NNC-52-1246, -Drug Synthesis Database

【结构式】

【药物名称】NNC-52-1246

【化学名称】7(S)-(5-Hydroxy-1H-indol-2-ylcarboxamidomethyl)-2-(oxaloamino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid
　　　　　　N-[3-Carboxy-7(S)-(5-hydroxy-1H-indol-2-ylcarboxamidomethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]oxamic acid

【CA登记号】390426-18-3, 390426-20-7 (enantiomer), 390426-19-4 (trifluoroacetate), 390425-78-2 (undefined stereochem.)

【分子式】C₂₀H₁₈N₄O₇S

【分子量】458.45306

【开发单位】Novo Nordisk (Originator), Ontogen (Originator)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Protein Tyrosine Phosphatase PTP-1B Inhibitors

合成路线1 合成路线2

合成路线1

Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.

参考文献中间体

【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(II)	48591	Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester	924-44-7	C₄H₆O₃	详情	详情
(III)	58785	ethyl 2-{[(1S)-1-phenylethyl]imino}acetate		C₁₂H₁₅NO₂	详情	详情
(IV)	18557	1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane	38053-91-7	C₇H₁₄OSi	详情	详情
(V)	58786	ethyl (2R)-4-oxo-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate		C₁₆H₂₁NO₃	详情	详情
(VI)	58787	ethyl (2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate		C₂₀H₃₁NO₄	详情	详情
(VII)	58788	{(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methanol		C₁₈H₂₉NO₃	详情	详情
(VIII)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(IX)	58789	2-({(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione		C₂₆H₃₂N₂O₄	详情	详情
(X)	58790	2-({(2R)-4-oxo-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione		C₂₂H₂₂N₂O₃	详情	详情
(XI)	14330	tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate	1116-98-9	C₇H₁₁NO₂	详情	详情
(XII)	58791	tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₂₉H₃₁N₃O₄S	详情	详情
(XIII)	58792	tert-butyl (5R)-2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₂₉H₃₁N₃O₄S	详情	详情

合成路线2

The desired minor isomer (XII) was subjected to hydrazinolysis to provide amine (XIV). Selective acylation at the aliphatic amino group of (XIV) with 5-hydroxyindole-2-carboxylic acid (XV) in the presence of EDC as the coupling reagent furnished amide (XVI). The remaining primary amino group of (XVI) was subsequently acylated by the oxalyl imidazolide (XVII) producing oxalamide (XVIII). The chiral auxiliary alpha-methylbenzyl group of (XVIII) was then removed by transfer hydrogenolysis with formic acid and Pd/C, producing the secondary amine (XIX). Finally, tert-butyl esters cleavage in (XIX) was accomplished by treatment with trifluoroacetic acid to yield the corresponding dicarboxylic acid.

参考文献中间体

【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	58791	tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₂₉H₃₁N₃O₄S	详情	详情
(XIV)	58793	tert-butyl (7S)-2-amino-7-(aminomethyl)-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₂₁H₂₉N₃O₂S	详情	详情
(XV)	58796	5-Hydroxy-2-indolecarboxylic acid; 5-Hydroxyindole-2-carboxylic acid	21598-06-1	C₉H₇NO₃	详情	详情
(XVI)	58794	tert-butyl (7S)-2-amino-7-({[(5-hydroxy-1H-indol-2-yl)carbonyl]amino}methyl)-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₃₀H₃₄N₄O₄S	详情	详情
(XVII)	58795	tert-butyl 2-(1H-imidazol-1-yl)-2-oxoacetate		C₉H₁₂N₂O₃	详情	详情
(XVIII)	58797	tert-butyl (7S)-2-{[2-(tert-butoxy)-2-oxoacetyl]amino}-7-({[(5-hydroxy-1H-indol-2-yl)carbonyl]amino}methyl)-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₃₆H₄₂N₄O₇S	详情	详情
(XIX)	58798	tert-butyl (7S)-2-{[2-(tert-butoxy)-2-oxoacetyl]amino}-7-({[(5-hydroxy-1H-indol-2-yl)carbonyl]amino}methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate		C₂₈H₃₄N₄O₇S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)