3-cyanobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】20406

【品名】3-cyanobenzoic acid

【CA登记号】1877-72-1

【分子式】C₈H₅NO₂

【分子量】147.13324

【元素组成】C 65.31% H 3.43% N 9.52% O 21.75%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

The chiral intermediate (X) was synthesized from 3-cyanobenzoic acid (I) through the following sequence. Hydrogenation of the cyano group over Raney-nickel provided 3-(aminomethyl)benzoic acid (II), which was protected as the tert-buyl carbamate (III) with Boc2O. Subsequent hydrogenation of the benzene ring of (III) over PtO2 yielded the racemic amino acid (IV), predominantly as the cis isomer. The chiral resolution of (IV) with (S)-a-methylbenzyl amine (V) in EtOAc provided the optically pure 1(R),3(S) compound (VI), which was then reduced with borane in THF. The resulting aminoalcohol (VII), after conversion to mesylate (VIII) with methanesulfonyl chloride, was treated with NaN3 to give azide (IX), and this was then reduced to amine (X) with H2 over Pd/C.

参考文献中间体

合成目标

【1】 Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175.

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)	20406	3-cyanobenzoic acid	1877-72-1	C₈H₅NO₂	详情	详情
(II)	20407	3-(aminomethyl)benzoic acid		C₈H₉NO₂	详情	详情
(III)	20408	3-[[(tert-butoxycarbonyl)amino]methyl]benzoic acid		C₁₃H₁₇NO₄	详情	详情
(IV)	20409	3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid		C₁₃H₂₃NO₄	详情	详情
(V)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(VI)	20411	(1R,3S)-3-(Tert-butoxycarbonylamino)cyclohexanecarboxylic acid (S)-1-phenylethylamine salt		C₂₁H₃₄N₂O₄	详情	详情
(VII)	20412	tert-butyl [(1S,3R)-3-(hydroxymethyl)cyclohexyl]methylcarbamate		C₁₃H₂₅NO₃	详情	详情
(VIII)	20413	((1R,3S)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexyl)methyl methanesulfonate		C₁₄H₂₇NO₅S	详情	详情
(IX)	20414	tert-butyl [(1S,3R)-3-(azidomethyl)cyclohexyl]methylcarbamate		C₁₃H₂₄N₄O₂	详情	详情
(X)	20415	tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate		C₁₃H₂₆N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Synthesis of intermediate (VIII): Hydrogenation of m-cyanobenzoic acid (I) with H2 over Raney-Ni in ammonia gives amine (II), which is treated with Boc2O and NaOH in dioxane to provide protected amine (III). Reduction of (III) by means of PtO2 and H2 in acetic acid yields a 10:1 mixture of cis/trans ciclohexane derivatives (rac)-(IV)/(rac)-(V). The racemic cis compound obtained is enantiomerically resolved and stereomer (V) is then reduced with BH3.Me2S in THF providing alcohol (VI), which is converted into azide (VII) after treatment with NaN3 in DMF of the mesylate derivative obtained by treatment of (VI) with Et3N, DMAP and MsCl. Finally amino derivative (VIII) is obtained by hydrogenation of azide (VII) over Pd/C in MeOH. Synthesis of intermediate (XII): beta-Methyl-D-tryptophan methyl ester (IX) reacts with piperidine derivative (X) in presence of DSC and DIEA in CH2Cl2 to afford (XI), whose methyl ester is hydrolyzed in THF with LiOH in EtOH/H2O. Synthesis EN 269873: Finally intermediate (XII) is coupled with (VIII) with EDC and HOBt, and the Boc group is removed with TFA in CH2Cl2 to yield the desired product.

参考文献中间体

合成目标

【1】 Patchett, A.A.; Yang, L.; Pasternak, A.; Berk, S. (Merck & Co., Inc.); Somatostatin agonists. EP 1023061; US 6057338; WO 9844921 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(rac)-(IV)	41637	(rac)-(1S,3S)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid		C₁₃H₂₃NO₄	详情	详情
(rac)-(V)	41638	(rac)-(1S,3R)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid		C₁₃H₂₃NO₄	详情	详情
(I)	20406	3-cyanobenzoic acid	1877-72-1	C₈H₅NO₂	详情	详情
(II)	20407	3-(aminomethyl)benzoic acid		C₈H₉NO₂	详情	详情
(III)	20408	3-[[(tert-butoxycarbonyl)amino]methyl]benzoic acid		C₁₃H₁₇NO₄	详情	详情
(V)	41639	(1S,3R)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid		C₁₃H₂₃NO₄	详情	详情
(VI)	20412	tert-butyl [(1S,3R)-3-(hydroxymethyl)cyclohexyl]methylcarbamate		C₁₃H₂₅NO₃	详情	详情
(VII)	20414	tert-butyl [(1S,3R)-3-(azidomethyl)cyclohexyl]methylcarbamate		C₁₃H₂₄N₄O₂	详情	详情
(VIII)	20415	tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate		C₁₃H₂₆N₂O₂	详情	详情
(IX)	29274	methyl (2R,3S)-2-amino-3-(1H-indol-3-yl)butanoate		C₁₃H₁₆N₂O₂	详情	详情
(X)	12138	1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine	20662-53-7	C₁₂H₁₅N₃O	详情	详情
(XI)	29401	methyl (2R,3S)-3-(1H-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butanoate		C₂₆H₂₉N₅O₄	详情	详情
(XII)	29402	(2R,3S)-3-(1H-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butyric acid		C₂₅H₂₇N₅O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IA)

3-Cyanobenzoic acid (Ia) is condensed with NH2OH in t-BuOH to yield oxime (IIa). Without isolation, compound (IIa) couples with 2-fluorobenzoyl chloride (III) in the presence of triethylamine to give oxime ester (IV), which is readily cyclized under reflux conditions (about 80 °C) (1).
Ataluren can also be obtained from its methyl ester precursor (V) by saponification with NaOH in t-BuOH/H2O (1) or THF/H2O (2) and subsequent acidification with H2SO4 (1) or HCl (2). Ataluren methyl ester (V) can be synthesized from methyl 3-cyanobenzoate (Ib) by subjecting it to either the same one-pot procedure as described above for 3-cyanobenzoic acid (Ia) (1) or, alternatively, to a similar non-one-pot procedure: condensation of (Ib) with NH2OH in EtOH at 100 ºC, coupling of the resulting oxime (IIb) with 2-fluorobenzoyl chloride (III) by means of DIEA in THF, and final cyclization of the isolated oxime ester (IVb) in toluene at 130 ºC (2). Methyl 3-cyanobenzoate (Ib) is prepared from the carboxylic acid (Ia) by methylation with CH3I in the presence of K2CO3 (2). Scheme 1.

参考文献中间体

合成目标

【1】 Almstead, N.G., Hwang, P.S., Pines, S., Moon, Y.-C., Takasugi, J.J. (PTC Therapeutics, Inc.). Processes for the preparation of 1,2,4-oxadiazole benzoic acids. WO 2008030570.
【2】 Karp, G.M., Amstead, N.G., Chen, G., Hwang, S. (PTC Therapeutics, Inc.). 1,2,4-Oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease. EP 1618098, JP 2006522286, US 2004204461, US 6992096, WO 2004091502.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IA)	20406	3-cyanobenzoic acid	1877-72-1	C₈H₅NO₂	详情	详情
(IB)	65721	Methyl 3-cyanobenzoate	13531-48-1	C₉H₇NO₂	详情	详情
(IIA)	65722			C₈H₈N₂O₃	详情	详情
(IIB)	65723			C₉H₁₀N₂O₃	详情	详情
(IVA)	65724			C₁₅H₁₁FN₂O₄	详情	详情
(IVB)	65725			C₁₆H₁₃FN₂O₄	详情	详情
(III)	19551	2-Fluorobenzoyl chloride	393-52-2	C₇H₄ClFO	详情	详情
(V)	65726			C₁₆H₁₁FN₂O₃	详情	详情

Extended Information