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ROLAPITANT HYDROCHLORIDE

  • Rolapitant HCl
  • Rolapitant hydrochloride
  • Sch 619734
  • SCH619734
  • UNII-57O5S1QSAQ

(5S ,8S)-8-[[(1R)-1-[3 ,5-
Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7-
diazaspiro[4.5]decan-2-one hydrochloride monohydrate.

CAS 914462-92-3

Empirical Formula: C25H26F6N2O2 · HCl · H2O, Molecular Weight:  555

USAN Name: Rolapitant hydrochloride, INN Name:  rolapitantum or rolapitant

CAS Number: 552292-08-7 (rolapitant free base); 914462-92-3 (rolapitant HCl monohydrdate).

ChemSpider 2D Image | rolapitant | C25H26F6N2O2

Rolapitant

  • Molecular FormulaC25H26F6N2O2
  • Average mass500.477 Da
(5S,8S)-8-({(1R)-1-[3,5-Bis(trifluorométhyl)phényl]éthoxy}méthyl)-8-phényl-1,7-diazaspiro[4.5]décan-2-one
1,7-Diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, (5S,8S)-
552292-08-7 [RN]
8882
NLE429IZUC
SCH 619734
SCH-619734
Varubi®
UNII-NLE429IZUC
(5S,8S)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one
Rolapitant Hydrochloride Hydrate was approved by the U.S. Food and Drug Administration (FDA) on Sep 1, 2015. It was developed by Tesaro, then marketed as Varubi® by Tesaro in US.
Rolapitant Hydrochloride Hydrate is a selective and competitive antagonist of human substance P/NK1 receptors used to treat chemotherapy-induced nausea and vomiting.
Varubi® is available as tablet for oral use, containing 90 mg of free Rolapitant. The recommended dose is 180 mg approximately 1 to 2 hours prior to the start of chemotherapy.
Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents. Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000-fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro.
In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy, rolapitant shows no inhibition of CYP3A4, eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h), providing potential opportunities for single- and prechemotherapy-based treatments.
In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.

It is in late-stage trials of its drug rolapitant, which showed promising mid-stage results in reducing nausea and vomiting in patients undergoing chemotherapy

Rolapitant hydrochloride is a tachykinin neurokinin 1 (NK1) antagonist in phase III clinical trials at Tesaro for the prevention of chemotherapy-induced nausea and vomiting (CINV). Phase II clinical trials are also under way at OPKO for this indication. At Merck & Co., phase II clinical studies were also under way for the treatment of chronic idiopathic cough and for the prevention of chemotherapy-induced nausea; however, no recent developments have been reported for these indications.

NK1 is a G-protein coupled receptor found in the central and peripheral nervous systems. Substance P is the endogenous ligand for this receptor, whose activation leads to the production of inositol triphosphate. NK1 is believed to be involved in the emetic response.

The drug candidate was originally developed by Schering-Plough (now Merck & Co.), and in 2009 it was licensed to OPKO for the prevention of nausea and vomiting related to cancer chemotherapy and surgery. In 2010, rolapitant was licensed by OPKO to Tesaro on a worldwide basis for the prevention of chemotherapy-induced nausea and vomiting.

Rolapitant is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM.  (source: Pharmacol Biochem Behav.2012 Mar 31.

Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions.  A randomized, multicenter, double-blind, dose-ranging study of rolapitant was conducted with placebo and active control groups. Six hundred nineteen adult women undergoing open abdominal surgery were randomly assigned in equal ratios to 1 of 6 study arms: oral rolapitant in 5-mg, 20-mg, 70-mg, or 200-mg doses; IV ondansetron 4 mg; or placebo, stratified by history of PONV or motion sickness. The primary study endpoint was absence of emetic episodes, regardless of use of rescue medication, at 24 hours after extubation.RESULTS: Groups assigned to rolapitant 20-mg, 70-mg, and 200-mg had a higher incidence of no emesis in comparison with placebo at 24 hours after surgery. A linear relationship between rolapitant dose and primary outcome was seen. The probability of an emetic episode was significantly lower in the rolapitant 70-mg and 200-mg groups in comparison with placebo (P ≤ 0.001 based on the log-rank test). No significant differences were noted between rolapitant and the active control (ondansetron) at 24 hours after surgery, but there was a higher incidence of no emesis (regardless of rescue medication use) in the rolapitant 200- and 70-mg groups at 72 and 120 hours, respectively. CONCLUSION: Rolapitant is superior to placebo in reducing emetic episodes after surgery and reduces the incidence of vomiting in a dose-dependent manner. No differences in side effect profile were observed between rolapitant and placebo.

Rolapitant (INN,[2] trade name Varubi /vəˈrbi/ və-ROO-bee in the US and Varuby in Europe) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor).[3] It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.[4][5][6][7

Medical uses

Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.[1] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT3 antagonist.[8]

Contraindications

Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.[9] Under the European approval, it is contraindicated in combination with St. John’s Wort, which is expected to accelerate inactivation of rolapitant.[8]

Side effects

In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).[9]

Overdose

Up to eightfold therapeutic doses have been given in studies without problems.[8]

Interactions

Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphanhave increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.[8]

Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.[8]

Pharmacology

Pharmacodynamics

Both rolapitant and its active metabolite M19 block the NK1 receptor with high affinity and selectivity: to block the closely related receptor NK2 or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.[10]

Pharmacokinetics

The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant).[8] The stereochemistry of the hydroxyl group is unknown.

Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.[8]

It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.[8]

Chemistry

The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4.[10]

Patents

WO 2003051840

PATENT

WO 2008118328

The preparation of diazaspirodecan-2-ones for example, 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one, for example, (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) has been described in U.S. Pat. No. 7,049,320 (the ‘320 patent), issued May 23, 2006, the disclosure of which is incorporated herein in its entirety by reference.

Figure US08552191-20131008-C00001

The compounds described in the ‘320 patent are classified as tachykinin compounds, and are antagonists of neuropeptide neurokinin-1 receptors (herein, “NK-1” receptor antagonists). Other NKreceptor antagonists and their synthesis have been described, for example, those described in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001) and in published international application no. WO05/100358, each of which are incorporated herein in their entirety by reference.

“NK-1” receptor antagonists have been shown to be useful therapeutic agents, for example, in the treatment of pain, inflammation, migraine, emesis (vomiting), and nociception. Among many compounds disclosed in the above-mentioned ‘320 patent are several novel diazaspirodecan-2-ones, including the compound of Formula I, which are useful in the treatment of nausea and emesis associated with chemotherapy treatments (Chemotherapy-induced nausea and emesis, CINE).

The synthesis method for preparing the compound of Formula I described in the ‘320 patent generally follows Scheme I in the provision of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxyl}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds.

Figure US08552191-20131008-C00002
Figure US08552191-20131008-C00003
Figure US08552191-20131008-C00004

The process for the preparation of the compound of Formula I described in the ‘320 patent is carried out in 18 individual steps from commercially available starting materials (see the ‘320 patent at col. 43, line 55 to col. 45, line 20; col. 75. line 55 to col. 80, line 21; col. 90 lines 35 to 63; and col. 98, line 1 to col. 99. line 24). In many steps of the process described in the ‘320 patent, intermediate compounds must be isolated or isolated and purified before use in a subsequent step, often utilizing column chromatography for this purpose.

PATENT

US7049320

Examples 72a and 72b

Figure US07049320-20060523-C00153

Step 1:

Figure US07049320-20060523-C00154

To a solution of crude Compound 53 (19 g) in CH2Cl(300 ml) at RT, DIEA (15 ml, 0.087 mol) was added, followed by triphosgene (4.34 g, 0.015 mol). The mixture was stirred at RT for 18 h and was filtered through a pad of silica. Solvents were removed in vacuum to give crude Compound 60 as yellow oil which was used in the next reaction without further purifications.

Step 2:

Figure US07049320-20060523-C00155

To the crude Compound 60 in THF (200 ml) at 0° C., LiBH(1.26 g, 0.058 mol) was added in small portions. The mixture was stirred at RT for 18 h before quenching with saturated NH4Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100×2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave Compound 61 (12.9 g, 62% overall) as white foam.

Step 3:

Oxalyl chloride (4.2 ml, 0.048 mol) was added to a solution of DMSO (6.8 m[, 0.096) in CH2Cl(300 ml) at −78° C. under N2. The mixture was stirred at −78° C. for 15 min before a solution of Compound 61 (8.5 g, 0.012 mol) in CH2Cl(100 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et3N (23.5 ml) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCOsolution. Layers were separated and the aqueous was extracted with CH2Cl(150 ml×2). The combined organic layers were dried (MgSO4) and filtered. Removal of solvents in vacuum gave an aldehyde as yellow oil. To a mixture of NaH (1.44 g, 0.036 mol) in THF at 0° C., methyl diethylphosphonoacetate (6.6 ml, 0.036 mol) was added. The mixture was stirred at 0° C. for 15 min and a solution of aldehyde in THF (100 ml) was added. The cooling bath was removed and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH4Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave an ester as white foam. The ester was dissolved in EtOH (100 ml) and a catalytic amount of palladium (1.28 g, 10% on carbon) was added. The mixture was shaken under H(50 psi) for 2 days. Catalytic amount of Pd(OH)(20% on carbon) was then added to the mixture and the mixture was again shaken under H(50 psi) for 5 h. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a white foam. The foam was then dissolved in CH2Cl(200 ml) and TFA (8.9 ml, 0.12 mol) was added. The mixture was stirred at RT for 18 h and was cooled at 0° C. before it was neutralized with saturated NaHCOsolution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum to give a yellow oil. The oil was dissolved in CH3OH (50 ml) and a catalytic amount of K2CO(166 mg, 0.0012 mol) was added. The mixture was heated at 60° C. for 2 h. After being cooled to RT, the mixture was filtered through a pad of silica and solvents were removed in vacuum. Purification by column chromatography (EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3 g, 38% overall) as white foam. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 95:5 (v/v)] gave the less polar major isomer Example 72a as white foam. Electrospray MS [M+1]+=501.1. Continuous elution with the same solvent system gave the more polar minor isomer Example 72b as colorless oil.

Electrospray MS [M+1]+=501.1.

PATENT

US8552191

Figure US08552191-20131008-C00028

Figure US08552191-20131008-C00029

Figure US08552191-20131008-C00030

Figure US08552191-20131008-C00031

Figure US08552191-20131008-C00032

Example 6 Preparation of Formula I Compound Salt: (5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride monohydrate

Figure US08552191-20131008-C00033

…………………

Figure US08552191-20131008-C00016

Figure US08552191-20131008-C00017

https://www.google.it/patents/US8552191?hl=it&dq=WO+2008118328&ei=alDCUs-_KYiIrQeg3oCwDw&cl=en

……………

update added

By RTT News,  May 12, 2014,

(RTTNews.com) – TESARO Inc. ( TSRO ) announced positive top-line results from the third and final Phase 3 trial of rolapitant, an investigational neurokinin-1 or NK-1 receptor antagonist in development for the prevention of chemotherapy-induced nausea and vomiting (CINV).

The rolapitant arm in this trial, which enrolled patients receiving cisplatin-based, highly emetogenic chemotherapy or HEC, successfully achieved statistical significance over the standard therapy arm for the primary and all secondary endpoints. The adverse event profile for rolapitant remains consistent with that seen in previous clinical studies.

The third Phase 3 study of rolapitant was an international, multicenter, randomized, double-blind, active-controlled study that enrolled 532 cancer patients receiving cisplatin-based chemotherapy regimens at a dose equal to or greater than 60 mg/m2. Patients were randomized to receive either control, which consisted of a 5-HT3 receptor antagonist plus dexamethasone, or 200 milligrams of oral rolapitant plus control. The rolapitant arm in this study successfully achieved statistical significance over the control arm for the primary endpoint of complete response (CR) in the delayed phase of CINV.

In addition, the rolapitant arm also successfully achieved statistical significance over the control arm for the key secondary endpoints of CR in the acute (0 to 24 hour) and overall (0 to 120 hour) phases of CINV, for the secondary endpoint of no significant nausea, and for all other secondary endpoints.

Safety and tolerability data for patients who received rolapitant were similar to the results for those who received control, and were consistent with earlier clinical studies. The most frequently observed adverse events were balanced across treatment arms and included fatigue, constipation and loss of appetite.

The company noted that preparations continue in support of a submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in mid-2014.

The oral rolapitant NDA will include data from one Phase 3 study in patients receiving moderately emetogenic chemotherapy (MEC), in addition to one Phase 2 and two Phase 3 trials in patients receiving cisplatin-based, highly emetogenic chemotherapy (HEC), including the trial announced today.

The top-line results of the Phase 3 trial in MEC and the prior Phase 3 trial in HEC were previously announced by TESARO in December 2013.

Rolapitant is an investigational agent and, as such, has not been approved by the U.S. FDA or any regulatory agencies.

CLIP

Rolapitant Hydrochloride Hydrate (Varubi)

Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents.(67) Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000-fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro.(68) In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy,(69) rolapitant shows no inhibition of CYP3A4,(68)eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h),(68, 70) providing potential opportunities for single- and prechemotherapy-based treatments.(71)
In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.(70, 72)
Rolapitant features a fascinating molecular architecture consisting of two tetrasubstituted stereogenic carbon centers situated at the 2- and 5-carbons within a central piperidine ring and a spirocyclic array residing at the 5-position and a phenyl ring and ethereal linkage branching from the 2-position (Scheme 17). The overall synthetic strategy to secure rolapitant hydrochloride hydrate relies upon the union of two advanced chiral building blocks that contain functional groups capable of securing the central piperidine ring. These two key intermediates, pyroglutamate derivative 93 and allylic amine 94, each bear one of the essential stereocenters embedded within the structure of the active pharmaceutical ingredient.(73) The first of these advanced intermediates, amidoaldehyde 93, is generated directly by base-mediated decomposition of pyroglutamic aminal 92, which was prepared according to the route shown in Scheme 18. Subjection of 92 to triethylamine in EtOH/H2O at ambient temperatures led to generation of chiral allyl aldehyde 93, which was not isolated but condensed immediately with amine 94 (Scheme 19) in the presence of refluxing toluene to provide divinyl imine 95, which underwent immediate reduction using NaBH(OAc)3 in AcOH/toluene to furnish the free amine.
The free amine was converted to the corresponding tosylate monohydrate salt and triturated, providing 96 as a white crystalline powder after subjection to TsOH·H2O in i-PrOH/H2O. Divinyl amine 96 could then be reacted with a solution of TsOH in toluene, distilled, and directly combined with a toluene solution of Hoveyda–Grubbs second-generation catalyst (HG-II) under heating conditions, leading to the desired ring-closing metathesis product 97 as the HCl salt (85% yield over two steps) after filtration, distillation, and workup with 12N HCl. Washing of a toluene solution of 97 with aqueous NaOH and subsequent treatment of the resulting organic solution with H2, wet Pd/C, and additional granular activated carbon (Nuchar Aquaguard) led to the fully reduced piperidine product in high yield (95%). Rolapitant hydrochloride hydrate XIII was accessed thereafter by precipitation from a solution of EtOH/i-PrOH/H2O/HCl, providing the product as a white solid (91% yield).(73)
 Figure
Scheme 17. Synthesis of Rolapitant Hydrochloride Hydrate (XIII)
Figure
Scheme 18. Synthesis of Fragment 92 of Rolapitant Hydrochloride Hydrate (XIII)
Figure
Scheme 19. Synthesis of Fragment 94 of Rolapitant Hydrochloride Hydrate (XIII)
Aldehyde precursor 92 was accessed in a four-step sequence starting from commercially available l-pyroglutamic acid 98 (Scheme 18).(73, 74) Condensation of 98 with trimethylacetaldehyde at elevated temperatures in the presence of methanesulfonic acid and NMP prior to careful addition of TFAA led to formation of pyrrolo-oxazolidone 99 in 72% yield. Deprotonation (LHMDS) and stereoselective alkylation of 99 with methyl formate, assisted by addition of copper chloride as a Lewis acid, provided access to carbaldehyde 100 in moderate yield (61%) as a single diastereomer(74) after aqueous workup and crystallization from MTBE.
Wittig olefination of aldehyde 100 (Ph3PCH3Br/LHMDS) followed by aqueous workup and precipitation of triphenylphosphine oxide via addition of MgCl2 constructed an allyl lactone intermediate in 63% yield as an off-white solid, which then immediately underwent partial reduction with LiAlH(Ot-Bu)3to smoothly deliver the key aldehyde precursor 92 in 83% yield as an inconsequential mixture of diastereomers (the stereocenter of consequence arose from the naturally occurring l-pyroglutamic acid 98), which could be employed directly in Scheme 17.(73)
Generation of 94 began with commercially available N-Cbz-(S)-phenylglycine 101 based on reports by O’Donnell and co-workers (Scheme 19).(75) Reaction of 101 with benzaldehyde dimethylacetal under Lewis acid conditions (BF3·Et2O) in diethyl ether led to high yield, diastereoselectivity, and enantioselectivity of trans-disubstituted oxazolidinone 102. In this case, selection of diethyl ether as a solvent was essential, as the use of DCM under similar reaction conditions favored formation of the undesired cis-product. Removal of the most acidic proton within 102 by means of KHMDS in toluene/THF, followed by alkylation with commercially available bromomethyl ether (103) in THF, led to 68% yield of 104 as a single diastereomer.(73, 76)
Reduction of 104 to the corresponding lactol (LiAlH4/Et2O) and subsequent ring opening with KHCO3/H2O in NMP yielded the intermediate aldehyde, which was readily converted to 105 via addition of the crude aldehyde solution to a mixture of Ph3PCH3Br and NaHMDS in toluene.
As described in Scheme 15, triphenylphosphine oxide scavenge by way of MgCl2 enabled generation of crude product in good purity after a simple filtration. TMSI-mediated Cbz removal converted 105to the resulting free amine. Formation of the maleic acid salt enabled the product to be isolated as a crystalline solid in high purity without chromatography. Treatment of the maleate salt with NaOH in toluene provided the free base 94, which was incorporated as previously described in Scheme 17 without the need for additional purification.(73)
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  2. 68.DuffyR. A.MorganC.NaylorR.HigginsG. A.VartyG. B.LachowiczJ. E.ParkerE. M. Rolapitant (SCH 619734): A Potent, Selective and Orally Active Neurokinin NK1 Receptor Antagonist with Centrally-mediated Antiemetic Effects in Ferrets Pharmacol., Biochem. Behav. 201210295– 100 DOI: 10.1016/j.pbb.2012.03.021

  3. 69.JanelsinsM. C.TejaniM. A.KamenC.PeoplesA. R.MustianK. M.MorrowG. R. Current Pharmacotherapy for Chemotherapy-induced Nausea and Vomiting in Cancer Patients Expert Opin. Pharmacother. 201314757– 766 DOI: 10.1517/14656566.2013.776541

  4. 70.NavariR. M. Rolapitant for the Treatment of Chemotherapy-induced Nausea and Vomiting Expert Rev. Anticancer Ther. 2015151127– 1133 DOI: 10.1586/14737140.2015.1088787

  5. 71.RomeroD. Chemotherapy Rolapitant – a New and Safer Antiemetic Agent Nat. Rev. Clin. Oncol. 201512,562 DOI: 10.1038/nrclinonc.2015.144

  6. 72.(a) SchwartzbergL. S.ModianoM. R.RapoportB. L.ChasenM. R.GridelliC.UrbanL.PomaA.;AroraS.NavariR. M.SchnadigI. D. Safety and Efficacy of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting after Administration of Moderately Emetogenic Chemotherapy or Anthracycline and Cyclophosphamide Regimens in Patients with Cancer: a Randomised, Active-controlled, Double-blind, Phase 3 Trial Lancet Oncol. 2015161071– 1078 DOI: 10.1016/S1470-2045(15)00034-0

    (b) RapoportB.SchwartzbergL.ChasenM.PowersD.AroraS.;NavariR.SchnadigI. Efficacy and Safety of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting Over Multiple Cycles of Moderately or Highly Emetogenic Chemotherapy Eur. J. Cancer 2016,5723– 30 DOI: 10.1016/j.ejca.2015.12.023

  7. 73.WuG. G.WerneG.FuX.OrrR. K.ChenF. X.CuiJ.SpragueV. M.ZhangF.XieJ.ZengL.;CastellanosL. P.ChenY.PoirierM.MergelsbergI. Process and Intermediates for the Synthesis of 8-[[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one Compounds. WO 2010028232A1, 2010.

  8. 74.DikshitD. K.MaheshwariA.PandayS. K. Self Reproduction of Chirality in Pyroglutamates: Reactions at α-Position with Electrophiles Tetrahedron Lett. 1995366131– 6134 DOI: 10.1016/0040-4039(95)01160-J

  9. 75.O’DonnellM. J.FangZ.MaX.HuffmanJ. C. New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the ″Self-regeneration of Stereocenters″ Method: α-Ethyl-α-phenylglycine Heterocycles 1997,46617– 630 DOI: 10.3987/COM-97-S83

  10. 76.PaliwalS.ReichardG. A.WangC.XiaoD.TsuiH.-C.ShihN.-Y.ArredondoJ. D.WrobleskiM. L.;PalaniA. Preparation of Pyrrolidine and Piperidine Derivatives for Therapeutic Use as Neurokinin 1 (NK1) Receptor Antagonists. WO 2003051840A1, 2003.

REF

HETEROCYCLES 1997 46  PG 617 630

Paper | Special issue | Vol 46, No. 1, 1997, pp.617-630
Published online, 1st January, 1970

DOI: 10.3987/COM-97-S83
■ New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the “Self-Regeneration of Stereocenters” Method: α-Ethyl-α-phenylglycine

Martin J. O’Donnell,* Zhiqiang Fang, Xiaojun Ma, and John C. Huffman

*Department of Chemistry, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202, U.S.A.

Abstract

The stereoselective room temperature ethylations of protected oxazolidinones from phenylglycine by phase-transfer catalysis or with KOtBu as base are used to prepare optically active α-ethyl-α-phenylglycine.

PATENT

https://patents.google.com/patent/CN106866669A/en

⑴ Route A:

Figure CN106866669AD00041

[0005] ⑵ Route B:

Figure CN106866669AD00051

[0007] (3) Route C:

Figure CN106866669AD00052

[0009] Scheme C, wherein the method further comprises synthesizing Via, namely:

Figure CN106866669AD00061

Won] now, with respect to the other two routes, from the reaction step, time costs, material costs, product yield and product purity of view, comparing the current line C is respected, it is more suitable for production. But even so, there are still a number of route C the following questions:

[0012] [1], the synthesis of compound V, there is a slow reaction, and the reaction was not complete and so on;

[0013] [2], when Via a salt, the desired product is low chiral purity and yield to be improved;

[0014] [3], when VIII recrystallized grain size to be improved.

CLIP

Image result for rolapitant synthesis

References

1: Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Mo Y, Huyck S, Creed MR, Cantillon M; Rolapitant Investigation Group. Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg.
2011 Apr;112(4):804-12. Epub 2011 Mar 8. PubMed PMID: 21385988.

2.  Reddy GK, Gralla RJ, Hesketh PJ. Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support Cancer Ther. 2006 Apr 1;3(3):140-2. PubMed PMID: 18632487.

3. Drug Data Rep 2003, 25(8): 703

4. A multicenter, randomized, double blind, active-controlled study of the safety and efficacy of rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (NCT01500226)
ClinicalTrials.gov Web Site 2012, February 06

5. Efficacy and safety of rolapitant, a novel NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting in subjects receiving highly emetogenic chemotherapy
48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 9077

6. Proposed international nonproprietary names (Prop. INN): List 97
WHO Drug Inf 2007, 21(2): 160

References

  1. Jump up to:a b “Varubi (rolapitant) Tablets, for Oral Use. Full Prescribing Information” (PDF). TESARO, Inc. 1000 Winter St., #3300, Waltham, MA 02451.
  2. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 59” (PDF). World Health Organization. p. 64. Retrieved 5 October 2016.
  3. ^ Duffy, R. A; Morgan, C; Naylor, R; Higgins, G. A; Varty, G. B; Lachowicz, J. E; Parker, E. M (2012). “Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets”. Pharmacol Biochem Behav102 (1): 95–100. doi:10.1016/j.pbb.2012.03.021PMID 22497992.
  4. ^ Jordan, K; Jahn, F; Aapro, M (2015). “Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review”. Ann Oncol26 (6): 1081–90. doi:10.1093/annonc/mdv138PMID 25755107.
  5. ^ Nasir, S. S; Schwartzberg, L. S (2016). “Recent Advances in Preventing Chemotherapy-Induced Nausea and Vomiting”. Oncology30 (8): 750–62. PMID 27539626.
  6. ^ Rapoport, B; Schwartzberg, L; Chasen, M; Powers, D; Arora, S; Navari, R; Schnadig, I (2016). “Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy”. Eur J Cancer57: 23–30. doi:10.1016/j.ejca.2015.12.023PMID 26851398.
  7. ^ Chasen, M. R; Rapoport, B. L (2016). “Rolapitant for the treatment of chemotherapy-induced nausea and vomiting: a review of the clinical evidence”. Future Oncol12 (6): 763–78. doi:10.2217/fon.16.11PMID 26842387.
  8. Jump up to:a b c d e f g h “Varuby: EPAR – Product Information” (PDF)European Medicines Agency. 2017-05-31.
  9. Jump up to:a b FDA Professional Drug Information on Varubi. Accessed 2017-10-11.
  10. Jump up to:a b “Varuby: EPAR – Public assessment report” (PDF)European Medicines Agency. 2017-05-31.
Rolapitant
Rolapitant.svg
Clinical data
Pronunciation /rˈlæpɪtænt/ roh-LAP-i-tant
Trade names Varubi (US), Varuby (EU)
Synonyms SCH 619734
AHFS/Drugs.com varubi
License data
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability nearly 100%
Protein binding 99.8%
Metabolism CYP3A4
Metabolites C4-pyrrolidine-hydroxylated rolapitant (major)
Elimination half-life 169–183 hours
Excretion Feces (52–89%), urine (9–20%)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C25H26F6N2O2
Molar mass 500.476 g/mol
3D model (JSmol)
/////////////ROLAPITANT, ロラピタント, FDA 2015, Schering-Plough, TESARO,
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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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