![tert-Butyl (1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate: Customization Case with Heavy Metals <3 ppm & Residual Solvents ≤200 ppm](/themes/simple/img/i-home.png "tert-Butyl (1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate: Customization Case with Heavy Metals <3 ppm & Residual Solvents ≤200 ppm")
As a new-type foreign trade service provider driven by technology transformation and dual-wheel foreign trade operations, HiSiaddi has established a "1+2+3+4=1" service system and can supply raw materials from well-known original manufacturers for tert-butyl (1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate. Endowed with R&D attributes, HiSiaddi, through technological transformation cooperation with factories and precise insight into market demands, has repeatedly resolved customized production demands for tert-butyl (1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate. Below is a case demonstrating how HiSiaddi addressed the customized production requirements of this product.
Please contact HiSiaddi customer service if you require further customized services.
The client is Novatech Pharma AG, a top biopharmaceutical group headquartered in Zurich, Switzerland, focusing on R&D and production of innovative drugs for diabetes and oncology. Its core product is a high-end sustained-release saxagliptin formulation for type 2 diabetes. The company fully complies with FDA, EMA and ICH Q7/Q14 full-process quality standards. Its annual demand for tert-butyl (1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (CAS: 361440-67-7, a key chiral intermediate of saxagliptin) reaches 150 kg. This product is an ultra-high-difficulty customized chiral intermediate with extremely stringent requirements for stereochemical purity, impurity control, batch stability and customized process parameters, representing a typical mid-to-high-end European and American client.
Featuring 3 consecutive chiral centers and a bridged ring structure, the intermediate poses extremely high synthesis challenges, with only two European and American enterprises capable of mass production globally. The product carries a steep price tag of approximately EUR 8,500/kg and a lead time of up to 12 weeks. Moreover, suppliers cannot meet customized impurity profile requirements, exclusive process parameters or flexible small-batch multi-batch production needs. The client previously partnered with three domestic manufacturers, yet all collaborations failed due to insufficient chiral resolution technology, uncontrolled bridged ring synthesis, unqualified impurities and inability to deliver customized adjustments. Confronted with three crises including stalled R&D, delayed product launch and excessive cost overruns, the client urgently entrusted HiSiaddi with full responsibility for customized synthesis, process development, quality control and mass production launch. The client required completion of lab testing → pilot trial → mass production within 60 days, with chiral purity ≥99.9%, single impurity ≤0.02%, total impurities ≤0.08%, and full compliance with customized specifications.
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Extremely Difficult Stereochemical Control & Unqualified Chiral Purity The molecule contains three consecutive chiral centers (1S,3S,5S) plus an aza-bicyclic bridged ring structure. Synthesis readily generates 5 stereoisomeric impurities, while conventional processes only deliver chiral purity of 95%-98%, far below the client’s ≥99.9% threshold. The bridged ring structure carries substantial steric hindrance leading to poor reaction selectivity. Chiral resolution incurs high costs with low efficiency, and configuration inversion or racemization frequently occurs.
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Stringent Impurity Control & Unachievable Customized Impurity Profiles Client specifications: single impurity ≤0.02%, total impurities ≤0.08%, no genotoxic impurities (GTIs), heavy metals <3 ppm, residual solvents ≤200 ppm. Conventional domestic factory processes yield single impurities ≥0.1% and total impurities ≥0.3%, alongside trace GTIs such as nitrosamines, failing to satisfy EMA’s zero-tolerance audit standards. The client additionally required customized removal of specific byproducts (e.g., de-Boc impurities and cyclization byproducts), for which no mature industrial processes existed.
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Multi-Step Complex Synthesis with Poor Stability & Scale-Up Performance The target product requires an 8-step linear synthesis + 2-step chiral resolution + 1-step bridged cyclization. Every reaction parameter (temperature, pH, catalyst dosage) demands precise regulation; minor parameter fluctuations trigger sharp purity declines and impurity surges. While lab-scale small trials proved feasible, scale-up to kilogram batches triggered runaway bridged cyclization reactions, plummeting yields from 65% to 30% and severe batch-to-batch inconsistencies, preventing stable mass production.
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Specialized Customization Requirements Discouraging Factory R&D Investment The client demanded exclusive process parameters (chiral catalyst type, recrystallization solvent system, reaction temperature range), full-chain batch traceability, English-language GMP documents and customized packaging. Domestic manufacturers declined to allocate core technical resources due to high R&D investment, small customized batch sizes and thin profit margins, only offering standardized products incompatible with client requirements.
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Screen qualified exclusive supplier: Terminated cooperation with the original three manufacturers. Through technical audits, sample evaluation and production capacity verification, Shanghai Hongbo Zhiyuan, a domestic leader in chiral intermediates with mature saxagliptin intermediate technology, CEP/COS certification and a track record of serving top European and American pharmaceutical giants, was selected as the customized synthesis base. Form dedicated taskforce: Assigned two PhD chiral synthesis specialists, three senior engineers and one EMA compliance expert, alongside factory core technical staff to establish a dedicated breakthrough team. A 60-day milestone plan was formulated with clear technical accountability and daily progress reviews.
Route optimization: Abandoned the traditional 8-step linear synthesis and adopted an innovative "4-step convergent synthesis + 1-step asymmetric cyclization + 1-step high-efficiency resolution" route to shorten production cycles and reduce impurity generation. Starting from Boc-L-methyl pyroglutamate, highly selective construction of the (1S,3S,5S) chiral centers was achieved via reduction, dehydration, cyclopropanation and amidation. Upgraded chiral catalysis: Proprietary chiral nickel catalysts replaced traditional resolution reagents, delivering asymmetric cyclization reaction selectivity of 99.95% and inhibiting stereoisomer formation at the source. Reaction temperature was precisely controlled at -15℃±0.5℃ to eliminate racemization and configuration inversion. High-efficiency resolution process: Optimized recrystallization solvent system (ethyl acetate / n-hexane = 1:3), lifting single-resolution chiral purity from 98.5% to 99.92% with resolution yield ≥85%, well above industry averages.
Source interception of process impurities: Optimized cyclization reactant ratios, catalyst dosages and reaction durations to completely eliminate de-Boc and cyclization byproducts. Cyanide-free and nitrosation-free processes were adopted to deliver non-detectable GTIs. Deep purification workflow: Added two activated carbon decolorization steps, one high-vacuum distillation step and two precision recrystallization steps, reducing single impurities from 0.12% to 0.015% and total impurities from 0.35% to 0.06%. Customized testing methodology: Co-developed exclusive HPLC/GC testing methods with Bureau Veritas (BV) to fully separate 5 stereoisomers and 3 process impurities. Each batch was accompanied by English COAs, chromatograms, impurity profiles and third-party test reports.
Lab trial phase (Days 1–15): Completed 50g lab-scale trials, optimizing all reaction parameters, purification conditions and impurity control protocols. Final purity metrics hit chiral purity 99.92%, single impurity 0.015% and yield 68%, fully meeting specifications. Pilot trial phase (Days 16–35): Scaled up to 5kg pilot batches, prioritizing mitigation of runaway bridged cyclization during scale-up via segmented temperature control, precise dropping rate regulation and online monitoring technology. Pilot batches achieved chiral purity 99.9%, single impurity 0.018% and yield 62% with stable batch consistency. Mass production phase (Days 36–60): 150kg mass production under full GMP control with electronic batch records and real-time monitoring of critical parameters. All batches delivered chiral purity ≥99.9%, single impurity ≤0.02%, total impurities ≤0.08% and batch-to-batch variation <0.05%, completely resolving scale-up stability challenges.
Exclusive process & traceability: Supplied client-exclusive process documents, parameter records and batch traceability reports enabling immutable full-chain traceability from raw materials to finished products, compliant with 21 CFR Part 11. Full set of compliance documents: Compiled English ASMF filings, ICH Q7 compliance statements, process validation reports, cleaning validation reports, stability data and GTI risk assessment reports to support EMA registration and audits. Customized packaging & delivery: Double aluminum foil bags with nitrogen blanketing and sterile packaging, printed with customized labels, batch numbers, expiry dates and REACH registration numbers. Shipment split into three 50kg batches, delivered in 58 days, two days ahead of schedule.
1. Core Quality Metrics (100% Compliant, Some Surpassing Custom Specifications
· Chiral purity: 99.93% (requirement ≥99.9%)
· Single impurity: 0.015% (requirement ≤0.02%)
· Total impurities: 0.06% (requirement ≤0.08%)
· GTIs: Not detected (zero tolerance requirement)
· Heavy metals: 2.1 ppm (requirement <3 ppm)
· Residual solvents: 150 ppm (requirement ≤200 ppm)
1. Full Satisfaction of Customized Requirements
· Exclusive process parameters fully aligned with client specifications, no third-party access
· Complete removal of target byproducts via customized impurity profiling, EMA audit compliant
· Consistent quality across three batches with inter-batch variation <0.05%
· Full English GMP/EMA compliance documents passing pre-review in one submission
1. Optimized Cost & Lead Time
· Unit price: EUR 4,200/kg, a 50% reduction versus European and American suppliers
· Lead time: 58 days, halved compared to overseas vendors
· Production capacity: Stable 150kg annual output, scalable up to 500kg/year
1. Client Verification & Successful Audit
· Client in-house laboratory testing confirmed full compliance with no objections
· EMA pre-review passed with complete, compliant and intact data packages
· Zero non-conformities identified during client on-site audit, with high recognition of customization capabilities, quality control and compliance systems
The client’s R&D Director commented: "HiSiaddi is a truly professional partner specializing in high-end chiral intermediate customization. Within 60 days, they fully resolved technical challenges that plagued us for two years—delivering a full closed-loop solution covering innovative synthetic route design, precise chiral control, customized impurity removal, stable mass production and compliance support. Their product quality far exceeded expectations, while drastically cutting costs and shortening lead times, completely removing bottlenecks for our R&D program. HiSiaddi is our most trusted Chinese customized synthesis partner!"
Deepened long-term strategic partnership milestones:
· The client entrusted HiSiaddi with customized synthesis, procurement and compliance services for the full saxagliptin intermediate portfolio plus intermediates for three follow-up diabetes drug candidates under development.
· HiSiaddi became the client’s exclusive Chinese supplier for customized synthesis, with annual procurement volume exceeding EUR 5 million.
· Joint chiral synthesis R&D initiatives launched, with two invention patents co-filed to drive technological upgrading of high-end chiral intermediates.
European and American mid-to-high-end clients sourcing high-difficulty chiral intermediates such as tert-butyl (1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate face core pain points including high technical barriers, difficult chiral control, strict impurity limits, poor scale-up stability and manufacturers’ reluctance to deliver customized services, which directly delay new drug R&D timelines, launch schedules and cost management.
HiSiaddi’s core value lies in accurately identifying high-difficulty customization pain points, integrating top-tier domestic technical resources, innovating customized processes, delivering full-process quality and compliance oversight, and efficiently launching mass production. Rather than operating as a simple trading entity, HiSiaddi delivers deep technical empowerment, end-to-end customized solutions and long-term value co-creation. The partnership enables clients to break through technical bottlenecks, fulfill customization demands, reduce costs, shorten lead times and accelerate new drug commercialization. Meanwhile, it propels China’s high-end pharmaceutical intermediate sector’s evolution from standardized mass production to tailored customization and from low-end to premium-grade manufacturing, fully embodying the core competitiveness of a technology-driven, customization-enabled, quality-guaranteed and win-win value-oriented specialized foreign trade service provider.
Please contact HiSiaddi customer service if you require further customized service support.
+86-13120989737 
info@hisiaddi.com 
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