2013年新药合成路线

Review

Synthetic approaches to the 2013new

drugs

Hong X.Ding a , ,Carolyn A.Leverett d ,à,Robert E.Kyne Jr.d ,§,Kevin K.-C.Liu b ,–,Sarah J.Fink c ,,Andrew C.Flick d , ,Christopher J.O’Donnell d ,?

a

Pharmacodia (Beijing)Co.,Ltd,Beijing 100085,China

b

Lilly China Research and Development Center,Shanghai 201203,China c

BioDuro Co.,Ltd,Shanghai 200131,China d

P?zer Worldwide Research and Development,Groton Laboratories,445Eastern Point Road,Groton,CT 06340,United States

a r t i c l e i n f o Article history:

Received 5January 2015Revised 20February 2015Accepted 26February 2015Available online 6March 2015Keywords:Synthesis

New drug molecules New chemical entities Medicine

Therapeutic agents

a b s t r a c t

New drugs introduced to the market every year represent privileged structures for particular biological targets.These new chemical entities (NCEs)provide insight into molecular recognition and also serve as leads for designing future new drugs.This annual review covers the synthesis of twenty-four NCEs that were approved for the ?rst time in 2013and two 2012drugs which were not covered during the previous edition of this review.

ó2015Elsevier Ltd.All rights reserved.

Contents 1.Introduction .......................................................................................................18962.Acotiamide hydrochloride hydrate (Acofide ò).............................................................................18963.Afatinib dimaleate (G iotrif ò,Gilotrif ò)...................................................................................18964.Canagliflozin hydrate (Invokana ò)......................................................................................18975.

Cetilistat (Oblean ò)......................

(1898)

https://www.sodocs.net/doc/2011366950.html,/10.1016/j.bmc.2015.02.056

0968-0896/ó2015Elsevier Ltd.All rights reserved.

Abbreviations:1,2-DAP,1,2-diaminopropane;1,2-DCE,1,2-dichloroethane;Ac,acetyl;aq,aqueous;Bn,benzyl;Bz,benzoyl;Boc,t -butoxycarbonyl;B 2(pin)2,bis(pinacolato)diboron;BINAP,2,20-bis(diphenylphosphino)-1,10-binaphthyl;BSA,N ,O -bistrimethylsilyl acetamide;CDI,N ,N 0-carbonyldiimidazole;CDMT,2-chloro-4,6-dimethoxy-1,3,5-triazine;DAP,diaminopropane;Dba,dibenzylideneacetone;DBU,1,5-diazabicycolo[4.3.0]non-5-ene;DCC,1,3-dicyclohexylcarbodiimide;DCE,dichloroethane;DCM,dichloromethane;DIAD,diisopropyl azodicarboxylate;DIC,1,3-diisopropylcarbodiimide;DIEA/DIPEA,diisopropylethylamine;(à)-DIP-chloride,(à)-diisopinocampheyl chloroborane;DMA,dimethylacetamide;DMAP,4-dimethylaminopyridine;DME,dimethoxyethane;DMF,N ,N -dimethylformamide;DMSO,dimethyl sulfoxide;DPPA,diphenylphosphoryl azide;EDCI,N -(3-dimethylaminopropyl)-N 0-ethylcarbodiimide;EDTA,ethylenediaminetrteaacetic acid;EEDQ,N -ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline;HBTU,2-(1H -benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate;HMDS,bis(trimethylsilyl)amide;HOBT,1-hydroxy-benzotriazole hydrate;IPA,isopropyl alcohol;IPAc,isopropyl acetate;LAH,lithium aluminum hydride;LHMDS,lithium bis(trimethylsilyl)amide;MIBK,methyl isobutyl ketone;MsOH,methansulfonic acid;MsCl,methanesulfonic chloride;MTBE,methyl tert -butyl ether;NaHMDS,sodium bis(trimethylsilyl)amide;NBS,N -bromosuccinimide;NMM,N -methylmorpholine;NMP,N -methyl-2-pyrrolidone;pin,pinacol;Py,pyridine;rt,room temperature;TBAB,tetrabutylammonium bromide;TBAF,t -butyl ammonium ?uoride;TFA,tri?uoroacetic acid;TFAA,tri?uoroacetic anhydride;THF,tetrahydrofuran;TMEDA,tetramethylethylenediamine;TMP,2,2,6,6-tetramethylpiperidine;TMSCl,trimethylsilyl chloride;TMSI,trimethylsilyl iodide;TBDPS,tert -butyl diisopropylsilyl;Ts,tosyl(p -toluenesulfonyl).?Corresponding author.Tel.:+18607154118.

E-mail addresses:Sheryl.ding@https://www.sodocs.net/doc/2011366950.html, (H.X.Ding),carolyn.a.leverett@p?https://www.sodocs.net/doc/2011366950.html, (C.A.Leverett),robert.kynejr@p?https://www.sodocs.net/doc/2011366950.html, (R.E.Kyne),Liu_kang_zhi_kevin@https://www.sodocs.net/doc/2011366950.html, (K.K.-C.Liu),Sarah.?nk@https://www.sodocs.net/doc/2011366950.html, (S.J.Fink),andrew.?ick@p?https://www.sodocs.net/doc/2011366950.html, (A.C.Flick),christopher.j.odonnell@p?https://www.sodocs.net/doc/2011366950.html, (C.J.O’Donnell).

Tel.:+861082826195.à

Tel.:+18604413936.§

Tel.:+18604411510.–

Tel.:+862120805590.k

Tel.:+862131752858.

Tel.:+18607150228.

6.Cobicistat(Tybostò) (1898)

7.Dabrafenib mesylate(Tafinlarò) (1900)

8.Dolutegravir sodium(Tivicayò) (1901)

9.Efinaconazole(Jubliaò) (1902)

10.Elvitegravir(Vitekaò) (1904)

11.Gemigliptin L-tartrate hydrate(Zemigloò) (1906)

12.Ibrutinib(Imbruvicaò) (1908)

13.Istradefylline(Nouriastò) (1909)

14.Levomilnacipran hydrochloride(Fetzimaò) (1910)

15.Lomitapide mesylate(Juxtapidò) (1912)

16.Macitentan(Opsumitò) (1912)

17.Olodaterol hydrochloride(Striverdi Respimatò) (1914)

18.Ospemifene(Osphenaò) (1914)

19.Pomalidomide(Pomalystò) (1914)

20.Riociguat(Adempasò) (1914)

21.Saroglitazar(Lipaglynò) (1916)

22.Simeprevir(Olysioò;Sovriadò) (1917)

23.Sofosbuvir(Sovaldiò) (1917)

24.Topiroxostat(Uriadecò;Topiloricò) (1917)

25.Trametinib dimethyl sulfoxide(Mekinistò) (1918)

26.Trastuzumab emtansine(Kadcylaò) (1918)

27.Vortioxetine(Brintellixò) (1919)

28.Conclusion (1919)

References and notes (1920)

1.Introduction

‘The most fruitful basis for the discovery of a new drug is to start with an old drug.’–Sir James Whyte Black,winner of the1988 Nobel Prize in medicine.1

This annual review was inaugurated twelve years ago2–12and presents synthetic methods for molecular entities that were approved for the?rst time in various countries during the past year.Given that drugs tend to have structural homology across similar biological targets,it is widely believed that the knowledge of new chemical entities and their syntheses will greatly enhance the ability to design new drugs more ef?ciently.The pharmaceuti-cal industry enjoyed a banner year in2013,with a total of56new products including new chemical entities,biological drugs,and diagnostic agents having reached the worldwide market for the ?rst time.Although an additional19new products were approved for the?rst time in2013,some were not launched before the end of the year,13and therefore this review focuses on the syntheses of twenty-four NCEs that were approved and launched for the?rst time in2013.It also includes two additional drugs that although were initially approved in2012,were not included in our prior review(Fig.1).12New indications for previously launched med-ications,new combinations,new formulations of existing drugs, and drugs synthesized purely via bio-processes or peptide synthe-sizers have been excluded from this review.Although the scale of the synthetic routes were not explicitly disclosed in most cases, this review covers,perceptibly,the most scalable routes that have been disclosed within published or patent literature beginning from commercially available starting materials.Drugs presented in this review are ordered alphabetically by generic name.

2.Acotiamide hydrochloride hydrate(Aco?deò)

Acotiamide hydrochloride trihydrate is the?rst drug to be approved in Japan for the treatment of functional dyspepsia(FD). The drug was discovered by Zeria Pharmaceuticals and jointly developed with Astellas Pharmaceuticals.14The drug blocks mus-carinic receptors and inhibits peripheral acetylcholine esterases, thereby increasing the concentration of acetylcholine,14ultimately improving the impaired gastric motility and delayed gastric emptying along with the additional symptoms associated with FD,such as post prandial fullness,upper abdominal bloating and early satiation.14–16Although multiple synthetic approaches to the drug have been reported,17,18the synthesis highlighted in Scheme1and described below represents the largest scale reported to date in a patent application.18

Commercial3,4,5-trimethoxybenzoic acid(1)was?rst con-verted to the corresponding acid chloride2,which was isolated by co-distillation with hexane.In re?uxing dichloroethane(DCE), the acid chloride was coupled with the commercially available thiazole amine(3)to give the desired amidothiazole4in89%yield. From this intermediate,amide linkage,selective demethylation of the2-methoxy group,salt formation,and recrystallization were accomplished in the following sequence:the thiazole ester4was reacted with N,N-diisopropyl ethylenediamine(5)in DMA at ele-vated temperatures.Upon cooling,the mixture was dissolved in n-butanol and washed with aqueous sodium hydroxide. Subsequent treatment with HCl gas in isopropanol gave the corresponding HCl salt as crystals that could be collected by?ltra-tion.The product obtained was further crystallized from4:1iso-propanol and water to give the desired product acotimide(I)as the hydrochloride trihydrate in71%yield.

3.Afatinib dimaleate(G iotrifò,Gilotrifò)

Afatinib dimaleate was approved by the U.S.Food and Drug Administration(FDA)in2013for the treatment of non-small cell lung cancer(NSCLC).19Speci?cally,it was approved for patients presenting with metastatic NSCLC tumors which contain epider-mal growth factor receptor(EGFR)exon19deletions or exon21 mutations.19Afatinib dimaleate is a covalent inhibitor of ErbB tyr-osine kinases(tyk),which downregulates ErbB signaling by irre-versible binding of EGFR tyk binding sites.19While no manufacturing route has been disclosed to date,20–24the most scal-able published route likely derives from two Boehringer Ingelheim patents(Scheme2).25,26

Nitroquinazolinone(6),which is commercially available,was ?rst chlorinated with phosphorous oxychloride(POCl3)followed by treatment with commercial3-chloro-4-?uoroaniline(7)to afford S N Ar adduct8in90%yield over two steps.Sulfonylation to

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afford9(86%)and subsequent displacement with(S)-tetrahy-drofuran-3-ol gave10in90%yield.25Raney–Nickel reduction of the nitro group delivered11in97%yield,which set the stage for the?nal side-chain functionalization.2-(Diethoxyphosphoryl) acetic acid and N,N0-carbonyldiimidazole(CDI)were pre-mixed and added to aniline11to afford12in70%isolated yield.Next,a Horner–Wadsworth–Emmons homologation gave the(E)-ole?n 13in quantitative yield,followed by maleate salt formation (92%)to deliver the?nal API.The?nal?ve steps of this synthesis have been successfully demonstrated on multi-kilogram scale.24,25 4.Canagli?ozin hydrate(Invokanaò)

Canagli?ozin,an orally active and selective sodium–glucose cotransporter2(SGLT2)inhibitor,was co-developed by Mitsubishi Tanabe Pharma and Johnson&Johnson(J&J)for the treatment of type2diabetes mellitus(T2DM)and obesity.The drug was approved in March by the U.S.FDA and launched in April2013in the U.S.SGLT2is involved in the glucose re-absorp-tion pathway in the kidney,and its inhibition increases urinary glucose excretion,and reduces plasma glucose and HbA1c levels.27 In addition,canagli?ozin is safe in combination with other com-monly used antidiabetic agents and has a signi?cant effect on body weight reduction.28A recently published process patent from ScinoPharm Taiwan describes the synthesis of canagli?ozin.The preparation of the drug involves a convergent strategy whereby the union of the aglycone and glycoside components of the mole-cule ultimately secure the atomic framework of the API—the syn-thesis of each region and their union are described in Scheme3.29 Synthesis of the aglycone region of canagli?ozin was described in a separate patent by?rst condensing commercially available5-bromo-2-methylbenzoyl chloride(14)and2-(4-?uorophenyl)-thiophene(15)under Friedel–Crafts acylation conditions to give ketone16in69%yield as a crystalline solid.29Ketone16was then reduced with triethylsilyl hydride in the presence of BF3áEt2O at low temperature to give aglycone bromide17in70%yield.The precursor for the glycoside moiety,commercially available gly-coside triol18,was selectively treated with t-butyldiphenylsilyl chloride(TBDPSCl)in THF in the presence of imidazole to give the bis-silyl ether19in81%yield.Next,a unique,stereospeci?c b-C-arylglucosidation was developed to secure the union of the aglyone-and glycoside-containing portions of canagli?ozin. Bromide17was subjected to magnesium powder under standard Grignard conditions prior to treatment with AlCl3in THF in situ. This resulting mixture was then exposed to a solution of com-pound19in PhOMe which had been pre-treated with n-BuLi,and

H.X.Ding et al./Bioorg.Med.Chem.23(2015)1895–19221897

the entire mixture was then warmed to150°C for5h to ultimately give the b-anomer20in56%yield.Finally,removal of the silyl groups within20with tetrabutyl ammonium?uoride(TBAF)in THF delivered canagli?ozin hydrate(III)in73%yield(Scheme3).

5.Cetilistat(Obleanò)

Cetilistat is a selective pancreatic lipase inhibitor which was approved in Japan in September2013for the treatment of obesity. The drug was discovered by Alizyme PLC and later co-developed with Takeda.Cetilistat demonstrated a lower incidence of adverse gastrointestinal events during a12week clinical trial,and the degree of weight loss associated with cetilistat is comparable to that of other approved antiobesity therapies.30The most likely pro-cess-scale preparation of cetilistat is described below in Scheme.4.31

Commercially available hexadecanol(21)was treated with phosgene in THF/toluene to give the corresponding chloroformate (22),which was immediately subjected to commercial2-amino-5-methylbenzoic acid(23)in pyridine.Subsequent slow addition of methyl chloroformate at room temperature resulted in the forma-tion of cetilistat(IV),which was produced in31%overall yield from hexadecanol.31

6.Cobicistat(Tybostò)

Cobicistat,a selective,mechanism-based CYP3A inhibitor,was discovered and developed by Gilead Sciences,Inc.In2013, European Medicines Agency(EMA)approved cobicistat(Tybostò) for the treatment of HIV-1infection in combination with protease inhibitors(PIs)atazanavir or darunavir.Interestingly,cobicistat does not interact with HIV directly,but instead serves as a pharmacokinetic enhancer to boost the anti-HIV effect of atazana-vir or darunavir through blockade of CYP3A.32Cobicistat slows CYP-mediated metabolism of atazanavir and darunavir,resulting in prolonged systemic exposure of the drug(s).32Cobicistat is also available as part of a?xed-dose combination tablet(Stribildò)of four additional drugs with CYP3A liabilities(elvitegravir,cobicistat, emtricitabine and tenofovir disoproxil fumarate),which was approved in U.S.in2012,and subsequently approved in Europe

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and Japan in2013.Although several synthetic routes have been reported,33–37the improved process route by Gilead Sciences is described in Schemes5and6.37

Commercial L-methionine(24)was treated with bromoacetic acid at elevated temperatures to afford aminolactone salt25in 70%yield.This material was then reacted with methyl aminomethylthiazole(26)in the presence of CDI and diisopropy-lethylamine to arrive at urea27in91%yield.Next,lactone27 underwent a ring-opening sequence upon exposure to trimethylsi-lyl iodide(TMSI)giving intermediate28.The iodide was then dis-placed by morpholine,followed by treatment with oxalic acid to deliver the L-thiazole morpholine ethyl ester as the oxalate salt

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29in71%yield for the sequence.Base-mediated hydrolysis of ethyl ester29,followed by treatment of carboxylate30with mono-car-bonate hydrochloride31in the presence of EDCI and HOBT,pro-vided cobicistat(V)in76%yield for two steps.

Of note,the preparation of mono-carbonate hydrochloride31 arose from commercially available(S)-2-benzylaziridine(32) which was?rst condensed with N,N-dimethylsulfamoyl chloride to obtain N-tosyl-protected aziridine33in77%yield(Scheme6). Next,a unique base-induced dimerization reaction was employed to convert aziridine33to alkene34.Presumably this proceeded through initial deprotonation at the methylene carbon within azir-idine33upon exposure to lithium2,2,6,6-tetramethylpiperidine (LiTMP)resulting in an unstable trans-R-lithiated terminal aziri-dine.This lithiate then underwent nucleophilic attack onto another molecule of33followed by elimination to give the2-ene-1,4-dia-mine34in72%yield.37–39Removal of the sulfonyl groups with 1,3-diaminopropane followed by hydrogenation of the alkene pro-vided diamine36in quantitative yield.Conversion to the diamine–dihydrogen chloride37through the use of HCl in dioxane was followed by a treatment with a single equivalent of base and 5-thiazolylmethyl carbonate38(prepared from bis-(4-nitro-phenyl)-carbonate(39)with5-hydroxymethylthiazole).This sequence furnished amino carbamate31,which then participated in the coupling with carboxylate fragment30to prepare cobicistat as described above.

7.Dabrafenib mesylate(Ta?nlarò)

Dabrafenib mesylate,sold by GlaxoSmithKline under the trade name Ta?nlarò,was approved by the U.S.FDA in May2013for the treatment of metastatic BRAF-mutant melanoma.Dabrafenib reversibly inhibits the BRAF(V600E)mutant kinase as a selective ATP-competitive inhibitor which results in tumor regression.40 While the process-scale route has not yet been disclosed,41–43the largest scale route to date is represented in Scheme7.44 Commercially available?uoroaniline4042was?rst converted to sulfonamide42in91%yield by treatment with2,5-di?uoroben-zenesulfonyl chloride(41)in the presence of pyridine.Next,depro-tonation of2-chloro-4-methylpyrimidine(43)with lithium bis(trimethylsilyl)amide(LHMDS)followed by addition to ester 42afforded chloropyrimidine44in72%yield.Bromination fol-lowed by thiazole formation through the use of2,2-dimethyl-propanethioamide gave the penultimate target45in80%over two steps.Chloropyrimidine45was subjected to S N Ar conditions

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with ammonium hydroxide to furnish the aminopyrimidine in88% yield,and this was followed by exposure to methanesulfonic acid to afford dabrafenib mesylate(VI)in85%yield.44

8.Dolutegravir sodium(Tivicayò)

Dolutegravir sodium(Tivicayò),developed and marketed by GlaxoSmithKline,45was approved by the FDA in August2013as a novel integrase inhibitor for the treatment of HIV infection.46 Dolutegravir was fast-tracked by the FDA in February2012,47and joins an important class of drugs known as Integrase Strand Transfer inhibitors(INSTi’s).48INSTi’s are characterized by their two-metal-chelating scaffolds,which are known to chelate Mg2+ cofactors in the enzyme active site,49,50l interrupting function of HIV-1integrase,which is essential for replication of viral DNA into host chromatin.49–52Other drugs in this class,raltegravir and elvitegravir,are known to require either high dosages53or PK boosting agents,54respectively,with raltegravir also exhibiting substantial loss of potency in several major HIV-1integrase muta-tion pathways.55Dolutegravir was pursued with the goal of devel-oping a novel INSTi with a once-daily,low-dosage treatment with improved resistance pro?le and without the need for the use of a PK boosting agent.51,56Dolutegravir sodium has been approved for treating a broad population of HIV-infected patients,including adults undergoing their?rst treatment as well as those who have been treated with other integrase transfer strand inhibiting agents.46

The most likely process-scale synthesis of dolutegravir sodium, as described in Scheme8,began with benzyl protection and alky-lation of pyrone46with benzaldehyde,yielding alcohol47in74%

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over2steps(Scheme8).57,58Alcohol mesylation and in situ elim-ination provided the styrenyl ole?n48in94%yield,which further underwent an oxidative cleavage of the ole?n to generate49by sequential addition of RuCl3/NaIO4and NaClO2(56%overall yield). Treatment of pyranone49with3-amino-propane-2-diol(50)in ethanol at elevated temperatures delivered the corresponding pyridinone in83%yield,and this was followed by esteri?cation and sodium periodate-mediated diol cleavage to furnish intermediate51in71%overall yield across the two-step sequence.57,58l Next,the key ring-forming step in the synthesis of dolutegravir sodium consisted of cyclization of51with(R)-3-amino-butan-1-ol,a process which relies on substrate control to provide the desired tricyclic carbamoylpyridone system52in high stereoselectivity(20/1in favor of the desired isomer).51Previously, cyclization of systems such as51with unsubstituted amino alco-hols were found to yield a mixture of diastereomeric products, therefore indicating the pivotal role of the chiral amino alcohol in in?uencing stereochemical bias during the overall cyclization step.51,56In practice,reaction of51with(R)-3-amino-butan-1-ol at90°C led to isolation of a single cyclization product52,after recrystallization from EtOAc.57,58From52,N-bromosuccinimide (NBS)bromination and subsequent treatment with amine53under palladium-catalyzed amidocarbonylative conditions led to amide 54in75%yield over2steps.Finally,removal of the benzyl group and subsequent crystallization using sodium hydroxide in water and ethanol provided dolutegravir sodium(VII)in99%yield.57,589.E?naconazole(Jubliaò)

E?naconazole,marketed and developed by Valeant Pharmaceuticals International,was?rst approved for use in Canada in October2013under the brand name Jubliaòfor the treatment of onychomycosis,a fungal infection of the nail. E?naconazole is believed to work by14a-demethylase inhibition, which is a key pathway in ergosterol synthesis.59Inhibition of ergosterol prevents secondary degenerative changes in the nail bed,plate,and surrounding tissue.59Although several syntheses of e?naconazole have been reported,none have reported on kilo-gram-scale.60–64However,as preparation of the penultimate epox-ide(60)has been described on hundred-kilogram scale in the synthesis of ravuconazole,65and?nal production of e?naconazole has been disclosed on a24g scale route,the presumed scale route is described in Scheme9.66

Commercially available(R)-methyl lactate(55)was?rst con-verted to THP protected alcohol57in4steps and78%yield via morpholino amide56.Grignard displacement of the morpholine afforded ketone58in81%yield.Next,ketone58was epoxidized by means of the Corey ylide followed by ring-opening of the epox-ide by triazole which had been activated by exposure to sodium t-butoxide.Finally,subjection to methanesulfonic acid furnished diol59in51%yield as the corresponding mesylate salt.Diol59 was then converted to epoxide60through the use of mesyl chlo-ride and triethylamine in78%yield and>99%ee.Finally,treatment

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of epoxide60with4-methylene piperidine–HBr in the presence of lithium hydroxide afforded e?naconazole(VIII)in87%yield.

10.Elvitegravir(Vitekaò)

Elvitegravir is a quinolone-containing HIV integrase inhibitor discovered by Japan Tobacco and licensed to Gilead Pharmaceuticals for worldwide development with the exception of Japan.67It was approved in Europe in2013for the treatment of HIV infection in adults having no known mutations associated with resistance to the drug.67The drug interferes with HIV replica-tion by preventing the virus from integrating into the DNA of human cells.67,68In addition to several patent applications that have been?led for the synthesis of elvitegravir,the discovery

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synthesis69has also been published.69–80The process route that has been reported on kilogram scale is highlighted in Scheme10. None of the synthetic intermediates reportedly were isolated but instead were carried forward in the sequence.Therefore,no yields were provided in the lead reference.76

Commercial2,4-dimethoxy-5-bromo benzoic acid(61)was reacted with0.5equiv of butylethylmagnesium to generate the dimagnesium salt in THF,which was then lithiated atà20°C to give the aryl lithium species.The aryl lithium species was then reacted with the2-?uoro-3-chloro benzaldehyde(62)to give

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alcohol63.Treatment with triethylsilane in TFA resulted in removal of the hydroxyl functionality to provide benzoic acid64. This acid was then reacted with carbonyldiimidazole and subse-quently magnesium malonate65to give ketoester66after workup.Next,condensation with DMF–DMA converted ketoester 66to the vinylogous amide67,and this material was immediately subjected to an addition–elimination reaction involving(S)-valinol (68)in toluene at ambient temperature to provide intermediate69. Warming the resulting intermediate69in the presence of N,O-bistrimethylsilyl acetamide(BSA)and potassium chloride in DMF furnished the ring-closed quinolone70.The ester70was saponi-?ed with potassium hydroxide in aqueous isopropanol and then acidi?ed and crystallized with the use of seed crystals.Upon cooling,the crystalline product elvitegravir(IX)was collected by ?ltration.

11.Gemigliptin L-tartrate hydrate(Zemigloò)

Gemigliptin is a prolyl-speci?c dipeptidyl aminopeptidase IV (DPP IV,DPP-4,CD26)inhibitor approved for the treatment of type 2diabetes mellitus by the Korean Food and Drug Administration in 2012.Gemigliptin was discovered and developed by LG Life Sciences81and is now the sixth DPP-4inhibitor approved for the treatment of type2diabetes.82At the time this review was pre-pared,there were no publications describing the discovery strategy and preclinical data that led to the advancement of gemigliptin to

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the clinic.Additionally,the synthesis of the drug has only been described in the patent literature.83–85

The molecule was prepared via a convergent route and the syn-thesis of the dihydropyridopyrimidine fragment is described in Scheme11.85Commercial N-Boc-3-piperidone(71)was treated with LHMDS followed by ethyl tri?uoroacetate to effect a Claisen condensation,producing diketone72in81%yield.Cyclization of 72with2,2,2-tri?uoroacetamide(73)gave bis-tri?uoromethyl dihydropyridopyrimidine74in23%yield.Removal of the Boc pro-tecting group ef?ciently provided amine75in96%yield.

The synthesis of the carbon skeleton of the di?uoropyridone fragment80is described in Scheme12.841,4-Addition of ethyl bro-modi?uoroacetate(76)to ethyl acrylate(77)in the presence of copper powder and tetramethylethylenediamine(TMEDA)gave diester78,which was selectively reduced with sodium borohy-dride(NaBH4)to give alcohol79in90%overall yield for the two-step procedure.Alcohol79was then treated with per?uo-robutanesulfonyl chloride and triethylamine to give activated alcohol80in75%yield.

The completion of the synthesis of gemigliptin is described in Scheme13.83,84Boc-L-aspartic acid4-tert-butyl ester(81)was trea-ted with ammonium bicarbonate and pyridine in the presence of di-tert-butyl dicarbonate to give formamide82.Dehydration of 82to give nitrile83was accomplished through reaction with cya-nuric chloride in95%overall yield for the two-step sequence. Hydrogenation of83in the presence of Pearlman’s catalyst

H.X.Ding et al./Bioorg.Med.Chem.23(2015)1895–19221907

provided butyl amine84.Alkylation of84with activated alcohol 80in triethylamine followed by cyclization in acetic acid afforded di?uoropyridone85.Acidic hydrolysis of the ester proceeded with concomitant removal of the Boc protecting group,and was fol-lowed by reprotection of the amine with di-tert-butyl dicarbonate to give acid86in84%overall yield for the three-step procedure in >97%ee.Coupling of86with fragment75in the presence of1-hy-droxybenzotriazole(HOBT)and1-ethyl-3-(3-dimethylamino-propyl)carbodiimide(EDC)gave amide87in51%yield.Removal of the Boc group with thionyl chloride in ethanol followed by neu-tralization with aqueous sodium hydroxide and salt formation with L-tartaric acid provided gemigliptin L-tartrate hydrate(X)in 97.5%yield.83

12.Ibrutinib(Imbruvicaò)

Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK)which was granted breakthrough status by the U.S.Food and Drug Administration in2013for the treatment of mantle cell lymphoma(MCL)and in2014for chronic lymphocytic leukemia (CLL).86In preclinical studies involving CLL cells,the drug effec-tively promoted apoptosis,inhibited proliferation,and also

1908H.X.Ding et al./Bioorg.Med.Chem.23(2015)1895–1922

prevented CLL cells from responding to survival stimuli provided by the microenvironment.87Ibrutinib demonstrated superiority over an anti-CD20antibody(atumumab)in terms of disease pro-gression measurements and overall survival of the patient.87The drug,which was discovered by Celera Pharmaceuticals and acquired by Pharmacyclics,was developed in partnership with Johnson&Johnson’s Janssen Pharmaceutical division.Although several different synthetic approaches to ibrutinib have been described in the patent literature,88–91the most likely scale route is described in Scheme14.92–95

Condensation of commercially available4-phenoxybenzoyl chloride(88)with malononitrile followed by acidic quench and O-methylation with dimethyl sulfate furnished vinyl dinitrile89 in84%yield over the three-step sequence.Next,treatment with hydrazine hydrate in re?uxing ethanol secured aminopyrazole90 and this was followed by treatment with neat formamide at ele-vated temperature to furnish pyrimidopyrazole91in excellent conversion.Selective alkylation of the pyrazole nitrogen with com-mercially-available(S)-piperidinyl tosylate(92)proceeded in32% yield.95Finally,liberation of the amide followed by pH adjustment and amide bond formation with acrolyl chloride furnished ibruti-nib(XI)in50%over the three-step sequence.

13.Istradefylline(Nouriastò)

Istradefylline(Nouriastò),a selective adenosine A2A inhibitor developed by Kyowa Pharmaceuticals,was approved in Japan in 2013as an adjunctive therapy for the treatment of Parkinson’s dis-ease(PD).96,97A majority of therapies for PD,including the primary treatment,Levodopa,98function via dopamine replacement.99These treatments are very effective in the early stages of PD but they often exhibit dyskinesias symptoms in long-term treatment, leading to the inability to control motor?uctuations and therefore resulting in involuntary movements in patients.100–102In contrast, istradefylline has been shown to reverse motor disability in mon-keys and provide anti-Parkinsonian effects without exhibiting tra-ditional symptoms of dyskinesias.103While the ability to completely reproduce these results in human PD patients with istradefylline therapy exclusively are still inconclusive,104this once-daily oral treatment has shown great potential for improving the quality of life for PD patients because of its effectiveness when used with other dopamine replacement treatments.102,105 Numerous synthetic approaches to istradefylline have been developed,with a large majority of these methods employing 5,6-amino-1,3-diethyluracil97as a key intermediate.106–109 Despite the commercial availability of96,most reported routes to istradefylline rely on sourcing of this intermediate via a well-established four-step synthesis from N,N-diethylurea(94)and cya-noacetic acid(95).106,110,111Speci?cally,6-amino-1,3-diethyluracil (96)can be formed by sequential treatment of94and95with Ac2O and NaOH.Nitrosation of96with NaNO2/AcOH/H2O,followed by Na2S2O4/NH3-mediated nitroso reduction provided5,6-amino-1,3-diethyluracil(97).110,111

Even though other groups have recently reported modi?ed scale routes to istradefylline,106the route described herein will focus on the sequence outlined by Kyowa Hakko Kogyo research laborato-ries during their initial development of istradefylline.109,112–114 EDC-mediated amine coupling involving97and3,4-dimethoxycin-namic acid(98)led to the corresponding amide intermediate.After aqueous workup,this crude amide intermediate underwent

H.X.Ding et al./Bioorg.Med.Chem.23(2015)1895–19221909

cyclization with aqueous sodium hydroxide to yield the desired purine dione99in47%yield over2steps.Methylation of99with MeI/K2CO3provided istradefylline(XII)in68%yield (Scheme15).109

14.Levomilnacipran hydrochloride(Fetzimaò)

Levomilnacipran(Fetzimaò)is a dual serotonin–norepinephrine reuptake inhibitor(SNRI)approved by the FDA in2013for the treatment of major depressive disorders(MDD).115–118Levomilnacipran is the most active enantiomer of the racemate Milnacipran,119which is currently used to treat pain associated with?bromyalgia.120,121The drug was developed by Forest Laboratories and the Pierre Fabre group.116,122

Although initial enantiopure samples of levomilnacipran could be obtained by chromatographic separation of Milnacipran,this method was unable to provide suf?cient quantities of material for pharmaceutical applications.123–125Enantioselective routes have also been pursued,119,126–128but most rely on the use of sodium azide,which suffers from toxicity and stability issues on

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large scale.129However,development of a scalable route to levo-milnacipran has now been accomplished via optically active intermediate 102.119,126,128This synthetic approach is described in Scheme 16.129

Reaction of phenylacetonitrile (100)and commercially available (R )-epichlorohydrin (101)with NaNH 2led to chloride displace-ment and intramolecular cyclopropanation,yielding lactone 102after a one-pot nitrile hydrolysis and acid-promoted lactonization

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(75%yield over3steps).Lactone ring-opening with Et2NH–AlCl3 complex provided amido-alcohol103,which was converted to its phthalimido derivative104by sequential treatment with thionyl chloride and potassium phthalimide in80%over three steps. Finally,levomilnacipran hydrochloride(XIII)was obtained in >95%optical purity after phthalimide cleavage,HCl salt formation, and crystallization from HCl/i-PrOH/i-PrAc.This sequence repre-sents a highly ef?cient route to levomilnacipran,requiring no iso-lation of intermediates,resulting in>40%overall yield,and allowing use of the same solvent solution(toluene)for all steps.

15.Lomitapide mesylate(Juxtapidò)

Lomitapide is an orally active microsomal triglyceride transfer protein(MTP)inhibitor for the treatment of hypercholes-terolemia.130The drug was developed by Aegerion Pharmaceuticals Inc.and licensed to Bristol–Myers Squibb Co. and the University of Pennsylvania.130Lomitapide effectively low-ered LDL–cholesterol,both as a single agent and in combination with commonly prescribed lipid-lowering therapies.130Sold under the trade name Juxtapidò,the drug offers a new treatment option to patients who cannot tolerate statin therapy or who experience insuf?cient LDL–cholesterol reduction with the currently available therapies,such as patients with homozygous familial hypercholes-terolemia caused by mutations in the LDLR gene.130The most likely scale synthetic route to lomitapide mesylate is described in Scheme17.131

Commercial9H-?uorene-9-carboxylic acid(105)was alkylated with1,4-dibromobutane in the presence of n-butyl lithium in THF to give9-(4-bromobutyl)-9H-?uorene-9-carboxylic acid (106)in85%yield.Next,activation of the acid as the acid chloride followed by coupling with(2,2,2-tri?uoroethylamine)provided amide107in71%yield for the two-step sequence.Displacement of the terminal bromide with the appropriate4-carbamoyl piperidine followed by removal of the Boc group furnished piperi-dinyl?uorine108in high yield.Amine108was then reacted with the acid chloride derived from acid109(derived from the Suzuki coupling of boronic acid110and o-iodobenzoic acid111)132to give lomitapide,and this was followed by salt formation with methane-sulfonic acid to afford lomitapide mesylate(XIV).131

16.Macitentan(Opsumitò)

Macitentan(Opsumitò)is an endothelin receptor antagonist marketed by Actelion,133and was?rst approved in the U.S.in October2013for the treatment of Pulmonary Arterial Hypertension(PAH).134,135Soon after,the drug obtained approval in Canada,and is currently under regulatory review in other coun-tries.136Macitentan exhibits greater inhibitory action of ET A versus ET B receptor agonists,137–139with higher potency than bosentan,138 allowing for once-daily dosing at signi?cantly lower levels.140The most likely scale worthy route of macitentan is described in Scheme18.139,141

The preparation of the drug began with reaction of commercial 4-bromophenylacetate(112)with dimethylcarbonate(113)under basic conditions to yield the malonate ester114.139,141Treatment of this diester with sodium methoxide and formamidine hydrochloride115provided the desired intermediate4,6-dihydroxypyrimidine as a tautomeric mixture;from this system, dichloride116was generated in60–80%yield upon treatment with warm phosphorus oxychloride in N,N-dimethylaniline.Reaction of 116with excess sulfonyl urea potassium salt117139provided chloropyrimidine118in high yield(83–93%).This was reacted with bromochloropyrimidine119in an S N Ar reaction to provide macitentan(XV)in88%yield.141

Synthesis of sulfamide potassium salt117was accomplished via sequential reaction of chlorosulfonyl isocyanate(120)with t-BuOH and propylamine/Et3N to provide ester sulfamide121,

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followed by Boc removal and treatment with potassium t-butoxide to yield117.This material could be isolated by trituration with diethyl ether.

17.Olodaterol hydrochloride(Striverdi Respimatò)

Olodaterol hydrochloride was approved for long-term,once-daily maintenance treatment of chronic obstructive pulmonary disease(COPD)in2013in the following countries:Canada, Russia,United Kingdom,Denmark,and Iceland.142,143The drug has been recommended by a federal advisory panel for approval by the FDA.142,143Developed and marketed by Boehringer Ingelheim,olodaterol is a long-acting b2-adrenergic receptor ago-nist with high selectivity over the b1-and b3-receptors(219-and 1622-fold,respectively).144Upon binding to and activating the b2-adrenergic receptor in the airway,olodaterol stimulates adenyl cyclase to synthesize cAMP,leading to the relaxation of smooth muscle cells in the airway.Administered by inhalation using the RespimatòSoft Mist inhaler,it delivers signi?cant bronchodilator effects within?ve minutes of the?rst dose and provides sustained improvement in forced expiratory volume(FEV1)for over24h.143 While several routes have been reported in the patent and pub-lished literature,144–146the manufacturing route for olodaterol hydrochloride disclosed in2011is summarized in Scheme19 below.147

Commercial20,50-dihydroxyacetophenone(122)was treated with one equivalent of benzyl bromide and potassium carbonate in methylisobutylketone(MIBK)to give the50-monobenzylated product in76%yield.Subsequent nitration occurred at the40-posi-tion to provide nitrophenol123in87%yield.Reduction of the nitro group followed by subjection to chloroacetyl chloride resulted in the construction of benzoxazine124in82%yield.Next,mono-bromination through the use of tetrabutylammonium tribromide occurred at the acetophenone carbon to provide bromoketone 125,and this was followed by asymmetric reduction of the ketone employing(à)-DIP chloride to afford an intermediate bro-mohydrin,which underwent conversion to the corresponding epoxide126in situ upon treatment with aqueous NaOH.This epoxide was ef?ciently formed in85%yield and98.3%enan-tiomeric excess.Epoxide126underwent ring-opening upon sub-jection to amine127to provide amino-alcohol128in in84–90% yield and89.5–99.5%enantiomeric purity following salt formation with HCl.Tertiary amine127was itself prepared in three steps by reaction of ketone129with methylmagnesium chloride,Ritter reaction of the tertiary alcohol with acetonitrile,and hydrolysis of the resultant acetamide with ethanolic potassium hydroxide. Hydrogenative removal of the benzyl ether within128followed by recrystallization with methanolic isopropanol furnished olo-daterol hydrochloride(XVI)in63–70%yield.Overall,the synthesis of olodaterol hydrochloride required10total steps(7linear)from commercially available acetophenone122.

18.Ospemifene(Osphenaò)

Ospemifene was approved by the U.S.FDA in February2013for treatment of moderate to severe dyspareunia(painful intercourse), a symptom of menopause-related vulvovaginal atrophy(VVA);it is the?rst non-hormonal treatment approved for this indication.148 Ospemifene was developed by QuatRx Pharmaceuticals,which acquired the drug as part of a merger with Hormos Medical in 2005,and was licensed to Shionogi for regulatory?ling and world-wide commercialization.148It is a selective estrogen receptor mod-ulator(SERM),and although it possesses a similar structure to tamoxifen and toremifene,ospemifene displays a unique set of tis-sue-speci?c estrogenic agonist/antagonist effects which includes an estrogen-like effect on vaginal epithelium.149Although several synthetic routes have been reported,150–154no manufacturing route for ospemifene has been disclosed to date.The shortest and largest scale route disclosed in the patent literature is sum-marized in Scheme20.155

The drug can be synthesized succinctly in two steps.First,alky-lation of commercially available4-hydroxybenzophenone(130) with ethylene carbonate and catalytic sodium iodide in re?uxing toluene provided benzophenone131in94%yield.This was fol-lowed by a McMurry coupling involving benzophenone131with chloropropiophenone132in the presence of zinc powder and tita-nium tetrachloride in2-methyltetrahydrofuran.This reaction gave rise to a mixture of triphenylethylenes directly as a5.5:1ratio of Z to E isomers which could be separated by crystallization in aque-ous methanol to give a mixture of ole?ns,98%of which was com-prised of the desired Z-isomer corresponding to ospemifene(XVII). The product purity was further improved by recrystallization to give99.9%of the Z-isomer in46%yield from131.Thus,ospemifene was synthesized in two steps and43%overall yield.

19.Pomalidomide(Pomalystò)

Pomalidomide,an anti-angiogenic derivative of thalidomide marketed by Celgene as Pomalystò,was originally discovered in the early1990s by D’Amato and co-workers at Boston Children’s Hospital.156The drug was approved in February2013by the U.S. Food and Drug Administration(FDA)for the treatment of relapsed and refractory multiple myeloma,and received similar approval from the European Commission in August2013(the drug will be marketed in Europe under the name Imnovidò).157Interestingly, the structural optimization of thalidomide and the related thera-peutic agent lenalidomide led to the discovery of pomalidomide (XVIII),which is10-fold more potent than lenalidomide as a TNF-a inhibitor and IL-2stimulator,and has been shown to be effective in overcoming resistance to lenalidomide and thalido-mide as well as the proteosome inhibitor bortezomib.158A scalable preparation of pomalidomide(which has been developed as a race-mate due to rapid interconversion of the R-and S-enantiomers in vivo)159,160involves the sequence described in Scheme21.161 First,condensation of commercially available3-nitrophthalic anhydride(133)and L-glutamine in warm DMF gave nitroph-thalimide134.161Although the authors from Celgene do not explicitly describe the racemization of the stereocenter derived from L-glutamine,scrambling of the stereocenter has been reported during this step under neutral conditions at elevated temperatures.161Next,hydrogenative reduction of the nitro group furnished the anilinophthalimide135,and this was followed by treatment with CDI in re?uxing acetonitrile to secure the piperi-done dione and ultimately furnish pomalidomide(XVIII)as the racemate in87%overall yield from134.

20.Riociguat(Adempasò)

Riociguat is a potent,oral stimulator of soluble guanylate cyclase(sGC).162Riociguat can sensitize sGC to endogenous nitric oxide(NO)by stabilizing NO–sGC binding,and also directly stimu-late sGC in a NO-independent manner to increase generation of cGMP to affect subsequent vasodilation.162,163Discovered by Bayer Healthcare,riociguat obtained approval in Canada for the treatment of adults with persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension(CTEPH),and was later approved by the U.S.FDA in2013for the treatments of both CTEPH and Pulmonary Arterial Hypertension(PAH).164Several strategies for the assembly of the drug have been reported,165–171and the process route is described below in Scheme22.171

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设计药物合成路线的方法

设计药物合成路线的方法 一．主要思路 二．主要步骤 1药物结构的剖析：在设计药物的合成路线时，首先应从剖析药物的化学结构入手，然后根据其结构特点，采取相应的设计方法。 2药物剖析的方法：对药物的化学结构进行整体及部位剖析时，应首先分清主环与侧链，基本骨架与功能基团，进而弄清这些功能基以何种方式和位置同主环或基本骨架连接。 研究分子中各部分的结合情况，找出易拆键部位。键易拆的部位也就是设计合成路线时的连接点以及与杂原子或极性功能基的连接部位。如：C －O 、C －S 、C －N 键等。 3考虑基本骨架的组合方式，形成方法；如：基本骨架是芳香环，可采用苯或者苯的同系物或衍生物为原料合成； 基本骨架为杂环化合物的，有一部分可以以天然来源的杂环化合物为原料，例如吡啶，但大部分需要采用缩合或者环合的方式合成。 以此化合物的合成为 例： 4.类型反应法 类型反应法—指利用常见的典型有机化学反应与合成方法进行的合成设计。 主要包括各类有机化合物的通用合成方法，功能基的形成、转换、保护的合成反应单元。 对于有明显类型结构特点以及功能基特点的化合物，可采用此种方法进行设计。 利用典型有机化学反应：如烷基化反应、酰基化反应、酯化反应、缩合反应等等。 例1 抗霉菌药物克霉唑（邻氯代三苯甲基咪唑） 药物合成工艺路线 和引入次序功能基和侧链形成方法功能基一侧链架组合方式主环形成方法或基本骨主环与基本骨架工艺路线设计??? ? ???????→→?

路线一： 路线二： Cl C 6 H C 6 H 5 5 N H N Cl CH 3 Cl CCl 3 Cl C 6 H 5 C 6 H 5 Cl Cl COOC 2 H 5 Cl C 6 H 5 C 6 H 5 OH Cl C 6 H 5 C 6 H 5 Cl Cl COOH Cl COCl Cl COC 6 H 5 Cl Cl C 6 H 5 Cl Cl C 6 H 5 C 6 H 5 Cl

工作计划路线图模板

工作计划路线图模板 篇一：“拜访计划、拜访内容和拜访路线”的标准流程模板 “拜访计划、拜访内容和拜访路线”的标准流程模板 一、拜访计划 制定拜访计划 合理的制定拜访计划可降低工作的盲目性，提升客户经理的工作效率。拜访计划制定包括月工作计划、周拜访计划、日计划。 月拜访计划 （1）制定时间：每月月末制定下个月工作计划，月初确认。 （2）月工作目标：客户经理根据客户服务中心的下达的月度营销计划任务，明确下月工作目标包括销量、重点品牌、重点品牌上柜率、卷烟销售结构等； （3）拜访计划：明确每项工作重点、工作需要达到的目标及工作时间等； （4）总结提升：制定月工作计划后，每月月末回顾月工作计划完成情况，月工作中的不足之处及改进行措施，对计划实施情况进行跟踪改进。 周拜访计划

（1）制定时间：每周五制定提交下周拜访计划 （2）细化目标：月计划中在本周完成的部分，上周未完成的计划，根据近期工作动态新增的计划，上级交办的任务及其它常规工作等。周计划要细化到每日工作，拜访对象，工作重点及工作需要达到的标准等。 （3）规划路线：根据本周重点拜访内容及对象将片区划分为若干走访路线，将集中的而且是同为当日或次日订货的客户确定为同一拜访线路。 （4）临时性工作：按照“时间四限性”法则评估临时性工作的重要性，按重要程度合理分配时间，临时性工作可先处理，但是用时不可超过预留时间；临时性工作确实无法在预留时间内完成的，可适当调整当日和次日拜访内容，确保当日拜访任务的完成。 （5）制定拜访时长，预留临时性工作和处理应急事件的时间，进行时间管理。 日拜访计划 （1）、制定时间：走访之前或走访日前一天 （2）、明确目标：将周计划工作目标细化至每个工作日，对当日工作目标进行再次确认，可适当进行微调。确定当日应走访客户名单及特殊情况应于当日走访的客户名单，并明确各客户的服务内容，明确当日走访路线。

杜邦康宽

杜邦康宽 杜邦?康宽?是新型水稻、玉米、甘蔗杀虫剂，具有新型作用机理。施药后让害虫立即停止取食，从而迅速保护作物。杀虫谱广，针对稻纵卷叶螟、二化螟、三化螟、大螟和稻水象甲等稻田害虫，玉米螟、小地老虎等玉米田害虫，蔗螟、小地老虎等甘蔗害虫均能高效防除。作为一款内吸性杀虫剂，杜邦?康宽?能有效保护全株作物，特别是新生叶片，因此持效期较长，帮助减少施药次数，且具耐雨水冲刷，水稻、玉米、甘蔗种植者使用更省工。较短的采收间隔期，为种植者提供极大的施药灵活性。微毒农药，正确使用对登记作物安全。杜邦?康宽?的独特作用机理含20%氯虫苯甲酰胺，可高效激活害虫鱼尼丁受体，释放细胞内贮存的钙离子，引起肌肉调节衰弱，麻痹直至最后害虫死亡。登记作物和使用方法针对水稻的防治对象大螟。制剂用药量为8.3-10毫升/亩。使用方法为喷雾。针对水稻的防治对象稻水象甲。制剂用药量为6.67-13.3毫升/亩。使用方法为喷雾。针对水稻的防治对象稻纵卷叶螟。制剂用药量为5-10毫升/亩。使用方法为喷雾。针对水稻的防治对象二化螟。制剂用药量为5-10毫升/亩。使用方法为喷雾。针对水稻的防治对象三化螟。制剂用药量为5-10毫升/亩。使用方法为喷雾。针对玉米的防治对象玉米螟。制剂用药量为4-5毫升/亩。使

用方法为喷雾。针对玉米的防治对象小地老虎。制剂用药量为3.3-6.6毫升/亩。使用方法为喷雾。针对甘蔗的防治对象蔗螟。制剂用药量为15-20毫升/亩。使用方法为喷雾。针对甘蔗的防治对象小地老虎。制剂用药量为6.7-10毫升/亩。使用方法为喷雾。使用说明水稻/稻纵卷叶螟、三化螟、二化螟：于稻纵卷叶螟、二化螟、三化螟卵孵高峰期，亩兑水30公斤茎叶均匀喷雾；稻纵卷叶螟发生严重时，可于14天后（按当地实际情况可适当缩短）再喷药一次。水稻/大螟：卵孵高峰期；稻水象甲：成虫开始出现时/移栽后1-2天，亩兑水30公斤茎叶均匀喷雾。玉米/玉米螟：卵孵高峰期，亩兑水30公斤茎叶均匀喷雾；小地老虎：害虫发生的早期/玉米2-3叶期，亩兑水30公斤茎基部均匀喷雾。甘蔗/蔗螟：害虫发生的早期（蔗螟卵孵盛期）/甘蔗移栽后30天左右；小地老虎：害虫发生的早期（甘蔗幼苗期）/甘蔗移栽后30天左右。

新药设计与合成考题

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16、药物在环境友好型介质中的合成及各自特点，举例说明。 三： 17、举例说明有哪些可以自发进行的共价反应（4个反应）。 18、化学生物学对药物研究的意义（某张PPT中应该有，如对活性分子优化，临床都有重要意义）。 19、如何利用细胞四个阶段设计药物。DNA作用过程中的复制叉。 20细胞的诊断过程：诊断试剂，细胞如何诊断（即诊断四种方法）----其一基于细胞表面受体（原理图，即诊断图），其二荧光能量转移技术（卡通图，酶切断笑脸、黑脸，更加增加 笑脸作用）其三基于核酸（如RNA），其四，FDT，氟标记的。。。

网络下载版 药物设计试题 1、名词解释合理药物设计首过效应药物体内过程ADME-T 竞争性酶抑制剂 软药双前药优对映体药效相反义药物 2、论述题 试说出先导发现的可能途径。 简述药物筛选技术的发展过程，分析现代药物筛选的优点。 举例说明酶过渡态类似物抑制剂在药物设计中的应用。 试举两个例子说明“蒙骗基团”的作用原理及其在药物设计中的应用。 试写出常见的前药形式。 简述药物代谢在药物设计与研究中的应用。

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农药氯虫苯甲酰胺的合成研究进展 发表时间：2018-03-19T15:08:18.883Z 来源：《防护工程》2017年第31期作者：吴刚 [导读] 我国为农业大国，但是病虫害繁多，农药尤其是杀虫剂的使用逐渐增多。 连云港华颐精细化工科技发展有限公司江苏连云港 222000 摘要：我国为农业大国，但是病虫害繁多，农药尤其是杀虫剂的使用逐渐增多，寻找一个新型的高效安全的作用靶点成为当前困扰很多学者的一大难题，因此鱼尼丁受体抑制剂以其广谱、高效、低毒和安全的特点成为农药研发的重要领域，也是未来农药生产发展的方向。此类抑制剂通过激活靶标害虫的鱼尼丁受体而防治害虫，鱼尼丁受体被激活后，可刺激昆虫释放横纹肌和平滑肌细胞内贮存的钙离子，使害虫停止取食、抽搐、呕吐、致昏、肌肉收缩僵直及致死。当前鱼尼丁受体抑制剂主要是通过从天然产物中提取和化学合成两种方法得到，从天然产物中提取鱼尼丁受体目前并无突破性进展，因此其主要来源还是通过化学合成的方法。而在化学合成方法中氯虫苯甲酰胺的应用最为广泛。 关键词：农药；氯虫苯甲酰胺；合成 1氯虫苯甲酞胺的研究现状 1.1双酞胺类杀虫剂 鱼尼丁曾在二十世纪中期作为一种生物源农药用来防治欧洲玉米螟，但是由于鱼尼丁对哺乳动物的毒性而未被广泛使用。后来又出现将鱼尼丁与其他的杀虫剂如除虫菊酯类药剂和鱼藤酮混合使用作为化学合成杀虫剂的替代品，但还是由于其中含有鱼尼丁而未能进入市场。此外，由于鱼尼丁的合成成本较高并且很难通过改造结构来增强杀虫剂的毒性，导致鱼尼丁始终没能成为商业化的杀虫剂。后来很多科学家仍然希望可以将鱼尼丁受体作为新的杀虫剂靶标来设计新药剂。上个世纪80年代，很多化工企业发现原叶琳原氧化酶抑制剂类除草剂在具有除草活性的同时，还具有一定的杀虫活性。随后，日本农药公司从1993年开始对一个弱活性的先导物进行深入研究，在1998年成功开发出全氟烃基取代含有苯胺基团的邻苯二酰胺侧链，这是双酰胺类杀虫剂研发史上的一个重大突破。全氟烃基取代物不仅对鳞翅目害虫具有高毒杀作用，而且对植物无毒。日本农药公司和拜耳公司在1998年对大量二酰胺系列的化合物进行筛选以及结构优化后，发现邻苯二甲酰胺类化合物氟虫酰胺，这种化合物对绝大多数的鳞翅目类害虫尤其是卷叶螟和二化螟具有很好的活性，而且具有作用速度快、持效期长等优点。2000年，杜邦公司在氟虫酰胺的结构基础上进行优化，发现了另外一个高活性的邻甲酰胺基苯甲酰胺类化合物:氯虫苯甲酰胺。该化合物具有比氟虫酰胺更强的杀虫活性以及更广的杀虫谱。氯虫苯甲酰胺不仅在结构上与氟虫酰胺相似，并且具有相同的作用机制，都作用于昆虫的鱼尼丁受体且都对哺乳动物安全。2007年，20%氯虫苯甲酰胺悬浮剂在我国获得临时登记，2010年获得我国政府正式登记。由于氟虫酰胺与氯虫苯甲酰胺都具有二酰胺结构，所以二者统称为双酰胺类杀虫剂。国际抗性行动委员会按二酰胺类杀虫剂的作用机理将作用于昆虫鱼尼丁受体的杀虫剂归为第28类杀虫剂。 目前以氯虫苯甲酰胺为主要成分的产品有35%氯虫苯甲酰胺水分散粒剂、200g/L氯虫苯甲酰胺悬浮剂、40%氯虫苯甲酰胺水分散粒剂及6%氯虫苯甲酰胺悬浮剂等等。拜耳公司和日本农药公司联合开发的邻苯二甲酰胺类杀虫剂氟虫双酰胺，2008-2009年也在我国获得临时登记，2011年获得正式登记。氟虫双酰胺单剂主要有8%氟虫双酰胺悬浮剂和20%氟虫双酰胺水分散粒剂。在后期对氯虫苯甲酰胺的研究中，通过改变其苯环上的极性基团，开发出具有内吸活性的溴氰虫酰胺，成为杜邦公司开发的第二代鱼尼丁受体抑制剂类杀虫剂。由于溴氰虫酰胺有根吸性，所以它能够在植物的木质部中传导。溴氰虫酰胺与氯虫苯甲酰胺相比，杀虫谱更为广泛，咀嚼式口器害虫和吸式口器害虫都有较好的防治效果，主要包括鳞翅目、同翅目和鞘翅目害虫。 1.2氯虫苯甲酰胺的作用机制 氯虫苯甲酰胺是美国杜邦公司于2007年将上市并商品化的杀虫剂，商品名为康宽。康宽是高效微毒鳞翅目害虫杀虫剂，具有新型作用机理。该药剂可以与昆虫的鱼尼丁受体结合，诱导其释放细胞内储存的Ca2+，使害虫失去对肌肉的调节能力而引起的肌肉持续松弛、麻痹直至死亡。氯虫苯甲酰胺对稻田害虫有很好的杀虫效果，作为一种微毒的内吸性杀虫剂，还能有效保护整棵植物，尤其是新叶子，作用时间长，不易受降水影响，省时省力。 氯虫苯甲酰胺杀虫剂对害虫具备专一高效的作用机理，主要是胃毒作用。 随着全球变暖，农作物受病虫害的影响越来越大，农药的用量随之增加，导致环境污染加重，人和其它哺乳动物农药中毒事件增多，农产品上农药残留带来一系列食品安全问题。研究开发高效、低毒、低残留、对环境友好型的杀虫剂成为各国杀虫剂研究者努力的方向，也是顺应社会可持续发展的要求，更是保障全球粮食供应的关键。 鱼尼丁是从南美的一种植物中提取的肌肉毒剂，对人畜具有很强的毒性，有记载狩猎者将该植物捣碎涂在箭头上用来捕猎。动物被射中后因全身肌肉抽搐紧张而死，昆虫则因过度兴奋导致瘫痪而死。虽然鱼尼丁对鳞翅目害虫具有特异的效果，但是对人畜也有危害，因而得不到推广应用。 Ca2+是细胞内最重要的第二信使之一，机体的活动与Ca2+密切相关，例如：机体的正常代谢，神经信号的传导，酶的合成与激活等。生物体内的某些生理活动与细胞内钙离子的浓度密切相关，钙离子可以维持正常的肌肉收缩以及神经与肌肉的信号传导能力。鱼尼丁受体能够调节细胞内钙离子的释放，而氯虫苯甲酰胺恰好作用于昆虫体内的鱼尼丁受体，与之结合后打开钙离子通道，使细胞内的Ca2+浓度降低，肌浆中的钙离子浓度升高，神经系统对肌肉失去收缩控制能力，害虫立即停止进食、乏力、厌食、肌肉瘫痪直至死亡。 2氯虫苯甲酰胺合成工艺 根据相关文献专利的报道，氯虫苯甲酰胺有如下四种合成路线： 路线一：以2-氨基-5-氮-N,3-二甲基苯酰胺与康宽酰氯为原料，以乙腈为溶剂，加热回流发生酰胺化反应合成氯虫苯甲酰胺。

康宽简介

一关于康宽－杜邦最新革命性杀虫剂 据杜邦公司介绍，康宽研制花时七年多，耗资高达一亿多美元。杜邦“康宽”的通用名是“20%氯虫苯甲酰胺”，它的杀虫机理是通过激活害虫肌肉中的鱼尼丁受体，导致内部钙离子无限制地释放，阻止肌肉收缩，从而使害虫迅速停止取食，出现肌肉麻痹、活力消失、瘫痪，直至彻底死亡。据称害虫从取食到瘫痪，停止危害，仅仅需要大约7分钟的时间。 杜邦“康宽”据称还是一种微毒级农药，对人等哺乳动物的毒性比平常吃的盐还要低，对鱼虾等水生生物以及蜜蜂、害虫天敌如捕食螨基本没有伤害，而对鳞翅目害虫的活性则是其他杀虫剂的10至100倍，根据杜邦公司在中国以及全球其他国家的试验，“康宽”可用于防治水稻稻纵卷叶螟和三化螟(二化螟)、小菜蛾、斜纹夜蛾、甜菜夜蛾、豆荚螟、玉米螟等几乎所有鳞翅目害虫。目前，该产品用于防治水稻稻纵卷叶螟已在我国取得农药登记。 杜邦“康宽”具有非常好的渗透性，又有优异的内吸性，施用到作物上后，可以很快被作物吸收，并通过作物的木质部在作物体内自下往上传导至作物的各个部位及组织，全面保护作物。由于有优异的内吸性，杀虫活性又极高，使“康宽”的药效期很长。根据华南农业大学等的试验报告，防治水稻稻纵卷叶螟和三化螟(二化螟)，每亩使用10毫升，可以维持一个月的高药效；而每30斤水使用“康宽”5毫升，防治小菜蛾、斜纹夜蛾、甜菜夜蛾，则可以维持半个月以上的高药效。“康宽”还可以有效杀死高龄害虫，农民使用也非常简便。比如用于防治小菜蛾、斜纹夜蛾、甜菜夜蛾，只要蔬菜叶子的正面均匀喷到药液，就可以表现高药效，而不像其他农药需要把蔬菜叶子的正反两方面都均匀喷到药液。 二、应用技术 1、根据浙江省植保部门应用在水稻田防治稻纵卷叶螟，每亩用10毫升， 用背负式手动喷雾器喷二桶，常规喷雾。七天后杀虫效果达到94.2%，保叶效果达到90.0%；十四天后杀虫效果达到86.0%，保叶效果达到83.9%。均优于常用5%氟虫腈每亩40毫升的防治效果。 2、根据四川省药检部门在水稻二化螟防治试验中应用，每亩用10毫升，用背负式手动喷雾器喷二桶，常规喷雾。二十天后白穗防效达到96.1%，虫伤株防效达到98.7%；杀虫效果达到93.6%。综合防效均优于常用5%氟虫腈每亩40毫升和20%三唑磷140毫升的防治效果。 综合全国各地的试验示范表明：一、安徽试验将装有4升水的桶里倒入5 毫升该品种农药，再放入活的金鱼。数小时后，金鱼仍在游动，说明对鱼的毒性非常低，可以证明对水生动物是安全的。二、在湖北、江苏、上海的水稻上防治稻纵卷叶螟、二化螟、三化螟、大螟试验示范，均表现为防治效果优于常规的国产和进口品种农药，因此在我国水稻产区常发性的害虫防治上应用潜力巨大。 三、应用推广注意事项 1、由于该农药具有较强的渗透性，药剂能穿过茎部表皮细胞层进入木质部，从而沿木质部传导至未施药的其它部位。因此在田间作业中，用弥雾或细喷雾喷雾效果更好。但当气温高、田间蒸发量大时，应选择早上10点以前，下午4点以后用药，这样不仅可以减少用药液量，也可以更好的增加作物的受药液量

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第九章药物合成设计原理和方法练习题 一、名词解释 1、靶分子： 2、合成子： 二、完成下列反应 1、生物碱鹰爪豆碱的合成 2、喜树碱中间体的喹啉环的合成 3、β- 咔啉的合成 4、合成 ArCHCOOH CH3 5、全身麻醉药氟烷的合成。 F3C CHBrCl

三、按要求完成下列化合物全合成。 1、采用逆合成分析法完成布洛芬(Ibuprofen)的逆推过程并写出合成的反应。 i-Bu COOH 2、采用逆合成分析法完成下面化合物的逆推过程并写出合成的反应。 CHO OH 3、采用逆合成分析法完成茉莉酮的逆推过程并写出合成的反应。 O 4、采用逆合成分析法完成下面化合物的逆推过程并写出合成的反应。 MeO2C CHO COOMe

5、采用逆合成分析法完成下面化合物的逆推过程并写出合成的反应。 CO 2Me OH 6、完成非那西丁(Phenacetin)的合成反应。 NHCOCH 3 OH 7、完成吲哚美辛(Indometacin)的合成反应。 CH 2COOH CH 3 CO Cl O H 3C 8、 完成芬太尼(Fentany Citrate)的合成。 CH 3CH 2CON N CH 2CH 2

9、完成盐酸多巴(Dopamine Hydrochloride)的合成。 OH OH NH2 HCl 10、完成盐酸可乐(Clonidine Hydrochloride)的合成。 Cl Cl N H H N HCl 11、完成硫酸沙丁胺醇(Sulbutamol sulfate)的合成。 OH CH2OH CHCH2NH(CH3)3 OH 1/2 H2SO4

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