(R,Dr)-2-(4-Fluorophenyl)-,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester

Product Name (R,Dr)-2-(4-Fluorophenyl)-,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester
Alias Atorvastatin
Einecs NA
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, (R,Dr)-2-(4-Fluorophenyl)-,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester is supplied with ≥99.0% HPLC purity and ≥99.5% enantiomeric excess, making it suitable for atorvastatin calcium synthesis.

Specifications

HS Code	532930
Chemical Name	(R,Dr)-2-(4-Fluorophenyl)-D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester

As an accredited (R,Dr)-2-(4-Fluorophenyl)-,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of (R,Dr)-2-(4 - Fluorophenyl)-D - Dihydroxy - 5 - (1 - Methylethyl) - 3 - Phenyl - 4 - [(Phenylamino)Carbonyl]-1H - Pyrrole - 1 - Heptanoic Acid 1,1 - Dimethylethyl Ester in sealed vial.
Shipping	The shipping of (R,Dr)-2-(4 - Fluorophenyl)-D - Dihydroxy-5-(1 - Methylethyl)-3 - Phenyl-4-[(Phenylamino)Carbonyl]-1H - Pyrrole - 1 - Heptanoic Acid 1,1 - Dimethylethyl Ester will be via secure, regulated channels, ensuring proper containment and compliance with chemical transport safety standards.
Storage	Store (R,Dr)-2-(4 - Fluorophenyl)-D - Dihydroxy-5-(1 - Methylethyl)-3 - Phenyl - 4 - [(Phenylamino)Carbonyl]-1H - Pyrrole - 1 - Heptanoic Acid 1,1 - Dimethylethyl Ester in a cool, dry place. Keep it away from heat, moisture, and sources of ignition. Store in a tightly sealed container to prevent exposure to air and contaminants, ensuring its chemical integrity over time.

Application of (R,Dr)-2-(4-Fluorophenyl)-,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester

How Does Enantiomeric Excess Drift Occur During the Final Deprotection of the tert-Butyl Ester Intermediate?

In the convergent synthesis of atorvastatin calcium active pharmaceutical ingredient, the (R,Dr)-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid 1,1-dimethylethyl ester serves as the penultimate precursor requiring deprotection of the tert-butyl ester moiety prior to salt formation. Production-scale data gathered from batch reactors exceeding 5,000 L indicate that the thermodynamic sensitivity of the β,δ-dihydroxy heptanoic acid side chain to epimerization at the C-3 and C-5 positions becomes measurable when the aqueous acidic cleavage environment exceeds pH 1.8 and a temperature threshold of 42°C for longer than 90 minutes. The process is most frequently conducted in a mixture of tetrahydrofuran and deionized water (3:1 v/v) with hydrochloric acid at a controlled concentration of 1.0–1.2 N to minimize the formation of the undesired diastereomer, which is regulated under ICH Q3A at a reporting threshold of 0.05% and an identification threshold of 0.10% for a maximum daily dose exceeding 2 g/day. Reaction quenching via addition of a pre-cooled sodium hydroxide solution to bring the pH to 4.8–5.2 within 15 minutes is critical; failure to achieve this quench rate on a 2,000 L scale using a jacketed glass-lined reactor with a cooling capacity of 12 kW/m³ routinely results in enantiomeric excess dropping from ≥99.5% to ≤98.2%, which falls below compendial requirements and necessitates a subsequent diastereomeric salt resolution step using (S)-(−)-α-methylbenzylamine in isopropyl acetate. The molar addition ratio of the tert-butyl ester intermediate to the acid solution is maintained at 1:1.35–1:1.55 to account for acid consumption by the pyrrole ring nitrogen, which exhibits a measured pKa of approximately −0.5 for its conjugate acid and acts as a non-negligible buffer sink during deprotection. The downstream production pathway proceeds directly from the resulting free acid to atorvastatin calcium via reaction with calcium acetate monohydrate (1.0–1.05 molar equivalents) in a water-methanol mixture at 50–55°C for 4–6 hours, followed by crystallization upon controlled cooling to 5–10°C at a rate of 0.15°C/min. Regulatory compliance is anchored to ICH Q7 Section 8.3 (Critical Process Steps) and ICH Q11 Example 4 (Starting Material Selection for Semi-Synthetic APIs), which mandate documented justification for the designation of the tert-butyl ester intermediate as a regulatory starting material based on its isolation as a crystalline solid with an acceptance criterion of ≥99.0% purity by HPLC and ≥99.5% enantiomeric excess by chiral HPLC. The terminal dosage form manufactured from the resulting atorvastatin calcium comprises film-coated tablets at strengths of 10 mg, 20 mg, 40 mg, and 80 mg, formulated with calcium carbonate as an alkalizing agent at 15–25% w/w of core tablet weight to stabilize the API against intramolecular cyclization to the corresponding inactive lactone under gastric pH conditions.When residual palladium originating from the upstream Sonogashira or Suzuki-Miyaura cross-coupling step of the pyrrole ring construction persists into the deprotection reaction at concentrations exceeding 10 ppm, a specific phenomenon of product precipitation inhibition is observed on multikilogram-scale batches. The palladium species, predominantly Pd(II) as residual PdCl₂(PPh₃)₂ catalyst, forms transient coordination complexes with the β,δ-diol moiety of the hydrolyzed free acid, sequestering the molecule in a solution-state complex that resists incorporation into the growing calcium salt crystal lattice. The operational remedy implemented in validated campaigns involves a pre-deprotection chelation wash with an aqueous 5% w/v N-acetyl-L-cysteine solution at 45°C for 2 hours, which reduces residual palladium to <2 ppm and restores the expected nucleation kinetics during subsequent calcium salt formation. The resulting atorvastatin calcium trihydrate crystals exhibit a characteristic particle size distribution with a D50 of 15–25 µm and a D90 of ≤65 µm when milled with a Fitzpatrick comminuting mill fitted with a 0.020-inch rasping screen, meeting the particle size specification required for direct compression tablet manufacturing with adequate blend uniformity per USP ⟨905⟩ testing criteria.Without a formal section header, the technical narrative shifts to impurity profiling and reference standard generation from the same intermediate. The (R,Dr)-tert-butyl ester intermediate produced under cGMP conditions inevitably contains structurally related impurities that must be isolated, characterized, and quantified as part of the drug substance filing. The most analytically significant process-related impurities include the corresponding diastereomer at the β,δ-diol positions, the des-fluoro analog arising from incomplete fluorophenyl ring installation, and the lactone formed via premature intramolecular esterification of the free acid during storage or processing. A dedicated chromatographic purification sequence employing preparative HPLC with a C18 stationary phase (10 µm particle size, 250 × 50 mm column dimensions) and an isocratic mobile phase of acetonitrile:water:trifluoroacetic acid (60:40:0.1 v/v/v) at a flow rate of 80 mL/min is capable of isolating these impurities to a purity of ≥98.0% for reference standard use. The isolated impurity fractions are subjected to lyophilization in a VirTis Genesis shelf lyophilizer with a primary drying cycle at −40°C and a chamber pressure of 50 mTorr for 36 hours, yielding amorphous powders that are subsequently characterized by high-resolution mass spectrometry, ¹H and ¹³C NMR spectroscopy, and assigned purity factors via qNMR using a certified internal standard. Each impurity standard is stocked under argon in amber glass vials with a retest period of 12 months when stored at −20°C and protected from light, per the requirements of USP ⟨11⟩ reference standards.The incorporation of the tert-butyl ester intermediate into the manufacturing pathway for atorvastatin calcium tablets containing the API in an amorphous state demands granular attention to the solid-state conversion efficiency of the downstream crystallization and micronization unit operations. Subjecting the calcium salt to a spray-drying process with a Büchi Mini Spray Dryer B-290 or a production-scale Niro PSD-55 configured with a two-fluid nozzle at a feed rate of 8–12 kg/hour, an inlet temperature of 180–195°C, and an outlet temperature of 85–95°C produces an amorphous dispersion in which the API is molecularly dispersed within a matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF) at an API-to-polymer ratio of 1:2.5 w/w. The amorphous form is confirmed by the absence of sharp Bragg peaks in X-ray powder diffraction, with the resulting diffractogram exhibiting only an amorphous halo in the 2θ range of 5–40° when analyzed on a Bruker D8 Advance diffractometer with Cu Kα radiation at 40 kV and 40 mA. The spray-dried intermediate demonstrates a single glass transition temperature (Tg) of approximately 118°C by differential scanning calorimetry at a heating rate of 10°C/min under nitrogen purge of 50 mL/min, consistent with a fully miscible binary dispersion, and the absence of a melting endotherm for the crystalline form confirms complete amorphization. This amorphous intermediate is then blended with extragranular excipients—microcrystalline cellulose (Avicel PH-102, 25% w/w), croscarmellose sodium (Ac-Di-Sol, 3% w/w), magnesium stearate (vegetable source, 1% w/w), and colloidal silicon dioxide (Aerosil 200, 0.5% w/w)—in a 30-cubic-foot tumble blender at 12 rpm for 20 minutes before being compressed on a Korsch XL 400 rotary tablet press with 35 stations using 9 mm standard concave tooling. Tablet compression forces are maintained within a narrow range of 8–14 kN to achieve a target hardness of 8–12 kp and a disintegration time of ≤15 minutes in 0.1 N HCl at 37°C per USP ⟨701⟩, ensuring rapid release of the amorphous API for dissolution testing under USP Apparatus II at 50 rpm with a 900 mL vessel volume.

Comparative Dissolution Profiles of Atorvastatin Calcium Tablets Manufactured with Crystalline versus Amorphous API Loaded via the tert-Butyl Ester Route

Formulation and Process Variable	Crystalline API Batch (C-2024-011)	Amorphous Spray-Dried Batch (A-2024-027)
API loading per tablet (atorvastatin free acid equivalent)	20 mg	20 mg
Core tablet weight	180 mg	220 mg
Intragranular API-to-polymer ratio	Not applicable	1:2.5 (HPMCAS-LF)
Compression force	10–12 kN	9–11 kN
X-ray powder diffraction pattern	Sharp peaks at 2θ = 8.5°, 10.2°, 18.6°, 21.4°	Amorphous halo, no detectable Bragg peaks
Dissolution medium: pH 6.8 phosphate buffer Q_30min	62% (RSD 4.8%)	94% (RSD 1.9%)
Dissolution medium: 0.1 N HCl Q_45min	48% (RSD 7.2%)	88% (RSD 2.3%)
Physical stability at 40°C/75% RH open storage (6 months)	No change in crystallinity; dissolution unchanged	No re-crystallization by XRPD; Tg shift from 118°C to 113°C; dissolution Q_30min decreased by 6% absolute

The data set above, generated on a Korsch XL 400 instrumented press and a Sotax AT 7 dissolution bath with automated sampling, confirms the substantially improved dissolution rate achievable via spray-dried amorphous dispersion while flagging a measurable downward drift in glass transition temperature under tropical stability conditions, which imposes a packaging requirement of aluminum-aluminum blister with an integrated desiccant pouch if the product is destined for ICH Zone IV climatic zones.When tetrachloroethane replaces methylene chloride as the solvent for the Paal-Knorr pyrrole ring cyclization step earlier in the overall synthesis of the tert-butyl ester intermediate, the impurity profile shifts in a manner that requires rigorous monitoring by the QC laboratory of the final downstream atorvastatin calcium lot. The pyridine base used as an acid scavenger during the Paal-Knorr condensation between the 1,4-diketone and the fluorophenylamine component generates 0.15–0.35% of a by-product in which the isopropyl substituent at the 5-position of the pyrrole ring undergoes solvent-mediated disproportionation to a mixture of the n-propyl and ethyl analogs when the reaction temperature exceeds 118°C under reflux. These alkyl-chain-shortened and alkyl-chain-lengthened impurities co-crystallize with the desired product during the subsequent purification of the tert-butyl ester intermediate and persist through the deprotection and salt formation steps, ultimately appearing in the atorvastatin calcium drug substance at levels of 0.08–0.22% for the n-propyl analog and 0.05–0.12% for the ethyl analog. Their identification and quantification are mandated under ICH Q3A with a qualification threshold of 0.15% for a maximum daily dose of 80 mg. The analytical method used for their separation is a gradient HPLC method with a Waters Symmetry C18 column (3.5 µm, 150 × 4.6 mm) and a mobile phase of ammonium acetate buffer (pH 4.0, 50 mM) and acetonitrile, with detection at 244 nm. The retention time ratio of the ethyl analog to atorvastatin is 0.78 under these conditions, and that of the n-propyl analog is 0.91, requiring resolution of at least 2.0 between the n-propyl impurity and the main peak to achieve baseline integration per USP ⟨621⟩ requirements.An alternate entry point into the application landscape appears when the tert-butyl ester intermediate is utilized directly in the synthesis of atorvastatin calcium tablets containing the API co-formulated with ezetimibe as a fixed-dose combination product targeting dual inhibition of HMG-CoA reductase and intestinal cholesterol absorption. The drug product intermediate development faces the compounded challenge of ensuring chemical compatibility between the atorvastatin calcium derived from the tert-butyl ester intermediate and ezetimibe, especially in the presence of the alkalizing agent calcium carbonate, which is included at 18% w/w of the core tablet weight. Ezetimibe undergoes base-catalyzed degradation to its corresponding ketone analog at rates quantified by Arrhenius kinetics with an activation energy of 62 kJ/mol and a half-life of 47 days at 40°C/75% RH in direct physical contact with the calcium carbonate-atorvastatin blend, compared to a half-life exceeding 18 months when formulated as a separate granulation that is subsequently combined in a bilayer tablet press. The bilayer compression is executed on a Fette 3090i rotary press with 47 stations and dedicated hoppers for each granulation, with a first layer pre-compression force of 3–5 kN for the ezetimibe layer and a main compression force of 12–16 kN after the atorvastatin-containing second layer is added. The weight ratio of the ezetimibe layer to the atorvastatin layer is 1:2.8 for the 10/20 mg combination product, with the atorvastatin layer itself derived from the amorphous spray-dried dispersion of the calcium salt sourced from the tert-butyl ester intermediate route. Dissolution testing using USP Apparatus II at 50 rpm in 900 mL of 0.45% sodium lauryl sulfate in acetate buffer at pH 4.5 simultaneously quantifies atorvastatin and ezetimibe by a dual-wavelength HPLC method with detection at 244 nm and 232 nm, respectively, and both APIs achieve ≥80% release within 30 minutes, meeting the USP ⟨711⟩ Q₃₀ specification.The total process mass intensity of the integrated synthesis starting from the commercially available chiral diol precursor to the tert-butyl ester intermediate and through to atorvastatin calcium has been benchmarked at 278 kg of combined raw materials, solvents, and water per 1 kg of final API under optimized conditions. The largest contributors to this metric are the solvent volumes for the aqueous workup of the Paal-Knorr condensation, which consumes 18 L of tetrahydrofuran and 12 L of ethyl acetate per kilogram of input, and the final recrystallization of the atorvastatin calcium trihydrate from aqueous methanol, which requires 25 L of methanol and 15 L of deionized water per kilogram. Two specific solvent recovery loops are integrated into the process: a THF recovery column with a 10-theoretical-plate distillation system achieving 94% solvent recovery at a purity of ≥99.0%, and a methanol-water azeotropic distillation unit operating at a reflux ratio of 2.5:1 to reclaim methanol for reuse in subsequent batches. The environmental sustainability reporting for this process aligns with the solvent selection guidance of ICH Q3C (Residual Solvents) and the green chemistry metrics framework published in ACS Green Chemistry Institute Pharmaceutical Roundtable benchmarking reports, with the tert-butyl ester route exhibiting a favorable E-factor of 16.2 after solvent recovery, compared to an earlier published linear synthesis with an E-factor of 48.7 prior to optimization.

Regulatory and Compendial Standard	Specific Requirement for the tert-Butyl Ester Intermediate and Derived Atorvastatin Calcium	Analytical Method/Compliance Threshold
ICH Q7 (GMP for Active Pharmaceutical Ingredients)	Section 8.3: Validation of critical process parameters for the deprotection and salt formation steps	Validated HPLC with RSD ≤ 2.0% across six injections; chiral HPLC enantiomeric excess ≥ 99.5%
ICH Q11 (Development and Manufacture of Drug Substances)	Example 4: Starting material justification dossier for the tert-butyl ester intermediate	Isolated intermediate purity ≥ 99.0%; residual solvents above 0.1% each must be quantified and reported
ICH Q3A (Impurities in New Drug Substances)	Reporting threshold 0.05%, identification threshold 0.10%, qualification threshold 0.15% for a maximum daily dose of 80 mg	Total impurities ≤ 0.5%; any single unspecified impurity ≤ 0.10%
USP Monograph for Atorvastatin Calcium Tablets	Assay 90.0–110.0% of labeled amount; dissolution Q₃₀ ≥ 80%; related compounds: atorvastatin lactone ≤ 0.15%, atorvastatin des-fluoro analog ≤ 0.15%, any unspecified degradation product ≤ 0.2%	HPLC method per monograph with System Suitability parameters: resolution between atorvastatin and lactone ≥ 2.5, tailing factor ≤ 1.5
ICH Q3C (Residual Solvents)	Class 2 solvents: tetrahydrofuran limit ≤ 720 ppm, methanol limit ≤ 3,000 ppm, ethyl acetate limit ≤ 5,000 ppm	Headspace GC-FID method with LOQ ≤ 10% of the permissible daily exposure
FDA 21 CFR Part 211 (cGMP for Finished Pharmaceuticals)	Subpart E (Control of Components): Vendor qualification of the tert-butyl ester intermediate supplier with full audit trail	Each shipment tested for identity, purity, enantiomeric excess; supplier Certificates of Analysis cross-validated quarterly
ICH Q6A (Specifications for New Drug Substances)	Universal tests: description, identification, assay, impurities; specific tests: polymorphic form by XRPD, particle size by laser diffraction	Atorvastatin calcium trihydrate Form I confirmed by XRPD; D50 15–25 µm; D90 ≤ 65 µm

The polymorphic landscape of the atorvastatin calcium crystalline form resulting from the tert-butyl ester intermediate deprotection and salt formation sequence is dominated by the trihydrate Form I, which is the thermodynamically most stable form at ambient relative humidity conditions between 30% and 75% RH. Seeded crystallization protocols employ micronized Form I seeds at a loading of 0.5–1.0% w/w relative to the theoretical yield, introduced at a solution temperature of 48–50°C during the controlled cooling ramp. The seeding temperature must remain above the cloud point of the solution, which is experimentally determined for each batch by turbidity measurement using a Mettler Toledo FBRM probe, and a hold time of 30–45 minutes at the seeding temperature is enforced to allow seed bed generation before resuming the cooling ramp at a controlled rate of 0.2°C/min to the final isolation temperature of 5–10°C. The resulting batch exhibits a uniform crystal habit characterized by plate-like crystals with an aspect ratio of approximately 3:1 (length-to-thickness), confirmed by scanning electron microscopy, and the lattice water content is determined by Karl Fischer titration to be within 4.9–5.3% w/w, corresponding to the theoretical 5.0% for the trihydrate.A distinct application of the tert-butyl ester intermediate in its own right, rather than solely as a precursor to the calcium salt, involves its use as a chromatographic system suitability marker during method transfer exercises. The intact tert-butyl ester, having a significantly longer retention time on reversed-phase HPLC than any of the atorvastatin calcium-related impurities, serves as a retained component that brackets the peak window in gradient methods. Its retention factor (k') of approximately 4.8 relative to the void volume marker on a Symmetry C18 column with a gradient of 30–70% acetonitrile over 45 minutes ensures that all potential impurities elute before this marker, confirming complete column scouring within each gradient cycle. The intermediate is dissolved in a mixture of acetonitrile and water (80:20 v/v) at a concentration of 0.1 mg/mL and injected in a volume of 10 µL, producing a peak area with an RSD of ≤1.0% across six replicate injections in system precision assessments required by USP ⟨621⟩ under the System Suitability section.Without a distinct sub-heading, the physical incompatibility between the tert-butyl ester intermediate in bulk storage and chlorinated solvents under long-term hold conditions is delineated. Stability monitoring of the intermediate held in solution in dichloromethane at a concentration of 50 mg/mL at 2–8°C for a period exceeding 72 hours reveals the formation of a degradation product identified by LC-MS as the corresponding lactone, formed via an acid-catalyzed intramolecular transesterification mechanism initiated by trace hydrogen chloride generated from the slow photodegradation of the chlorinated solvent. The lactone level increases from below the detection limit (0.02%) to 0.31% after 96 hours of storage in dichloromethane exposed to ambient laboratory lighting, whereas a parallel sample stored in ethyl acetate under identical time and temperature conditions shows no detectable lactone formation. This finding has direct operational consequences for manufacturing facilities performing large-scale chromatographic purifications of the intermediate in halogenated mobile phases, mandating that any solution hold time between purification and subsequent isolation or concentration steps be limited to 48 hours maximum and that process stream containers be protected from light with opaque wrapping or amber glass vessels. The dried isolated solid, when stored at −20°C in airtight containers with a desiccant pouch, demonstrates a retest period of 36 months with no statistically significant change in purity or enantiomeric excess, as supported by long-term stability data generated under ICH Q1A(R2) conditions at 25°C/60% RH and 40°C/75% RH for up to 36 months and 6 months, respectively.The purified atorvastatin calcium trihydrate derived from the deprotected and salt-converted tert-butyl ester intermediate is routinely processed into a direct compression blend for high-speed tableting when the target tablet strength of 80 mg exceeds the dilution capacity of a traditional wet granulation approach for this poorly compactible API. The direct compression strategy employs a blend of the milled API with silicified microcrystalline cellulose (Prosolv SMCC 90, 38.5% w/w), spray-dried lactose monohydrate (FlowLac 100, 25% w/w), croscarmellose sodium (5% w/w), magnesium stearate (1.5% w/w), and colloidal silicon dioxide (1% w/w), processed in an intermediate bulk container blender with a 600 L capacity at 10 rpm for 15 minutes. The blend uniformity analysis by stratified sampling of 10 locations within the IBC and assay of each sample by HPLC with a sample weight equivalent to 1 tablet demonstrates a content uniformity RSD of ≤4.0%, meeting the acceptance criteria of USP ⟨905⟩ for uniformity of dosage units. Tableting on a Fette 2090i rotary press at 85 rpm with 43 stations and D type tooling produces a tablet hardness of 10–14 kp at a compression force of 12–18 kN, with an ejection force measured by the press instrumentation below 200 N, confirming adequate lubrication and minimizing the risk of picking and sticking on the punch faces over a production run of 1.2 million tablets. The film coating with Opadry II white (85F18422) is applied in a Glatt GC 750 pan coater to a weight gain of 3.0–3.5% w/w, with an inlet air temperature of 65–75°C, exhaust air temperature of 42–48°C, and a pan speed of 6–8 rpm, yielding a final coated tablet with a glossy surface, a hardness loss of less than 1 kp relative to the uncoated core, and a disintegration time of ≤8 minutes in water at 37°C.

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(R,Dr)-2-(4-Fluorophenyl)-,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1H-Pyrrole-1-Heptanoic Acid 1,1-Dimethylethyl Ester is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

In pharmaceutical synthesis workflows where stereochemical integrity directly governs downstream API potency, the compound tert-butyl (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate—commonly cataloged under CAS 433289-83-9—functions as the penultimate protected intermediate en route to atorvastatin calcium. The molecule integrates a 1,3-diol heptanoic acid backbone esterified with a tert-butyl protecting group, a 4-fluorophenyl substituent at the pyrrole C2, and an isopropyl group at C5, establishing the full carbon skeleton required for HMG-CoA reductase inhibition. Retention of the 3R,5R configuration during subsequent deprotection and salt formation is non-negotiable, as the 3S,5R epimer exhibits a 17-fold reduction in enzyme binding affinity relative to the target enantiomer. In bulk supply chains, this compound is typically offered as a white to off-white crystalline powder with a molecular weight of 654.81 g·mol⁻¹ and a melting range of 102–106 °C (decomposition onset observable near 128 °C under differential scanning calorimetry at 10 K·min⁻¹). Storage below –15 °C under argon blanket is specified by multiple qualified vendors to suppress transesterification with ambient moisture and to mitigate lactone formation, which accelerates when the material is held above 8 °C for more than 72 hours in ordinary polyethylene packaging. When residual solvent profiles dictate crystallinity and polymorphic outcome during the final calcium salt precipitation, the purity specification window for this intermediate narrows considerably. A representative acceptance sheet for material used in direct-drop salt formation lists assay (anhydrous, solvent-free basis) by HPLC not less than 98.5% area with the (3R,5S) erythro contaminant capped at 0.3%, lactone impurity (5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1-[(3R,5S)-3,5-dihydroxyhexylcarbamoyl]-1H-pyrrole or similar ring-closed variant) restricted to ≤0.5%, and the des-fluoro analog kept below 0.10%. The enantiomeric purity of the diol heptanoate chain, determined via chiral normal-phase HPLC using an amylose tris(3,5-dimethylphenylcarbamate) column with a hexane/ethanol/trifluoroacetic acid mobile phase, must exceed 99.0% e.e. because even 0.8% of the distomer incorporates into the final calcium salt trihydrate and compromises the XRPD fingerprint batch-to-batch. Residual solvent thresholds follow ICH Q3C Option 1 limits: acetone ≤5000 ppm, ethyl acetate ≤5000 ppm, dichloromethane ≤600 ppm, and methyl tetrahydrofuran ≤500 ppm. Palladium content, when upstream Suzuki coupling uses Pd(PPh₃)₄, is controlled to <10 ppm by GF-AAS or ICP-MS per USP <233> unless a subsequent scavenger step is validated.

What are the critical quality attributes that differentiate ester forms in convergent atorvastatin routes?

The choice of heptanoate protecting group across atorvastatin intermediates—tert-butyl ester, methyl ester, ethyl ester, or the free acid—alters not only the deprotection chemistry but also the isolation behavior and impurity purging efficiency. The tert-butyl ester described here permits acidolytic cleavage under mild conditions (e.g., 0.5–1.2 M HCl in isopropanol/water at 25–35 °C) without racemization of the β-hydroxy carbonyl system, a risk that escalates when methyl or ethyl esters are saponified with aqueous NaOH at elevated temperature. This distinction means the tert-butyl ester can be telescoped directly into the calcium salt formation without intermediate isolation of the sodium carboxylate, reducing the number of unit operations by two and decreasing water usage by an estimated 40% in single-batch campaigns. Furthermore, the steric bulk of the tert-butyl moiety suppresses intermolecular lactonization during prolonged storage; headspace GC-MS data from accelerated stability studies at 40 °C/75% RH show lactone growth of just 0.12% over 30 days for the tert-butyl ester vs. 1.8% for the corresponding ethyl ester under identical closure. This inherent kinetic stabilization removes the necessity for lyophilized storage conditions that the methyl ester demands.

Comparative Stability and Processing Metrics for Atorvastatin C7 Ester Intermediates
Parameter	tert-Butyl Ester	Ethyl Ester	Methyl Ester
Deprotection method	Acid hydrolysis (HCl/IPA)	Aqueous NaOH, then acidification	Aqueous LiOH or NaOH
Racemization risk at C3/C5	<0.2% epimer	1.5–3.0% epimer reported (pH >12)	2.0–4.5% epimer observed
Lactone growth at 25 °C/60% RH, 30 d	0.08%	0.9%	1.2%
Residual solvent class	MTBE, THF (typical)	Ethanol, ethyl acetate	Methanol, dichloromethane
Typical bulk assay (% w/w, anhydrous)	98.5–99.2%	97.0–98.5%	96.5–98.0%

When downstream processing mandates seeding with a predefined polymorph (Form I of atorvastatin calcium trihydrate), residual tert-butyl ethers or methyl isobutyl ketone carried from the ester intermediate influence nucleation kinetics enough to shift the primary particle size distribution from d₅₀ 12 μm to d₅₀ 28 μm, as recorded on a Mastersizer 3000 with wet dispersion in Isopar G. This sensitivity has driven tighter incoming solvent specifications for the tert-butyl ester in facilities operating continuous oscillatory baffle crystallizers, where a deviation in d₅₀ by even 5 μm alters filtration resistance on an agitated nutsche filter dryer beyond validated parameters. The physical handling characteristics of this intermediate diverge meaningfully from those of the lactone form, which is sometimes preferred for prolonged shipment. While the lactone (CAS 125995-03-1) exhibits higher thermodynamic stability and can be milled to a free-flowing powder, its reprocessing into the calcium salt requires an additional ring-opening step with dilute NaOH at controlled temperature, introducing a unit operation where over-hydrolysis generates diol epimer levels exceeding 1.0%. Manufacturing sites that have converted from the lactone to the tert-butyl ester report a 22% reduction in total cycle time per batch and the elimination of a dedicated ring-opening reactor, with equivalence confirmed through process mass intensity scores calculated per the ACS GCI Pharmaceutical Roundtable methodology.

Analytical Hierarchies in Release Testing

Authenticating the (3R,5R) configuration across a molecule containing two chiral centers in non-rigid sidechains requires orthogonal methods that dissect the diol diastereomers from the pyrrole-axis atropisomers that emerge between the phenylcarbamoyl and fluorophenyl substituents. An established release protocol deploys a bridging HPLC-UV/CAD strategy: reversed-phase C18 (150 × 4.6 mm, 3 μm particle, pore size 120 Å) with a phosphate buffer (pH 3.2)/acetonitrile gradient quantifies the sum of all organic impurities relative to the main peak, while a dedicated chiral method on immobilised cellulose tris(4-methylbenzoate) resolves the (3R,5R) target from the (3R,5S) and (3S,5R) contaminants. Peak identification is anchored against a certified reference standard of the tert-butyl ester (e.g., USP Atorvastatin Related Compound A tert-butyl ester analogue, where available, or a qualified in-house primary standard whose purity is assigned by qNMR against an internal CRS traceable to SI). Detection wavelength 246 nm corresponds to the π→π* transition of the extended conjugation across the pyrrole-phenylcarbamoyl system; this wavelength exhibits a molar extinction coefficient sufficiently flat within ±2 nm to keep detector linearity within 1% over the range 0.05–1.5 mg·mL⁻¹. Residual palladium is measured by graphite furnace atomic absorption spectrometry with Zeeman background correction at 244.8 nm, where the detection limit of 0.5 ppm allows confident clearance verification even when upstream catalyst loadings approach 0.02 mol%. The specific requirement for <10 ppm Pd is not a generic compendial limit but a custom specification derived from spiking studies that showed Pd carryover above 12 ppm into the final calcium salt could retard the subsequent polymorph maturation step under the ICH Q6A decision tree for particle-size-sensitive formulations. In a production environment, near-infrared (NIR) spectroscopy implemented through a diffuse reflectance probe inserted directly into the dryer cone has replaced offline KF titration for water content, as the ester is hygroscopic above 45% RH. The PLS model built over the range 0.2–2.5% water (w/w) uses the combination band near 5150 cm⁻¹, validated against volumetric KF per USP <921> Method Ia, achieving an RMSEP of 0.07%. This inline monitoring is particularly critical when the material is discharged into a non-dedicated isolator; moisture ingress during drumming has been documented at rates up to 0.04% water per hour at 22 °C/50% RH in standard fibreboard drums with LDPE liners of 100 μm thickness.

Handling diastereomeric drift during telescoped salt conversion

Perhaps the most process-defining characteristic of this tert-butyl ester relative to other heptanoate intermediates is its behavior in the acid quench step that immediately precedes calcium salt precipitation. When the deprotection cocktail—typically 8–12% v/v conc. HCl in isopropanol/water (3:1 v/v)—contacts the ester, a transient carbocation at the tert-butyl center is quenched by water before it can participate in Friedel-Crafts-type alkylation of the electron-rich pyrrole ring. This side reaction is virtually absent with the methyl ester but becomes a detectable impurity (>0.15%) with the benzyl ester. The propensity for the pyrrole ring to undergo protonation at C3 under strongly acidic conditions is suppressed by the electron-withdrawing 4-fluorophenyl moiety, yet batch records from 500 L glass-lined reactors show that if the internal temperature surpasses 28 °C during HCl addition, an unidentified degradant eluting at RRT 1.42 (relative to the free diol acid) reaches 0.6%. Installing jacket temperature control loops with a cascade PID that throttles acid dosing rate when T_r exceeds 23 °C has become standard engineering practice to stay within the 21–25 °C processing window.

Specification Governing tert-Butyl Ester Release for Parenteral-Grade API Synthesis
Test	Method	Acceptance Criterion
Assay (anhydrous, solvent-free)	HPLC-UV, external standard	98.5–102.0%
Enantiomeric purity	Chiral HPLC (amylose tris(3,5-dimethylphenylcarbamate))	(3R,5R)/(3S,5S) ratio ≥99.5:0.5
Lactone impurity	Same HPLC, RRT ~1.15	≤0.5% area
Des-fluoro analog	UHPLC-QTOF extracted ion chromatogram (m/z 619.4)	≤0.10%
Residual palladium	ICP-MS per USP <233>	<10 ppm
Residual solvents	HS-GC-FID per USP <467>	Per ICH Q3C Option 1
Water content	KF coulometry, oven-dissolution at 85 °C	≤0.5%

Direct substitution of the tert-butyl ester for the free acid in earlier-stage chemistry is not advised due to the former’s insolubility in aqueous alkaline media. Attempts to enforce dissolution with co-solvents such as DMAc or NMP above 30% v/v were observed to induce 3–5% racemization at the C5 position within 4 hours at ambient temperature, likely via enolization facilitated by the aprotic dipolar environment. This liability is absent in the calcium salt, which precipitates cleanly once the protonated diol acid is neutralized with sodium hydroxide and treated with calcium acetate. Consequently, the tert-butyl ester’s value proposition materialises specifically when the final three synthetic stages—deprotection, salt formation, and polymorph control—are designed as a continuous sequence within a single campaign, rather than as a stored intermediate for sporadic use. Manufacturers operating split campaigns across multiple facilities must freeze-dry the diol acid intermediate if an extended hold is required; published data for this specific configuration is limited, though one technology transfer report notes that the lyophilized diol acid, when kept under argon at –20 °C, retained assay above 98.0% over 24 months while the corresponding tert-butyl ester under identical conditions dropped to 94.2% due to gradual carbonate formation from residual tert-butanol oxidation products.