelwa nguNovozyme 435 kunye ne-VOSO4, iyasebenza ngokubhekiselele ekuguquleni kunye nexesha lokuphendula xa kuthelekiswa ne-setch up-up, njengoko kuboniswe ukungena 6 (Ithebula 4) . Akukho phuculo olongezelelweyo lokuguqulwa komphendulelo lungabonwa kwandisa ixesha lokuphendula, elibonakala liyimida kule nkalo ethile. Ukwandisa ixesha lokuhlala ngokusetyenziswa kwezinga eliphantsi lokuhamba kwamanzi akukhokelela ekuguquleni okungcono kunye nokunciphisa okuncinci kwi-esantiomeric ngaphezu kwemveliso kunokugqalwa (ukungena 7-9, Ithebula 4). Ku-0.5 mL.min? I-1 into ephuculweyo yokuguqulwa kokuphendulela ingafumaneka xa kuthelekiswa nenkqubo yeetch, kubalulekile ukuba uqaphele ukuba nangona impendulo yenziwe ngeentsuku ze-5, ixesha elifanelekileyo loqhagamshelwano phakathi kwama-reagents kunye ne-catalysts ngaphantsi kuba isebenza kwindlela yokuvala ivalwe. Enye inzuzo ye-DKR yinto yokuba izinto eziqalayo zokuqala zikwazi ukuphinda zisetyenziswe kwiprogram eyahlukileyo ngaphandle kokuhlambulula.


6.Ukupheliswa kweCrizotinib powderaasraw

Ekugqibeleni siye savelisa iindlela ezahlukahlukeneyo malunga nokuveliswa kwe-chiral 1- (2,6-dichloro-3-fluorophenyl) ethanol (2), ebalulekileyo phakathi kweCrizotinib powder (1) synthesis. Isisombululo seKinetic senziwa ngokuguqulwa kakuhle kakhulu kunye nokukhetha okuphezulu ngenkqubela yekinetic enamandla, nangaphantsi kweemeko zentlambo ezifumanekayo iziphumo ezigugu zokuguqulwa ngokugqithiseleyo okuninzi kwemveliso. Uphuculo olongezelelweyo lufumene ukuguqulela isisombululo se-kinetic esishukumisayo kwiprotokhothi eqhubekayo apho ukuguqulwa kunokuphuculwa kunye nokukhetha okulungileyo.


7.Kuphi Thenga i-Crizotinib powder?aasraw

I-AASraw ingomnye wemithombo esemthethweni yokukhetha, ukuba ulwazi olungaphezulu. kufuneka ukwazi, nceda Qhagamshelana nathi.


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