Alectinib hydrochloride (Alecensa Ò )
Alectinib hydrochloride, developed by Chugai Pharmaceutical/
Alecensa (alectinib), developed by Hoffman-La Roche, received approval in Japan in April 2014 for treating advanced or recurrent non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion-gene positivity This highly selective second-generation ALK inhibitor has demonstrated a 93.5% objective response rate in phase II clinical trials and has been granted orphan drug designation in Japan Alectinib not only offers rapid treatment response but also boasts a 76% two-year progression-free survival rate While crizotinib, the first ALK inhibitor, has significantly improved patient outcomes compared to traditional chemotherapy, drug resistance remains a challenge However, early studies suggest that alectinib may effectively address this issue, showing promise in overcoming resistance associated with other ALK inhibitors.
The synthetic pathway to alectinib, as detailed by Chugai, initiates with 7-methoxy-2-tetralone The process involves bis-methylation using tetrabutylammonium hydrogen sulfide and aqueous potassium hydroxide, followed by methyl iodide, resulting in bromo-tetralone with a yield of 67% across two steps This intermediate is then reacted with 3-hydrazinobenzonitrile and trifluoroacetic acid to continue the synthesis.
In 2014, the approval of 38 new chemical entities (NCEs) showcased significant advancements in pharmaceutical research The synthesis process involved the use of trifluoroacetic acid (TFA), which successfully facilitated the formation of the desired Fischer indole product However, this reaction produced a 1:1 mixture of regioisomers, specifically compounds 3 and 4 These regioisomers were subsequently advanced as a mixture for oxidation using 2,3-dichloro-5,6-dicyano.
1,4-benzoquinone (DDQ) It is important to note that although rep- resentative procedures are published describing the conversion of
Alectinib (I) did not yield specific results for the transformations conducted After oxidation, the target product could be successfully isolated as a single isomer through precipitation from the crude reaction mixture The incorporation of the 4-morpholino-piperidine moiety was achieved in three steps starting from the product.
N-methyl-2-pyrrolidone (NMP) and sodium methoxide (NaOMe) facilitate the methyl cleavage process The resulting phenol is efficiently transformed into a triflate intermediate, which is subsequently reacted with 4-(piperidin-4-yl)morpholine at elevated temperatures to yield intermediate 7 This intermediate undergoes cross-coupling with ethynyl triisopropylsilane, leading to further synthesis.
The synthesis of alectinib hydrochloride involves Pd-catalyzed cross-coupling using Pd(CH3CN)2Cl2 and XPhos under reflux conditions, followed by the cleavage of the resulting alkylsilane with tetrabutylammonium fluoride (TBAF) to produce the ethynyl precursor Subsequent hydrogenation of this unsaturated compound using hydrogen gas and Pd/C, along with the formation of the HCl salt, ultimately yields the final drug target, alectinib hydrochloride (I).
Apatinib mesylate
Apatinib mesylate, an oral tyrosine kinase inhibitor developed by Advenchen Laboratories in the USA and Jiangsu Hengrui Medicine Co Ltd in China, received approval from the Chinese Food and Drug Administration (CFDA) in October 2014 for treating metastatic gastric carcinoma This medication selectively targets and inhibits the vascular endothelial growth factor receptor 2 (VEGFR2), effectively preventing tumor growth.
Apatinib has demonstrated selective inhibition of the VEGF signaling pathway, particularly affecting tumor tissue, with an impressive IC50 value of 1 nM for VEGFR-2 in in vitro studies Currently, a multicenter phase II clinical trial is evaluating the efficacy of apatinib in patients with non-triple-negative metastatic breast cancer Additionally, non-clinical research suggests that apatinib may reverse the effects of the ATP-binding cassette subfamily B member 1 and subfamily G member 2.
(ABCB1- and ABCG2, respectively)-mediated multidrug resistance which allows cancer cells to circumvent certain conventional anti- neoplastic drugs, suggesting that apatinib could be effective as a combination therapy 35
The synthetic route of apatinib mesylate (II) described in
Scheme 2is based on a patent disclosure 36,37 The synthesis started with commercially available 1-phenyl cyclopentane carbonitrile
(8), which was nitrated to provide nitrobenzene9 Subsequent reduction of9gave aniline10, which was coupled with 2-chloron- icotinoyl chloride (11) to afford aryl amide12 Subjection of the
The synthesis of apatinib (14) from 2-pyridyl chloride and pyridin-4-ylmethanamine (13) was conducted in hot pentanol, yielding 14 Previous reports indicated that the preparation of apatinib from starting material 8 was performed on a gram or milligram scale without specifying the yield A total of 170 g of apatinib (14) was combined with methylsulfonic acid in a 95% isopropanol–water solution, resulting in 161.5 g of apatinib mesylate (II) with a yield of 77%.
Apremilast (Otezla Ò )
Apremilast is the first and only oral phosphodiesterase IV (PDE-
Celgene launched an inhibitor and anti-tumor necrosis factor alpha (TNFa) agent in the USA for the treatment of active psoriatic arthritis (PsA), known as Apremilast This medication was also approved for moderate to severe plaque psoriasis in the USA and later received approval in the European Union for both indications Various synthesis methods for Apremilast have been documented, with the most feasible process likely being scalable.
XXII Netupitant XXI Naloxegol Oxalate
Fig 1 (continued) approach involves the construction of the challenging stereogenic benzylic carbon center by catalytic asymmetric hydrogenation, and this is described inScheme 3.
Dimethyl sulfone was first subjected to n-butyllithium in tetrahydrofuran (THF) prior to exposure to commercially available
At low temperatures, 3-ethoxy-4-methoxybenzonitrile (15) was transformed into enamine 16 with an impressive yield of 83%, likely as a single E-isomer Extensive research by Celgene focused on the reduction of this enamine and other substrates, leading to the successful reduction of enamine 16 under asymmetric hydrogenation conditions using [Rh.
(COD)2]OTf and (S,R)-t-Bu Josiphos in trifluoroethanol (TFE) at
At 50°C and 90 psi of hydrogen pressure, the product was immediately exposed to N-acetyl-L-leucine in methanol, resulting in the formation of the corresponding benzylamine salt with an 80% yield and over 99% enantiomeric excess (ee) Subsequently, compound 18 was reacted with commercially available N-(phthalimid-3-yl)acetamide in refluxing acetic acid, yielding apremilast with an 83% yield and 99.4% ee.
Asunaprevir (Sunvepra Ò )
Asunaprevir, marketed as SunvepraÒ, has been approved in Japan for use in combination therapy to treat the hepatitis C virus (HCV) This innovative treatment works alongside daclatasvir, offering a unique approach to managing HCV without the common drawbacks associated with other therapies.
XXVI Oritavancin Diphosphate XXV Ombitasvir Hydrate
Fig 1 (continued) both interferon and ribavirin and is administered orally This direct-acting anti-viral, which was developed by Bristol–Myers
Squibb (BMS) has developed an NS3/4A protease inhibitor, offering a significant treatment alternative for patients who cannot tolerate or do not respond to standard therapies like peginterferon/ribavirin While the specific manufacturing process remains undisclosed, various synthetic methods are documented in the literature The most probable scalable route aligns with patent literature detailing the production of the active pharmaceutical ingredient by BMS In a retrosynthetic analysis, asunaprevir can be divided into three key components: a chloroisoquinolino-xy proline derivative, a vinylcyclopropane amino acid, and commercially available N-Boc-3-methyl-L-valine The synthesis of these subunits is illustrated in the corresponding schemes.
The synthesis of chloroquinoline began with the bromination of acetophenone on a large scale, utilizing a reactor with an HBr scrubbing system to produce a-bromoketone This was followed by a nucleophilic displacement using sodium diformamide under phase transfer conditions, yielding an intermediate that underwent in situ deprotection and cyclization to form isoquinolone with a 78% yield in a one-pot reaction Subsequently, methylation of the hydroxyl group at C-4 was performed using methanolic methanesulfonic acid, and excess acid was neutralized with aqueous ammonium hydroxide Finally, treatment with phosphorus oxychloride resulted in the formation of dichloroisoquinoline in good yield.
Fig 1 (continued) employing potassium t-butoxide was used to establish an aryl- pyrrolidino ether linkage and, upon workup with mildly acidic con- ditions, the proline derivative27emerged in 59% yield 46
Researchers at BMS have detailed the synthesis of the asunaprevir vinyl cyclopropane subunit, yet it's noteworthy that this subunit and its structural derivatives have garnered significant interest.
XPhos, Pd(CH 3 CN) 2 Cl 2
1) TBAHS, MeI, THF aq KOH, ↑↓, 73%
Scheme 1 Synthesis of alectinib hydrochloride (I).
H 2 N no yield reported no yield reported
Scheme 2 Synthesis of apatinib mesylate (II). found within a number of other antiviral drugs, particularly those which target inhibition of NS3 protease as its mechanism of action.
Researchers at Boehringer-Ingelheim have developed a scalable synthesis of (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid, also known as vinyl-ACCA, to integrate this subunit into their antiviral agent BILN 2061 Additionally, a macrocyclic variant of this cyclopropane system is present in the antiviral agent paritaprevir hydrate, created by Enanta and AbbVie, while a saturated version is found in vaniprevir.
Merck's research, detailed later in this review, outlines the preparation of compound 32 by Beaulieu and colleagues on a pilot-plant scale, with the conversion to compound 35 described in the BMS patent The process begins with commercially available methyl glycine HCl (28), which undergoes condensation with benzaldehyde using trimethyl orthoformate and a base to form the transient imine 29 This imine then participates in a highly diastereoselective alkylation reaction, where treatment with lithium t-butoxide and 1,4-dibromo-2-butene facilitates an S N 2–S N 2' reaction Following acidification and Boc protection, the resulting compound 30-rac is produced as a racemate, existing as a single diastereomer with the vinyl and ester groups in a cis configuration The authors suggest that the lithium enolate intermediate formed during the initial alkylation plays a crucial role in this process.
1) N-Boc-3-(R)-hydroxy-L-proline t-BuOK, DMSO, 10 °C N
2) aq NH 4 OH, MeOH, 5 °C 90% for 2 steps
2) aq HCl to pH = ~ 5, EtOAc, rt
Scheme 4 Synthesis of asunaprevir chloroisoquinolinoxy proline subunit 27.
1) Rh(cod) 2 OTf, H 2 , TFE (S, R)-t-Bu Josiphos, 50 °C
The synthesis of apremilast (III) involves the selective saponification of the undesired enantiomer 31b using the enzyme calase 2.4 L, which efficiently resolves racemic esters under basic conditions, yielding 49% of the desired ester 31a Following a straightforward aqueous workup to eliminate the undesired acid, methyl ester 31a undergoes saponification with methanolic lithium hydroxide to produce intermediate 32 This compound is then coupled with cyclopropanesulfonamide 33, resulting in an excellent yield of product 34 The Boc group is subsequently removed using TFA, and salt formation with ethereal HCl yields the crucial cyclopropane subunit 35.
The synthesis of asunaprevir (IV) involves the coupling of cyclopropyl amine (35) with proline derivative (27) under standard amide bond-forming conditions, followed by the acid-mediated removal of the Boc protecting group from the pyrrolidine nitrogen This process is completed with the coupling of N-Boc-3-methyl valine (37), resulting in good yields throughout each step.
1) 1,4-dibromo-2-butene t-BuOLi, NMP, TBME
Scheme 5 Synthesis of asunaprevir vinyl cyclopropyl subunit 35.
Scheme 6 Endgame synthesis of asunaprevir (IV).
Ataluren (Translarna Ò )
Ataluren is a drug marketed under the trade nameTranslarna Ò which was developed by PTC Therapeutics and approved by the
European Union in May 2014 for the treatment of Duchenne’s mus- cular dystrophy (DMD) and potentially other genetic disorders 50
Ataluren renders ribosomes less sensitive to premature stop or
Read-through codons are believed to offer therapeutic benefits for conditions like Duchenne muscular dystrophy (DMD) and cystic fibrosis Among the various synthetic methods developed for ataluren, the most promising approach is outlined in Scheme 7, which has been demonstrated at a kilogram scale.
The synthesis of ataluren, as outlined by PTC Therapeutics, begins with commercially available methyl 3-cyanobenzoate This ester undergoes a reaction with hydroxylamine in aqueous tert-butanol, gently warmed until complete The resulting mixture is then treated dropwise with 2-fluorobenzoyl chloride and triethylamine to control exothermic reactions and minimize byproducts After the starting materials are fully consumed and the amidooxime is formed, the aqueous mixture is heated to proceed with the synthesis.
To achieve the formation of 1,2,4-oxadiazole and successfully synthesize the tri-cyclic ester 40, a temperature of 85°C was utilized, yielding excellent results across three steps The subsequent saponification of ester 40 using sodium hydroxide, followed by an acidic quench, resulted in the production of ataluren (V) with a remarkable 96% yield over the two-step process.
Belinostat (Beleodaq Ò )
Belinostat, marketed as Beleodaq by Onxeo, is a histone deacetylase (HDAC) inhibitor developed by Spectrum Pharmaceuticals, receiving FDA fast track designation and approval in 2014 for treating hematological malignancies and solid tumors associated with peripheral T-cell lymphoma (PTCL) It is the third HDAC inhibitor to gain accelerated approval for PTCL, following vorinostat and pralatrexate Although not approved in Europe as of August 2014, belinostat demonstrates an acceptable safety profile, with less than 25% of patients experiencing adverse effects, primarily nausea, fatigue, pyrexia, anemia, and emesis Various synthetic methods for belinostat and related HDAC inhibitors have been reported, with a notable process-scale approach detailed in a patent application by Reisch and colleagues at Topotarget UK, showcasing kilogram-scale synthesis.
1) NH 2 OH, aq t-BuOH, 45 ºC
2) 2-fluorobenzoyl chloride, Et 3 N aq t-BuOH, 35 ºC
2) NH 2 OH, THF, i-PrOAc, H 2 O, 10 ºC
N OH ethyl acrylate, Pd(OAc)2, (o-Tol)3P aq Na2CO3, aniline
Scheme 8 Synthesis of belinostat (VI).
Commercially available 3-bromobenzenesulfonyl chloride was reacted with aniline in the presence of aqueous sodium carbonate, yielding sulfonamide in 94% yield This aryl bromide underwent a Heck reaction with ethyl acrylate to produce cinnamate ester, which was then saponified under basic conditions and acidic workup to yield the corresponding acid The acid was converted to its acid chloride form and reacted with hydroxylamine under basic conditions to form hydroxamic acid Finally, the hydroxamic acid was recrystallized from an 8:1 ethanol/water mixture with a catalytic amount of sodium bicarbonate, resulting in crystalline belinostat.
(VI) in 87% overall yield from acid44 61
Ceritinib (Zykadia Ò )
Ceritinib, known commercially as Zykadia and developed by Novartis, has recently gained FDA approval for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) This drug belongs to a class of ALK inhibitors and has received 'breakthrough therapy' designation due to its demonstrated superior anti-tumor efficacy compared to the previously approved ALK inhibitor crizotinib, as well as its effectiveness in overcoming resistance to crizotinib Currently, ceritinib is indicated as a second-line treatment for NSCLC, particularly for patients who are intolerant to crizotinib or who experience disease progression while on it.
Scheme 9 Synthesis of ceritinib hydrochloride (VII).
Recent research is ongoing globally to evaluate the effectiveness of ceritinib as both a first and second-line treatment option for patients with ALK-positive non-small cell lung cancer (NSCLC), particularly following the administration of crizotinib.
The critical step in the synthesis of ceritinib involves a late- stage Buchwald–Hartwig coupling of two advanced intermediates, anilino piperidine 50 and arylsulfonyl chloro-pyrimidine 51
In the synthesis of ceritinib, microwave-mediated conditions have been utilized, similar to another Suzuki coupling in the sequence However, to our knowledge, no alternative methods have been reported that effectively facilitate the construction of ceritinib on a process scale.
Construction of anilino piperidine 50 commenced with 2- chloro-4-fluoro-1-methylbenzene (45) Nitration with KNO3/
H2SO4 and subsequent reaction withi-PrOH/Cs2CO3 at elevated temperatures provided the 5-isopropoxy chloride intermediate
The Suzuki coupling of compound 46 with 4-pyridine boronic acid (47) resulted in a 73% yield of compound 49, which underwent platinum oxide-catalyzed hydrogenation in the presence of acetic acid and trifluoroacetic acid to produce a piperidinyl aniline intermediate This intermediate was immediately protected with Boc to generate the Buchwald–Hartwig coupling precursor (50) with a 60% yield over two steps The crucial Buchwald–Hartwig coupling between precursor 50 and compound 51 formed the ceritinib framework Finally, the Boc group was removed using TFA, and precipitation with 1 M HCl yielded ceritinib (VII) as the HCl salt with a 35% yield from precursor 50.
Chidamide (Epidaza Ò )
Chidamide (Epidaza Ò ), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in
December 2014 for the treatment of recurrent of refractory periph- eral T-cell lymphoma Chidamide, also known as CS055 and HBI-
Chidamide, an orally bioavailable benzamide HDAC inhibitor, targets isoenzymes class I 1–3 and class IIb 10, demonstrating potential anti-neoplastic activity by increasing histone protein H3 acetylation This compound inhibits signaling kinases in the PI3K/Akt and MAPK/Ras pathways, potentially leading to cell cycle arrest and tumor cell apoptosis Currently, phases I and II clinical trials are investigating its efficacy in treating non-small cell lung cancer and breast cancer The synthetic route to chidamide involves the condensation of nicotinaldehyde and malonic acid, followed by activation and reaction with 4-aminomethyl benzoic acid, yielding amide 56 Subsequent activation of amide 56 with CDI, followed by treatment with 4-fluorobenzene-1,2-diamine and TFA in THF, produces chidamide with an overall yield of 38% Notably, no publications have reported the use of mono-N-Boc-protected bis-aniline in the synthesis of chidamide.
Daclatasvir dihydrochloride (Daklinza Ò )
Daclatasvir dihydrochloride is an NS5A replication complex inhibitor used to treat hepatitis C virus (HCV) Initially approved in Japan, it is designed for genotype 1 HCV patients who do not respond to interferon and ribavirin therapy Additionally, the drug is also approved for patients with untreated chronic HCV who meet eligibility criteria.
3) Cuno Zeta Carbon TM 55SP MeOH; acetone
Scheme 11 Synthesis of daclatasvir dihydrochloride (IX). for interferon Additionally, in Europe, daclatasvir was approved for use in combination with other products across genotype 1–4 HCV.
Daclatasvir, developed by Bristol–Myers Squibb, emerged from a phenotypic screening program and a strategic medicinal chemistry approach, as detailed in recent reports The compound has been synthesized through two distinct methods, with the process outlined in Scheme 11.
Bromination of commercial 4,4 0 -diacetylbiphenyl (58) gave
4,4 0 -bis(bromoacetyl)biphenyl 59 in 82% yield Alkylation of N-
Boc-L-proline (60) reacted with compound 59 to yield diester 61, which was cyclized using ammonium acetate to form bis-imidazole 62 with a 63% yield over two steps The Boc protecting groups were then removed under acidic conditions, and recrystallization resulted in bis-pyrrolidine 63 in high yield Acylation of compound 63 with N-(methoxycarbonyl)-L-valine (64) was achieved using EDC and HOBT, leading to the synthesis of daclatasvir The dihydrochloride salt of daclatasvir was obtained, treated with Cuno Zet Carbon Ò, and subsequently crystallized from acetone, resulting in daclatasvir dihydrochloride (IX) with a 74% yield.
Dasabuvir sodium (Exviera Ò )
Dasabuvir sodium (Exviera Ò), an oral non-nucleoside NS5B polymerase inhibitor developed by Abbvie, is a key component of the all-oral hepatitis C treatment regimen Viekira Pak Approved by the US FDA in December 2014, it is designed for adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection This investigational regimen includes a fixed-dose combination of paritaprevir (XXVII) (veruprevir, ABT-).
450,vide infra) with ritonavir booster (150/100 mg) co-formulated with the NS5A inhibitor ombitasvir (XXV) (ABT-267, vide infra)
Scheme 12 Synthesis of dasabuvir sodium hydrate (X).
Dasabuvir (X) is a nonnucleoside NS5B polymerase inhibitor, administered at a dosage of 250 mg twice daily, with or without weight-based ribavirin Additionally, a 25 mg dose is given once daily This medication received breakthrough therapy designation from the US FDA in May 2013.
AbbVie's application is backed by data from six Phase III studies involving over 2,300 patients across 25 countries, making it one of the largest clinical programs in hepatitis C research These studies demonstrated remarkable efficacy, with a 12-week treatment regimen achieving a 99% sustained virologic response in certain patient populations.
Although several syntheses of dasabuvir sodium (X) have been disclosed, 89–91 the most likely scale approach is outlined in
Commercially available 2-tert-butyl phenol underwent polyiodination to yield diiodophenol with a 93% efficiency Subsequently, the phenol was methylated to produce methyl phenyl ether at a remarkable 99% yield Following this, sequential couplings were utilized to construct the peripheral structure around the central phenyl core, starting with a Goldberg coupling of methyl phenyl ether with pyrimidine-2,4-(1H,3H)-dione.
In the presence of CuI (10 mol %), compound 70 was synthesized with a 70% yield The remaining iodide underwent Suzuki coupling with boronic acid, facilitated by Pd2(dba)3, resulting in high yields of naphthol 73 This naphthol was then transformed into polyfluorinated naphthol sulfonate 75, which was subsequently converted to dasabuvir through a palladium-mediated installation of methyl sulfonamide 76 Finally, dasabuvir sodium (X) was crystallized by treating it with aqueous NaOH in i-PrOH and DMSO, achieving an 88% yield.
Delamanid (Deltyba Ò )
Delamanid, marketed by Otsuka, received approval in 2014 from both the European Union and Japan for use in combination therapies targeting multi-drug resistant tuberculosis (TB) Its lack of adverse drug–drug interactions makes it a valuable option alongside standard antiretroviral medications for TB treatment Delamanid works by inhibiting mycolic acid biosynthesis in Mycobacterium tuberculosis, facilitating the penetration of small molecule antivirals into the bacterial cell wall.
82, Pd 2 (dba) 3 , t-BuXPhos NaOt-Bu, PhMe, 70 °C then TsOHãH 2 O 86%
Scheme 13 Synthesis of delamanid (XI).
Ti(Oi-Pr) 4 , 80% cumene hydroperoxide, -10 °C to rt
Scheme 14 Synthesis of delamanid diol subunit 82.
Delamanid features a linear structure that allows for multiple retrosynthetic disconnections The most feasible synthesis method is a convergent approach utilizing two primary synthons: diol 82 and piperidine 81, as depicted in Scheme 13.
Preparation of 82 proceeded through a Sharpless Asymmetric
Epoxidation of commercial alcohol86, followed by a diastereose- lective epoxide ring opening with 4-bromophenol to afford key diol82in 76% for the two step sequence (Scheme 14) 93–96
Piperidine 81 was concurrently prepared by first generating biaryl ether79, which arose from a substitution reaction between pyridineN-oxide77 and phenol78that proceeded in 86% yield.
The removal of the N-oxide functionality through catalytic hydrogenation under mild pressure and neutral conditions successfully yielded diaryl ether 80 in excellent quantities Additionally, the reduction of pyridine to piperidine 81 was achieved using catalytic hydrogenation under acidic conditions and higher pressures compared to the N-oxide reduction Subsequently, piperidine 81 was subjected to Buchwald–Hartwig conditions in the presence of diol subunit 82.
The preparation of diol 83, as outlined in Scheme 14, involves a two-step elimination process that leads to the formation of enantiopure epoxide 84 This sets the stage for a cascade reaction to synthesize delamanid (XI) directly The process begins with the alkylation of the epoxide by imidazole 85 under basic conditions using sodium acetate This is followed by an intramolecular nucleophilic substitution reaction, where the liberated alcohol reacts with the pendant imidazole chloride in the presence of sodium hydroxide The entire reaction sequence achieves a yield of 73%, resulting in delamanid (XI) as a free base.
Eliglustat tartrate (Cerdelga Ò )
Eliglustat tartrate, developed by Genzyme Corporation (a Sanofi subsidiary), received US FDA approval in August 2014 for treating nonneuropathic (type 1) Gaucher disease (GD1) in both treatment-naïve and treatment-experienced adults This medication is notable for being the first oral treatment approved for first-line use in patients with Gaucher disease type 1, a rare lysosomal storage disorder marked by the accumulation of glucocerebrosides.
4) oxalic acid, MIBK, rt 2 oxalic acid
1) aq NaHCO3, EtOAc, PhMe, rt
Scheme 15 Synthesis of eliglustat tartrate (XII).
4) AlCl 3 , Et 3 SiH, DCM, MeCN, 10 to 20 °C
Scheme 16 Synthesis of empagliflozin (XIII).
4) 30% HCl to pH = 5-6 90% for 4 steps
Finafloxacin (XIV) synthesis is relevant in the context of Gaucher disease (GD1), which is caused by insufficient production of the enzyme glucosylceramidase, leading to lipid glucosylceramide (GL-1) accumulation Clinical complications associated with GD1 include hepatosplenomegaly, anemia, thrombocytopenia, and bone involvement Eliglustat, a specific inhibitor of glucosylceramide synthase with an IC50 of 10 ng/mL, serves as substrate reduction therapy for GD1 Phase III trials have shown that eliglustat is non-inferior to the current standard of care, enzyme replacement therapy.
The largest reported process-scale route to eliglustat tartrate involves the condensation of commercially available S-(+)-2-phenyl glycinol with phenyl bromoacetate in acetonitrile, utilizing N,N-diisopropylethylamine as a catalyst.
(DIPEA) provided morpholin-2-one89upon treatment with HCl.
Neutralization with NaHCO 3 followed by coupling with aldehyde
90 in refluxing EtOAc/toluene yielded oxazine adduct91, which was isolated as a precipitate from methyl-tert-butyl ether (MTBE).
The stereochemistry of the three new stereocenters in compound 91 can be explained by the cycloaddition of an ylide intermediate in the sterically-favored S-configuration, formed from morpholinone 89 and aldehyde 90 In a chair conformation with the phenyl group in an equatorial position, the dipolarophile approaches the less-hindered face of the ylide endo axially This is followed by a ring flip to a boat conformation, which arranges all exocyclic aryl substituents in a pseudoequatorial configuration The subsequent opening of oxazine 91 with pyrrolidine in refluxing THF, along with the addition of HCl in refluxing MeOH, leads to the formation of an amide.
The synthesis of eliglustat began with the reduction of compound 92 to amine 93 using LiAlH4 in refluxing THF Following this, hydrogenation with Pd(OH)2 in ethanol cleaved the phenylethanol group, yielding the free amine, which was then converted to dioxalate salt 94 by treating it with oxalic acid in methyl isobutylketone (MIBK) The resulting aminoethanol 94 was subjected to aqueous sodium hydroxide and subsequently coupled with palmitic acid N-hydroxysuccinimide (NHS)-ester 95, producing eliglustat as the freebase 96 with an overall yield of 9.5% from compound 87 Finally, the formation of the salt with L-tartaric acid (0.5 equiv) resulted in the creation of eliglustat tartrate (XII).
2) TsNH 2 , 45% NaOH NBu 4 HSO 4 , PhMe
1) 33% HBr/glacial HOAc anisole, 60 °C 82% for 2 steps
Scheme 18 Synthesis of finafloxacin pyrrolo-oxazine fragment 111.
1) (COCl) 2 , cat DMF, THF rt
Scheme 19 Synthesis of idelalisib (XV).
1)n-BuLi, i-Pr2O, PhMe, -33 to -43 °C then 128, -65 to -73 °C
3) Ac 2 O, pyridine, DMAP, 2 °C to rt
Scheme 20 Synthesis of ipragliflozin L -proline (XVI).
Scheme 21 Synthesis of intermediate 136 of ledipasvir (XVII).
Empagliflozin (Jardiance Ò )
Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibi- tor, was originally discovered by Boehringer Ingelheim and co- developed and co-marketed through research collaboration with
Eli Lilly and Co 107 It was first approved by European Medicine
Agency (EMA) in May 2014, followed by the approval of the US
In August 2014, the FDA approved SGLT2 inhibitors, a novel class of glucose-lowering medications designed specifically for managing type 2 diabetes mellitus These agents work through a mechanism that does not rely on pancreatic beta-cell function or the level of insulin resistance, offering a unique treatment option for patients.
SGLT2 inhibitors, such as empagliflozin, offer promising benefits as both standalone therapies and in combination with various glucose-lowering medications, including insulin By selectively inhibiting SGLT2, empagliflozin effectively reduces glucose reabsorption, leading to increased glucose excretion in the urine.
The synthesis outlined in Scheme 16 is notable for being the largest scale reported in a patent application, despite various synthetic methods for the drug being documented Initially, commercial 5-iodo-2-chlorobenzoic acid was transformed into its corresponding acid chloride This intermediate was then reacted with fluorobenzene under Friedel–Crafts conditions, yielding the desired fluorobenzophenone with a 94% yield after recrystallization from aqueous isopropanol Subsequently, the fluorobenzophenone was combined with (S)-3-hydroxytetrahydrofuran and potassium tert-butoxide in THF to produce ethereal benzophenone Finally, the ketone functionality was removed using 1,1,3,3-tetramethyldisiloxane in the presence of aluminum chloride in toluene, resulting in the formation of diaryl iodide.
102 This iodide was subsequently converted to the corresponding
The Grignard reagent reacts with gluconolactone to form an intermediate lactol, which is subsequently processed with aqueous citric acid, methanolic HCl, and triethylsilyl hydride along with aluminum trichloride This sequence of reactions ultimately yields empagliflozin (XIII).
73% yield across the four-step protocol.
Finafloxacin (Xtoro Ò )
Finafloxacin, an antimicrobial agent of the 8-cyano subclass of fluoroquinolones, was approved by the US FDA in December
In 2014, finafloxacin was introduced for the treatment of acute otitis externa, also known as swimmer's ear, which is primarily caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus This antibiotic was developed through a collaboration between MerLion Pharmaceuticals and Bayer.
Health Care Pharmaceuticals, and the drug was licensed by Mer-
Lion has partnered with Alcon, a division of Novartis, to develop and commercialize a new treatment for ear infections in North America Unlike other fluoroquinolones that lose efficacy in slightly acidic conditions, finafloxacin shows enhanced antibacterial activity at pH levels between 5 and 6, with minimum inhibitory concentrations that are 4 to 8 times lower than those observed at neutral pH This drug selectively targets bacterial type II topoisomerases, crucial for DNA processes, and demonstrates broad-spectrum antibacterial effectiveness against both Gram-positive and Gram-negative bacteria, including strains resistant to ciprofloxacin.
The synthesis of finafloxacin begins with 5-fluoro-1,3-xylene, utilizing catalytic chlorination with FeCl3 in 1,2-dichloroethane, followed by photochemical chlorination to produce a polychlorinated intermediate in 45% yield This intermediate is hydrolyzed with concentrated sulfuric acid to yield 3-formyl-benzoic acid, which is then converted to a nitrile and acid chloride through a two-step process involving hydroxylamine hydrochloride and thionyl chloride, achieving a 62% yield The acid chloride is transformed into quinolone through a four-step sequence without isolating intermediates, resulting in an ethyl ester with a remarkable 90% yield Hydrolysis of this ester yields acid, which couples with pyrrolo-oxazine to produce finafloxacin in 90% yield The synthesis of the pyrrolo-oxazine fragment begins with (Z)-butene-1,4-diol, undergoing mesylation and reaction with tosylamide to form dihydropyrrole Subsequent epoxidation and ethanolamine treatment lead to trans aminoalcohol, which is tosylated and cyclized to yield a bis-toluenesulfonamide, resolved to >99% ee to obtain the desired (S,S)-enantiomer.
116using hydrobromic acid in glacial acetic acid preceded treat- ment with KOH to finally furnish pyrrolo-oxazine111.
Idelalisib (Zydelig Ò )
Idelalisib is a potent and selective oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kd), initially developed by Calistoga Pharmaceuticals and acquired by Gilead in April 2014 In July 2014, it received FDA approval for treating relapsed chronic lymphocytic leukemia and has obtained several oncology orphan drug designations The drug's specific inhibition of PI3Kd, primarily expressed in blood cell lineages, allows for localized therapeutic effects while minimizing interference with the signaling of other PI3K isoforms essential for the normal functioning of healthy cells The synthesis of idelalisib likely follows the route outlined in Scheme 19.
The synthesis of idelalisib (XV) began with the treatment of commercial 2-fluoro-6-nitrobenzoic acid with oxalyl chloride and DMF in DCM, producing 2-fluoro-6-nitrobenzoyl chloride as a brown syrup This intermediate was then coupled with aniline under Schotten-Baumann conditions, yielding 2-fluoro-6-nitro-N-phenylbenzamide (118) in a remarkable 99% yield Next, coupling 118 with N-Boc-2(S)-aminobutyric acid in the presence of Et3N in DCM resulted in imide (119) with a yield of 66% The subsequent reductive cyclization of nitro imide 119 using zinc dust in acetic acid produced the cyclized quinazolinone (120) in 69% yield, which was then deprotected with TFA in DCM to yield the free amine (121) Finally, a substitution reaction between amine 121 and 6-bromopurine (122) in the presence of DIPEA in t-BuOH afforded idelalisib (XV) as a solid product with a yield of 50%.
Ipragliflozin L -proline (Suglat Ò )
Ipragliflozin L-proline, approved in Japan in January 2014 for type 2 diabetes treatment, was discovered by Astellas Pharma and co-developed with Kotobuki Pharmaceutical and Merck Sharp Dohme under the brand name Suglat This sodium-glucose co-transporter-2 (SGLT2) inhibitor effectively prevents glucose reabsorption by promoting its excretion in urine, demonstrating significant selectivity over SGLT-1, with a ratio exceeding 250.
The synthesis outlined in Scheme 20 is the most extensive preparation of the drug reported in a patent application, despite various synthetic methods being documented In this process, commercially available 5-bromo-2-fluorobenzaldehyde (123) undergoes nucleophilic attack by lithiated benzo[b]thiophene (124), resulting in the formation of dibenzylic alcohol 125.
The alcohol yielded 85% and was subsequently halogenated using thionyl chloride in acetonitrile, resulting in compound 126 This compound was then treated with sodium borohydride, leading to the formation of 2-(5-bromo-2-fluorophenyl)-1-benzothiophene (127), which was crystallized from a mixture of 2-propanol and methanol with an overall yield of 81% across both steps Following this, bromide 127 underwent lithium–halogen exchange before being treated with 2,3,4,6-tetrakis-O-(trimethylsilyl)-.
D-glucono-1,5-lactone (128) in toluene Without workup, the resulting mixture was treated with a solution of methanol and
The reaction of HCl at 0°C produced a globally desilylated α-glucopyranoside intermediate, which, when treated with acetic anhydride and 4-dimethylaminopyridine, yielded tetra-O-acetyl ipragliflozin (129) with a 75% yield over three steps Following this, polyacetate 129 was saponified using aqueous sodium hydroxide, and the resulting product was crystallized from methanol and water Finally, treatment with D-proline in ethanol led to the formation of the desired ipragliflozin D-proline (XVI) with a yield of 68%.
Ledipasvir (Harvoni Ò )
Ledipasvir is a powerful NS5A inhibitor approved for use alongside sofosbuvir, a nucleotide polymerase inhibitor, to treat chronic hepatitis C virus genotype 1 infection This effective combination was developed by Gilead Sciences and is marketed under the brand name Harvoni The synthesis of ledipasvir has been documented in scientific literature, detailing various synthesis routes.
22–24 below represent the most efficient and largest scale sequence reported in the patent literature 133,134 The synthesis of the spirocyclopropane proline intermediate 136 is described in
Scheme 21 Bis-iodination of cyclopropane-1,1-diyldimethanol
(131) in the presence of triphenylphosphine gave diiodide132in
The synthesis of N-Boc-glycine ethyl ester (133) yielded 70% after treatment with sodium hydride and diiodide (132), resulting in the protected proline analog (134) with a 61% yield Subsequent saponification of the ester and classical resolution using (1S,2R)-amino-indanol produced enantiomerically pure salt (135) The free acid was liberated using 1 M HCl, and treatment with potassium tert-butoxide yielded enantiopure potassium salt (136) in high yield.
The synthesis of the difluoro-fluorene Suzuki coupling intermediate is illustrated in Scheme 22 The process begins with the iodination of 2-bromofluorene, yielding aryl iodide in a remarkable 95% yield This iodide is subsequently reacted with lithium hexamethyldisilazide and N-fluorobenzenesulfonimide (NFSI) to produce the difluoro intermediate.
The Grignard reagent was formed with an 82% yield using isopropylmagnesium chloride, which subsequently reacted with Weinreb amide to produce chloroketone in a 71% yield Additionally, the potassium salt of the cyclopropyl proline intermediate was synthesized.
(described inScheme 21) was coupled with141to give keto ester
142in high yield Heating142with ammonium acetate resulted in formation of the imidazole ring in intermediate 143 in 77% yield.
The completion of the synthesis of ledipasvir is described in
Scheme 23 Commercially available (1R,3S,4S)-N-Boc-2-azabicyclo
[2.2.1]heptane-3-carboxylic acid (144) was coupled to 4-bromo-
The synthesis of 1,2-benzenediamine (145) utilized EDC/HOBt to produce a mixture of amides 146a and 146b with a yield of 72% Subsequent heating of this mixture with acetic acid facilitated the cyclization to benzimidazole 147, achieving a 94% yield A palladium-mediated coupling of bromide 147 with bis(pinacolato)diboron yielded intermediate 148, which was then coupled in the same reaction vessel with bromide 143, as outlined in Scheme 22 This process was followed by the formation of the oxalate salt, resulting in the protected central core of ledipasvir (149) with a good overall yield The removal of the amine protecting groups produced diamine 150, which was subsequently coupled with two equivalents of Moc-valine (151) via EDC/HOBt, yielding ledipasvir XVII in 73%.
Lobeglitazone sulfate (Duvie Ò )
Lobeglitazone sulfate is an innovative oral dual agonist targeting peroxisome proliferator-activated receptors (PPARa/c), developed by Chong Kun Dang Pharmaceutical in Korea for diabetes treatment With IC50 values of 20 nM and 18 nM for PPARa and PPARc respectively, it stands out from existing PPAR agonists like pioglitazone and rosiglitazone.
—which lack PPARa activity 135 The most likely process- scale preparation of lobeglitazone sulfate follows the route described in a process communication from Chong Kun Dang Pharmaceutical 136
Commercially available 4,6-dichloropyrimidine was reacted with p-methoxyphenol in the presence of KF and warm DMF, yielding pyrimidine in high yield after adding 2-methylaminoethanol Subsequently, the resulting alcohol underwent a substitution reaction with p-fluorobenzaldehyde under basic conditions, leading to the formation of alkoxy benzaldehyde This intermediate was then converted to benzylidene thiazolidindione through Knoevenagel conditions with 2,4-thiazolidinedione, achieving a 90% yield Finally, the reduction of olefin was accomplished using Hantzsch ester and methanolic sulfuric acid at low temperatures, resulting in the production of lobeglitazone sulfate with a yield of 90%.
Luseogliflozin hydrate (Lusefi Ò )
Luseogliflozin hydrate, an SGLT2 inhibitor, was approved in Japan in March 2014 for managing type 2 diabetes Discovered by Taisho Pharmaceutical and co-developed with Novartis under the brand name Lusefi, Luseogliflozin selectively targets and inhibits human SGLT2, demonstrating a binding affinity (aKio) of 1.10 nM and an IC50 value of 2.26 nM.
Taisho has reported a synthetic route for producing luseogliflozin at a process scale, as illustrated in Scheme 25 The process begins with the bromination of commercially available 4-methoxy-2-methyl-benzoic acid, yielding a 1:1 mixture of 3- and 5-bromo derivatives, which can be separated through recrystallization from methanol, achieving a 34% yield for the desired regioisomer Subsequently, benzoic acid is treated with oxalyl chloride to form the corresponding acyl chloride, which then undergoes a Friedel–Crafts reaction with ethoxybenzene, resulting in a product yield of 82% for this two-step sequence Finally, the dibenzylic ketone is reduced using triethylsilane and boron trifluoride to produce the aglycon.
165 in 99% yield The Grignard reagent prepared from bromide
The compound 165 was alkylated with thiolactone 166, derived from 5-thio-D-glucose penta-O-acetate (169), yielding hemithioacetal 167 with a 75% yield This intermediate was then subjected to stereoselective reduction, producing thioglycoside 168 at a 77% yield Subsequent hydrogenation of 168 led to global debenzylation, ultimately resulting in the formation of the target product, luseogliflozin (XIX), with an 81% yield.
The synthesis of key thiolactone 166 began with 5-thio-D-glucose penta-O-acetate (169), which can be synthesized in eight steps from commercially available D-glucurono-3,6-lactone The anomeric acetyl group of 169 was selectively removed using hydrazine and acetic acid at room temperature, yielding compound 170 with a 70% yield The anomeric hydroxyl group of 170 was then protected with tetrahydropyran Following this, all acetyl groups in 171 were eliminated through Zemplén deacetylation, leading to the generation of hydroxyl groups in 172, which were subsequently protected with benzyl groups using benzyl bromide and sodium hydride to form 173 Finally, the tetrahydropyranyl group in 173 was removed using pyridinium p-toluenesulfonate (PPTS).
DMSO oxidation to provide166in 82% yield, by way of174.
Morinidazole (迈灵达 Ò )
Morinidazole (迈灵达 Ò ), discovered and developed by Jiangsu
Hansoh Pharmaceutical, was approved by the CFDA in February
Morinidazole, a third-generation 5-nitroimidazole antimicrobial agent introduced in 2014, is effective in treating amoebiasis and anaerobic bacterial infections, such as appendicitis and pelvic inflammatory disease This drug operates through the nitroreduction of pathogen molecules and, as a metronidazole analog, demonstrates enhanced antiparasitic potency against Trichomonas vaginalis and amoebic protozoa, while exhibiting lower toxicity in vitro and in preclinical studies compared to metronidazole.
The preparation strategy for morinidazole, which exists as a racemate, closely parallels that of ornidazole This process involves the reaction of commercially available epichlorohydrin with 2-methyl-5-nitro-1H-imidazole, yielding ornidazole with a 51% yield Subsequently, the treatment of ornidazole leads to the formation of epoxide, achieving an 84% yield.
TBAF in aqueous sodium hydroxide Subsequently, the ring of epoxide178was opened with the treatment of morpholine (179) to afford morinidazole (XX) in 75% yield.
Naloxegol oxalate (Movantik TM , Moventig Ò )
Naloxegol oxalate (XXI) is a peripherally acting l-opioid receptor antagonist approved in the USA and EU for treating opioid-induced constipation in adults with chronic non-cancer pain This pegylated version of naloxone minimizes central nervous system penetration and inhibits opioid binding in the gastrointestinal tract Developed by Nektar and licensed to AstraZeneca, naloxegol oxalate's synthesis is not extensively documented, but related analogs have been reported, highlighting improvements in selectivity during the reduction step and salt formation of the final product The likely synthesis involves treating naloxone with methoxyethyl chloride in the presence of Hunig’s base to create a protected ketone, which is then reduced to an α-alcohol using potassium tri-sec-butylborohydride The alcohol is deprotonated with sodium hydride and alkylated with CH3(OCH2CH2)7Br to yield a pegylated intermediate Finally, the methoxyethyl ether protecting group is removed, followed by treatment with oxalic acid, resulting in naloxegol oxalate (XXI) in good yield.
Netupitant (Akynzeo Ò )
Netupitant, originally developed by Helsinn Healthcare and later licensed to Eisai, Inc., was approved in the USA in October
Akynzeo® is a fixed-dose combination of netupitant and the previously approved 5-HT3 antagonist palonosetron, specifically designed for the treatment of chemotherapy-induced nausea and vomiting While palonosetron effectively addresses acute nausea and vomiting within the first 24 hours post-chemotherapy, netupitant enhances its efficacy by preventing nausea and vomiting in the later stages (25-120 hours after treatment) Clinical trials have demonstrated that the combination of netupitant and palonosetron significantly increases the percentage of patients who remain free from nausea and vomiting compared to those treated with palonosetron alone Netupitant belongs to the selective Neurokinin-1 (NK1) receptor antagonists class, further contributing to its effectiveness in managing chemotherapy-induced symptoms.
Scheme 22 Synthesis of intermediate 143 of ledipasvir (XVII). their use for treating chemotherapy-induced nausea and emesis, also play an important role as therapies for depression and anxiety 167
As shown inScheme 29, the most likely process-scale synthesis of netupitant begins with 6-chloronicotinic acid (185) 168–170 From
The one-pot 1,4-Grignard addition/oxidation reaction, referred to as 185, offers an enhanced method for synthesizing NK 1 receptor antagonists This innovative approach was utilized to directly add the C4-o-tolyl substituent to 6-chloronicotinic acid (185) through the reaction with o-tolyl magnesium chloride, followed by oxidation using manganese.
The reaction of (OAc)2 in THF/AcOH produced the theo-tolyl nicotinic acid intermediate with an overall yield of 51% This intermediate allowed for a one-pot amide formation, achieving high yields through the conversion of the acid to its acyl chloride followed by the addition of NH4OH.
(95% yield) Chloride displacement with 1-methyl piperazine under heating conditions provided intermediate 189 in 95% yield.
Utilizing the Hoffman reaction conditions established by Senanayake, the rearrangement of amide 189 with NBS/NaOMe/MeOH successfully produced carbamate 190 in quantitative yield The subsequent reduction of the carbamate with Red-Al yielded the desired mono-methylated amine To synthesize the final drug target, netupitant (XXII), the intermediate methyl amine was acylated with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (191), achieving an 81% yield Given the high cost of the acid precursor to 191 and challenges in isolating pure intermediates, a novel synthetic route was developed, starting with the inexpensive bromide 192 This new two-step synthesis of 193 involves the formation of a Grignard reagent, quenching with acetone to create an intermediate tertiary alcohol, followed by carbonylation.
EDC•HCl, HOBt, DMF, rt NMM, 0 °C to rt, 73%
EDC•HCl, HOBt DMA, NMM
PdCl 2 [P(t-Bu) 2 Ph] 2 potassium propionate
The synthesis of ledipasvir (XVII) involves the treatment of 2-(3,5-bis(trifluoromethyl)-phenyl)-2-methylpropanoic acid with NaOH in water, leading to the formation of the desired compound Subsequently, the conversion of this acid to the acyl chloride is achieved using oxalyl chloride in dichloromethane, resulting in a quantitative yield of acyl chloride (191) with 86% purity.
Nintedanib esylate (Ofev Ò )
Nintedanib esylate, developed by Boehringer Ingelheim, is a powerful oral triple angiokinase inhibitor that effectively targets proangiogenic and pro-fibrotic pathways associated with vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor families, along with Src and Flt-3 kinases Approved by the US FDA in October 2014 and by the EMA in January 2015 for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive lung scarring condition, nintedanib esylate received multiple designations, including fast-track, priority review, orphan product, and breakthrough status from the FDA.
In 2014, nintedanib was approved for the treatment of non-small cell lung cancer in combination with docetaxel following first-line chemotherapy Various synthetic methods for producing the freebase of nintedanib and its esylate salt have been documented, with the latest process developed by Boehringer Ingelheim detailed in recent reports.
The synthesis of indolinone197commenced with commercial
The esterification of 4-chloro-3-nitro-benzoic acid leads to the displacement of chloride by dimethyl malonate, resulting in the formation of nitrobenzene Subsequent hydrogenation of nitrobenzene under acidic conditions produces 6-methoxycarbonyl-substituted oxindole through decarboxylative cyclization.
The acylation of indolinone 197 with chloroacetic anhydride in refluxing toluene yielded indolone 198 with an impressive 86% yield over two steps Although a one-pot protocol using acetic anhydride has been suggested, the stepwise method is preferred for large-scale synthesis due to reduced complications from side products Further processing of indolone 198 with methanolic potassium hydroxide, followed by condensation with an aniline fragment in refluxing methanol, and treatment with aqueous ethanesulfonic acid in methanol, successfully produced nintedanib esylate (XXIII) with an overall yield of 82% across the three-step sequence.
The aniline fragment 199 was synthesized in three steps with an overall yield of 82% The process began with the acylation of N-methyl-4-nitroaniline using chloroacetyl chloride This was followed by the displacement of the α-amidochloride with N-methylpiperazine, and finally, the nitro group was reduced through hydrogenative reduction to yield the desired aniline.
Olaparib (Lynparza Ò )
Olaparib, known by the brand name Lynparza and marketed by AstraZeneca, received FDA approval in December 2014 as a targeted therapy for advanced ovarian cancer linked to germline BRCA mutations Originally developed by KuDOS Pharmaceuticals, this poly ADP ribose polymerase (PARP) inhibitor is specifically indicated for patients who have undergone three or more chemotherapy treatments Clinical trials have demonstrated that Olaparib significantly extends progression-free survival for those with platinum-sensitive recurrent serous ovarian cancer.
Scheme 24 Synthesis of lobeglitazone sulfate (XVIII).
Br 2 , Fe, CHCl 3 (COCl) 2 , DMF O
Et 3 SiH, BF 3 Et 2 O, CHCl 3
1) Mg, BrCH 2 CH 2 Br, THF, ↑↓
Scheme 25 Synthesis of luseogliflozin (XIX).
Scheme 26 Synthesis of luseogliflozin thioglycoside fragment 166. currently in various phases of investigation for treatment of breast, gastric, prostate, pancreatic and non-small cell lung cancer 186
A newly optimized synthesis route for olaparib has been developed, eliminating the need for chromatographic separations and enabling the isolation of the final product as a high-purity single crystal This method starts with the reaction of dimethyl phosphite and 2-carboxybenzaldehyde, yielding a phosphonate ester with 95% yield and purity after aqueous workup The subsequent addition of aldehyde to this phosphonate ester, in the presence of triethylamine, results in the formation of olefins in a 96% yield as a 1:1 mixture of E/Z isomers.
A one-pot, three-step sequence was developed from olefins 203a/203b to synthesize dihydrophthalazinyl acid 204 The process began with the lactone ring-opening and nitrile hydrolysis using aqueous sodium hydroxide at elevated temperatures, which facilitated the in situ formation of the dihydrophthalazine intermediate upon adding hydrazine hydrate Acidification with 2 N HCl resulted in the isolation of the desired product with a yield of 77% and purity of 96% The subsequent coupling of carboxylic acid 204 with Boc-piperazine 205, utilizing HBTU, DIPEA, and DMA, yielded intermediate 206 in 46% yield, achieved through a pH-controlled workup that ensured high purity (94%) without the need for chromatography The final step involved treating piperazine 206 with cyclopropane carbonyl chloride 207 and triethylamine, culminating in the isolation of olaparib with an impressive yield of 90% and purity of 99.3% after distillation.
Ombitasvir (Viekira Pak TM ) (Technivie Ò )
Ombitasvir hydrate is a non-nucleoside polymerase inhibitor approved for use in a four-drug combination therapy for adults with genotype 1 hepatitis C virus infection, including those with compensated cirrhosis This combination, marketed as Viekira Pak™ and developed by AbbVie, includes ombitasvir, paritaprevir, ritonavir, and dasabuvir, providing an all-oral treatment option that eliminates the need for pegylated interferon injections The synthesis of ombitasvir hydrate involves alkylation of 1-(4-nitrophenyl)ethanone with 2-bromo-1-(4-nitrophenyl)ethanone in the presence of zinc chloride, yielding diketone in 61% Subsequent asymmetric reduction using N,N-diethylaniline borane and (S)-()-α,α-diphenyl-2-pyrrolidinemethanol produces diol in 61% yield with 99.3% enantiomeric excess The diol is then converted to a bis-mesylate, which reacts with 4-tert-butylaniline to form pyrrolidine in 51% yield across the two steps, with hydrogenolysis of the nitro groups achieved using Raney nickel.
Scheme 27 Synthesis of morinidazole (XX).
MEMCl, DIPEA KBH(s-Bu) 3 , THF
Scheme 28 Synthesis of naloxegol oxalate (XXI). nickel catalyst to give bis-aniline214 Separately, (L)-valine (216,
In Scheme 35, methyl chloroformate was reacted to produce methyl carbamate with a 90% yield, which was subsequently coupled with L-proline benzyl ester using EDC and HOBt, resulting in a dipeptide also at 90% yield The benzyl ester group of the protected dipeptide underwent hydrogenolysis with a Pd/alumina catalyst, yielding dipeptide acid 215 Aniline 214 was then treated with two equivalents of acid 215 in the presence of 1-propanephosphonic acid cyclic anhydride (T3P) The crude product was purified by recrystallization from ethanol and heptane, ultimately yielding ombitasvir hydrate.
(XXV) No yields were provided to the final steps of this synthesis.
Oritavancin diphosphate (Orbactiv Ò )
Oritavancin diphosphate is a glycopeptide antibiotic analog of vancomycin that disrupts bacterial cell-wall synthesis by inhibiting transpeptidase and transglycosylation processes Initially discovered and developed by Eli Lilly and Co., the compound's development was later transferred to Intermune and subsequently to Targanta, which was eventually acquired.
The Medicines Company received US FDA approval for oritavancin, a drug effective against acute bacterial skin and skin-structure infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) The synthesis of oritavancin involves treating commercial eremomycin with 4-chlorobiphenylcarboxaldehyde and sodium cyanoborohydride in refluxing methanol, resulting in a 69% crude yield and a final yield of 16–18% after high-performance liquid chromatography (HPLC) purification Notably, the three amino groups in eremomycin can undergo reductive alkylation, with the reaction preferentially occurring at the disaccharide amino group.
No experimental details were found describing the preparation of the diphosphate salt, but presumably this occurs through treat- ment with phosphoric acid and crystallization to give oritavancin diphosphate (XXVI).
Paritaprevir (Technivie Ò )
Paritaprevir hydrate, a second-generation NS3/4A protease inhibitor, is a component of the all-oral, interferon-free hepatitis
Enanta Pharmaceuticals and AbbVie developed a combination therapy for chronic hepatitis C virus (HCV) genotype 1, which received approval in the USA and EU in 2014 This fixed-dose tablet includes paritaprevir, an NS3/4A replication complex inhibitor, ombitasvir, an NS4A replication complex inhibitor, and ritonavir, a cytochrome P450 inhibitor, alongside dasabuvir, an NS5B polymerase inhibitor.
Scheme 29 Synthesis of netupitant (XXII).
193 191 oxalyl chloride DMF, DCM quant (86% pure)
In 2015, the US FDA approved paritaprevir for the treatment of genotype 4 chronic HCV infection without cirrhosis, demonstrating high sustained virological response rates after 12 weeks of combination therapy Paritaprevir, an NS3/4A inhibitor, is effective against HCV genotype 1a and 1b strains, with EC50 values of 1.0 and 0.21 nM, respectively To enhance paritaprevir's efficacy, it is co-administered with ritonavir, a CYP3A inhibitor, which increases its plasma half-life to approximately 5.5 hours, allowing for once-daily dosing Although various development routes for paritaprevir have been documented, no specific process has been disclosed However, a scalable synthesis route is noted, with a related compound synthesized by AbbVie on a kilogram scale.
Commercial (2S,4R)-N-Boc-4-hydroxyproline was reacted with 6-chlorophenanthridine in NMP using sodium t-butoxide, leading to the formation of acid 221 This acid was then coupled with vinylcyclopropylamine fragment 222 through the use of HATU and DIPEA, resulting in peptide 223 after Boc deprotection The final product was crystallized by neutralizing with NaOH, and amine 223 was subsequently coupled with acid.
The synthesis of linear tripeptide 225 involved the reaction of acid 224, derived from Boc-(2S)-amino-non-8-eic acid (229) and 5-methyl-2-pyrazine carboxylic acid (230) This process included Boc deprotection and peptide coupling, utilizing N,N'-disuccinimidyl carbonate and 4-dimethylaminopyridine (DMAP) to activate acid 230 The reaction was facilitated by EDC and N-hydroxy-5-norbornene-2,3-di-carboximide (HONB) in the presence of N,N-dimethylethylene diamine.
The Boc-protected linear tripeptide 225 underwent ring-closing metathesis with the Zhan-B catalyst (226) in toluene, utilizing imidazole to quench the catalyst post-reaction On a kilo-scale, a similar metathesis reaction yielded the desired Z-isomer at 61% efficiency Subsequent removal of the Boc carbamate resulted in the formation of macrocyclic intermediate 227 Hydrolysis of the ester with lithium hydroxide, followed by acidification, produced acid 228, which was then coupled with cyclopropylsulfonamide (33) using CDI and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) The resulting product was dissolved in i-PrOAc, diluted with ethanol, and water was added gradually, allowing for the isolation of crystalline paritaprevir hydrate (XXVII) through filtration.
Scheme 31 Synthesis of nintedanib esylate (XXIII).
82% for 3 stepsScheme 32 Synthesis of nintedanib aniline fragment 199.