1-Benzhydralazetan-3-ol(KSM-I)
| Name of Product | 1-Benzhydralazetan-3-ol(KSM-I) |
|---|---|
| CAS No | 18621-17-5 |
| Therapeutic use:- | Calcium channel blocker (Hypertension) |
| API Name | Azelnidipine |
| Form:- | API Powder |
| Status | Commercial |
Product Overview
1-Benzhydrylazetidin-3-ol, also written 1-(diphenylmethyl)azetidin-3-ol or 1-benzhydryl-3-azetidinol, is supplied under CAS 18621-17-5 with the molecular formula C₁₆H₁₇NO and a molecular weight of 239.31.
It is also available as the hydrochloride salt, with a molecular weight of 275.77.
The molecule is a four-membered azetidine ring carrying a hydroxyl at position three and a benzhydryl group on the nitrogen.
Those three features together make it one of the standard entry points into azetidine chemistry: the ring provides the constrained scaffold, the hydroxyl is the handle for further elaboration, and the benzhydryl both blocks the nitrogen and makes the compound a tractable, purifiable solid rather than a volatile, water-soluble small amine.
The alcohol is the starting point for most of what follows. Oxidising it gives 1-benzhydrylazetidin-3-one, which is itself a heavily used building block olefination of that ketone leads to the 3-alkylidene azetidines that appear in kinase inhibitor side chains.
Esterifying it instead leads to compounds such as azelnidipine, where the benzhydryl azetidine is retained in the finished drug.
The compound is made by reacting benzhydrylamine with epichlorohydrin and cyclising the resulting amino alcohol.
That route is short, but it is neither clean nor high yielding, and it determines what the specification has to control.
We supply the material with residual epichlorohydrin, benzhydrylamine and the open-chain amino alcohol reported individually on every certificate.
Actiza Pharma has over 12 years of B2B pharmaceutical export experience, 500+ global clients and a supply footprint across 40+ countries, backed by WHO-GMP and ISO-certified group manufacturing infrastructure in Gujarat, India.
Key Highlights
Residual epichlorohydrin reported individually a recognised genotoxic impurity from the route.
Residual benzhydrylamine and the open-chain amino alcohol reported individually.
Form stated explicitly free base or hydrochloride, with the assay basis.
Achiral no stereochemical specification required, unlike most of this catalogue.
Serves both routes benzhydryl retained in the drug, or removed as a protecting group.
Available at kilogram and gram scale for API and discovery customers respectively.
No CWC or Australia Group listing.
Certificate of Analysis and GHS-format Safety Data Sheet with every batch.
12+ years of export experience across 40+ countries.
The Route Determines the Specification
Almost everything worth controlling in this material traces to one reaction, and understanding it explains the whole certificate.
Epichlorohydrin and a Four-Membered Ring
Benzhydrylamine is reacted with epichlorohydrin. The amine opens the epoxide to give an open-chain amino chlorohydrin, and that amino alcohol then has to cyclise by displacing the chloride with the nitrogen closing a strained four-membered ring.
Four-membered rings do not form readily. Published process work reports the reaction run in methanol at room temperature for three days and then at reflux for a further three days, isolating the hydrochloride in around 43 percent yield.
Other published work notes that early attempts in organic solvents failed to cyclise at all, and that the reaction had to be run in water, or later in triethylamine as solvent, with iodide added as a phase transfer catalyst to accelerate it.
A six-day reaction at 43 percent yield tells you two things: there is a lot of unconverted and mis-converted material to remove, and the purification step is doing most of the quality work.
Residual Epichlorohydrin
This is the parameter that matters most. Epichlorohydrin is a reactive epoxide and alkyl chloride, a recognised structural alert under ICH M7, and a compound with a substantial carcinogenicity record.
Any customer carrying this material into a regulated route has to demonstrate that epichlorohydrin is controlled to very low levels in their drug substance, which requires a sensitive, validated method.
A supplier who reports it numerically shortens that work considerably. A supplier who does not leaves the customer to develop the method and test every incoming batch themselves.
The Open-Chain Amino Alcohol
Incomplete cyclisation leaves the open-chain amino chlorohydrin.
That compound has both a reactive chloride and a free secondary amine, so in the customer’s next step it behaves as a bifunctional electrophile-nucleophile and gives products they did not plan for.
It is also, on its own account, an alkylating species. Reported individually.
Residual Benzhydrylamine
Unreacted benzhydrylamine is a primary amine.
In an esterification or acylation it competes directly with the intended alcohol and gives an amide instead of an ester the same failure mode described on the 1-methyl-3-pyrrolidinol page, and one the customer’s work-up will not correct.
What We Control
Residual epichlorohydrin, with method and limit of quantitation appropriate to a genotoxic impurity.
Open-chain amino chlorohydrin reported individually.
Residual benzhydrylamine reported individually.
Benzhydrol and benzophenone, the oxidative degradation products of the benzhydryl group.
Water content by Karl Fischer.
Assay stated numerically with the method and the form disclosed.
Support for the buyer’s ICH M7 mutagenic impurity assessment.
A Second Handling Point – Benzhydryl and Acid
The benzhydryl group is a protecting group precisely because it can be removed.
On many routes it is cleaved by hydrogenolysis, but it is also susceptible to acid, because a benzhydryl cation is strongly stabilised by its two aromatic rings.
For this product the consequence is a storage instruction rather than a stereochemical one, since the molecule is achiral.
Acid exposure begins removing the protecting group prematurely, liberating the free azetidin-3-ol, which is a small, polar, water-soluble amine that behaves nothing like the product.
Keep the material away from acids and acidic residues.
Application in Synthesis
| Transformation | Product | Where it goes |
|---|---|---|
| Oxidation of the alcohol | 1-Benzhydrylazetidin-3-one | Published conditions use pyridine sulfur trioxide in DMSO; the ketone is a major building block in its own right |
| Olefination of that ketone | 3-Alkylidene azetidines, including the cyanomethylene compound | Kinase inhibitor side chains |
| Esterification of the alcohol | Azetidin-3-yl esters | Azelnidipine and related dihydropyridines, where the benzhydryl azetidine is retained |
| Deprotection | Azetidin-3-ol | The free azetidine for onward elaboration in discovery and development chemistry |
Industry Segments Served
Azelnidipine and dihydropyridine API manufacturers.
Kinase inhibitor and small-molecule API manufacturers using azetidine scaffolds.
CDMOs and contract synthesis organisations.
Building block distributors and discovery chemistry groups.
Impurity and reference standard suppliers.
Technical Specifications
| Parameter | Specification |
|---|---|
| Chemical Name (IUPAC) | 1-(Diphenylmethyl)azetidin-3-ol |
| Common Names | 1-Benzhydrylazetidin-3-ol; 1-benzhydryl-3-azetidinol; 1-(diphenylmethyl)-3-hydroxyazetidine; NSC 319045 |
| CAS Number | 18621-17-5 (free base) |
| Molecular Formula | C₁₆H₁₇NO hydrochloride C₁₆H₁₈ClNO |
| Molecular Weight | 239.31 g/mol hydrochloride 275.77 g/mol |
| Form Supplied | Free base or hydrochloride, stated on every document |
| MDL / EC Number | Available on request |
| Appearance | Available on request |
| Stereochemistry | Achiral position 3 of the azetidine ring is not a stereocentre |
| Assay / Purity | Available on request |
| Residual Epichlorohydrin | Reported on every certificate; method and LOQ available on request |
| Open-Chain Amino Chlorohydrin | Available on request |
| Residual Benzhydrylamine | Available on request |
| Benzhydrol / Benzophenone | Available on request |
| Other Related Substances | Individual and total limits as per in-house standard; reported on COA |
| Water Content (Karl Fischer) | Available on request |
| Identification | IR and ¹H-NMR conform to reference standard |
| Melting Range | Available on request |
| Stage of Synthesis | Key starting material / building block |
| Downstream | Azelnidipine; azetidine-containing kinase inhibitors; azetidin-3-ol |
| Residual Solvents | As per ICH Q3C, with methanol addressed given its role in the cyclisation |
| Elemental Impurities | Controlled; ICH Q3D statement supplied on request |
| Solubility | Available on request |
| Storage Condition | Store cool and dry in tightly closed original packing, protected from light, air and acids |
| Shelf Life | As stated on the batch COA, in unopened original packing under recommended storage |
| GHS Classification | Available on request |
| Transport Classification | Available on request |
Handling & Storage Guidance
Store cool and dry in tightly closed containers, protected from light and air.
Keep away from acids and acidic residues acid removes the benzhydryl protecting group prematurely.
Keep away from oxidising agents; the benzhydryl position oxidises to benzhydrol and onward to benzophenone.
Allow containers to reach room temperature before opening to prevent condensation.
Minimise open-container time and re-seal immediately after dispensing.
Note the residual epichlorohydrin consideration and handle accordingly; consult the Safety Data Sheet supplied with the batch.
Re-test assay and related substances on any consignment that has darkened or shows evidence of moisture ingress.
Regulatory & Documentation Support
Control Status
1-Benzhydrylazetidin-3-ol is not listed under the Chemical Weapons Convention Schedules and is not on the Australia Group precursor list.
The downstream medicines are prescription products and are not scheduled controlled substances.
Documentation is limited to standard commercial paperwork, and we confirm destination-specific import requirements before dispatch.
Documentation Supplied
Certificate of Analysis batch-specific, with assay, residual epichlorohydrin and named related substances, and the form stated.
Analytical method details shared as part of the Technical Data Package.
Material Safety Data Sheet in GHS format, with destination-language versions on request.
Technical Data Package manufacturing flow, analytical methods, specification rationale, impurity profile.
GMP Starting Material declaration under ICH Q7 principles, where the GMP grade is ordered.
Support for the buyer’s ICH M7 mutagenic impurity assessment.
ICH Q3C residual solvent and ICH Q3D elemental impurity statements.
Certificate of Origin, Non-GMO declaration, BSE/TSE-free and allergen statements.
Written change-notification commitment, including any change of epichlorohydrin source.
Site audit access, subject to prior scheduling and confidentiality agreement.
Packaging, MOQ & Logistics
| Parameter | Details |
|---|---|
| Standard Packing | Sealed, light-protected containers with desiccant, segregated from acidic materials |
| Pack Sizes | Gram, hundred-gram and kilogram quantities |
| Minimum Order Quantity | Available on request |
| Production Lead Time | Available on request |
| Monthly Capacity | Available on request |
| Sampling | Samples readily available no export control and no significant dangerous-goods burden |
| Shipping Terms | FOB / CIF / CFR / EXW, as agreed |
| Mode of Transport | Sea and air freight both available, subject to DG classification confirmation |
| Port of Loading | Available on request |
| Export Documentation | Standard commercial documentation, with the form stated throughout |
Why Choose Us as Your Supplier
Residual Epichlorohydrin Reported
The route runs through epichlorohydrin, and it is a recognised genotoxic impurity with a significant carcinogenicity record.
We report it numerically with the method, which removes the most demanding item from your ICH M7 assessment.
The Cyclisation By-Products Named
A six-day reaction at around 43 percent yield leaves a lot behind.
We report the open-chain amino chlorohydrin and residual benzhydrylamine individually rather than inside a total, because both react in your next step and neither is removed by your work-up.
The Form Stated, Always
Free base and hydrochloride are different articles with different molecular weights and different assay bases. We put the form on every quotation, certificate and label.
Two Scales, One Supplier
Kilogram quantities for API manufacture and gram quantities for discovery and development chemistry, from the same qualified source.
Export & Client Support
With 12+ years of B2B pharmaceutical export experience, 500+ global clients and shipments across Asia, Africa, Latin America, the CIS region and the Middle East, our commercial and documentation teams work across time zones.
Frequently Asked Questions
Do I get the free base or the hydrochloride?
Both are commercial. The free base is C₁₆H₁₇NO at 239.31, the hydrochloride is 275.77, and published process work isolates the hydrochloride directly from the cyclisation.
They have different assay bases and different handling, so we state the form on every document and will not substitute one for the other.
Why do you report residual epichlorohydrin?
Because the compound is made from benzhydrylamine and epichlorohydrin, and epichlorohydrin is a reactive epoxide and alkyl chloride a recognised structural alert under ICH M7 with a substantial carcinogenicity record.
You have to control it to very low levels in your drug substance, which needs a sensitive validated method.
We report it numerically so your assessment starts from data rather than from your own method development.
Why is the yield of this compound so low?
Because closing a four-membered ring is difficult. The amine opens the epoxide easily enough, but the resulting amino chlorohydrin then has to cyclise onto itself against considerable ring strain.
Published process work runs the reaction for three days at room temperature and three more at reflux for around 43 percent yield, and earlier work found that the cyclisation failed entirely in ordinary organic solvents.
The practical consequence for you is that the purification does most of the quality work, which is why the by-product specification matters.
What is the open-chain impurity?
The amino chlorohydrin formed before cyclisation.
It carries both a reactive chloride and a free secondary amine, so in your next step it acts as a bifunctional species and gives products you did not intend.
It is also an alkylating compound in its own right. We report it individually.
Is the compound chiral?
No. Position three of the azetidine ring carries a hydroxyl, a hydrogen and two ring carbons that are equivalent by the ring’s symmetry, so it is not a stereocentre.
That makes this one of the few products in our range needing no stereochemical specification at all.
Why should I keep it away from acid?
Because the benzhydryl group is removable, and acid is one of the ways it comes off benzhydryl cations are strongly stabilised by their two aromatic rings.
Acid exposure in storage starts deprotecting the material prematurely, liberating azetidin-3-ol, which is a small polar amine that behaves nothing like the product.
Store it away from acids and acidic residues.
Will the benzhydryl group stay in my final molecule?
That depends on your route, and it is worth telling us which you are on.
In azelnidipine the benzhydryl azetidine is retained and forms part of the drug substance.
In most kinase inhibitor and discovery routes the benzhydryl is a protecting group removed later by hydrogenolysis.
The two customers need different things from this material, and we would rather specify against yours.
Is an export licence required?
No. The compound is not CWC-scheduled and is not on the Australia Group precursor list, and the downstream medicines are not controlled substances.
Documentation is limited to standard commercial paperwork.
Request a Quote
Tell us which form you need, whether the benzhydryl group will be retained or removed, the quantity and the destination, and our team will respond with pricing, lead time and the documentation set for CAS 18621-17-5.