Azilsartan kamedoxomil (Edarbi Ò )
Azilsartan kamedoxomil, a medication developed by Takeda Pharmaceuticals, is approved for hypertension treatment and marketed in the U.S as Edarbi This prodrug quickly hydrolyzes to release azilsartan, its active component (TAK-536) As the eighth angiotensin receptor blocker (ARB) introduced globally, azilsartan kamedoxomil offers an effective option for managing high blood pressure.
In 2011, 26 new drugs were introduced to the market, including azilsartan kamedoxomil, which can be used alone or in combination with other antihypertensive medications Clinical studies have demonstrated that azilsartan kamedoxomil exhibits superior antihypertensive effects and a favorable safety and tolerability profile compared to established treatments such as valsartan, olmesartan medoxomil, candesartan, and telmisartan.
XIV Icotinib hydrochloride XIII Gabapentin enacarbil
Takeda has received FDA approval for Edarbyclor™, a fixed-dose combination tablet of azilsartan kamedoxomil and chlorthalidone The synthesis process of azilsartan kamedoxomil is detailed in Scheme 5, beginning with the commercially available methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate.
(30), which can also be prepared by several different routes 41,42
Alkylation of30with diaryl bromide 31gave benzylamine32in
78% yield, which was followed by deprotection with 30% ethanolic
The synthesis of amine 33 achieved a 77% yield through HCl and alkalinization The nitro group in compound 33 was successfully reduced using hydrazine hydrate and a catalytic amount of ferric chloride, yielding 2,3-diaminobenzoate 34 at 64% Ring formation occurred when compound 34 was treated with tetraethoxymethane and acetic acid, resulting in benzimidazole 35 with a 91% yield The addition of hydroxylamine to the cyano group of 35 produced amidoxime 36 in 55% yield, which underwent cyclization with 2-ethylhexyl chloroformate in refluxing xylenes to yield oxadiazolone 38 at 52% Hydrolysis of oxadiazolone 38 led to the formation of azilsartan (39, TAK-536) with a 94% yield Furthermore, in the presence of perchlorobenzoyl chloride and triethylamine, carboxylic acid 39 was converted to a mixed acid anhydride intermediate, which when condensed with alcohol 41 produced benzoate 42 at a 50% yield The preparation of the salt from benzoate 42 using potassium 2-ethylhexyl carboxylate resulted in azilsartan kamedoxomil (V) with a 63% yield.
Bilastine (Bilaxten Ò )
Bilastine is a selective H1 histamine antagonist approved for treating allergic rhinoconjunctivitis and urticaria Discovered by the Spanish company FAES Farma, it received European Union approval in 2010 and has shown good tolerance in toxicology studies In 2011, Collier and colleagues detailed the original synthesis of bilastine and an improved method suitable for gram-scale production Their second-generation synthesis utilizes a convergent approach, combining piperidinyl benzimidazole with a fully functionalized phenethyl electrophile Additionally, coupling commercially available bromophenyl acetate with cyclic trioxatriborane under conventional Suzuki conditions successfully produced styrene.
The vinylation reaction of compound 46 yielded 46 in good yield, and when performed under Stille conditions using tributyl vinyl stannane, it achieved an 83% yield Hydroboration–oxidation of 46 produced phenethyl alcohol 47, which was subsequently mesylated under basic conditions in toluene to form adduct 48 This sulfonate was then reacted with piperidine 49, whose preparation is detailed in Scheme 7, followed by the saponification of the resulting ester 50, ultimately leading to bilastene (VI) with a 26% overall yield from compound 44 The preparation of bilastine involved protecting commercially available piperidine 51 as outlined in Scheme 7.
Pd(PPh 3 ) 2 Cl 2 , 2 M Na 2 CO 3
Scheme 1 Synthesis of abiraterone acetate (I).
Scheme 2 Synthesis of alcaftadine (II).
Cu(PPh 3 ) 3 Br, Cs 2 CO 3 toluene, ↑↓, 6 h, 77%
Scheme 3 Synthesis of apixaban (III).
Scheme 4 Synthesis of avanafil (IV).
Boc-carbamate52prior to alkylation of the benzimidazole nitro- gen atom with 1-chloro-2-ethoxyethane53, providing compound
54 The Boc group of54was removed under acidic conditions to give fragment49 This sequence produced the desired piperidine component in 86% overall yield from51 49
Boceprevir (Victrelis Ò )
Boceprevir is an oral HCV NS3/4A protease inhibitor used for treating chronic hepatitis C genotype infections It is approved for use in combination with Peg-IFN-alpha and ribavirin for adult patients with compensated liver disease, whether they are treatment-naive or have previously failed interferon and ribavirin therapy.
Boceprevir, developed by Schering-Plough and marketed by Merck & Co since its acquisition in 2009, has been the subject of multiple publications detailing its evolution from a potent undecapeptide lead structure to a drug candidate with strong activity and favorable pharmacokinetic properties Numerous patents have been issued, including those covering the preparation of essential fragments and the complete synthesis of boceprevir The drug can be retrosynthetically analyzed into three or four key fragments, which can be assembled through a convergent synthesis method.
The synthesis of t-butyl urea fragment began with the esterification of t-butyl amino acid using TMSCl and triethylamine, resulting in silyl ester This silyl ester was subsequently reacted with t-butyl isocyanate to yield urea with a 74–89% yield over two steps While various methods for preparing azabicyclo[3.1.0]hexane ester have been reported, the latest process-scale synthesis utilized enzymatic desymmetrization of azabicyclo[3.1.0]hexane This involved enzymatic oxidation followed by the trapping of the resulting imine with bisulfate to produce sulfonate, which was obtained under manufacturing conditions with 95% and 99% enantiomeric excess The sulfonate salt was then reacted with sodium cyanide in cyclopentyl methyl ether to generate transnitrile.
A yield of 90% was achieved for compound 64 from compound 61, likely due to the elimination of the sulfonate, which regenerates imine 62 This process is followed by the addition of a nitrile group from the opposite face of the dimethylcyclopropyl group The nitrile 64 was then reacted under Pinner conditions using hydrochloric acid and methanol.
NH 2 OH HCl, DMSO, Et 3 N
Scheme 5 Synthesis of azilsartan kamedoxomil (V). to give ester salt56in 56% overall yield with greater than 99% ee after recrystallization from MTBE.
The preparation of cyclobutyl amides involves several steps, as detailed in Scheme 11 Initially, a benzophenone-derived imine is alkylated with bromomethylcyclobutane in the presence of a base, yielding an alkylated intermediate This intermediate is then treated in situ with HCl to produce an aminoester, which is subsequently protected as a Boc-carbamate Following this, the ester undergoes reduction to form the corresponding alcohol, which is crystallized from heptane, achieving an overall yield of 43% The alcohol is oxidized using TEMPO, sodium bromide, and sodium hypochlorite in DCM at temperatures between 5 to 0°C, resulting in an aldehyde with a yield of 91% After solvent exchange, the aldehyde is reacted with acetone cyanohydrin at room temperature to generate an intermediate, which is then treated with potassium carbonate to remove excess cyanohydrin and hydrolyzed with hydrogen peroxide at 40°C to yield 90% of the desired amide.
Under acidic conditions, hydroxyl amide was deprotected to yield hydrochloride salt Additionally, alcohol was oxidized using EDCI, DMSO, and dichloroacetic acid in ethyl acetate, resulting in a keto amide with a 70% yield Further treatment with HCl in isopropyl alcohol produced salt with a 91% yield.
The final target was efficiently assembled using a convergent approach, as outlined in Scheme 12 Initially, carboxylic acid fragment 55 was coupled with azabicyclo[3.2.1]cyclohexane amine ester salt 56, utilizing EDCI as the coupling reagent in basic conditions to form amide 74 Following this, the hydrolysis of the methyl ester with lithium hydroxide, along with subsequent salt formation, resulted in carboxylate salt 75 with an impressive overall yield of 90% Finally, under acidic conditions, salt 75 was directly coupled with cyclobutyl keto.
Scheme 6 Synthesis of bilastine (VI).
Scheme 7 Synthesis of fragment 49 for bilastine (VI).
The retrosynthetic analysis of boceprevir (VII) involves the coupling of amide salt 57 with EDCI, HOBt, and N-methylmorpholine in acetonitrile, yielding boceprevir in an impressive 85–90% yield after subsequent acidic and basic work-ups Additionally, an alternative method includes the coupling of salt 75 with cyclobutyl alcohol amide salt 73 using EDCI.
HOBt and diisopropylethyamine (DIPEA) to give alcohol 76 in
The oxidation of the alcohol intermediate 76 using TEMPO and NaOCl in the presence of KBr successfully produced boceprevir (VII) with a remarkable yield of 93% This process follows acid and base work-ups and crystallization, achieving an overall yield of 90%.
Brentuximab vedotin (Adcetris Ò )
Brentuximab vedotin is an antibody-drug conjugate that combines an anti-CD30 antibody with the potent tubulin inhibitor monomethyl auristatin E (MMAE), linked by a maleimide conjugation handle featuring an enzyme-cleavable valine-citrulline-para-aminobenzylcarbamate group This unique structure allows MMAE to be released after the cancer cell internalizes the conjugate Developed by Seattle Genetics in collaboration with Millennium Pharmaceuticals, Brentuximab vedotin has received approval for treating relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) and Hodgkin’s lymphoma Additionally, it is being investigated in clinical trials for CD30-expressing cutaneous T-cell lymphoma and other CD30-positive hematologic malignancies Although categorized as a biologic, Brentuximab vedotin is included in this review due to the total synthesis of its small molecule component.
The synthesis of brentuximab vedotin and monomethyl auristatin E (MMAE) has primarily been documented on a small scale, but large-scale preparation adheres to the established strategy for the total synthesis of dolastatin 10, initially outlined by the Pettit research group at the University of Arizona MMAE is a pentapeptide that features two unique gamma amino acids, dolaproine (Dap) and dolaisoleuine (Dil).
Scheme 9 Synthesis of fragment 55 for boceprevir (VII).
Scheme 10 Synthesis of fragment 56 for boceprevir (VII).
1 (a) KO t- Bu, THF, -30 °C to 0 °C (b) bromomethylcyclobutane, RT
Scheme 11 Synthesis of fragment 57 for boceprevir (VII).
The synthetic strategy to enable the preparation of brentuximab vedotin is highly convergent and requires the preparation of a
Val-Val-Dil tripeptide, a Dap-norephederine dipeptide and the
The synthesis of Val-Val-Dil commenced with Cbz-protected N-methyl-isoleucine, which was reduced to the corresponding alcohol using borane and then oxidized to Cbz-protected isoleucinal with dimethyl sulfoxide and sulfur trioxide–pyridine complex, achieving high overall yield without epimerization The subsequent aldol condensation of the aldehyde with tert-butyl acetate, facilitated by LDA, yielded a 4:3 mixture of diastereomers, allowing for the isolation of the desired alcohol diastereomer in 34% yield Finally, methylation of the isolated diastereomer with trimethyloxonium tetrafluoroborate produced the methyl ether.
The synthesis of the Dil coupling partner (81) was achieved through hydrogenolysis with 5% palladium on carbon in an ethyl acetate/methanol solvent system, yielding 63% with minimal formation of lactam by-products Peptide coupling with Cbz-protected valine (82) using PyBrop resulted in a 55% yield Following Cbz deprotection via hydrogenolysis to produce compound 84, an additional peptide coupling with Fmoc-protected methyl Val (85) was conducted using diethyl cyanophosphonate (DEPC) as the coupling reagent, yielding the protected Val-Val-Dil tripeptide (86) at 50%.
Scheme 12 Synthesis of boceprevir (VII).
O O n- BuLi, i- Pr 2 NH, THF t- BuOAc, -78°C, 34%
Scheme 13 Synthesis of fragment 86 for brentuximab vedotin (VIII).
The synthesis of the Dap-norephederine dipeptide began with a 1,2 addition of cispotassium crotyltrifluoroboronate to Boc-protected prolinal, yielding alcohol in 89% with a 94:6 diastereomeric ratio This was followed by methylation of the hydroxy group using sodium hydride and methyl iodide, resulting in the formation of ether.
76% yield, which was followed by oxidative cleavage of the double bond with ruthenium oxide, furnishing Boc protected Dap90in
75% yield 77 Amide coupling to (1S,2R)-norephederine 91 using
DEPC gave rise to the Dap coupling partner92in 84% yield.
The synthesis of the MalC-Val-Cit-PABA linker fragment was initiated with condensation of succinate ester Fmoc-Val93 with citrulline (94) to give protected Val-Cit 95 in 78% yield
(Scheme 15) 78 EEDQ-mediated coupling topara-aminobenzylalco- hol provided protected Val-Cit-PABA96in 80% yield Removal of the Fmoc protecting group with diethylamine delivered free amine
The activated ester was condensed with compound 97 to yield MalC-Val-Cit-PABA in high yield The alcohol was activated using para-nitrophenyl chloroformate, resulting in the linker coupling partner with a yield of 15%.
The MalC-Val-Cit-PABC-MMAE linker/payload was synthesized by first combining tripeptide 86 and dipeptide 92, followed by treatment with trifluoroacetic acid to remove their protecting groups This mixture was then treated with DEPC, yielding Fmoc-protected MMAE 101 at a 91% yield The Fmoc group was subsequently removed using diethylamine, resulting in MMAE, which was coupled to linker 100 in the presence of HOBt, producing MalC-Val-Cit-PABC-MMAE 103 with a 57% yield.
H N n- Bu 4 NI, CH 2 Cl 2 , H 2 O HO
Scheme 14 Synthesis of fragment 92 for brentuximab vedotin (VIII).
Na 2 CO 3 , DM E, H 2 O THF, RT, 78%
Scheme 15 Synthesis of fragment 100 for brentuximab vedotin (VIII).
The synthesis of brentuximab vedotin involves the complete reduction of disulfide bonds in CD30 mAb104 using DTT in a pH 8.0 buffer, resulting in approximately eight free sulfhydryl groups These thiol groups then react with the linker/payload, and the remaining disulfide bonds are re-oxidized with cysteine, yielding brentuximab vedotin (VIII) with an average drug to antibody ratio of 4.
Ceftaroline fosamil acetate (Teflaro Ò )
Ceftaroline fosamil acetate (Teflaro Ò ) is a novel broad-spectrum cephalosporin effective against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), as well as common gram-negative pathogens This N-phosphono type aqueous prodrug of ceftaroline exhibits increased solubility compared to its parent compound and was developed by Takeda Pharmaceutical through structural modifications of the fourth-generation cephalosporin, cefozopran Approved by the FDA for treating community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), including MRSA, ceftaroline's enhanced anti-MRSA activity is attributed to the 5-membered thiazole ring at the 3-position of the cephalosporin nucleus and the ethoxyimino-acetamido group in the C-7 acyl moiety.
Takeda's reports detail the 100 g scale preparation process of ceftaroline fosamil, which involves the assembly and un-ion of fragments 112 and 114 The synthesis of fragment 112 starts with the commercially available benzhydryl 7b-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4-carboxylate (106) The hydroxyl group in cephem 106 is reacted with methanesulfonyl chloride to yield mesylate 107 in 94% yield Subsequently, mesylate 107 undergoes condensation with 4-(pyridin-4-yl)thiazole-2-thiol 108 in the presence of sodium methoxide, resulting in compound 109 with a yield of 78%.
103 (mc-Val-Cit-PABC-MMAE)
Scheme 16 Synthesis of fragment 103 for brentuximab vedotin (VIII).
Scheme 17 Synthesis of brentuximab vedotin (VIII). arose in quantitative yield upon subjection of109to iodomethane.
Sequential deprotections of the amino group with phosphorous pentachloride and ester group with concentrated HCl afforded the dihydrochloride salt112in good yield.
Acyl halide fragment 114 was synthesized from (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic acid (113) with a 60% yield through dichlorophosphorylation of the amino group, leading to the formation of the acid chloride This acid chloride 114 was then reacted with dihydrochloride salt 112 in the presence of sodium acetate, resulting in N-phosphono cephem 115 with a yield of 77% The crystallization of 115 in an aqueous acetic acid solution produced the stable acetic acid solvate ceftaroline fosamil acetate (IX).
Crizotinib (Xalkori Ò )
Crizotinib, marketed as Xalkori, is a selective inhibitor of mesenchymal epithelial transition factor and anaplastic lymphoma kinase (cMET/ALK), developed by Pfizer for treating advanced or metastatic non-small cell lung cancer (NSCLC) associated with the EML4-ALK mutation It is also being evaluated for other cancers that express the ALK mutation, including advanced disseminated anaplastic large-cell lymphoma and neuroblastoma Various synthetic routes for crizotinib's preparation have been reported, all employing a similar convergent strategy, with one method detailed for producing over 100 kg of the compound.
Mesylation of tert-butyl-4-hydroxypiperidine-1-carboxylate
The synthesis of iodopyrazine involved the displacement of 4-iodopyrazole, yielding 50-60% overall for the two steps The reaction of iodide with i-PrMgCl produced the corresponding Grignard reagent, which was subsequently quenched with borolane, resulting in an arylboronate with a yield of 70-80% after crystallization from ethanol and water The Suzuki coupling partner, bromide, was prepared through several steps beginning with enzymatic reduction.
HCl (conc.), MeCN EtOAc, RT, 5 h , 74%
Scheme 18 Synthesis of fragment 112 for ceftaroline fosamil acetate (IX).
2 1% HOAc (aq), SP-207 column 77% (2 steps)
Scheme 19 Synthesis of ceftaroline fosamil acetate (IX). of 2,6-dichloro-3-fluoroacetophenone (121) using an engineered ketoreductase process, providing alcohol122in 94% yield and in
>99% ee Mitsunobu reaction with 3-hydroxy-2-nitropyridine
Nitropyridine was successfully synthesized with an 80–85% yield through crystallization from ethanol, maintaining full enantiopurity The chemoselective reduction of the nitro group was achieved via hydrogenation using a 10% sponge-nickel catalyst, resulting in the formation of amine.
The compound 125 achieved a 95% yield after crystallization from methanol Regioselective bromination of 125 was performed using N-bromosuccinimide (NBS) in a mixture of acetonitrile and dichloromethane This was followed by a bisulfate quench and an Et3N wash to remove any residual succinimide, ultimately leading to the crystallization of the product from methanol.
Miyaura coupling partner126in 80–85% yield Coupling of arylbr- omide 126 with arylboronate 120 was accomplished using
Using 0.8 mol % PdCl2(dppf) in CH2Cl2 as a catalyst and treating the mixture with cysteine on silica-alumina effectively removes residual palladium The coupled product can be crystallized from heptanes, achieving a yield of 76-80% Following this, the Boc protecting group is removed through acid treatment, and further crystallization is performed.
CH3CN/H2O produced crizotinib (X) in 75–80% yield.
Edoxaban tosilate (Lixiana Ò )
Daichi Sankyo's edoxaban tosilate is an oral anticoagulant that inhibits factor Xa, approved in Japan for preventing venous thromboembolic events (VTE) in patients undergoing total knee or hip arthroplasty, as well as hip fracture surgery This medication is noted for its rapid onset of action, providing effective anticoagulation for surgical patients.
Edoxaban tosilate, marketed as Lixiana, reaches its maximum concentration (T max) within 1 to 2 hours after dosing and maintains this level for up to 24 hours Currently, it is undergoing phase III clinical trials in the United States aimed at preventing stroke and systemic embolic events in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) The synthesis of edoxaban tosilate involves the integration of three essential structural components.
Cl F ketoreductase, Na-NADP GDH, glucose, N(EtOH) 3
1 PdCl 2 (dppf )ãCH 2 Cl 2 ,120, Cs 2 CO 3
Bu 4 NBr, toluene/H 2 O, 70 °C; cysteine on silica-alumina; heptane crystallization 76 – 80%
2 HCl, EtOH/EtOAc/CH 2 Cl 2 MeCN/H 2 O crystallization 75 – 85%
The retrosynthetic analysis of edoxaban (XI) involves key intermediates such as diamino cyclohexane, pyridyl amino oxoacetate, and thiazole acid, as illustrated in Scheme 21 Numerous publications have detailed the synthesis of these compounds, while several patents have emerged focusing on improved synthesis methods for the diamino and thiazole intermediates, including a more efficient route for edoxaban Notably, the latest patents emphasize a synthesis process that eliminates the need for chromatographic purification, making it the most viable method for large-scale production, as highlighted in Schemes 21-23.
The synthesis of tetrahydropyridyl thiazolo acid involves treating N-Methyl piperidone with catalytic pyrrolidine, cyanamide, and sulfur in warm isopropanol to produce aminothiazole Subsequently, the thiazole amine undergoes diazotization with sodium nitrite and 48% HBr at 30°C, resulting in the formation of thiazole bromide, which is then converted directly into tosylate salt.
The synthesis of thiazole acid hydrochloride salt (129) was achieved in a 90% yield through a two-step process starting from piperidone130 Initially, the salt was free-based using sodium hydroxide, followed by treatment with n-BuLi and carbon dioxide to form lithium carboxylate salt133 Subsequent acidification of this salt with ethanolic HCl yielded the desired product.
The synthesis of edoxaban tosilate is shown inScheme 23 Com- mercially available epoxide ester 134 was reacted with sodium azide to afford the corresponding hydroxyazide intermediate
Scheme 22 Synthesis of fragment 129 for edoxiban tosilate (XI).
1 MsCl, Et 3 N, CH 2 Cl 2 -10 °C to RT, 2 h
2 Me 2 NH HCl, EDCl, HOBt
CH 2 Cl 2 , Et 3 N, RT, 4 d 76% (2 steps)
2 129, HOBt, EDCI, Et 3 N MeCN, 0 °C to RT, 16 h 93% (2 steps)
The synthesis of edoxaban tosilate (XI) was achieved regiospecifically and quantitatively The intermediate was then catalytically hydrogenated in the presence of Boc2O, yielding alcohol 135 in 68% yield This alcohol was converted to the corresponding mesylate, which was subsequently treated with sodium azide to primarily produce cis-azide 136 in 32% yield after diastereomer separation Following the reduction of the azide and Cbz protection, carbamate 137 was obtained in 67% yield Hydrolysis of the ester group in 137 with lithium hydroxide, followed by reaction with dimethylamine, resulted in N,N-dimethylamide 138 in a 76% yield over two steps Finally, the Cbz group of 138 was removed via catalytic hydrogenation, and the resulting amine was converted to the oxalate salt.
Amine127was then condensed with the key pyridylamino oxoace- tate128, prepared in 96% yield by reacting 5-chloropyridin-2-amine
The synthesis of edoxaban involved the reaction of ethyl 2-chloro-2-oxoacetate with warm acetonitrile, yielding amide 139 with an 86% yield Subsequently, the Boc protecting group was removed using methanesulfonic acid, followed by EDCI-mediated coupling with tetrahydropyridyl thiazolo acid 129, resulting in edoxaban with a 93% yield The final step included treatment with TsOH, leading to the isolation of edoxaban tosilate (XI).
Eldecalcitol (Edirol Ò )
Eldecalcitol, a vitamin D3 analog developed by Chugai in collaboration with Taisho, is approved in Japan for osteoporosis treatment This hormonally active calcitriol analog effectively regulates calcium and bone metabolism Its approval was based on phase III randomized, double-blinded studies over three years, demonstrating a significant reduction in new vertebral fractures compared to alfacalcidol Research on the discovery and structure-activity relationship (SAR) of vitamin D3 analogs has led to the identification of eldecalcitol, with multiple syntheses reported in various publications and patents.
3 KOH, MeOH, RT HO CH 2 Cl 2 , RT
HO microbial-25-hydroxylation Amycolata autotrophica ATCC33796 64%
Scheme 24 Synthesis of eldecalcitol (XII). vitamin D3 analog synthesis that was recently disclosed, based on an earlier reported route for the commercial synthesis of alfacalcidol, will be discussed here (Scheme 24) 119,120
An Oppenauer oxidation successfully transformed commercially available cholesterol into enone with an 80% yield A subsequent oxidation using DDQ yielded dienone at a 75% rate When dienone was treated with sodium ethoxide in ethanol, the enone double bond migrated into the B-ring, resulting in olefin with a 53% yield The stereo-specific reduction of ketone produced alcohol at a 53% yield, which was then protected as an acetate using acetic anhydride.
The B-ring underwent further dehydrogenation via radical bromination using NBS and catalytic AIBN, followed by elimination with collidine, resulting in the formation of the key diene To achieve selective epoxidation of the A-ring olefin, a novel protection strategy utilizing phenyl was implemented.
1,2,4-triazole-3,5-dione (PTAD) Diels–Alder reaction between diene147and PTAD produced cycloadduct148in 80% overall yield from acetate146 121 Protection of the alcohol as the corresponding
TBS ether underwent regio- and stereospecific epoxidation with m-CPBA, yielding 1,2a-epoxide in 78% The Diels–Alder adduct was then subjected to thermal conditions to facilitate a retro-[4+2] reaction, producing diene The fluoride-mediated removal of the TBS group resulted in the formation of 3b-alcohol with a 95% yield Finally, a ring-opening reaction with 1,3-propanediol in the presence of potassium t-butoxide yielded 3-hydroxy propoxy ether.
29% yield Microbial oxidation of intermediate153 was accom- plished using anAmycolata autotrophicaATCC 33796 culture to ob- tain eldecalcitol derivative154in 64% yield Subjection of154to
400 watt light followed by thermolysis provided eldecalcitol (XII) in 29% yield.
Gabapentin enacarbil (Horizant Ò )
Gabapentin enacarbil is a prodrug of gabapentin (Neurontin Ò ,
Gabapentin enacarbil, developed by XenoPort in collaboration with GlaxoSmithKline and marketed as Horizant™, is approved for treating moderate to severe restless leg syndrome This drug enhances the absorption of gabapentin by interacting with sodium-dependent multivitamin transporter (SMVT) and monocarboxylate transporter type 1 (MCT-1), leading to improved oral bioavailability and more consistent exposure compared to its parent compound Additionally, gabapentin enacarbil binds to the a2-d subunit of L-type voltage-regulated calcium channels, which reduces the release of various neurotransmitters Several related syntheses of gabapentin enacarbil have been documented.
Gabapentin was treated with chlorotrimethylsilane and triethylamine, followed by acylation with 1-chloroethyl chloroformate to yield an acid after hydrolysis of the intermediate silyl ester This acid, used without purification, reacted with isobutyric acid and triethylamine, resulting in gabapentin enacarbil with a 9.1% overall yield post-crystallization Alternatively, gabapentin reacted directly with a fully elaborated p-nitrophenyl activated side chain in the presence of potassium carbonate The resulting mixture was treated with 10% Pd/C and potassium formate, followed by acidic workup to remove aniline, ultimately providing gabapentin enacarbil in a 36% overall yield after crystallization The activated side chain was synthesized from p-nitrophenol through a two-step, one-pot process involving acylation with 1-chloroethyl chloroformate, leading to an intermediate that was alkylated with isobutyric acid, resulting in the mixed carbonate.
Icotinib hydrochloride (Conmana Ò )
Icotinib hydrochloride, a powerful small molecule EGFR tyrosine kinase inhibitor, is designed for treating non-small cell lung cancer (NSCLC) Developed by Zhejiang Bata Pharma Inc., it received approval from China's SFDA and was launched in mid-2011 under the brand name Conmana Ò, marking a significant achievement in Chinese pharmaceutical R&D.
Icotinib hydrochloride, the third EGFR-TKI drug for NSCLC therapy, shares a similar structure with gefitinib and erlotinib A randomized, double-blind phase III clinical study involving 399 patients with advanced NSCLC revealed that icotinib offers comparable efficacy to gefitinib, while demonstrating improved tolerability in patients who had previously undergone one or two chemotherapy treatments.
Et 3 N, CH 2 Cl 2 , 30 °C; crystallization from Et 2 O/CH 2 Cl 2 9% overall yield
161, K 2 CO 3 , H 2 O, toluene, 40 °C; 10% Pd/C, KHCO 3 crystallization from heptane/EtOAC, 36% over all yield
Scheme 25 Synthesis of gabapentin enacarbil (XIII).
Icotinib was prepared by a similar process approach to that of erlotinib (Scheme 26) 131 Beginning from commercially available
The synthesis of icotinib hydrochloride (XIV) begins with the bis-tosylation of 2,2-(ethylenedioxy)diethanol, leading to the formation of crown-4-ether in 96% yield through bis-alkylation with a commercially available catechol derivative Subsequent nitration of the resulting polyether using concentrated nitric and sulfuric acids yields nitroarene in 65% yield This nitroarene undergoes catalytic hydrogenation to produce amine in 85% yield The amine then condenses with formamide in the presence of ammonium formate, resulting in quinazolinone in 80% yield Chlorination of quinazolinone with POCl3 gives quinazolyl chloride in 77% yield, which, when treated with amine and followed by HCl salt formation, successfully produces icotinib hydrochloride in good yield.
Scheme 26 Synthesis of icotinib hydrochloride (XIV).
Scheme 27 Synthesis of linagliptin (XV).
Linagliptin (Trajenta Ò )
Linagliptin, an orally active dipeptidyl peptidase-IV (DPP-4) inhibitor, was discovered by Boehringer Ingelheim and co-developed with Eli Lilly It is designed to improve glycemic control in adults with type II diabetes as an adjunct to diet and exercise Linagliptin offers superior benefits for managing blood sugar levels.
DPP-4 IC50value of 1 nM, compared with 19 nM for sitagliptin Ò ,
Alogliptin, saxagliptin, and vildagliptin demonstrate DPP-4 inhibition at concentrations of 24 nM, 50 nM, and 62 nM, respectively Linagliptin, on the other hand, is notable for its extended pharmacodynamic activity and sustained DPP-4 inhibition across various preclinical models Phase II clinical trials indicated linagliptin's efficacy at doses as low as 5 mg, with no hypoglycemia observed even at doses up to 600 mg Its long-lasting pharmacological effects and favorable safety profile were key factors in linagliptin's approval.
The synthesis of linagliptin began from commercially available
8-bromo-3-methylxanthine (171) (Scheme 27) 137 Sequential alky- lations of guanine derivative171atN-7 with butyn-2-yl bromide in the presence of N,N-diisopropylethylamine and N-1 with 2-
(chloromethyl)-4-methylquinazoline (173) in the presence of potassium carbonate, yielded N1,N7-dialkylated xanthine 174 in
The synthesis of linagliptin (XV) achieved an impressive 85% yield through a series of reactions Initially, aminopurine dione 176 was produced in an 88% yield by condensing (R)-3-Boc-aminopiperidine (175) with potassium carbonate The final step involved liberating the primary amine from 176 using trifluoroacetic acid in methylene chloride, resulting in a 91% yield of linagliptin.
Lurasidone hydrochloride (Latuda Ò )
Lurasidone hydrochloride is an antipsychotic developed by the
Japanese firm Dainippon Sumitomo and approved by the U.S.
Lurasidone, recently approved by the FDA for treating schizophrenia, demonstrates significant antagonist effects on D2, 5-HT2A, and 5-HT7 receptors, which are associated with learning and cognition Unlike traditional antipsychotics, lurasidone does not produce anticholinergic side effects, offering an enhanced safety profile compared to existing treatments.
Latuda Ò is a medication characterized by its linear molecular structure, which consists of three distinct regions: a piperazine benzothiazole, a fused succinimide derived from a [2.2.1]-bicycloheptane, and a trans-1,2 disubstituted cyclohexane.
The large-scale synthesis of lurasidone involves a ring-opening alkylation reaction of a spirocyclic tetralkyl ammonium salt, yielding the 1,2-trans-substituted cyclohexane subunit The process begins with the bis-mesylation of a commercially available diol, resulting in a high-yield disulfone This bis-electrophile undergoes dialkylation with piperazine under basic conditions, producing an ammonium species isolated as a mono-mesylate salt with an 80% yield Subsequently, this compound is subjected to alkylative conditions with succinimide, leading to lurasidone being obtained in a 94% yield, followed by the formation of lurasidone hydrochloride through a salt formation procedure.
Mirabegron (Betains Ò )
Mirabegron, an orally active β3-adrenoceptor agonist developed by Astellas Pharma, is designed for treating overactive bladder (OAB) by promoting bladder relaxation and alleviating symptoms such as increased urinary urgency and frequency, as well as urgency incontinence This drug exhibits a nanomolar EC50 against human β3-ARs with notable selectivity over β1- and β2-ARs However, it is important to note that mirabegron acts as a cytochrome P450 2D6 inhibitor, raising potential concerns regarding drug-drug interactions with other substrates of this enzyme The synthesis of mirabegron involves a condensation reaction between (R)-styrene oxide and 4-nitrophenylethylamine, yielding an aminoalcohol that is subsequently protected and transformed through hydrogenative reduction and amide formation, showcasing a complex but efficient synthetic pathway.
187 in 85% yield Removal of the Boc group was affected with
4 N HCl solution in a 2:1 volume ratio in ethyl acetate to obtain mirabegron HCl in 52% yield The HCl salt was neutralized with
1 N NaOH to deliver mirabegron (XVII).
Retigabine/Ezogabine (Trobalt Ò /Potiga Ò )
Retigabine, also known as ezogabine, is an antiepileptic medication that functions by opening neuronal voltage-gated potassium channels of the KCNQ family and enhancing GABA-mediated brain currents Originally discovered and developed by Asta Medica, it was later licensed to Xcel and acquired by Valeant Valeant, in collaboration with GlaxoSmithKline, completed the drug's development, and it is now approved for the adjunctive treatment of partial-onset seizures in adults with epilepsy.
H 2 HCl, acetone, H 2 O, 60 °C, 1 h no yield reported.
Lurasidone hydrochloride (XVI), also referred to as ezogabine in the U.S and retigabine internationally, can be synthesized through various methods This article will outline two specific preparation techniques for this compound.
Commercially available 4-fluorobenzaldehyde (188) was con- densed with 4-amino-2-nitroaniline (189) and the resulting imine was reduced with sodium borohydride to give aniline 190 in
Aniline was acylated with diethylcarbonate, yielding nitrobenzene in 80–88% The subsequent catalytic hydrogenation of the nitro group resulted in retigabine/ezogabine with a yield of 70–90% Alternatively, nitrobenzene could be reduced using Zn/NH4Cl before undergoing acylation with diethylcarbonate.
Scheme 29 Synthesis of mirabegron (XVII).
Scheme 30 Synthesis of retigabine/ezogabine (XVIII).
Scheme 31 Synthesis of rilpivirine hydrochloride (XIX). ethyl chloroformate/Hunig’s base, providing retigabine/ezogabine
Rilpivirine hydrochloride (Edurant Ò )
Rilpivirine hydrochloride (Edurant Ò) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the U.S FDA and E.U EMA in 2011 for treating HIV-1 infection in treatment-naive adults Developed by Janssen Pharmaceuticals and its subsidiary Tibotec Pharmaceuticals, this second-generation NNRTI offers enhanced potency and a longer half-life, requiring only a 25 mg once-daily dose, in contrast to the 200 mg BID dosing of efavirenz (Sustiva Ò) In late 2011, fixed-dose combination products of rilpivirine hydrochloride with two nucleoside reverse transcriptase inhibitors (RTIs), including emtricitabine, were also introduced.
Scheme 33 Retrosynthetic analysis of telaprevir (XXI).
2 Recrystallization from MeOH/ i- PrOH/ n -heptane 90%, 99.8% ee
Ruxolitinib phosphate (XX) and tenofovir disoproxil fumarate, co-developed by Gilead Science and Tibotec, have received approval from both the FDA and EMA under the brand names Complera Ò and Eviplera Ò, respectively Rilpivirine hydrochloride, like efavirenz, is classified as a diarylpyrimidine.
(DAPY) compound, and the large-scale process synthesis begins with commercially available 2-methylthio-4-pyrimidinone (193) shown inScheme 31 158–161
Thioether 193 was reacted with 4-cyanoaniline (194) at high temperature, yielding diarylamine 195 with a 77% efficiency The subsequent treatment of pyrimidone 195 with refluxing POCl3 resulted in the formation of chloride 196, also at a 77% yield In the presence of K2CO3, chloride 196 was then reacted with (E)-cinnamonitrile aniline 200, leading to the successful synthesis of rilpivirine hydrochloride (XIX) in a good yield Aniline 200 was synthesized through a Heck reaction involving commercially available 4-iodo-2,6-dimethyl-benzeneamine (197) and acrylonitrile (198), producing compound 199 as a 4:1 mixture of E and Z isomers.
Zisomers The distribution ofE/Z olefins was increased to 98:2 by salt formation and recrystallization to ultimately provide pure(E)-200in 64% yield for two steps 162
Ruxolitinib phosphate (Jakafi Ò )
Ruxolitinib phosphate is a highly selective ATP competitive inhibitor targeting JAK1 and JAK2 tyrosine-protein kinases, effectively reducing cytokine signaling and inducing apoptosis Developed by Incyte and marketed as Jakafi, Ò, it is approved for treating myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF Additionally, Ruxolitinib is currently being evaluated in clinical trials for various cancer types, such as metastatic prostate cancer, pancreatic cancer, multiple myeloma, leukemia, and non-Hodgkin lymphoma.
2,6-dimethylpyridine O TFA, CH 2 Cl 2 , RT, 85%
Scheme 34 Discovery synthesis of fragment 213 of telaprevir (XXI).
Scheme 35 Large scale synthesis of fragment 213 of telaprevir (XXI).
NH 3 + 2 Boc 2 O, DMAP t- BuOH, MTBE, RT
The synthesis of the oxalic acid salt of fragment 217 of telaprevir (XXI) is notable in the context of ruxolitinib, which is under investigation for treating conditions such as breast cancer, psoriasis, and thrombocytopenia Ruxolitinib features one chiral center, and its preparation can be approached through three main strategies: racemic synthesis with subsequent chiral separation, an aza-Michael addition of the pyrazole fragment to 3-cyclopentylpropiolonitrile followed by asymmetric hydrogenation, and an organocatalytic, asymmetric aza-Michael addition The method highlighted in Scheme 32 employs the first strategy, which is recognized as the most scalable approach reported to date.
The synthesis was initiated by SEM protection of commercially available chloropyrrolopyrimidine 201 to provide the protected chloropyrrolopyrimidine202in 89% yield Suzuki coupling of202 with the pyrazole pinacolatoboronate203 gave pyrazole 204 in
64% yield.aza-Michael reaction of pyrazole204with 3-cyclopenty- lacrylonitrile205was accomplished in the presence of DBU to fur- nish SEM-protected ruxolitinib206in 98% yield as the racemate.
The desired enantiomer207was isolated via chiral column separa- tion in 93.5% yield and 99.4% ee, on 100 kg scale Removal of the
SEM group was accomplished through a two step process via treat- ment with lithium tetrafluoroborate and aqueous ammonium hydroxide, ultimately giving rise to ruxolitinib208in 84% yield.
The preparation of ruxolitinib phosphate involved treating the phosphate salt with phosphoric acid, followed by crystallization from a mixture of MeOH, i-PrOH, and n-heptane, achieving an impressive overall yield of 99.8% enantiomeric excess (ee) Additionally, pyrazole pinacolatoboronate was synthesized from pyrazole through iodination using N-iodosuccinimide, followed by a reaction with trimethyl silyl chloride, resulting in a high yield of the protected iodopyrazole.
Reaction of210withi-PrMgCl to form the corresponding Grignard reagent followed by reaction with isopropylpinacolborane 211 provided Suzuki boronate synthon203in 55% yield.
Telaprevir (Incivek Ò )
Telaprevir is a powerful peptide mimetic that inhibits the Hepatitis C virus (HCV) by binding reversibly to the NS3/4A protease enzyme Developed by Vertex Pharmaceuticals, it is marketed as an oral treatment for HCV infection in conjunction with Peg interferon and ribavirin for patients who do not respond to standard therapy The initial structure-activity relationship (SAR) studies and the discovery of telaprevir have been documented, along with a comprehensive review of the discovery process and the various synthesis iterations that led to its development Recently, a concise synthesis method utilizing enzymatic de-symmetrization and a multicomponent reaction (MCR) has been reported This review will concentrate on the process-scale synthesis employed in the production of telaprevir.
For preparation of bulk API, a convergent synthetic strategy was utilized as described in Scheme 33 Retrosynthetically the penultimate intermediate 212, which was coupled with amine
213 for the final step, was prepared by coupling bicyclic amine
217 with amino acids216 and215 and then with pyrazine acid 214.
In the initial development phase, the cyclopropyl amide fragment was synthesized through a multi-component reaction (MCR) by combining aldehyde with cyclopropyl isocyanide and trifluoroacetic acid, yielding amide alcohol at an 85% efficiency The subsequent removal of the Cbz group via hydrogenolysis produced the key cyclopropyl amide alcohol in a 95% yield Although this method was more efficient in terms of steps, it faced challenges for large-scale production due to the complexities involved in handling isocyanide.
Scheme 37 Synthesis of telaprevir (XXI).
Thus, for large-scale synthesis, the route depicted inScheme 35 was utilized Commercially available Cbz-protected amino acid
221was converted to the corresponding Weinreb amide222using
The process began with CDI as the activating agent, followed by LAH reduction to yield aldehyde 218 in a 73% yield from compound 221 Aldehyde 218 was then reacted with sodium cyanide under neutral to mildly basic conditions, facilitating the straightforward workup of the cyanohydrin, which was subsequently hydrolyzed by refluxing in 4 N hydrochloric acid in dioxane to produce hydroxy acid HCl salt 223 The formation of the acyloin led to the removal of the Cbz protecting group, necessitating its reinstatement before conventional amide bond formation via the succinate ester of compound 224 This ultimately resulted in the desired amide alcohol 220, achieved in a 56% yield from 223 Finally, hydrogenolysis of Cbz carbamate 220 yielded the requisite intermediate amine (213) with a 73% yield.
The large-scale synthesis of bicyclic pyrrolidine was successfully achieved using commercially available 3-aza-bicyclo[3.3.0]nonane hydrochloride Initially, this compound was protected as a Boc carbamate, yielding 90% Following this, deprotonation of the bicyclic pyrrolidine carbamate with sec-BuLi, and subsequent quenching with carbon dioxide and sodium hydrogen sulfate, produced racemic acid in an 80% yield.
Racemate 227 was resolved using (S)-tetrahydronapthalamine
(228) in ethyl acetate and isopropanol at 70–75°C This mixture was allowed to cool down slowly to effect the crystallization of the optically enriched chiral salt229in 83% yield with greater than
The enantioenriched salt, with a purity of 99.5%, was synthesized from sodium hydrogen sulfate and transformed into t-butyl ester 230 using Boc anhydride and DMAP The secondary amine in compound 230 was then released at room temperature with methane sulfonic acid, followed by the formation of oxalic acid salt 231 through reaction with oxalic acid in isopropyl acetate, achieving an overall yield of 81% across three steps.
The synthesis of teleprevir progressed with the successful coupling of key intermediates Fragment 217 was combined with Cbz-protected valine (216) through EDCI and HOBt, resulting in intermediate 232 with an impressive yield of 87% Following this, the Cbz group was removed to continue the synthesis process.
232via catalytic hydrogenolysis, the resulting amine was coupled with cyclohexyl amino acid215to give dipeptide intermediate233 in 89% yield over 2 steps Sequential cleavage of the Cbz group in
The synthesis process began with the coupling of compound 233 and commercially available pyrazine acid 214, resulting in the formation of the expected pyrazine amide intermediate This intermediate underwent hydrolysis of the t-butyl ester using concentrated acid in DCM, yielding the crucial tripeptidic acid (212) with a 68% overall yield across three steps The tripeptide (212) was then coupled with cyclopropyl amide amine (213) using EDCI, HOBt, and N-methyl morpholine (NMM), which produced the penultimate intermediate alcohol (234) with a remarkable 95% yield Finally, the intermediate alcohol (234) was oxidized using Dess–Martin periodinane (DMP) in t-butanol and DCM, resulting in the successful synthesis of telaprevir (XXI) with an 85% yield.
Ticagrelor (Brilique Ò )
Ticagrelor, a reversible P2Y12 receptor antagonist developed by AstraZeneca, was approved in the European Union in 2010 and subsequently launched in Germany and the UK in 2011 for treating acute coronary syndromes (ACS) It later received approval in the United States and Canada.
2011 following successful clinical trial results in patients with ACS which showed it to be superior to preexisting drugs for reduc-
Scheme 38 Retrosynthetic analysis of ticagrelor (XXII).
HO OAc NaN(Boc) 2 , cat Pd(PPh 3 ) 4
1 6 N HCl, MeOH, H 2 O cat OsO 4 , NMO HO N
Ticagrelor (XXII) is an oral medication prescribed alongside acetylsalicylic acid (aspirin) to prevent atherothrombotic events in adults experiencing acute coronary syndrome (ACS), which includes unstable angina and non-ST elevation myocardial infarction This drug is crucial in reducing the risk of vascular-related deaths, with a notable impact on patient outcomes.
Ticagrelor, unlike prasugrel and clopidogrel, is not a prodrug and does not need bioactivation, allowing for a rapid onset of action It offers relatively quick reversibility, greater potency, and consistent platelet inhibition, making it a valuable option in the treatment of NSTEMI and STEMI.
Ticagrelor reaches its maximum concentration (C max) approximately 1.5 hours after dosing, producing a major metabolite that has intrinsic activity equivalent to the parent compound The drug's initial discovery and structure-activity relationship (SAR) studies were published in 2007, along with initial patent applications Since then, several patents have been issued detailing improvements for large-scale synthesis of ticagrelor The molecule has been synthesized through various modifications of common intermediates, with large-scale preparation utilizing a convergent strategy that involves the coupling of three key intermediates.
Various methods for synthesizing cyclopentyl amino alcohol have been documented, primarily involving the reaction of commercially available cyclopentene acetate with suitable amines Notably, one innovative approach aimed at deuterated ticagrelor utilized a nitroxide Diels–Alder reaction with cyclopentadiene to integrate the amine into the cyclopentane ring structure.
The most likely process-scale preparation of the key cyclopentyl amine required for ticagrelor is highlighted inScheme 39 185,186
Enantiopure acetate 238 was reacted with sodium di-tert-butyloxy diimide under palladium-mediated amination conditions, yielding bis-Boc amide 239 with a 92% efficiency The subsequent dihydroxylation of cyclopentene 239 using catalytic osmium tetraoxide and N-methyl morpholine N-oxide in a THF/water mixture produced cis-diol 240 in quantitative yield The free amine was then released with 6 N HCl, leading to the in situ ketalization of the cis-diol hydrochloride salt 241, which achieved a 92% yield Finally, Cbz carbamate 242 was synthesized quantitatively from compound 241 under standard conditions.
242was treated with potassiumt-butoxide and bromoethyl ace- tate (243), the ester intermediate of which was reduced in situ with lithium borohydride to alcohol 244 in 86% overall yield
Hydrogenolysis conducted at 1.2 bar of hydrogen pressure using 5% Pd/C resulted in an amino alcohol intermediate (235) with an impressive yield of 83% This intermediate was then combined with oxalic acid to produce the oxalate salt, achieving an 82% yield, which was ultimately utilized in the final synthesis of ticagrelor.
The synthesis of dichloroamino pyrimidine thioether, essential for the large-scale preparation of ticagrelor, involves multiple reported methods The process begins with the formation of thiol barbituric acid, which is synthesized through the reaction of dimethyl malonate.
(245) with thiourea (246) in the presence of sodium methoxide. These conditions provided the sodium salt of the pyrimidone thiol
The synthesis process began with the isolation of compound 247 in 83% yield through filtration This compound was then reacted with propyliodide in an aqueous methanolic sodium hydroxide solution, followed by an HCl quench, resulting in thioether 248 with a yield of 76% The nitration of thioether 248 was performed using fuming nitric acid in acetic acid, yielding nitro pyrimidinol 249 at 75% Further transformation involved bis-chlorination with POCl3, converting 249 to dichloropyrimidine thioether 250 in nearly quantitative yield An earlier study highlighted the selective reduction of nitro dichloropyrimide thioether 250 via hydrogenation at 3 bar pressure with a 3% Pt/0.6% V/C catalyst, achieving a 95% yield of amino dichloropyrimidine thioether 236 Notably, for larger kilo-scale reactions, selective hydrogenation was successfully conducted using a Pt/V/C catalyst containing 2% Pt and 1% V on carbon.
8 bar of hydrogen pressure to give the crude amino dichloropyrim- idine thioether236 187
The large-scale preparation of cyclopropyl amine intermediate involves the condensation of malonic acid and 3,4-difluorobenzaldehyde with piperidine in pyridine, yielding acid in 88% after acidic work-up Acid chloride is synthesized using thionyl chloride, followed by esterification with L-menthol and pyridine to produce L-menthol ester in 93% yield over two steps Cyclopropanation with dimethylsulfoxonium methylide in DMSO results in the formation of the desired trans-cyclopropane with a yield of 40% and 92% enantiomeric excess after recrystallization Hydrolysis of the ester and subsequent reaction with thionyl chloride leads to acid chloride with an overall yield of 61% across two steps.
The synthesis of fragment 236 of ticagrelor (XXII) involved reacting chloride 257 with sodium azide, using sodium carbonate and tetrabutyl ammonium bromide in a biphasic mixture of toluene and water This reaction yielded the acyl azide intermediate, which was then treated with warm toluene, followed by acidic workup, resulting in the formation of the key intermediate cyclopropyl amine 237 with an impressive yield of 88% and an enantiomeric excess (ee) of 92% Subsequently, this enantioenriched intermediate was combined with R-()-mandelic acid to produce the mandelic acid salt of amine 237 (258).
With all three intermediates available from the above men- tioned routes, the final assembly of ticagrelor was accomplished as outlined inScheme 42 187 First, oxalate salt of cyclopentyl amine
235was coupled with dichloroaminopyrimidine thioether236in
L -menthol, pyridine toluene, 65 °C, then at RT, 93%
Scheme 41 Synthesis of fragment 237 of ticagrelor (XXII).
30 min toluene, 15 °C HCl (conc.), MeOH 90% (3 steps)
The synthesis of ticagrelor (XXII) involves the reaction of a diamine intermediate, achieved with triethylamine and elevated temperature, yielding an 88% crystallization success Subsequently, the diamine undergoes diazotization using sodium nitrite in a mixture of acetic acid and toluene at 30°C, resulting in the formation of a triazole intermediate This triazole is then promptly reacted with another compound to continue the synthesis process.
(madelic acid salt of cyclopropyl amine237) to give intermediate
The final deprotection step involved the reaction of ketal 261 with concentrated HCl in methanol and toluene at 15°C, yielding ticagrelor (XXII) with an impressive yield of 82–90% over three steps.
Vandetanib (Caprelsa Ò , Zactima Ò , Zictifa Ò )
Vandetanib, an oral inhibitor targeting VEGF, EGF, and RET receptor tyrosine kinases, was developed by AstraZeneca specifically for treating symptomatic or aggressive medullary thyroid cancer (MTC) in patients with advanced or metastatic disease This medication marks a significant milestone as the first approved treatment for MTC Additionally, clinical trials are currently investigating its efficacy in other cancer types, including small-cell lung cancer (SCLC), breast cancer, head and neck cancer, colorectal cancer, hormone-resistant prostate cancer, and papillary thyroid cancer.
AstraZeneca's ZD-4190 shows comparable efficacy and pharmacokinetics to vandetanib, which has notably enhanced solubility Vandetanib features a 4-anilinoquinazoline scaffold, akin to other EGFR inhibitors, with its synthesis outlined in a recent patent (Scheme 43).
Commercially available vanillic acid was reacted with benzyl bromide, DIPEA, and Et3N to produce ethereal ester in 93% yield This compound underwent nitration to yield nitroarene in 86% yield, which was then reduced with sodium dithionite to obtain aniline in 92% yield Aniline was treated with formidine acetate in isobutanol, leading to an intramolecular cyclization that produced dihydroquinazolin-4-one in 98% yield The resulting heterocycle was reacted with phosphorous oxychloride to form a quinazoline chloride, which was then combined with 4-bromo-2-fluoroaniline and trifluoroacetic acid, yielding hydroxyaniline in 90% for the three-step sequence Finally, phenolic azacycle was alkylated with sulfonate to produce piperidine in 77% yield, and subsequent treatment with formic acid and aqueous formaldehyde at elevated temperatures resulted in vandetanib with a 91% yield.
Vemurafenib (Zelboraf Ò )
Vemurafenib, an oral BRAF inhibitor co-developed by Roche and Plexxikon, was initially discovered at Plexxikon for treating patients with BRAFV600E mutation-positive metastatic melanoma It demonstrates strong potency and selectivity for the V600E mutation, with an IC50 range of 3.2–14 nM, compared to the wild-type BRAF's IC50 range of 21–370 nM Although Vemurafenib is less potent in in vitro kinase assays than other BRAF inhibitors from Plexxikon, it was chosen for clinical development due to its targeted efficacy.
BnBr, DIPEA, Et 3 N CH 2 Cl 2 , H 2 O, CH 3 COOH
Scheme 43 Synthesis of vandetanib (XXIII). based on its enhanced potency against the BARFV600E-containing
A374 melanoma cell line 199 The synthesis described below is based on a recent process patent (Scheme 44) 201
Commercially available 2-amino-5-bromopyridine (271) was treated with 4-chlorophenylboronic acid (272) in the presence of
In a series of reactions, Na2CO3 and a catalytic amount of Pd(OAc)2/PdCl2(dppf)CH2Cl2 were used to synthesize Suzuki product 273 with an impressive yield of 83% This compound underwent iodination with NIS and TFA, resulting in iodide 274 with a yield of 98% Subsequently, iodide 274 was coupled with pinacol vinylboronate 275 under Suzuki conditions, followed by acid treatment to initiate a tandem coupling-cyclization sequence, yielding pyrimidyl pyrrole 276 in good yield Finally, this product was treated with aluminum trichloride and reacted with the acyl chloride of commercially available sulfonamide acid 277, leading to a Friedel-Crafts reaction.
Crafts reaction providing vemurafenib (XXIV) in 85% yield.
Vilazodone hydrochloride (Viibryd Ò )
Vilazodone hydrochloride, marketed as Viibryd, is a unique antidepressant that functions as both a serotonin reuptake inhibitor (SSRI) and a partial agonist of the 5-HT1A receptor Developed by Merck KGaA, Viibryd received FDA approval for depression treatment on January 21, 2011 Clinical studies indicate that vilazodone is well-tolerated at higher doses, with notable advantages such as minimal weight gain and preserved sexual desire and function, making it a favorable alternative to traditional antidepressants.
Although several synthetic approaches have been reported, 204–207 a process-scale synthesis of vilazodone consists of the union of an indole-containing butyl tosylate284with a benzofuranyl piperazine
280, 208 whose synthesis is described below (Scheme 45) Piperazine
Scheme 45 Synthesis of vilazodone hydrochloride (XXV).
1% Pd(OAc) 2 , 1% PdCl 2 (dppf) CH 2 Cl 2 dioxane/H 2 O, Na 2 CO 3
PdCl 2 (dppf) CH 2 Cl 2 LiOH, DMF, 70 ° C
Scheme 44 Synthesis of vemurafenib (XXIV).
The synthesis of compound 280 involves a Buchwald coupling of benzofuranyl bromide with piperazine, utilizing a specialized catalyst system with the DavePhos ligand, achieving a 70% yield on a multigram scale without the need for protecting group chemistry To create the essential indole subunit, a Friedel-Crafts acylation of 5-cyano-indole at the 3-position with 4-chlorobutanoyl chloride resulted in an 82% yield Subsequently, the chloroketone was treated with sodium borohydride in refluxing isopropanol, yielding the corresponding terminal alcohol.
283 Tosylation of this alcohol was followed by displacement with piperazine 280 to give vilazodone hydrochloride (XXV) after acidification 208
Zucapsaicin (Zuacta Ò )
Zucapsaicin, a topical analgesic derived from capsaicin, was developed by Winston Pharmaceuticals and approved in Canada in July 2010 for treating severe knee osteoarthritis pain in adults It offers advantages over natural capsaicin, including reduced local irritation and enhanced efficacy in preclinical pain models Both zucapsaicin and capsaicin exert their analgesic effects through the TRPV1 channel, which is found in the spinal cord, brain, and sensory neurons The large-scale preparation of zucapsaicin follows the method established by Gannett and colleagues, involving the coupling of vanillylamine with (Z)-8-methylnon-6-enoyl chloride, further refined by Orito and co-workers for gram-scale production.
Commercial 6-bromohexanoic acid (285) was activated as the
Prior to condensation with isobutylaldehyde in the presence of a strong base, Wittig salt generates an 11:1 ratio of E/Z-olefinic acids, favoring the Z-isomer The removal of the minor isomer was efficiently accomplished through short-path distillation Notably, the authors observed that olefin isomerization of the Z-isomer occurred readily when exposed to nitric acid at elevated temperatures.
Recrystallization of the E-isomer yielded capsaicin in a substantial quantity of 77% on a multi-gram scale, indicating a viable method for large-scale production For zucapsaicin synthesis, acid 286 was transformed into its acid chloride using thionyl chloride, followed by immediate reaction with commercially available vanillylamine (287) This process involved two recrystallization steps, resulting in a total yield of 66% for gram-scale quantities of zucapsaicin (XXVI).
The authors thank Dr Carolyn Leverett and Dr Robert Kyne Jr. for their extremely helpful suggestions in preparing this review. References and notes
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Scheme 46 Synthesis of zucapsaicin (XXVI).
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