Abaphakathi bawuhlobo olubaluleke kakhulu lwemikhiqizo emihle yamakhemikhali. Ngamafuphi, ziwuhlobo "lwemikhiqizo ephelile", esetshenziswa kabanzi ekuhlanganiseni imithi, izibulala-zinambuzane, izambatho, odayi nezinongo.

Kwezokwelapha, abaphakathi basetshenziselwa ukukhiqiza ama-API.

Ngakho-ke iyini imboni ye-niche yabaphakathi kwezemithi?

01

Lokho okubizwa ngokuthi abaxhumanisi bemithi empeleni kungamakhemikhali athile asetshenziswayo noma imikhiqizo yamakhemikhali esetshenziswa ekuhlanganiseni kwezidakamizwa.
Ikhemikhali, engadingi ilayisense yokukhiqiza izidakamizwa, ingakhiqizwa embonini yamakhemikhali evamile futhi, lapho ifinyelela emazingeni athile, ingasetshenziswa ekuhlanganiseni izidakamizwa.

Isithombe

Njengamanje, izinhlobo ezithembisayo kakhulu zama-intermediates emithi ikakhulukazi zimi kanje:

I-Nucleoside intermediate.
Lolu hlobo lokuhlanganiswa okumaphakathi kwemithi elwa nengculazi ngokuyinhloko i-zidovudine, evela e-United States Glaxo.
UWellcome noBristol-Myers Squibb bayakwenza.

Imithambo yenhliziyo.
Isibonelo, ama-sartan okwenziwa asetshenziswa kabanzi ekwelapheni umfutho wegazi ophakeme ngenxa yomphumela wawo ophelele we-antihypertensive, imiphumela emibi embalwa, ukusebenza kahle okude (ukulawulwa okuzinzile komfutho wegazi amahora angama-24) kanye nekhono lokusetshenziswa ngokuhambisana namanye ama-sartan.
Ngokwezibalo, ngo-2015, isidingo somhlaba wonke sezinto ezisebenzayo zesidakamizwa i-sartan (i-losartan potassium, i-olmesartan, i-valsartan, irbesartan, i-telmisartan, i-candesartan) sifinyelele amathani angu-3,300.
Ukuthengiswa okuphelele bekungamaRandi ayizigidi eziyizinkulungwane ezingama-21.063.

Fluorinated intermediates.
Izidakamizwa ezine-fluorinated ezihlanganiswe kulaba abaphakathi ziye zakhula ngokushesha eminyakeni yamuva nje ngenxa yokusebenza kahle kwazo. Ngo-1970, ama-2% kuphela ezidakamizwa ezine-fluorinated emakethe; ngo-2013, ama-25% ezidakamizwa ezine-fluorinated ayesemakethe.
Imikhiqizo emele efana ne-fluoroquinolone anti-infective drugs, i-antidepressant fluoxetine kanye ne-akhawunti ye-antifungal fluconazole ngenani eliphezulu ekusetshenzisweni komtholampilo, phakathi kwayo i-fluoroquinolone anti-infective drugs ithatha cishe u-15% wesabelo semakethe yomhlaba wonke semithi elwa namagciwane.
Ngaphezu kwalokho, i-trifluoroethanol iyingxenye ebalulekile yokwenziwa kwemithi ebulala izinzwa, kuyilapho i-trifluoromethylaniline iyingxenye ebalulekile yokuhlanganiswa kwezidakamizwa ezilwa nomalaleveva, izidakamizwa ezilwa nokuvuvukala kanye ne-analgesic, izidakamizwa ezilwa ne-prostate kanye nama-anti-depressants, futhi ithemba lemakethe libanzi kakhulu. .

I-Heterocyclic intermediates.
Njengoba i-pyridine ne-piperazine njengabameleli, isetshenziswa ngokuyinhloko ekuhlanganiseni kwezidakamizwa zokulwa nezilonda, izidakamizwa zesisu eziningi, izidakamizwa ezilwa nokuvuvukala kanye nezifo ezithathelwanayo, izidakamizwa ezisebenza kahle kakhulu ze-antihypertensive kanye nezidakamizwa ezintsha zomdlavuza webele i-letrozole.

02

Abaphakathi kwezemithi bayisixhumanisi esibalulekile ochungechungeni lwemboni yezemithi.

Isithombe

I-Upstream yizinto eziyisisekelo zamakhemikhali asetshenziswayo, iningi lazo okuyimikhiqizo ye-petrochemical, njenge-acetylene, i-ethylene, i-propylene, i-butene ne-butadiene, i-toluene ne-xylene.

Ama-intermediate emithi ahlukaniswe abe yi-primary intermediate kanye ne-advanced intermediate.
Phakathi kwabo, abahlinzeki abayinhloko abaphakathi banganikeza kuphela ukukhiqiza okuphakathi okulula futhi bangaphambili kochungechunge lwezimboni ngengcindezi yokuncintisana enkulu kakhulu kanye nengcindezi yamanani. Ngakho-ke, ukuguquguquka kwentengo yezinto ezisetshenziswayo zamakhemikhali ayisisekelo kunomthelela omkhulu kuzo.

Ngakolunye uhlangothi, abahlinzeki abaphakathi abathuthukile abagcini nje ngokuba namandla okuxoxisana aqinile phezu kwabaphakeli abayinhloko, kodwa okubaluleke nakakhulu, ngoba benza ukukhiqizwa kweziphakathi ezithuthukisiwe ezinokuqukethwe okuphezulu kobuchwepheshe futhi bagcina ukuxhumana okuseduze nezinkampani zamazwe ngamazwe, abathinteki kancane ngokuguquguquka kwentengo. yezinto zokusetshenziswa.

Indawo emaphakathi ingeyemboni yekhemikhali emihle yezemithi.
Abakhiqizi bemithi ephakathi kwemithi bahlanganisa ama-intermediate noma ama-API angcolile, futhi bathengise imikhiqizo ngendlela yemikhiqizo yamakhemikhali ezinkampanini ezithaka imithi, eziyicwengayo bese ziyithengisa njengezidakamizwa.

Imithi ephakathi kwemithi ihlanganisa imikhiqizo ejwayelekile kanye nemikhiqizo eyenziwe ngokwezifiso. Ngokwezigaba ezihlukene zensizakalo yokukhishwa kwemisebenzi, amamodeli ebhizinisi enziwe ngokwezifiso abaphakathi nendawo ngokuvamile angahlukaniswa abe yi-CRO (ucwaningo lwenkontileka nokuthuthukiswa kwangaphandle) kanye ne-CMO (ukukhishwa kwenkontileka yokukhiqiza).

Esikhathini esedlule, imodi yokukhipha ibhizinisi ye-CMO yayisetshenziswa kakhulu ekuxhumaneni kwezemithi.
Ngaphansi kwemodeli ye-CMO, izinkampani ezenza imithi zikhiphela ozakwethu ukukhiqiza.
Ngakho-ke, uchungechunge lwebhizinisi ngokuvamile luqala ngezinto zokusetshenziswa ezikhethekile zemithi.
Izinkampani zezimboni zidinga ukuthenga izinto ezingasetshenzisiwe zamakhemikhali eziyisisekelo futhi zizihlukanise futhi zizicubungule zibe izinto ezisetshenziswayo ezikhethekile zemithi, bese zizicubungula zibe izinto zokuqala ze-API, i-cGMP intermediates, ama-API namalungiselelo.

Kodwa, njengoba izinkampani zezidakamizwa zokulawula izindleko kanye nezidingo zokusebenza kahle, izinsizakalo zokukhiqiza ezilula azikwazanga ukuhlangabezana nesidingo sebhizinisi, imodi ye-CDMO (ucwaningo lokukhiqiza kanye nokukhishwa kwentuthuko) ivela ngesikhathi esiyingqopha-mlando, i-CDMO idinga amabhizinisi okukhiqiza ngokwezifiso ukuze abambe iqhaza. ikhasimende kunqubo yocwaningo nentuthuko, ukuhlinzeka ngokuthuthukiswa kwenqubo noma ukwenza kahle, ukubona ikhwalithi yokukhiqiza enkulu, ukunciphisa izindleko zokukhiqiza,
Inamamajini enzuzo aphezulu kunemodeli ye-CMO.

I-downstream iyimboni yokukhiqiza ye-API, futhi i-API isebudlelwaneni bochungechunge lwezimboni olukhuphuka nomfula ongezansi ngokulungiselela.
Ngakho-ke, isidingo sokusetshenziswa kokulungiswa kwezidakamizwa ezingezansi sizothinta ngqo isidingo se-API, bese sithinta isidingo samaphakathi.

Ngokombono walo lonke uchungechunge lwezimboni, abaphakathi kwezemithi basesesigabeni sokukhula okwamanje, futhi isilinganiso senzuzo iyonke ngokuvamile singu-15-20%, kuyilapho isilinganiso senzuzo yenzuzo ye-API singu-20-25%, kanti isilinganiso Izinga lenzuzo eliphelele lamalungiselelo emithi asezansi nomfula liphezulu njenge-40-50%. Ngokusobala, inani lenzuzo eliphelele lengxenye engezansi liphezulu kakhulu kunalelo lengxenye ekhuphuka nomfula.
Ngakho-ke, amabhizinisi amaphakathi emithi angaqhubeka nokunweba uchungechunge lomkhiqizo, andise inzuzo yomkhiqizo futhi athuthukise ukuzinza kokuthengiswayo ngokukhiqiza i-API esikhathini esizayo.

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Ukuthuthukiswa okuphezulu kwemboni ye-pharmaceutical intermediates e-China kwaqala ngo-2000.

Ngaleso sikhathi, izinkampani ezenza imithi emazweni athuthukile zanaka kakhulu ucwaningo lwemikhiqizo kanye nokuthuthukiswa kanye nokuthuthukiswa kwemakethe njengokuncintisana kwazo okuyinhloko, futhi zasheshisa ukudluliselwa kokuhlanganiswa kwezidakamizwa okusebenzayo emazweni asathuthuka anezindleko eziphansi.
Ngakho-ke, imboni ephakathi kwemithi e-China izuze intuthuko enhle kakhulu ngokuthatha leli thuba.
Ngemva kweminyaka engaphezu kweshumi yentuthuko eqhubekayo, ngokwesekwa yimithethonqubo kazwelonke kanye nezinqubomgomo, i-China isibe isizinda sokukhiqiza esibalulekile esimaphakathi emkhakheni womhlaba wonke wabasebenzi embonini yezemithi.

Kusukela ngo-2012 kuya ku-2018, ukukhiqizwa kwemboni yaseShayina ephakathi kwezemithi kukhuphuke kusuka kumathani ayizigidi eziyisi-8.1 enosayizi wemakethe ongaba ama-yuan ayizigidi eziyizinkulungwane eziyi-168.8 ukuya cishe kumathani ayizigidi eziyi-10.12 enosayizi wemakethe wamayuan ayizigidi eziyizinkulungwane ezingama-2010.7.

Isithombe

Imboni yaseShayina ephakathi kwemithi izuze ukuncintisana okuqinile kwemakethe, futhi ngisho namanye amabhizinisi okukhiqiza aphakathi nendawo akwazile ukukhiqiza abaxhumanisi abanesakhiwo samangqamuzana esiyinkimbinkimbi kanye nezidingo eziphezulu zobuchwepheshe. Inani elikhulu lemikhiqizo enethonya seliqalile ukubusa imakethe yamazwe ngamazwe.

Kodwa-ke, ngokuvamile, imboni ephakathi eShayina isesikhathini sokuthuthukiswa kokuthuthukiswa kwesakhiwo somkhiqizo nokuthuthukiswa, futhi izinga lobuchwepheshe lisephansi kakhulu.
Abaphakathi kwezemithi abayinhloko kuseyimikhiqizo eyinhloko embonini yemithi ephakathi kwemithi, futhi kukhona amabhizinisi ambalwa akhiqiza inani elikhulu labaphakathi kwemithi ethuthukisiwe kanye nemikhiqizo esekelayo ephakathi yemithi emisha enelungelo lobunikazi.

Njengamanje, izinkampani ezincintisana kakhulu ezisohlwini lwe-A-share embonini emaphakathi yi-Yaben Chemical, i-Lianhua Technology, i-Boten, ne-Wanrun, ehlela ukutshala ama-yuan ayizigidi ezingama-630 ekwakhiweni kwamaphrojekthi aphakathi kwezemithi kanye namaphrojekthi we-API anenani eliphelele lamathani ayi-3,155. /unyaka.
Bayaqhubeka nokuthuthukisa uhla lwemikhiqizo ngocwaningo nokuthuthukiswa, ukuze bathole izindlela ezintsha.

I-Yaben Chemical Co., Ltd. (300261) : Imikhiqizo yethu eyinhloko ihlanganisa i-antitumor drug intermediate, i-antiepileptic intermediate kanye ne-antiviral intermediate.
Phakathi kwazo, i-ABAH, isidakamizwa esinqamula isithuthwane esiphakathi, yafakwa ngokusemthethweni ekukhiqizweni ngo-Okthoba 2014, enamandla amathani ayi-1,000.
Ubuchwepheshe bokuvutshelwa kwe-enzyme yethulwa ngempumelelo phakathi kwenhliziyo nemithambo yegazi ukuthuthukisa ukuncintisana kwemikhiqizo.
Ngo-2017, inkampani yathola i-ACL, inkampani esebenzayo eyenza imithi eMalta, isheshisa ukwakheka kwayo emakethe yezokwelapha yamazwe ngamazwe futhi iqhubekisela phambili ukuguqulwa nokuthuthukiswa kwesizinda sasekhaya.

I-BTG (300363) : igxile kuma-intermediates ezidakamizwa ezisha /ibhizinisi le-CMO elenziwe ngokwezifiso ze-API, imikhiqizo eyinhloko yimithi ephakathi kwe-anti-hepatitis C, i-anti-AIDS, i-hypolipidemia kanye ne-analgesia, futhi ingumnikezeli oyinhloko we-Sofebuvir intermediates ye-anti-hepatitis yase-Gileyadi. C umuthi.
Ngo-2016, imali ephelele yezidakamizwa ezilwa nesifo sikashukela + i-anti-hepatitis C ephakathi yafinyelela ezigidini ezingu-660, ezibalelwa ku-50% wesamba semali engenayo.
Kodwa-ke, kusukela ngo-2017, ngenxa yokwelashwa kancane kancane kweziguli ze-hepatitis C kanye nokuncipha kwenani leziguli, ukuthengiswa kwemithi ye-hepatitis C yaseGileyadi kwaqala ukwehla. Ngaphezu kwalokho, ngokuphelelwa yisikhathi kwamalungelo obunikazi, izidakamizwa ezengeziwe zokulwa ne-hepatitis C zaqalwa, futhi ukuncintisana kwaqhubeka nokuqina, okuholela ekwehleni kwama-oda aphakathi kanye nemali engenayo.
Njengamanje, inkampani isishintshile isuka ebhizinisini le-CMO yaya ebhizinisini le-CDMO ukuze yakhe inkundla yesevisi yomhlaba wonke ehamba phambili yamabhizinisi emithi.

I-Alliance Technology (002250) :
Imikhiqizo ephakathi kwemithi ibandakanyeka kakhulu emithini ye-antitumor, i-autoimmune, izidakamizwa ze-antifungal, izidakamizwa zenhliziyo, izidakamizwa zesifo sikashukela, ama-antidepressants, izidakamizwa ezilwa nomfutho wegazi ophakeme, izidakamizwa ezilwa nomkhuhlane, ezifana neziyisisekelo zonke zisezindaweni zokwelapha endaweni ethandwa kakhulu futhi ebanzi yemakethe. , ukukhula okusheshayo eminyakeni yamuva nje, izinga lokukhula elihlanganisiwe lemali engenayo elingaba ngu-50%.
Phakathi kwazo, "umkhiqizo wonyaka wamathani angu-300 we-Chunidine, amathani angu-300 we-Fluzolic Acid kanye namathani angu-200 we-Cyclopyrimidine Acid Project" afakwe ekukhiqizeni ngokulandelana kusukela ku-2014.