Li-intermediates ke mofuta oa bohlokoa haholo oa lihlahisoa tse ntle tsa lik'hemik'hale. Ha e le hantle, ke mofuta oa "lihlahisoa tse feliloeng ka halofo", tse sebelisoang haholo ha ho etsoa meriana, chefo e bolaeang likokoanyana, liaparo, lidae le linoko.

Meriana, li-intermediate li sebelisoa ho hlahisa li-API.

Joale indasteri ea niche ea li-intermediates tsa meriana ke eng?

01

Seo ho thoeng ke li-intermediate tsa meriana ha e le hantle ke lisebelisoa tse ling tsa lik'hemik'hale kapa lihlahisoa tsa lik'hemik'hale tse sebelisoang ha ho etsoa lithethefatsi.
K'hemik'hale, e sa hlokeng lengolo la tumello ea ho etsa lithethefatsi, e ka hlahisoa femeng e tloaelehileng ea lik'hemik'hale 'me, ha e fihla maemong a itseng, e ka sebelisoa ha ho etsoa lithethefatsi.

Setšoantšo

Hajoale, mefuta e tsebahalang haholo ea li-intermediate tsa meriana ke tse latelang:

Nucleoside intermediates.
Mofuta ona oa motsoako o mahareng oa litlhare tse thibelang AIDS haholo-holo ke zidovudine, ho tsoa United States Glaxo.
Wellcome le Bristol-Myers Squibb ba e etsa.

Mehato ea methapo ea pelo.
Mohlala, li-sartan tsa maiketsetso li se li sebelisoa haholo kalafong ea khatello ea mali ka lebaka la phello ea tsona e felletseng ea antihypertensive, litlamorao tse fokolang, katleho e telele (taolo e tsitsitseng ea khatello ea mali bakeng sa lihora tse 24) le bokhoni ba ho sebelisoa hammoho le li-sartan tse ling.
Ho ea ka lipalo-palo, ka 2015, tlhoko ea lefats'e ea lintho tse sebetsang tsa sartan tse sebetsang (losartan potasiamo, olmesartan, valsartan, irbesartan, telmisartan, candesartan) e fihlile ho lithane tse 3,300.
Kakaretso ea thekiso e ne e le $ 21.063 limilione tse likete.

Fluorinated intermediates.
Lithethefatsi tse nang le fluorinated tse entsoeng ho tloha lipakeng tse joalo li tsoetse pele ka potlako lilemong tsa morao tjena ka lebaka la ts'ebetso ea tsona e babatsehang. Ka 1970, ke 2% feela ea lithethefatsi tse nang le fluorinated tse neng li le 'marakeng; ka 2013, 25% ea lithethefatsi tse nang le fluorinated li ne li le 'marakeng.
Lihlahisoa tsa moemeli tse kang fluoroquinolone anti-infective drugs, antidepressant fluoxetine le antifungal fluconazole account bakeng sa karolo e phahameng ea tšebeliso ea meriana, eo har'a eona lithethefatsi tse thibelang likokoana-hloko tsa fluoroquinolone li etsang karolo ea 15% ea 'maraka oa lefats'e oa lithethefatsi tse thibelang tšoaetso.
Ntle le moo, trifluoroethanol ke karolo ea bohlokoa ea lipakeng bakeng sa tlhahiso ea lithethefatsi tse thethefatsang kutlo, athe trifluoromethylaniline ke karolo ea bohlokoa ea ho kopanya lithethefatsi tse thibelang malarial, anti-inflammatory le analgesic drugs, anti-prostate drugs le anti-depressants, 'me tebello ea 'maraka e pharaletseng haholo. .

Heterocyclic lipakeng.
Ka pyridine le piperazine e le baemeli, e sebelisoa haholo-holo ha ho etsoa lithethefatsi tse khahlanong le seso, lithethefatsi tse ngata tsa gastric, li-anti-inflammatory le anti-infective drugs, lithethefatsi tse matla haholo tsa antihypertensive le lithethefatsi tse ncha tsa kankere ea matsoele letrozole.

02

Li-intermediates tsa meriana ke sehokelo sa bohlokoa ho ketane ea indasteri ea meriana.

Setšoantšo

Holimo ke lisebelisoa tsa motheo tsa lik'hemik'hale tse tala, tseo boholo ba tsona e leng lihlahisoa tsa petrochemical, tse kang acetylene, ethylene, propylene, butene le butadiene, toluene le xylene.

Li-intermediate tsa meriana li arotsoe ka li-intermediate tse ka sehloohong le tse tsoetseng pele.
Har'a bona, barekisi ba mantlha ba mahareng ba ka fana ka tlhahiso e bonolo feela ea mahareng mme ba ka pele ho ketane ea indasteri e nang le khatello e kholo ea tlholisano le khatello ea theko. Ka hona, ho fetoha ha theko ea lisebelisoa tsa motheo tsa lik'hemik'hale ho na le tšusumetso e kholo ho bona.

Ka lehlakoreng le leng, barekisi ba mahareng ba tsoetseng pele ha ba na matla a matla a ho buisana ho bafani ba thepa ea mantlha, empa ho bohlokoa le ho feta, hobane ba etsa tlhahiso ea li-intermediate tse tsoetseng pele tse nang le litaba tse phahameng tsa tekheniki mme ba boloka kamano e haufi le lik'hamphani tsa machaba, ha ba amehe haholo ke ho fetoha ha theko. ea lisebelisoa tse tala.

Libaka tse bohareng ke tsa indasteri ea lik'hemik'hale e ntle ea meriana.
Baetsi ba li-intermediates tsa meriana ba kopanya li-intermediate kapa li-API tse tala, 'me ba rekisa lihlahisoa ka mokhoa oa lihlahisoa tsa lik'hemik'hale ho lik'hamphani tsa meriana, tse li hloekisang ebe li li rekisa e le lithethefatsi.

Li-intermediate tsa meriana li kenyelletsa lihlahisoa tse tloaelehileng le lihlahisoa tse ikhethileng. Ho ea ka mekhahlelo e fapaneng ea lits'ebeletso tsa ts'ebeletso ea kantle ho naha, mefuta ea khoebo e ikhethileng ea batho ba lipakeng ka kakaretso e ka aroloa ka CRO (lipatlisiso tsa konteraka le nts'etsopele ea kantle ho naha) le CMO (ho fana ka tlhahiso ea konteraka).

Nakong e fetileng, mokhoa oa ho fana ka khoebo oa CMO o ne o sebelisoa haholo ho li-intermediate tsa meriana.
Tlas'a mohlala oa CMO, lik'hamphani tsa meriana li fana ka tlhahiso ho balekane.
Ka hona, ketane ea khoebo hangata e qala ka lisebelisoa tse khethehileng tsa meriana.
Likhamphani tsa indasteri li hloka ho reka lisebelisoa tsa mantlha tsa lik'hemik'hale 'me li li arole le ho li sebelisa hore e be lisebelisoa tse ikhethang tsa meriana, ebe li li sebelisa hape ka lisebelisoa tsa ho qala tsa API, li-intermediate tsa cGMP, li-API le litokisetso.

Empa, joalo ka ha lik'hamphani tsa lithethefatsi bakeng sa taolo ea litšenyehelo le litlhoko tsa ts'ebetso, lits'ebeletso tse bonolo tsa tlhahiso ea kantle ho naha ha li khone ho fihlela tlhoko ea khoebo, mokhoa oa CDMO (lipatlisiso tsa tlhahiso le nts'etsopele ea nts'etsopele) o hlaha ka nako ea nalane, CDMO e hloka likhoebo tsa tlhahiso ea tlhahiso ho nka karolo ho moreki ha a ntse a etsa lipatlisiso le nts'etsopele, ho fana ka ntlafatso ea ts'ebetso kapa ts'ebetso, ho hlokomela boleng ba tlhahiso e kholo, ho fokotsa litšenyehelo tsa tlhahiso,
E na le menyetla e phahameng ea phaello ho feta mohlala oa CMO.

Sebaka se tlase haholo ke indasteri ea tlhahiso ea API, 'me API e le kamanong ea ketane ea indasteri e holimo le e ka tlaase le litokisetso.
Ka hona, tlhoko ea tšebeliso ea boitokisetso ba lithethefatsi tse tlase e tla ama ka kotloloho tlhoko ea API, ebe e ama tlhoko ea mahareng.

Ho ea ka pono ea ketane eohle ea liindasteri, li-intermediate tsa meriana li ntse li le boemong ba kholo hona joale, 'me karolelano ea phaello ea kakaretso ke 15-20%, ha phaello ea kakaretso ea API e le 20-25%, le karolelano Sekhahla sa phaello e felletseng ea litlatsetso tsa litlama tse tlase ke 40-50%. Ho hlakile hore phaello ea kakaretso ea karolo e tlase e phahame haholo ho feta ea karolo e ka holimo.
Ka hona, likhoebo tsa lipakeng tsa meriana li ka eketsa ketane ea lihlahisoa, tsa eketsa phaello ea sehlahisoa le ho ntlafatsa botsitso ba thekiso ka ho hlahisa API nakong e tlang.

03

Tsoelo-pele e phahameng ea indasteri ea meriana ea meriana Chaena e qalile ka 2000.

Ka nako eo, lik'hamphani tsa meriana linaheng tse tsoetseng pele li ile tsa ela hloko haholoanyane lipatlisiso tsa lihlahisoa le nts'etsopele le nts'etsopele ea 'maraka e le tlhōlisano ea bona ea mantlha,' me ba potlakisa ho fetisetsoa ha li-intermediate le tse sebetsang tsa lithethefatsi linaheng tse tsoelang pele ka litšenyehelo tse tlaase.
Ka hona, indasteri ea li-intermediate tsa meriana Chaena e fihletse tsoelo-pele e babatsehang ka ho nka monyetla ona.
Ka mor'a lilemo tse fetang leshome tsa tsoelo-pele e tsitsitseng, ka tšehetso ea taolo le maano a naha ka kakaretso, Chaena e fetohile setsi sa bohlokoa sa tlhahiso ea lipakeng karolong ea lefats'e ea basebetsi indastering ea meriana.

Ho tloha 2012 ho isa 2018, tlhahiso ea indasteri ea lipakeng tsa meriana ea China e eketsehile ho tloha ho lithane tse ka bang limilione tse 8.1 ka boholo ba mmaraka bo ka bang li-yuan tse limilione tse likete tse 168.8 ho isa ho lithane tse ka bang limilione tse 10.12 ka boholo ba mmaraka ba li-yuan tse limilione tse likete tse 2010.7.

Setšoantšo

Indasteri ea lipakeng tsa meriana ea Chaena e fihletse tlholisano e matla ea 'maraka, esita le likhoebo tse ling tse mahareng tsa tlhahiso li khonne ho hlahisa li-intermediate tse nang le sebopeho se rarahaneng sa limolek'hule le litlhoko tse phahameng tsa tekheniki. Palo e kholo ea lihlahisoa tse nang le tšusumetso e se e qalile ho laola 'maraka oa machaba.

Leha ho le joalo, ka kakaretso, indasteri ea mahareng Chaena e ntse e le nakong ea nts'etsopele ea ntlafatso ea sebopeho sa sehlahisoa le ntlafatso, 'me boemo ba theknoloji bo ntse bo le tlase haholo.
Li-intermediate tsa mantlha tsa meriana e ntse e le lihlahisoa tse ka sehloohong indastering ea li-intermediate tsa meriana, 'me ho na le likhoebo tse fokolang tse hlahisang palo e kholo ea li-intermediate tse tsoetseng pele tsa meriana le tse tšehetsang lihlahisoa tsa lipakeng tsa meriana e mecha e nang le tokelo ea molao.

Hajoale, lik'hamphani tse nang le tlholisano ea A-share indastering e mahareng ke Yaben Chemical, Lianhua Technology, Boten, le Wanrun, e rerileng ho tsetela li-yuan tse limilione tse 630 kahong ea li-intermediate tsa meriana le merero ea API ka kakaretso ea lithane tse 3,155. /selemo.
Ba tsoela pele ho hlahisa lihlahisoa tse ngata ka lipatlisiso le nts'etsopele, e le ho fumana litsela tse ncha.

Yaben Chemical Co., Ltd. (300261) : Lihlahisoa tsa rona tse ka sehloohong li kenyelletsa li-intermediate tsa lithethefatsi tsa antitumor, li-intermediate tsa antiepileptic le li-antiviral intermediates.
Har'a bona, ABAH, sethethefatsi se thibelang lefu la sethoathoa, se ile sa kenngoa ka molao tlhahiso ka Mphalane 2014, se nang le matla a lithane tse 1,000.
Theknoloji ea ho belisoa ha enzyme e kentsoe ka katleho lipakeng tsa pelo le methapo ho matlafatsa tlholisano ea lihlahisoa.
Ka 2017, k'hamphani e ile ea fumana ACL, k'hamphani e sebetsang ea meriana e Malta, e potlakisang sebopeho sa eona 'marakeng oa machaba oa bongaka le ho tsamaisa phetoho le ntlafatso ea setsi sa lehae.

BTG (300363) : e tsepamisitse maikutlo ho li-intermediate tse ncha tsa lithethefatsi / API customized CMO khoebo, lihlahisoa tse ka sehloohong ke meriana ea meriana bakeng sa anti-hepatitis C, anti-AIDS, hypolipidemia le analgesia, 'me ke mofani oa mantlha oa Sofebuvir intermediates bakeng sa anti-hepatitis ea Gileade. C sethethefatsi.
Ka 2016, kakaretso ea chelete ea li-anti-diabetes + intermediate anti-hepatitis C e fihlile ho limilione tse 660, e leng karolo ea 50% ea chelete eohle.
Leha ho le joalo, ho tloha ka 2017, ka lebaka la ho fola butle-butle ha bakuli ba lefu la sebete la mofuta oa C le ho fokotseha ha palo ea bakuli, thekiso ea meriana ea lefu la sebete sa Gileade e ile ea qala ho theoha. Ho feta moo, ka ho fela ha litokelo tsa litokelo tsa molao, lithethefatsi tse khahlanong le lefu la sebete la C li ile tsa qalisoa, 'me tlhōlisano e ile ea tsoela pele ho matlafala, e leng se ileng sa fella ka ho fokotseha ha litaelo le chelete e kenang lipakeng.
Hajoale, k'hamphani e fetohile ho tloha khoebong ea CMO ho ea khoebong ea CDMO ho aha sethala se etelletseng pele sa lits'ebeletso tsa lefats'e bakeng sa likhoebo tsa meriana.

Alliance Technology (002250) :
Lihlahisoa tsa meriana ea meriana li ameha haholo ho lithethefatsi tsa antitumor, li-autoimmune, lithethefatsi tsa antifungal, lithethefatsi tsa pelo, lithethefatsi tsa lefu la tsoekere, li-antidepressants, lithethefatsi tsa antihypertensive, lithethefatsi tse khahlanong le feberu, tse kang tsa motheo, kaofela li libakeng tsa phekolo ea libaka tse tummeng ka ho fetisisa le tse pharaletseng tsa mmaraka. , kholo e potlakileng lilemong tsa morao tjena, sekhahla sa kholo ea chelete e kenang se ka bang 50%.
Har'a bona, "phello ea selemo le selemo ea lithane tsa 300 tsa Chunidine, lithane tse 300 tsa Fluzolic Acid le lithane tse 200 tsa Cyclopyrimidine Acid Project" li kentsoe tlhahiso ka ho latellana ho tloha 2014.