Attempted synthesis of ethyl 3,4‐dihydro‐2<i>H</i>‐1,4‐benzoxazine‐3‐carboxylate and 3‐acetate derivatives

Mayer, Stanislas; Arrault, Axelle; Guillaumet, Gérald; Mérour, Jean‐Yves

doi:10.1002/jhet.5570380133

Cited by 13 publications

(6 citation statements)

References 22 publications

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“…Ethyl 2,3,5,6-Tetrahydro[1,4]oxazino[2,3,4- ij ]indole-2-carboxylate (33). Same procedure as for 2 , starting from 7-hydroxyindoline; , yield 83%; oil. IR (film) υ(cm -1 ) 1753 (CO); 1 H NMR (pyridine- d 5 , 400 MHz) δ 1.15 (t, 3H, J = 7.0 Hz, CH 3 ); 2.70−2.80 (m, 2H, CH 2 ); 2.89 (q, 1H, J = 8.9 Hz, NCH 2 ); 3.03 (dd, 1H, J = 2.8 Hz, 12.0 Hz H 3a ); 3.20−3.28 (m, 1H, NCH 2 ); 3.49 (dd, 1H, J = 4.3 Hz, 12.0 Hz, H 3b ); 4.29 (m, 2H, J = 7.0 Hz, OCH 2 ); 5.23 (dd, 1H, J = 2.8 Hz, 4.3 Hz, H 2 ); 6.67−6.75 (m, 2H, H ar ); 6.90−6.95 (m, 1H, H ar ).…”

Section: Methodsmentioning

confidence: 99%

“…So we decided to generate the 1,4-oxazine ring after the synthesis of the five-membered ring. The five-membered ring was present in 7-hydroxyindoline which was reacted with ethyl 2,3-dibromopropanoate to generate the 1,4-oxazino compound 33 in an 83% yield (Scheme ). Compound 33 was easily oxidized with DDQ into the indolic compound 34 in a moderate 50% yield.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Biological Evaluation of New 2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine Derivatives

et al. 2003

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2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine derivatives and tricyclic analogues with a fused additional ring on the nitrogen atom of the benzoxazine moiety have been prepared and evaluated for their cardiovascular effects as potential antihypertensive agents. The imidazoline ring was generated by reaction of the corresponding ethyl ester with ethylenediamine. Affinities for imidazoline binding sites (IBS) I(1) and I(2) and alpha(1) and alpha(2) adrenergic receptors were evaluated as well as the effects on mean arterial blood pressure (MAP) and heart rate (HR) of spontaneously hypertensive rats. With few exceptions the most active compounds on MAP were those with high affinities for IBS and alpha(2) receptor. Among these, compound 4h was the most interesting and is now, together with its enantiomers, under complementary pharmacological evaluation.

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Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Synthesis and Biological Evaluation of New 2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine Derivatives

et al. 2003

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“…Intermediate 29 was synthesized by condensation of 2-aminophenol 28 with ethyl-2,3-dibromopropionate using reported method. 26 The intermediate 30 was obtained by reacting intermediate 29 with benzoyl chloride, using triethyl amine as base. The ester 30 was reduced to alcohol by NaBH Compounds 3, 9−20 were synthesized as described in Scheme 3.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism

Shukla,

Sadasivam,

Sarde

et al. 2023

J. Med. Chem.

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The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pK a. A systematic optimization of cinacalcet to reduce its cLogP and pK a yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.

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“…36 It is interesting to note that, while our targeted scaffold 1 is a key synthon for the design of promising therapeutic drugs (Figure 1), its synthesis and characterizations (optical rotation and electronic circular dichroism [ECD]) as enantiomers were never described in the literature. Rac-1 is mainly synthesized by reacting 2-aminophenol and racemic ethyl 2,3 dibromopropionate rac-2 with anhydrous K 2 CO 3 in refluxing dry acetone, 9,11,[37][38][39][40] but to date, its enantioselective version has never been reported for two reasons. First, both enantiomers of 2 have been just recently isolated by our team through a preparative HPLC enantioseparation of racemate on multigram scale.…”

Section: Introductionmentioning

confidence: 99%

Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate

et al. 2021

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Racemic ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate is a key synthon for the design of promising therapeutic drugs. It is mainly synthesized from racemic ethyl 2,3-dibromopropionate and 2-aminophenol in presence of K 2 CO 3 in refluxed acetone. Unfortunately, synthesis of (R)-and (S)enantiomers using the enantioselective version of this reaction, which should normally be performed with a double S N 2 mechanism, is unsuitable due to a racemization process involving the dehydrobromination of enantiopure ethyl 2,3-dibromopropionate into ethyl 2-bromoacrylate. For the first time, the enantioselective version is studied (ee ≈ 55-66%), and the percentage of racemization process has estimated to around 34-46% after determination of the optimal experimental conditions for analytical HPLC enantioseparation of racemate. The influence of the experimental and purification conditions on

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Attempted synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐3‐carboxylate and 3‐acetate derivatives

Cited by 13 publications

References 22 publications

Synthesis and Biological Evaluation of New 2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine Derivatives

Synthesis and Biological Evaluation of New 2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine Derivatives

Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism

Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate

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