161511-85-9

Basic information

• Product Name: (S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL
• Synonyms: TERT-BUTYL (2S)-2-(HYDROXYMETHYL)AZETIDINE-1-CARBOXYLATE;(S)-N-TERT-BUTYLOXYCARBONYL-2-AZETIDINYLMETHANOL;(S)-N-TERT-BUTOXYCARBONYL-2-AZETIDINYLMETHANOL;(S)-1-BOC-2-AZETIDINEMETHANOL;(S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL;(S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHAOL;(S)-1-(Tert-Butoxycarbon;(S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate
• CAS NO: 161511-85-9
• Molecular Formula: C₉H₁₇NO₃
• Molecular Weight: 187.24
• Product Categories: Azetidines;Chiral Building Blocks;Glycidyl Compounds, etc. (Chiral);Simple 4-Membered Ring Compounds;Synthetic Organic Chemistry;Heterocycle-other series
• Mol File: 161511-85-9.mol

Chemical Properties

• Boiling Point: 270.349 °C at 760 mmHg
• Flash Point: 117.303 °C
• Appearance: /
• Density: 1.05
• Vapor Pressure: 0.001mmHg at 25°C
• Refractive Index: -74 ° (C=1, MeOH)
• Storage Temp.: 2-8°C
• PKA: 14.77±0.10(Predicted)
• CAS DataBase Reference: (S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL(161511-85-9)
• EPA Substance Registry System: (S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL(161511-85-9)

Safety Data

• Hazard Codes: T
• Statements: 25
• Safety Statements: 45
• RIDADR: UN2811
• Hazardous Substances Data: 161511-85-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Research:
(S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL is used as a synthetic intermediate for the development of new pharmaceutical compounds. Its unique structure allows it to be a valuable building block in the synthesis of various molecules, particularly those targeting specific receptors in the body.
Used in the Synthesis of PET Ligands:
(S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL is used as a key component in the synthesis of the PET (positron emission tomography) ligand [18F]fluoroazetidinylmethoxypyridine. This ligand is designed for the study of nicotinic receptor binding, which is important for understanding the role of these receptors in various neurological and neurodegenerative diseases.
Used in the Study of Nicotinic Receptor Binding:
(S)-1-(TERT-BUTOXYCARBONYL)-2-AZETIDINEMETHANOL plays a crucial role in the development of PET ligands that can be used to study the binding properties of nicotinic receptors. By understanding how these receptors interact with different molecules, researchers can gain insights into the potential therapeutic applications of targeting these receptors for the treatment of various conditions, such as Alzheimer's disease, Parkinson's disease, and schizophrenia.

InChI:InChI=1/C9H17NO3/c1-9(2,3)13-8(12)10-5-4-7(10)6-11/h7,11H,4-6H2,1-3H3/t7-/m1/s1

Upstream product

• 51077-14-6 (S)-1-(t-butoxycarbonyl)azetidine-2-carboxylic acid 
• 107020-12-2 methyl N-tert-butyloxycarbonyl-L-azetidine-2-carboxylate 
• 351075-53-1 (S)-1-(t-butoxycarbonyl)-2-{[(t-butyldimethyl)silyloxy]methyl}azetidine 
• 24424-99-5 di-tert-butyl dicarbonate 
• 2133-34-8 (2S)-azetidine-2-carboxylic acid 
• 351075-72-4 (2R,4S)-1-(t-butoxycarbonyl)-4-{[(t-butyldimethyl)silyloxy]methyl}azetidine-2-carbaldehyde 
• 351075-51-9 (2R,4S)-1-(t-butoxycarbonyl)-4-{[(t-butyldimethyl)silyloxy]methyl}azetidine-2-methanol 
• 351075-52-0 (2R,4S)-1-(t-butoxycarbonyl)-4-{[(t-butyldimethyl)silyloxy]methyl}azetidine-2-carboxylic acid 
• 677-22-5 tert-butylmagnesium chloride 
• 155878-39-0 (S)-4-isopropoxycarbonyl-2-azetidinone 
• 104587-62-4 (S)-azetidine-2-methanol 
• 2517-04-6 Azetidine-2-carboxylic acid 

Downstream Products

• 872254-09-6 tert-butyl (S)-2-(phenoxymethyl)azetidine-1-carboxylate 
• 186593-31-7 (S)-2-(5-bromo-pyridin-3-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester 
• 209530-92-7 2-nitro-3-<2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy>pyridine 
• 209328-53-0 ((S)-1-(tert-butoxycarbonyl)azetidin-2-yl)methyl 4-methylbenzenesulfonate 
• 51077-14-6 (S)-1-(t-butoxycarbonyl)azetidine-2-carboxylic acid 
• 1215230-34-4 tert-butyl (2S)-2-{[2-{[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxylate 
• 1217413-60-9 tert-butyl (2S)-2-{[2-({(3E)-5-tert-butyl-1-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-1,2-dihydro-3H-pyrazol-3-ylidene}carbamoyl)-4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxylate 
• 1222137-99-6 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxyl]-5-[(1S,2S)-2-(phenoxymethyl)cyclopropyl]pyridine 
• 1228453-12-0 (S)-tert-butyl-2-(((perfluorophenoxy)carbonothioyloxy)methyl)azetidine-1-carboxylate 
• 1231955-34-2 tert-butyl (2S)-2-{[2-{[(2Z)-5-tert-butyl-3-(2-methylpropyl)-1,3-thiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxylate 
• 1375143-21-7 C₁₉H₂₅N₃O₄ 
• 1375143-22-8 C₁₉H₂₄FN₃O₄ 
• 1375143-23-9 C₂₀H₂₅N₃O₆ 
• 1434047-75-2 (S)-tert-butyl 2-((5-(phenylethynyl)pyridin-3-yloxy)methyl)azetidine-1-carboxylate 

Relevant articles and documents

Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors

This paper reports the synthesis of 2-fluoro-3-[2(S)-2- azetidinylmethoxy]pyridine and its radiolabeling with fluorine-18 ([18F]FK- K222) by nucleophilic aromatic nitro-to-fluoro substitution in DMSO by conventional heating at 150°C for 20 min or by microwave activation at 100 Watt for 1 min. This fluoro compound is a closely related analog of the high affinity nicotinic ligand A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine). This compound is the lead compound of a novel 3-pyridyl ether series of new nAChR ligands recently published, and possesses not only subnanomolar comparable to that of epibatidine, for the α4β2 subtype, but also a weaker affinity for the other subtypes or nAChRs. 110-140 mCl (4.1-5.2 GBq) of pure 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) could be obtained in less than 2 hours, with specific radioactivities of 3-5 Ci/μmol (111-185 GBq/μmol) calculated for End of Bombardment (or 1.5-2.5 Ci/μmol (55.5-92.5 GBq/μmol) at End of Synthesis) for a 20 μA, 30 min (36000 μC) irradiation of a 95% enriched [18O]water target with a 16 MeV proton beam [18O(p,n)18F]. Yield (with respect to [18F]fluoride ion) : decay-corrected 49-64% ; non-decay corrected 25-33%. Total synthesis time from EOB : 105-110 min (this includes the recovery of the [18F]fluoride ion from the target and the [18F]FK-K222-complex preparation). Preliminary results in rats showed a substantial uptake of the ligand in the thalamus (1% I.D./g tissue at 30 min) while the cerebellar uptake was 2-fold lower. Thalamic uptake was reduced by 75-85% following a pre treatment with nicotine, cytisine, epibatidine or fluoro-A-85380. The full pharmacological profile and the potential for eventual clinical applications of this ligand as a tracer for PET experiments are currently under investigation.

Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: A new positron emission tomography ligand for nicotinic receptors

The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human α4β2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3[(S)- 2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [3H]cytisine or [3H]epibatidine with K(i) values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine- 18(t( 1/2 ) (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[18F]F-K222 complex with (3-[2(S)-N-(tert- butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl)trimethylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50- 53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [18F]fluoride ion radioactivity, were 68- 72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/μmol (148-259 GBq/μmol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to α7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.

Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase

Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.

Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380: An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain

We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT–A–E)with high affinity for nicotinic acetylcholine receptors (nAChRs)using (2(S)-azetidinylmethoxy)-pyridine (A-85380)as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR)was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR–A–E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT–A–E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT–A–E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT–A–E in the thalamus (characterized by the high nAChR density)when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT–A–E to the brain, [99mTc]CPTT–A–E met the basic requirements for nAChR imaging.

Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (99mTc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled with 99mTc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a 99mTc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4β2-nAChR in both the docking simulation (?19.3 kcal/mol) and binding assay (Ki = 0.4 ± 0.04 nM). Further, 99mTc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that 99mTc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.

Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

Mechanistic interrogation of the asymmetric lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine

A fundamental mechanistic study of the s-BuLi/chiral diamine-mediated lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine is reported. We show that lithiated thiopivalamides are configurationally unstable at -78 °C. Reaction then proceeds via a dynamic resolution of diastereomeric lithiated intermediates and this accounts for the variable sense and degree of asymmetric induction observed compared to N-Boc heterocycles.

COMBINATION OF CHIMERIC ANTIGEN RECEPTOR THERAPY AND AMINO PYRIMIDINE DERIVATIVES

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with a BTK inhibitor, e.g., an amino pyrimidi

NOVEL AMINO PYRIMIDINE DERIVATIVES

The present invention describes new amino pyrimidine derivatives and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.

NOVEL AMINO PYRIMIDINE DERIVATIVES

The present invention describes new amino pyrimidine derivatives of formula (I) and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.