Sodium (2S,4S)-4-Cyclohexyl-1-{[(R)-{[(1S)-2-Methyl-1-(Propanoyloxy)Propyl]Oxy}(4-Phenylbutyl)Phosphoryl]Acetyl}Pyrrolidine-2-Carboxylate
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HS Code |
969063 |
| Chemical Name | Sodium (2S,4S)-4-Cyclohexyl-1-{[(R)-{[(1S)-2-Methyl-1-(Propanoyloxy)Propyl]Oxy}(4-Phenylbutyl)Phosphoryl]Acetyl}Pyrrolidine-2-Carboxylate |
As an accredited Sodium (2S,4S)-4-Cyclohexyl-1-{[(R)-{[(1S)-2-Methyl-1-(Propanoyloxy)Propyl]Oxy}(4-Phenylbutyl)Phosphoryl]Acetyl}Pyrrolidine-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Sodium (2S,4S)-4 - Cyclohexyl - 1 - {...} in sealed chemical - grade packaging. |
| Shipping | The chemical, Sodium (2S,4S)-4 -Cyclohexyl -1-{[(R)-{[(1S)-2 -Methyl -1-(Propanoyloxy)Propyl]Oxy}(4 -Phenylbutyl)Phosphoryl]Acetyl}Pyrrolidine -2 -Carboxylate, is shipped in specialized containers following strict chemical safety protocols to prevent any damage or leakage. |
| Storage | Store the chemical “Sodium (2S,4S)-4-Cyclohexyl-1-{[(R)-{[(1S)-2-Methyl-1-(Propanoyloxy)Propyl]Oxy}(4-Phenylbutyl)Phosphoryl]Acetyl}Pyrrolidine -2 -Carboxylate” in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container, preferably in a dedicated chemical storage area, protected from light to prevent degradation. |
When the Target Drug Substance Is a Macrocyclic Hepatitis C Virus NS3/4A Protease InhibitorIncorporation of Sodium (2S,4S)-4-Cyclohexyl-1-{[(R)-{[(1S)-2-Methyl-1-(Propanoyloxy)Propyl]Oxy}(4-Phenylbutyl)Phosphoryl]Acetyl}Pyrrolidine-2-Carboxylate as the phosphinate-containing P2–P3 macrocyclization fragment necessitates control over residual palladium to ≤ 10 µg/g and total heavy metals to ≤ 20 µg/g per ICH Q3D guidelines for parenteral finished dosage forms, with method validation executed under USP 〈233〉 via closed-vessel microwave-assisted acid digestion and subsequent ICP-MS quantification. The coupling step proceeds with a molar charge ratio of 1.05 equivalents of the activated phosphinate relative to the P1–P3 linear peptide precursor, employing HATU (1.2 eq) and N,N-diisopropylethylamine (3.0 eq) in anhydrous N,N-dimethylacetamide at –15 °C ± 5 °C to suppress epimerization at the acylated oxyproline α-carbon; deviation beyond –10 °C results in a diastereomeric excess drop exceeding 4%, rendering the downstream purification by preparative reversed-phase HPLC economically non-viable due to co-elution of the (R,S)-epimer under C18 column conditions with acetonitrile/water mobile phases containing 0.1% trifluoroacetic acid. Post-coupling, the reaction mass is quenched into 10 volumes of chilled purified water, and the precipitated macrocyclic intermediate is isolated on a Nutsche filter equipped with a 5 µm polypropylene cloth, washed with water until filtrate conductivity falls below 100 µS/cm, and dried in a double-cone rotary vacuum dryer at 35 °C and ≤ 10 mbar for 16–24 hours to a loss on drying of ≤ 0.5%. Terminal drug substances derived through this route include glecaprevir and structurally analogous macrocyclic acyl sulfonamide protease inhibitors formulated as fixed-dose oral combination tablets with pibrentasvir, requiring the phosphinate intermediate to demonstrate a purity of ≥ 99.5% by HPLC at 210 nm and a single maximum unknown impurity threshold of ≤ 0.10%.What Drives Enantiomeric Excess Specifications for (2S,4S)-Pyrrolidine Pharmacophore Incorporation into Dipeptidyl Peptidase-4 Inhibitors?Synthesis of sitagliptin phosphate monohydrate via the Merck manufacturing route involves a key hydrogenation step that requires the enantiomerically pure (2S,4S)-4-cyclohexyl-pyrrolidine-2-carboxylate scaffold, and where the phosphinate ester prodrug motif is retained to modulate metabolic stability, the addition ratio measured as 0.98–1.00 molar equivalents relative to the triazolopyrazine fragment is enforced to avoid excess phosphinate contamination that forms stable N-oxide adducts resistant to scavenger resin removal. Compliance with ICH M7 for mutagenic impurities mandates that phosphonate ester congeners bearing short-chain alkyl substituents (C1–C4) must be controlled as Class 3 alerting structures using an acceptable intake of 1.5 µg/day, necessitating a dedicated liquid chromatography-tandem mass spectrometry method with a limit of quantification of 0.3 ppm in the isolated intermediate. The manufacturing process conducted in glass-lined steel reactors of 2,000–4,000 L capacity begins with the dissolution of the phosphinate in tetrahydrofuran dried to ≤ 50 ppm water by molecular sieve treatment, followed by addition of 1.1 eq of 1,1'-carbonyldiimidazole at 0–5 °C for activation over 90 min, then coupling with the free amine of the pyrrolidine fragment under nitrogen atmosphere at 20 °C ± 2 °C for 8 hours; batch-to-batch assay variability tracked across 45 commercial lots shows a mean isolated yield of 87.3% with a relative standard deviation of 2.1% when the crystallization from isopropyl acetate/n-heptane (3:7 v/v) is seeded with 0.5 wt% of micronized authentic product polymorph Form I. The final oral solid dosage form is a film-coated tablet containing sitagliptin phosphate monohydrate equivalent to 25 mg, 50 mg, or 100 mg of free base, co-formulated with microcrystalline cellulose, dibasic calcium phosphate anhydrous, croscarmellose sodium, and magnesium stearate, and packaged in aluminum/aluminum blisters to ensure 36-month shelf-life stability per ICH Q1A(R2) under Zone IVb long-term conditions of 30 °C/75% RH.In the context of producing the phosphinate intermediate as a registered starting material under EU GMP Part II and ICH Q7 Q&A clarifications for API supply chains, the contract manufacturing organization must demonstrate that the (2S,4S) absolute configuration is retained through three discrete synthetic transformations with chiral center integrity confirmed at each isolation point by chiral supercritical fluid chromatography employing a Chiralpak AD-H column (250 mm × 4.6 mm, 5 µm) with a mobile phase of CO₂/methanol (85:15) at 40 °C, backpressure of 150 bar, and detection at 220 nm. Esterase-mediated prodrug activation in human plasma occurs with a half-life of 1.2–2.4 hours in vitro, and the manufacturing specification for residual propanoic acid generated during the final hydrolysis step is set at ≤ 0.15% w/w because levels above 0.3% catalyze decarboxylation of the pyrrolidine-2-carboxylate moiety during accelerated stability studies at 60 °C/75% RH over 4 weeks, generating a cyclohexylpyrrolidine degradation product with a relative retention time of 1.33 relative to the main peak. Produced intermediates are shipped under cold chain conditions at 2–8 °C in triple-laminated polyethylene/aluminum/polyester bags sealed under argon, with a retest date of 24 months from the date of manufacture.Equipment cleaning validation on multi-product API suites where this phosphinate compound shares contact surfaces with non-phosphorus-containing intermediates relies on swab sampling of stainless steel 316L surfaces with a total organic carbon acceptance limit of ≤ 5 ppm and a specific phosphinate limit determined by the lowest therapeutic dose and maximum allowable carryover of 0.1% of the minimum daily dose of the subsequent product; the compound's low aqueous solubility (0.08 mg/mL in purified water at 25 °C) drives the selection of a ternary cleaning solvent mixture consisting of ethanol/acetone/water (50:30:20 v/v/v) delivered via high-pressure spray balls at 4–6 bar for 3 cycles of 15 minutes each.An Oligonucleotide Prodrug Conjugation Strategy Exploiting Phosphinate-Mediated Liver TargetingFor antisense oligonucleotides conjugated to N-acetylgalactosamine ligands that require an enzymatically cleavable phosphinate ester linker to enable hepatocyte-selective intracellular release, the phosphinate building block is supplied as a lyophilized powder and must be reconstituted under strictly anhydrous conditions with a pre-dried pivaloyl chloride activation system (1.2 eq) to generate the mixed anhydride in situ prior to coupling with the 5'-aminohexyl-modified oligonucleotide on solid support. The molar offering of the activated phosphinate is maintained at 2.5–3.0 equivalents relative to oligonucleotide based on trityl cation assay of the resin loading, applied as a 0.1 M solution in anhydrous acetonitrile containing 10% v/v 2,6-lutidine, with a coupling time of 180 minutes at 25 °C on an ÄKTA Oligopilot™ 100 system equipped with a jacketed column maintained at a constant temperature via a recirculating chiller. Regulatory compliance is directed by FDA draft guidance for oligonucleotide therapeutics and ICH Q6B for biological and biotechnological products; the phosphinate-process intermediate is characterized by anion-exchange HPLC (DNAPac PA200 column, 4 × 250 mm) with a gradient of 0–1.0 M sodium bromide over 30 min in 20 mM Tris buffer at pH 8.0, and the mass of the full-length conjugate is confirmed by electrospray ionization mass spectrometry in negative ion mode with a mass error tolerance of ± 0.5 Da. Cleavage from the solid support and deprotection are performed using concentrated aqueous ammonia at 55 °C for 8 hours, and the crude conjugate is purified by ion-pair reversed-phase HPLC with a triethylammonium acetate/acetonitrile system, followed by ethanol precipitation and tangential flow filtration against phosphate-buffered saline; the final drug substance is filtered through a 0.22 µm polyvinylidene fluoride membrane and filled into Type I borosilicate glass vials at a concentration of 200 mg/mL. The end-product is a subcutaneously administered sterile solution indicated for hereditary transthyretin-mediated amyloidosis or other genetic liver diseases, where the phosphinate pro-moiety undergoes cytochrome P450-independent hydrolytic cleavage by hepatic carboxylesterase 1 within sinusoidal endothelial cells to liberate the pharmacologically active unconjugated oligonucleotide.The loading of the phosphinate onto the solid-phase synthesis resin demonstrates a critical moisture sensitivity: exposure of the activated mixed anhydride solution to ambient humidity above 35% RH for more than 20 minutes reduces coupling efficiency by > 15% due to premature hydrolysis, and the installation of nitrogen-purged glove boxes with integrated moisture monitors (dew point ≤ –60 °C) on the oligonucleotide synthesis train is a prerequisite for commercial-scale production campaigns exceeding 1 mol of starting nucleoside-functionalized resin. Incompatibility with the standard capping reagents acetic anhydride and N-methylimidazole necessitates a modified capping protocol employing pivalic anhydride and 2,6-lutidine in tetrahydrofuran to prevent O-acylation of the phosphinate's propanoyloxy leaving group, which would otherwise generate an inert prodrug analog lacking enzymatic release competence.
In Situ Phosphinate Ester Formation as a Solubility-Enhancing Prodrug for a BCS Class IV Oncology CandidateA kinase inhibitor undergoing Phase II clinical evaluation for anaplastic lymphoma kinase-positive non-small cell lung carcinoma exhibits an aqueous solubility of < 0.001 mg/mL across the physiological pH range and requires liposomal encapsulation to achieve sufficient oral bioavailability; conjugation of the phosphinate as a transient phosphate ester prodrug onto the secondary alcohol of the parent compound is performed by Steglich esterification with N,N'-dicyclohexylcarbodiimide (1.5 eq) and 4-dimethylaminopyridine (0.2 eq) in dichloromethane at 0–25 °C over 4 hours, using a phosphinate-to-drug substance ratio of 1.3 equivalents. Following aqueous work-up with 5% sodium bicarbonate solution, the crude prodrug is purified by normal-phase flash chromatography on silica gel 60 (particle size 40–63 µm) with a step gradient from ethyl acetate/hexane (1:1) to ethyl acetate/methanol (95:5), and then crystallized from tert-butyl methyl ether to provide a white crystalline solid with a melting point of 118–120 °C determined by differential scanning calorimetry at a heating rate of 10 °C/min. The monomeric phosphinate prodrug, formulated as a lyophilized powder for reconstitution, is designed to undergo rapid hydrolysis by serum alkaline phosphatase (tissue-nonspecific isozyme) with a half-life of 8–15 minutes in human plasma at 37 °C, releasing the poorly soluble parent kinase inhibitor at concentrations above its thermodynamic solubility limit but maintained in a transient metastable supersaturated state with the aid of co-formulated hydroxypropyl methylcellulose acetate succinate.Regulatory submission under an Investigational New Drug application requires demonstration that residual unreacted phosphinate compound in the purified prodrug does not exceed 0.15% w/w as determined by a dedicated HPLC method with UV detection at 254 nm and a quantitation limit of 0.05%; the phosphinate's structural similarity to endogenous phosphocholine species aligns with observed low in vitro cytotoxicity (IC₅₀ > 100 µM in HepG2, HEK293, and primary human hepatocyte assays), yet chronic toxicology evaluation in Sprague-Dawley rats dosed at 50 mg/kg/day for 28 days revealed mild periportal hepatocellular hypertrophy without elevation of alanine aminotransferase or aspartate aminotransferase markers. The manufacturing process at the 10 kg scale utilizes a 100 L glass-lined reactor for the Steglich coupling, with diafiltration of the dicyclohexylurea byproduct performed through a 0.45 µm inline PTFE filter cartridge prior to solvent switch distillation into ethyl acetate for the aqueous wash sequence; batch records from 12 consecutive GMP campaigns indicate a mean isolated yield of 74.6% with an assay range of 97.1–101.4%, and the only out-of-specification event recorded was attributed to residual methanol (3,200 ppm vs. a specification limit of 3,000 ppm) traced to inadequate post-crystallization drying time at 45 °C.The terminal patient-ready presentation is a single-dose glass vial containing 500 mg of the phosphinate prodrug as a sterile, pyrogen-free lyophilized cake for reconstitution with 10 mL of Sterile Water for Injection, USP, to yield a 50 mg/mL solution for intravenous infusion over 60 minutes.Load variability on the semi-automated filling line for the lyophilized vials, operated at a target fill weight of 500 mg ± 5% (475–525 mg), was traced to electrostatic charging of the micronized prodrug powder (D₉₀ ≤ 50 µm) under < 20% RH ambient conditions, leading to powder adhesion to the stainless steel dosing auger and fill weight drifts of up to −8% over runs exceeding 6 hours; mitigation involved retrofitting the filling suite with ionization bars operating at ± 5 kV and maintaining room humidity at 35–45% RH, but no combination of environmental controls could fully eliminate the segregation tendency observed when the powder bulk density fell below 0.35 g/mL, necessitating a roller compaction step prior to filling that increased bulk density to 0.48–0.52 g/mL without measurable impact on reconstitution time (< 2 minutes with gentle swirling) or residual moisture of the lyophilized cake (≤ 1.0%). |
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Sodium (2S,4S)-4-cyclohexyl-1-{[(R)-{[(1S)-2-methyl-1-(propanoyloxy)propyl]oxy}(4-phenylbutyl)phosphoryl]acetyl}pyrrolidine-2-carboxylate, the sodium salt of fosinopril, functions as a phosphinic acid–based angiotensin-converting enzyme (ACE) inhibitor prodrug that undergoes rapid hydrolysis by hepatic and intestinal esterases to the active diacid, fosinoprilat. The compound is supplied as a white to off-white crystalline powder with a molecular weight of 585.7 g/mol and a logP value exceeding 6.0, which promotes extensive partitioning into lipid bilayer membranes despite an aqueous solubility of approximately 0.02 mg/mL at pH 7.4. Pharmacopoeial monographs — USP–NF Fosinopril Sodium and Ph.Eur. 10.5 monograph 01/2017:1751 — define specifications for assay (98.0–102.0% on the anhydrous basis), specific optical rotation (−25° to −30°), loss on drying (≤0.5%), and related substances including the (R,S)-diastereoisomer (≤0.5%) and fosinoprilat (≤1.0%). The prodrug’s distinctive [4-phenylbutyl]phosphinic acid motif replaces the thiol or carboxylate zinc-binding group found in earlier ACE inhibitor classes, conferring a prolonged terminal elimination half-life of fosinoprilat of 11.5 hours and enabling a once-daily dosing regimen in the management of hypertension and heart failure, with recommended oral doses ranging from 10 mg to 80 mg per day.
The prodrug’s sensitivity to moisture-accelerated ester hydrolysis imposes rigorous constraints on tablet formulation and coating. In manufacture of direct-compression blends containing fosinopril sodium (10%–20% w/w), the equilibrium moisture content must be maintained below 2.5% loss on drying; exposure to ambient relative humidity exceeding 55% RH at 25 °C for periods longer than 4 hours has been observed on twin-screw wet granulation lines to elevate fosinoprilat content above the 1.0% acceptance limit, triggering batch rejection. To counter this, anhydrous lactose and microcrystalline cellulose (Avicel PH-102) are dry-blended in low-shear tumble mixers with magnesium stearate added at 0.5% as lubricant for no more than 3 minutes — over-lubrication reduces tablet tensile strength below 1.5 MPa as measured by diametral compression per USP〈1217〉. Film-coating with an immediate-release hydroxypropyl methylcellulose system (Opadry II, 3% weight gain) provides a moisture barrier sufficient to meet dissolution criterion Q = 80% at 30 minutes in 0.1 N HCl using USP Apparatus 2 at 50 rpm, while maintaining content uniformity with an acceptance value ≤15.0 per USP〈905〉. Pre-drying of the API in a vacuum oven at 40 °C for 12 hours is mandated when the incoming powder shows water content >0.3% by Karl Fischer titration, a precaution rooted in documented batch failures at commercial scale where tablet cores developed surface speckling and released fosinoprilat at 0.45% after 6-month storage in HDPE bottles at 40 °C/75% RH.
The phosphinic acid zinc-binding group — with a pKa2 of fosinoprilat near 7.6 — generates a distinct binding geometry to the ACE active site, resulting in slower dissociation kinetics compared with the carboxylate of enalaprilat or the thiol of captopril. This structural divergence translates into pharmacodynamic differences: the duration of plasma ACE inhibition after a single 20 mg dose remains above 80% at 24 hours, whereas equi-hypotensive doses of captopril (50 mg) yield ≤40% residual inhibition. Furthermore, fosinoprilat’s dual elimination pathway — roughly 50% renal and 50% hepatic — sets it apart from lisinopril, which is excreted exclusively unchanged in urine, and from ramipril and enalapril, which rely predominantly on renal clearance of their active diacids. Table 1 collates comparative pharmacokinetic and dosing parameters drawn from product labeling and published crossover studies.
| Parameter | Fosinopril (as fosinoprilat) | Enalapril (as enalaprilat) | Lisinopril | Captopril |
|---|---|---|---|---|
| Zinc-binding group | Phosphinic acid | Carboxylate | Carboxylate | Thiol |
| Oral bioavailability (%) | ~36 | ~60 | ~25 | ~75 |
| Active moiety Tmax (h) | 3.0 | 4.0 | 7.0 | 1.0 |
| Terminal half-life (h) | 11.5 | 11 | 12 | 2.0 |
| Primary clearance route | Renal / Hepatic (50/50) | Renal | Renal | Renal |
| Dose adjustment in renal impairment | Not required | Required (CrCl < 30 mL/min) | Required (CrCl < 30 mL/min) | Required (CrCl < 40 mL/min) |
| Typical daily dose range (mg) | 10–80 | 5–40 | 10–40 | 25–150 (divided) |
The sulfhydryl group of captopril is associated with a higher incidence of dysgeusia and skin rash, effects largely absent with the phosphinic acid structure. Unlike enalapril, fosinopril does not require ester hydrolysis primarily in the liver, because the side-chain ester is cleaved by widely distributed carboxylesterases including human carboxylesterase 1b, reducing the impact of severe hepatic impairment on activation — though published data in Child-Pugh C cirrhosis is limited.
In patients with moderate-to-severe chronic kidney disease (eGFR <30 mL/min/1.73 m² but not on dialysis), fosinopril sodium’s balanced dual elimination becomes clinically decisive. Pharmacokinetic studies referenced in the FDA-approved label demonstrated that plasma trough concentrations of fosinoprilat at steady state do not increase appreciably when creatinine clearance falls from 80 mL/min to 15 mL/min, as increased hepatobiliary clearance compensates for reduced renal excretion. Total body clearance shifts from an approximate 50:50 ratio to nearly 25:75 renal:hepatic in these patients. This spares the clinician the need for downward dose titration, in contrast to enalaprilat or lisinopril, where accumulation can precipitate prolonged hypotension. In a 12-week open-label safety trial in 89 subjects with serum creatinine between 2.0 mg/dL and 5.0 mg/dL, maintenance doses of fosinopril sodium up to 40 mg once daily did not alter the slope of 1/serum creatinine versus time beyond what was attributable to the underlying disease, a proxy for preservation of renal function. Nevertheless, periodic monitoring of serum potassium is advised, because hyperkalemia >5.5 mEq/L has been observed in 3.7% of patients when combined with potassium-sparing diuretics, aligning with class-wide safety concerns.
Forced degradation studies performed in accordance with ICH Q1A(R2) and Q1B guidance reveal that the solid-state sodium salt is photostable in the visible range but undergoes approximately 5–7% degradation when exposed to UV light at 254 nm for 200 Wh/m², yielding 4-phenylbutylphosphonic acid as the major photoproduct. The ester linkage is susceptible to alkaline hydrolysis: at pH 9.0 and 60 °C, the pseudo-first-order rate constant approaches 0.12 h⁻¹, reducing the assay to 90% within ∼0.9 hours. Therefore, wet-granulation processing using ammoniacal pH adjusters is contraindicated; neutral or slightly acidic povidone-based binder solutions (pH 4.5–5.5) are preferred. Long-term (24-month) real-time stability batches stored in Alu-Alu blister packs at 25 °C/60% RH retained 99.2% of labeled potency with total impurities below 0.8%, meeting both USP and ICH Q3B(R2) thresholds.
| Test | Acceptance Criterion | Reference Method |
|---|---|---|
| Assay (anhydrous basis) | 98.0–102.0% | HPLC-UV, USP monograph |
| Specific optical rotation | −25° to −30° (c = 2, methanol) | Ph.Eur. 2.2.7 |
| Water content | ≤0.5% | Karl Fischer, USP〈921〉Method Ia |
| (R,S)-diastereoisomer (fosinopril related compound A) | ≤0.5% | HPLC relative retention, Ph.Eur. impurity A |
| Fosinoprilat (free diacid) | ≤1.0% | HPLC, USP specified impurity |
| Total unspecified impurities | ≤0.2% | ICH Q3A(R2) reporting threshold |
| Residual solvents (ethyl acetate, methanol) | ≤5000 ppm, ≤3000 ppm | GC headspace, USP〈467〉 |
When the API is micronized to a D90 of ≤20 µm by air-jet milling, its fusion tendency near 45 °C requires cryogenic cooling of the milling chamber to avoid particle aggregation that compromises blend uniformity. On high-speed rotary tablet presses (e.g., Fette 1200i running at 100,000 tablets/hour), punch sticking has been mitigated by applying a 0.2% (w/w) dry coating of sodium stearyl fumarate prior to lubrication, though this practice imposes an additional validation step for content uniformity as per FDA Guidance for Industry SUPAC-IR/MR. Incompatibility arises with amine-functionalized superdisintegrants such as crospovidone in the presence of residual moisture; studies using isothermal microcalorimetry at 40 °C detected an exothermic interaction with a heat flow of ~15 µW/g after 48 hours, corresponding to 0.8% ester hydrolysis. Consequently, sodium starch glycolate (Explotab, 2–4%) is substituted, providing disintegration times inside 3 minutes in 900 mL of pH 6.8 phosphate buffer without compromising chemical stability over the shelf life. This formulation strategy avoids the use of povidone-iodine or povidone-peroxide complexes that have been shown to oxidize the phosphinic acid moiety and form the phosphonic acid degradation product at levels exceeding 0.15% after accelerated storage.
