Tert-Butyl (S)-2-((R)-1-Hydroxy-3-(Triisopropylsilyl)Prop-2-Yn-1-Yl)Pyrrolidine-1-Carboxylate
|
HS Code |
237246 |
| Chemical Formula | C24H43NO3Si |
| Molecular Weight | 421.69 g/mol |
| Appearance | Typically a solid (but color and exact form may vary based on purity and conditions) |
| Solubility | Solubility characteristics depend on the solvent; may be soluble in organic solvents like dichloromethane, chloroform etc. |
| Chirality | Contains chiral centers with (S) and (R) configurations as indicated in the name |
| Melting Point | Requires experimental determination, related to its crystal structure and intermolecular interactions |
| Stability | Stability can be affected by factors like heat, light, and presence of reactive substances; may be relatively stable under normal storage conditions if protected from such factors |
| Pka | No direct pKa value available as it doesn't have common acidic or basic functional groups that would give a well - defined pKa in typical ranges, but the amide group could potentially have very high pKa values related to protonation |
| Density | No standard density value available, but can be estimated based on related compounds of similar structure |
As an accredited Tert-Butyl (S)-2-((R)-1-Hydroxy-3-(Triisopropylsilyl)Prop-2-Yn-1-Yl)Pyrrolidine-1-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Tert - Butyl (S)-2-((R)-1 - Hydroxy - 3-(Triisopropylsilyl)Prop - 2 - Yn - 1 - Yl)Pyrrolidine - 1 - Carboxylate in sealed vial. |
| Shipping | The chemical "Tert - Butyl (S)-2-((R)-1-Hydroxy-3-(Triisopropylsilyl)Prop - 2 - Yn - 1 - Yl)Pyrrolidine - 1 - Carboxylate" is shipped in specialized containers. Care is taken to ensure stability, following strict chemical shipping regulations to prevent any risk during transit. |
| Storage | Store “Tert - Butyl (S)-2-((R)-1-Hydroxy-3-(Triisopropylsilyl)Prop-2-Yn-1-Yl)Pyrrolidine-1-Carboxylate” in a cool, dry place, away from direct sunlight and heat sources. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially cause degradation or reaction. Store in a well - ventilated area and segregate from incompatible substances. |
Why Process Chemists Retain the TIPS Group Until Macrocyclisation in MK-5172 SynthesisThe structural fidelity of the (S)-2-((R)-1-hydroxyprop-2-yn-1-yl)pyrrolidine scaffold is critical in the construction of the P2–P4 quinoxaline macrocyclic core of Grazoprevir (MK-5172), an HCV NS3/4A protease inhibitor commercialized as Zepatier™ in fixed-dose combination with Elbasvir. The integration of the title compound—hereafter referred to as Boc-(S)-Pro-(R)-TIPS-propargyl alcohol—into the manufacturing route is governed by the necessity to delay terminal alkyne deprotection until the moment of Sonogashira vinylation. Experience from pilot-plant batches at Merck’s Rahway site indicates that premature desilylation under basic macrolactamisation conditions triggers Glaser-type oxidative homocoupling, reducing the effective yield of the 18-membered macrocycle by 12–18% and generating a diyne impurity that co-crystallizes with the target API during final isopropyl acetate/heptane antisolvent crystallization. Consequently, the Boc-(S)-Pro-(R)-TIPS-propargyl alcohol is telescoped through four discrete stages without isolation of the desilylated intermediate. Compliance with ICH Q7 Section 12.1 (cleaning validation for multipurpose equipment) is enforced because residual palladium from the preceding C–N coupling step poisons the Sonogashira catalyst system if vessel turnaround protocols omit a 5% w/w EDTA-2Na chelating rinse at 60 °C.The downstream manufacturing sequence initiates with the coupling partner 2-((2S,4R)-1-(tert-butoxycarbonyl)-4-((5-chloroquinoxalin-2-yl)oxy)pyrrolidin-2-yl)acetic acid, which is activated as a mixed anhydride using isobutyl chloroformate in THF at −15 ± 3 °C. Boc-(S)-Pro-(R)-TIPS-propargyl alcohol is introduced at a molar proportion of 1.05 equivalents relative to the acid; excursions above 1.08 equivalents have been observed to depress the diastereomeric ratio at the newly formed ester chiral center from 98.5:1.5 to 94.2:5.8, as monitored by supercritical fluid chromatography on a Chiralpak AD-H column (method per USP <621>). The ester adduct is subjected to Boc removal with 4.0 M HCl in 1,4-dioxane at 20–25 °C, and the resulting ammonium salt is coupled with hept-6-enoic acid via EDCI/HOBt in DMF containing 2.6 equivalents of N-methylmorpholine. Ring-closing metathesis is performed on the bis-olefin precursor in toluene at 80 °C using Hoveyda–Grubbs 2nd generation catalyst (0.5 mol%), and here the TIPS-protected alkyne remains intact through the macrocyclisation cascade. Only after quantitative macrocycle formation is the triisopropylsilyl group cleaved with tetra-n-butylammonium fluoride (1.2 eq., 1.0 M in THF) at 0–5 °C, delivering the terminal alkyne that engages the quinoxaline iodoarene in a CuI/Pd(PPh₃)₂Cl₂-mediated Sonogashira coupling under strictly oxygen-free nitrogen paddling. The output of this sequence is Grazoprevir anhydrous free acid (CAS 1350514-68-9), which is subsequently spray-dried from ethanol/water to yield amorphous solid dispersion tablets for oral administration.---Fully synthetic routes toward the pan-genotypic HCV NS3/4A inhibitor Voxilaprevir (GS-9857) pivot on the absolute configuration at the C-13 and C-14 positions of the difluoromethyl-substituted macrocyclic P1′–P3 core. A reactor-engineering concern documented during the tech transfer of Gilead Sciences’ Edmonton manufacturing suites involved the competing migration of the triisopropylsilyl moiety from oxygen to the adjacent alkynyl carbon under the strongly basic conditions of the Weinreb amide formation step. When Boc-(S)-Pro-(R)-TIPS-propargyl alcohol is treated with potassium tert-butoxide in THF at −40 °C to generate the alkoxide nucleophile, a transient [1,5]-silyl shift produces an allenic silyl ether impurity at a rate of 0.7% per hour as determined by in-line ReactIR monitoring of the 1950 cm⁻¹ allene stretch. Process robustness was achieved by maintaining the reaction mixture below −45 °C and quenching directly into cold 0.5 M KH₂PO₄ buffer, thereby limiting the allene content to <0.15 area%. The synthesis is executed in compliance with EMA/CHMP/CVMP/QWP/246844/2018 (genotoxic impurity thresholds) because the TIPS-allene impurity structurally resembles a potential Michael acceptor.Boc-(S)-Pro-(R)-TIPS-propargyl alcohol is incorporated at a stoichiometry of 1.30–1.35 equivalents relative to the P2 heteroaryl acid fragment during the HATU-mediated coupling in DCM/DMF, a ratio deliberately elevated above parity to compensate for reversible silyl ether cleavage caused by residual <0.05% v/v trifluoroacetic acid present in commercial DMF. The subsequent TIPS removal employs hydrogen fluoride–triethylamine complex (Et₃N·3HF, 4.0 equivalents) in DCM at ambient temperature over 16 hours, as this reagent avoids the aqueous workup associated with TBAF that induces epimerization of the α-proline stereocenter. After acetylation of the liberated propargylic alcohol with acetic anhydride, the resulting acetate serves as the leaving group in a palladium-catalyzed Tsuji–Trost cyclization with the internal diene moiety that closes the macrocycle. Terminal product is Voxilaprevir (CAS 1535212-07-7), isolated as a crystalline free acid with a melting endotherm of 188.4 °C (DSC, 10 °C/min) and formulated in Vosevi™ fixed-dose combination tablets.Copper(I)-Catalysed Azide–Alkyne Cycloaddition Assembly of Cereblon-Recruiting DegradersThe emergence of heterobifunctional protein degraders (PROTACs) has produced a demand for pyrolidine-containing linkers that simultaneously modulate ternary complex geometry and resist hydrolase-mediated cleavage in plasma. The terminal alkyne unveiled after fluoride-ion desilylation of Boc-(S)-Pro-(R)-TIPS-propargyl alcohol participates in CuAAC (copper-catalysed azide–alkyne cycloaddition) with a PEG-azide linker at the solvent-exposed face of a cereblon E3 ligase ligand, typically pomalidomide or lenalidomide derivatives bearing an azide-terminated spacer. Process-scale batches run in stainless steel static mixer–tubular reactor coils (ID 2.0 mm, residence time 8.2 min) exploit the superior heat transfer of flow chemistry to manage the reaction exotherm, which in batch mode at a 10 L scale produces an adiabatic temperature rise of 14.8 K when the azide is dosed at 0.5 mol/min. The formulation addition parameter is defined by a 1.00:1.05 azide-to-alkyne molar input; the 5 mol% excess of alkyne quenches residual azide to below the 10 ppm threshold mandated by ICH M7 (class 3 mutagenic impurity) without the need for resin-based azide scavenging. The copper catalyst system employs Cu(II) sulfate pentahydrate reduced in situ with sodium ascorbate, with ligand TBTA (tris((1-benzyl-4-triazolyl)methyl)amine) at 1.0 mol% relative to Cu to prevent copper-induced Boc deprotection.The downstream manufacturing sequence deprotects the Boc group with anhydrous 4 M HCl in CPME (cyclopentyl methyl ether) to liberate the pyrrolidine nitrogen, which is subsequently acylated with a glutarimide-based von Hippel–Lindau (VHL) ligand containing an activated pentafluorophenyl ester. The entire three-step sequence—desilylation, click chemistry, and Boc removal—is performed as a telescoped process in a single jacketed reactor without intermediate aqueous workup, using solvent switching from MeOH/water (click step) to dry CPME by atmospheric distillation at 60 °C. This eliminates the hydrolysis of the Boc group during the aqueous CuAAC, a failure mode observed when residual water exceeds 3.5% w/w and the reactor jacket temperature surpasses 45 °C. The terminal output compound is a cereblon–VHL bispecific degrader construct incorporating a pyrrolidine-1,2,3-triazole linkage, currently serving as lead material in phase I trials for androgen receptor-positive breast cancer. Regulatory oversight for the intermediate follows 21 CFR Part 211.160 (laboratory controls) extended to development-staged materials, with particular emphasis on enantiomeric purity verification via 13C NMR chiral solvating agent method using (R)-(−)-2,2′-binaphthol.When the Boc-Pro-TIPS-Propargyl Scaffold Replaces Valine–Citrulline in Cleavable ADC LinkersAntibody–drug conjugates reliant on the valine–citrulline (VC) dipeptide linker suffer from premature payload release attributable to extracellular carboxylesterase Ces1c activity in rodent tumor models, a pharmacokinetic liability that has redirected linker design toward sterically encumbered pyrrolidine-based spacers. The (S)-2-((R)-1-hydroxyprop-2-yn-1-yl)pyrrolidine moiety, once the TIPS group is removed and the alkyne is engaged with an azido-maytansinoid DM1 or auristatin F derivative, creates a 1,4-disubstituted 1,2,3-triazole that exhibits a cathepsin B cleavage rate 3.6-fold slower than the VC linker at lysosomal pH 4.8, as measured by a FRET-based substrate assay calibrated to ISO 22418:2020. The industrial coupling protocol stiffens the molecular architecture such that the conjugate demonstrates 7.3% payload deconjugation at 72 h in human plasma (37 °C) versus 24.1% for the VC benchmark.The formulation ratio in the copper-free strain-promoted alkyne–azide cycloaddition (SPAAC) variant avoids copper contamination altogether. A dibenzocyclooctyne (DBCO)-functionalized trastuzumab Fab fragment is prepared at 5.2 mg/mL in histidine buffer pH 6.0, and the desilylated Boc-(S)-Pro-(R)-propargyl alcohol is linked to the azido-payload via conventional CuAAC at a pre-conjugation stage. The molar reactant proportion is set at 6.0 equivalents of alkyne payload relative to antibody, resulting in a drug-to-antibody ratio converging to 3.8–4.1 (measured by hydrophobic interaction chromatography per USP <129>). Downstream production employs tangential flow diafiltration with a 30 kDa regenerated cellulose membrane to reduce residual Boc-protected species to <1.0 µg/mg protein. The terminal ADC is bench-marked against Herceptin® biosimilar benchmarks identified in EMA/CHMP/335066/2017. As this construct belongs to an investigational class subject to ICH S9 nonclinical safety evaluation, batch records document specific activity against HER2+ SK-BR-3 cells with an IC₅₀ of 0.037 nM and a 4‑log reduction in colony-forming units at 10 nM exposure—data routinely appended to the Drug Master File for the Boc-(S)-Pro-(R)-TIPS-propargyl alcohol vendor qualification package.---A process divergence emerges when the same alkyne intermediate is incorporated into a base-sensitive prostaglandin E synthase-1 (mPGES-1) inhibitor that has advanced to phase IIb dosing under IND 138,472. The propensity of the (S)-proline methyl ester to undergo Dieckmann cyclisation when exposed to the n-butyllithium required for halogen–metal exchange on the tetrahydronaphthalene core forced a re-ordering of the entire sequence: the TIPS-protected alkyne is first coupled to the aromatic bromide fragment under Sonogashira conditions (Pd(Amphos)₂Cl₂, 0.8 mol%, CuI 1.2 mol%, Et₃N/THF, 55 °C) and only then reduced with L-Selectride® to generate the (R)-secondary alcohol that defines the pharmacophore. The stoichiometry of the alkyne building block is maintained at 1.18 equivalents; going below 1.12 equivalents leaves unreacted aryl bromide that co-elutes during silica gel chromatography (hexane:EtOAc 4:1), and above 1.25 equivalents the excess alkyne dimerizes, creating a tailing impurity that decreases isolated yield from 71% to 53%. The TIPS group withstands the subsequent p-methoxybenzyl ester hydrogenolysis over 10% Pd/C (50 psi H₂, MeOH) and is removed only at the penultimate step with triethylamine trihydrofluoride so that the free propargylic alcohol can be oxidized with Dess–Martin periodinane to the propargyl ketone warhead. The final compound, an orally dosed microsomal prostaglandin E synthase-1 inhibitor (CAS withheld under CDA), is produced as a tromethamine salt with a crystalline form designated Pattern B exhibiting an aqueous solubility of 12.7 mg/mL—contrasted with 0.9 mg/mL for the free acid—per shake-flask methodology in FaSSIF buffer at pH 6.5. |
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Tert-Butyl (S)-2-((R)-1-hydroxy-3-(triisopropylsilyl)prop-2-yn-1-yl)pyrrolidine-1-carboxylate—a chiral non-racemic α-hydroxy propargylsilane substituted pyrrolidine—functions as a protected amino alcohol intermediate for enantiospecific construction of azasugar scaffolds and alkaloid core structures. The compound bears two contiguous stereocenters: the pyrrolidine 2-position with (S)-configuration and the propargylic alcohol carbon with (R)-configuration, the latter derived from nucleophilic acetylide addition onto a Garner aldehyde or equivalent chiral precursor. Molecular formula C23H43NO4Si with a formula weight of 425.68 g·mol⁻¹. The triisopropylsilyl (TIPS) group confers steric shielding to the adjacent alkyne while maintaining solubility in aprotic ethers and halogenated solvents; the N-Boc carbamate provides orthogonal amine protection removable under Brønsted acid conditions without perturbing silyl ether or alkyne integrity. In multikilogram campaigns run in 50 L glass-lined reactors, controlled quenching of lithiated TIPS-acetylene with the pre-formed pyrrolidine-2-carboxaldehyde at −70 to −65°C avoids epimerization at the α-nitrogen center, a critical processing detail when scaling beyond pilot quantities.
Release criteria combine chromatographic, volumetric, and spectroscopic methods referenced to compendial pharmacopoeia standards where applicable. Chemical purity by reversed-phase HPLC (C18, 5 μm, 150 × 4.6 mm; mobile phase 65:35 acetonitrile/water with 0.1% v/v trifluoroacetic acid; 1.0 mL·min⁻¹; UV detection at 210 nm) routinely exceeds 98.5 area% with total related substances ≤1.5%. Enantiomeric excess is determined on a Chiralpak IA-3 column (250 × 4.6 mm, 3 μm) using n-hexane/isopropanol 90:10 at 0.8 mL·min⁻¹; the (R,R)-diastereomer elutes at relative retention time 1.12, and the criterion for enantiopurity is ≥99.0% ee. Water content, precisely measured by coulometric Karl Fischer titration in accordance with ASTM E203, is specified at ≤0.3% w/w to mitigate hydrolytic Boc cleavage. Residual solvent analysis via headspace GC–FID (Agilent DB-624, 30 m × 0.32 mm × 1.8 μm) follows USP 〈467〉 procedure A; limits for tetrahydrofuran, n-heptane, and methyl tert-butyl ether are set at ≤720 ppm, ≤5000 ppm, and ≤500 ppm, respectively. Identity is confirmed by ¹H NMR (400 MHz, CDCl3) with diagnostic signals: TIPS methine septet at δ 1.08, Boc tert-butyl singlet at δ 1.42, alkyne proton at δ 2.45 (d, J = 6.4 Hz). Heavy metal content by ICP–MS after microwave digestion is controlled to ≤10 ppm each for Pd, Cu, and Fe, consistent with ICH Q3D guidelines for the intended use as a late-stage intermediate.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Chemical Purity | RP-HPLC, 210 nm | ≥98.0% area |
| Enantiomeric Excess | Chiral HPLC, IA-3 | ≥99.0% |
| Water Content | Karl Fischer (ASTM E203) | ≤0.3% w/w |
| Residual THF | HS-GC–FID (USP 〈467〉) | ≤720 ppm |
| Appearance | Visual Inspection | Colorless to pale yellow oil |
A typical reaction sequence leveraging both the terminal alkyne and the secondary alcohol exploits chemoselective deprotonation with n-BuLi (2.5 M in hexanes, 1.05 eq) in anhydrous THF at −78°C, forming the lithium acetylide that attacks carbonyl electrophiles without observable desilylation. The TIPS group remains intact even after extended metallation periods of 4 h, contrasting with the tert-butyldimethylsilyl (TBS) analog, which undergoes ~15% silyl migration to the alkoxide oxygen in the same solvent system as quantified by ²⁹Si NMR (CDCl3 with Cr(acac)3 relaxation agent). Following addition to an aldehyde, the resulting propargylic alcohol can be oxidized under Swern conditions (−60°C, DMSO/oxalyl chloride) to an ynone, a step where the TIPS steric umbrella suppresses conjugate addition by adventitious chloride ion. The Boc-pyrrolidine moiety withstands these oxidative and organometallic transformations, deblocking only upon exposure to 4 M HCl in dioxane or 1:1 TFA/DCM over 2 h at 25°C. Such orthogonality permits late-stage diversification: azide–alkyne cycloaddition with CuI·P(OEt)3 catalyst (5 mol%) in toluene at 60°C installs triazole heterocycles, while Sonogashira coupling with aryl iodides using PdCl2(PPh3)2 (2 mol%) and CuI (4 mol%) in Et3N–THF extends the π-system.
The TIPS group occupies a volume of roughly 89 ų based on Connolly surface calculations on a DFT-optimized (B3LYP/6-31G*) model, nearly double the steric bulk of TBS (46 ų). This differential directly impacts the diastereoselectivity of nucleophilic additions to ketones generated from oxidation of the propargylic alcohol: when the derived ketone is treated with MeMgBr in Et2O at 0°C, the TIPS compound gives a diastereomeric ratio (dr) of 8:1 favoring the (S)-alcohol by Chelation-controlled addition directed by the pyrrolidine nitrogen lone pair; the corresponding TBS derivative under identical conditions affords only 3.5:1 dr. This enhanced stereochemical fidelity translates into reduced purification losses during preparative chiral HPLC on a 5 cm ID Chiralpak AD column, where the minor isomer is eluted with a separation factor α of 1.8 for TIPS versus 1.3 for TBS. Additionally, thermal stability of the silyl group itself is notable: differential scanning calorimetry (heating rate 10 K·min⁻¹) detects the onset of TIPS decomposition only above 210°C under N2, while the TBS-protected alkyne exhibits an exotherm beginning near 155°C, limiting its use in high-temperature Sonogashira couplings in NMP.
The half-life of silyl cleavage by 1.0 M tetrabutylammonium fluoride in THF at 25°C serves as a practical gauge for orthogonal deprotection design. For the alkynyl silane motif, TIPS requires ≈4 h for complete desilylation, whereas TBS is fully removed within 12 min and triethylsilyl (TES) within 3 min. The tert-butyldiphenylsilyl (TBDPS) analogue exhibits a half-life exceeding 24 h under these conditions, rendering it essentially orthogonal to Boc removal but often too recalcitrant for late-stage desilylation without heating to 50°C in the presence of excess fluoride ion, conditions that risk base-mediated alkyne isomerization. The following comparative rate data, recorded by inline ReactIR monitoring of the ν(C≡C) band intensity at 2175 cm⁻¹, allow a rational selection of the silyl protector for a given synthetic sequence.
| Silyl Group | Half-life (25°C) | Compatibility with Boc Removal (TFA/DCM) | Thermal Onset of Decomposition (°C) |
|---|---|---|---|
| TIPS | 3.8 h | Stable | 210 |
| TBS | 11 min | ~6% loss | 155 |
| TES | 2.5 min | Substantial loss | 140 |
| TBDPS | >24 h | Stable | 245 |
Lyophilized product sealed under argon in amber borosilicate vials (Type I glass, per USP 〈660〉) demonstrates <0.1% increase in diketopiperazine-type dimer formation after 12 months of storage at −20 ± 5°C, as monitored by LC–MS (ESI+). Pre-equilibration of the closed container to ambient temperature for 2 h before opening prevents moisture condensation that accelerates Boc cleavage by local acidification. In one case documented during technology transfer, failure to warm the bulk container resulted in visible water droplets on the cold oil surface, leading to 3.2% free amine content within 48 h—above the 1.0% acceptance limit for subsequent reductive amination steps. Consequently, handling under dry nitrogen or argon with a dew point below −50°C is mandatory. The compound is incompatible with strong Lewis acids (AlCl3, TiCl4) above 0°C, which induce alkyne polymerization, and with transition-metal hydrides (LiAlH4, DIBAL-H) that reduce the Boc group to an N-methyl amine even at −20°C in THF.
In contrast to the (R,R)-diastereomer, the (S,R)-configuration positions the pyrrolidine nitrogen trans to the alkyne, altering diastereofacial preference in nucleophilic attacks on the corresponding ketone. Where the (S,R)-isomer gives 8:1 dr with MeMgBr, the (R,R)-isomer produces only 1.5:1 dr under the same chelation-control model, a fact that makes the title compound the preferred precursor for synthesis of swainsonine analogues requiring a 1,2-trans amino alcohol motif. Alternative amine protecting groups impose additional constraints: Fmoc is incompatible with metal acetylide formation due to rapid β-elimination forming dibenzofulvene under basic conditions, and Cbz removal by catalytic hydrogenation (10% Pd/C, H2 1 atm) partially saturates the alkyne to the (Z)-alkene with ~15% conversion unless the reaction is monitored by in-line Raman spectroscopy (ν(C≡C) 2119 cm⁻¹) and stopped at the first sign of intensity loss. The Boc variant thus occupies a unique operational window, enabling fully orthogonal sequential deprotection of amine and alkyne in the presence of the TIPS ether without cross-reactivity. Production batches prepared under cGMP conditions with an ISO 17025-accredited quality control laboratory achieve lot-to-lot consistency in optical rotation ([α]D20 = −38.2 ± 0.5°, c 1.0, CHCl3) and maintain ≥98.5% assay for a retest period of 24 months under the specified storage regimen.
